Joshua A.

Zeichner Editor

Acneiform Eruptions
in Dermatology

A Differential Diagnosis
Acneiform Eruptions in Dermatology
Joshua A. Zeichner
Editor

Acneiform Eruptions
in Dermatology
A Differential Diagnosis
Editor
Joshua A. Zeichner, M.D.
Assistant Professor
Director of Cosmetic and Clinical Research
Dermatology Department
Mount Sinai Medical Center
New York, NY, USA

ISBN 978-1-4614-8343-4 ISBN 978-1-4614-8344-1 (eBook)

DOI 10.1007/978-1-4614-8344-1
Springer New York Heidelberg Dordrecht London

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To Cori, Jake, and Chloe, whose bright
smiles and unconditional love inspire me
every day. To my parents, without whose
support I would not be where I am today.

Joshua A. Zeichner, M.D.

Preface

An estimated 40–50 million people in the United States suffer from acne, and up to
85 % of people experience acne at some point in their lives. Dermatologists, pri-
mary care doctors, and pediatricians see these patients every day in practice. It is
important to treat the skin effectively not only to reduce the risk of physical scarring
but also to address the negative psychosocial impact this disease carries. Improving
the skin can improve self-confidence, interpersonal relationships, and performance
in school or at work.
While the majority of acne patients seen in practice truly have run-of-the-mill
acne, not all “acne” is really acne vulgaris. It may be exception rather than the rule
for a patient to have a condition that mimics acne, but it is our responsibility as health
care providers to be up to date and educated on acne’s broad differential diagnosis. If
patients do not have any comedonal lesions, if they have an atypical medical history,
or if they are not responding to traditional therapies, then alternative diagnoses
should be considered. Proper diagnosis will allow us to prescribe proper treatments
and ultimately improve clinical outcomes and patient satisfaction.
This book will help to provide a broad overview of acne vulgaris itself as well as
conditions that manifest with acneiform eruptions in the skin.

New York, NY, USA Joshua A. Zeichner, M.D.

vii
Acknowledgment

We are all influenced by the people with whom we surround ourselves. I have had
the privilege of learning from the greatest minds in Dermatology, who have
shaped the person I am today. While I have had countless mentors touch my career,
I must take this opportunity to acknowledge one person in particular. Dr. Mark
Lebwohl is truly a mentor of mentors. He has taught me not only how to be a
good dermatologist, but also, more importantly, how to be a great doctor, colleague,
and teacher. This book would not have been possible without his support, advice,
and encouragement.

ix
Contents

Part I Acne Vulgaris

1 Acne Pathophysiology ............................................................................. 3

Shinjita Das and Rachel Reynolds
2 Clinical Presentation of Acne ................................................................. 13
Guy F. Webster
3 Topical Therapies for Acne .................................................................... 19
Mary-Margaret Kober, Whitney P. Bowe, and Alan R. Shalita
4 Systemic Therapies for Acne.................................................................. 27
Marisa Kardos Garshick, Alexa Kimball, and Lynn Drake
5 Laser and Light Based Therapies for Acne .......................................... 35
Jeremy B. Green, Annelyse Ballin, and Joely Kaufman

Part II Infectious Diseases Mimicking Acne Vulgaris

6 Bacterial Folliculitis ................................................................................ 43

Jessica Gjede and Emmy Graber
7 Gram-Negative Folliculitis ..................................................................... 49
Ani L. Tajirian and Leon H. Kircik
8 Hot-Tub Folliculitis ................................................................................. 55
Paula S. Malhotra and Joseph F. Fowler Jr.
9 Malassezia Folliculitis ............................................................................. 59
Patricia K. Farris and Andrea Murina
10 Tinea Barbae ........................................................................................... 67
Lauren Kole and Boni Elewski

xi
xii Contents

11 Flat Warts ................................................................................................ 71

Ted Rosen and Sara Risner-Rumohr
12 Molluscum Contagiosum ........................................................................ 79
Yvonne Clark and Lawrence F. Eichenfield
13 Herpes Simplex Virus ............................................................................. 85
Rachel Gordon and Stephen Tyring
14 Varicella Zoster Virus ............................................................................. 95
Rachel Gordon, Stephen Tyring, Whitney Lapolla, and Rana Mays

Part III Variants of Acne Vulgaris

15 Acne Conglobata ..................................................................................... 107

Jonathan S. Weiss and Elijah Wilder
16 Acne Excoriée .......................................................................................... 111
Jillian Wong Millsop and John Y.M. Koo
17 Acne Fulminans....................................................................................... 117
Alison Schram and Misha Rosenbach
18 Acne Mechanica ...................................................................................... 125
Zoe Diana Draelos
19 Cushing’s Syndrome ............................................................................... 129
Nick Zilieris, Cheryl J. Gustafson, and Steven R. Feldman
20 PAPA Syndrome ...................................................................................... 137
Fan Liu and Kanade Shinkai
21 Polycystic Ovary Syndrome ................................................................... 149
Joslyn Kirby
22 Pomade Acne ........................................................................................... 155
Oge Onwudiwe and Valerie D. Callender
23 Post-adolescent Female Acne ................................................................. 161
Gillian Heinecke and Diane Berson
24 SAPHO Syndrome .................................................................................. 169
Caroline L. LaRosa and Andrea L. Zaenglein

Part IV Genetic Syndromes Mimicking Acne Vulgaris

25 Apert Syndrome ...................................................................................... 179

Yasser Albahrani and Joshua A. Zeichner
26 Birt-Hogg-Dubé Syndrome .................................................................... 183
Kristina Goldenberg and Gary Goldenberg
Contents xiii

27 Brooke-Spiegler Syndrome .................................................................... 191

Bradley Glodny and Joshua A. Zeichner
28 Cowden Syndrome .................................................................................. 195
Rita V. Linkner and Joshua A. Zeichner
29 Gardner Syndrome ................................................................................. 201
Alexandra Golant and Joshua A. Zeichner
30 Gorlin Syndrome ..................................................................................... 207
Madelaine Haddican and James Spencer
31 Muir-Torre Syndrome ............................................................................ 215
Adam J. Luber and Joshua A. Zeichner
32 Reed’s Syndrome..................................................................................... 221
Kristen Pacific and Jason Emer
33 Tuberous Sclerosis ................................................................................... 229
Omar Pacha and Adelaide Hebert

Part V Other Mimickers of Acne Vulgaris

34 Acne Scarring .......................................................................................... 237

Neal Bhatia, Consuelo Veronica David, Salar Hazany,
and Aman Samrao
35 Eosinophilic Pustular Folliculitis ........................................................... 245
Joy Makdisi and Adam Friedman
36 Favre-Racouchot Syndrome ................................................................... 253
Silvina Pugliese, Andrea Smith, Rachel Epstein, and Abel Torres
37 Hidradenitis Suppurativa ....................................................................... 259
Deanna M. Sikorski and Kenneth J. Tomecki
38 Perioral Dermatitis ................................................................................. 265
Bryan Gammon and Bethanee J. Schlosser
39 Photocontact Dermatitis ......................................................................... 273
Nicholas Gulati and Emma Guttman-Yassky
40 Post-inflammatory Pigment Alteration ................................................. 279
Rajiv I. Nijhawan and Andrew F. Alexis
41 Pseudofolliculitis Barbae ........................................................................ 289
Angela Lamb and Gregory N. Yañez
42 Pustular Psoriasis .................................................................................... 295
Sebastian Bernardo and Mark Lebwohl
xiv Contents

43 Rosacea..................................................................................................... 309
Joseph Bikowski
44 Rosacea Fulminans ................................................................................. 317
Cristina Caridi and Joshua A. Zeichner
45 Sarcoidosis ............................................................................................... 321
Laura Thornsberry and Joseph English III
46 Seborrheic Dermatitis............................................................................. 329
Elizabeth Farhat and Linda Stein Gold
47 Steatocystoma Multiplex ........................................................................ 343
Alejandra Vivas and Jonette Keri
48 Xanthomas ............................................................................................... 349
Libby Rhee and Mark Kaufmann

Part VI Pediatric Dermatoses Mimicking Acne

49 Periorificial Granulomatous Dermatitis ............................................... 359

Jacquelyn Levin, James Del Rosso, and Richard Miller
50 Keratosis Pilaris Atrophicans ................................................................ 367
Omar Pacha and Adelaide Hebert
51 Neonatal and Infantile Acne .................................................................. 371
Hilary Baldwin
52 Papular Granuloma Annulare ............................................................... 375
Rebecca Smith
53 Precocious Puberty and Acne ................................................................ 381
Maria Miyar and Moise L. Levy

Part VII Drug-Induced Acneiform Eruptions

54 Drug-Induced Acneiform Eruptions ..................................................... 389

Ha K. Do, Navid Ezra, and Stephen E. Wolverton

Index ................................................................................................................. 405

Contributors

Yasser Albahrani, M.D. Department of Dermatology, Mt. Sinai School of

Medicine, New York, NY, USA
Andrew F. Alexis, M.D., M.P.H. Department of Dermatology, St. Luke’s-Roosevelt
Hospital Center, New York, NY, USA
Hilary Baldwin, M.D. Department of Dermatology, SUNY Downstate School of
Medicine, Brooklyn, NY, USA
Annelyse Ballin, M.D. Private Practice, Dr. Brandt Dermatology Associates,
Coral Gables, FL, USA
Sebastian Bernardo, M.D. Department of Dermatology, Mt. Sinai School of
Medicine, New York, NY, USA
Diane Berson, M.D. Department of Dermatology, Weill Cornell Medical College,
New York, NY, USA
Neal Bhatia, M.D. Division of Dermatology, Harbor-UCLA Medical Center,
Torrance, CA, USA
Joseph Bikowski, M.D. Director, Bikowski Skin Care Center, Sewickley, PA,
USA
Whitney P. Bowe, M.D. Department of Dermatology, SUNY Downstate Medical
Center, Brooklyn, NY, USA
Valerie D. Callender, M.D. Callender Dermatology & Cosmetic Center, Glenn
Dale, MD, USA
Cristina Caridi, B.A. Department of Dermatology, Mt. Sinai School of Medicine,
New York, NY, USA
Yvonne Clark, MPAS-C Department of Dermatology, Sharp Rees-Stealy, La Mesa,
CA, USA

xv
xvi Contributors

Shinjita Das, M.D. Department of Dermatology, Harvard Combined Dermatology

Residency Program, Boston, MA, USA
Consuelo Vera David, M.D. Division of Dermatology, Harbor-UCLA Medical
Center, Torrance, CA, USA
James Del Rosso, D.O. Touro University College of Osteopathic Medicine,
Henderson, NV, USA
Ha K. Do, M.D. Department of Dermatology, Indiana University School of Medicine,
New York, NY, USA
Zoe Diana Draelos, M.D. Department of Dermatology, Duke University School
of Medicine, Durham, NC, USA
Lynn A. Drake, M.D. Department of Dermatology, Massachusetts General
Hospital, Boston, MA, USA
Lawrence F. Eichenfield, M.D. Division of Pediatric and Adolescent Dermatology,
Rady Children’s Hospital, San Diego, San Diego, CA, USA
Boni Elewski, M.D. Department of Dermatology, University of Alabama,
Birmingham, Birmingham, AL, USA
Jason Emer, M.D. Department of Dermatology, Mount Sinai School of Medicine,
New York, NY, USA
Joseph C. English III, M.D. Department of Dermatology, University of
Pittsburgh, Pittsburgh, PA, USA
Rachel Epstein, D.O. Department of Dermatology, Loma Linda University, Loma
Linda, CA, USA
Navid Ezra, M.D. Department of Dermatology, Indiana University School of
Medicine, New York, NY, USA
Elizabeth Farhat, M.D. Department of Dermatology, Henry Ford Health System,
West Bloomfield, MI, USA
Patricia K. Farris, M.D. Department of Dermatology, Old Metairie Dermatology,
Metairie, LA, USA
Steven R. Feldman, M.D., Ph.D. Department of Dermatology, Pathology, and
Public Health Sciences, Wake Forest University Baptist Medical Center, Winston-
Salem, NC, USA
Joseph F. Fowler Jr., M.D. Division of Dermatology, University of Louisville,
Louisville, KY, USA
Adam Friedman, M.D. Department of Dermatology, Montefiore – Albert Einstein
College of Medicine, Bronx, NY, USA
Bryan Gammon, M.D. Department of Dermatology, Northwestern University,
Chicago, IL, USA
Contributors xvii

Marisa Kardos Garshick Department of Dermatology, Massachusetts General

Hospital, Boston, MA, USA
Jessica Gjede, M.D. Department of Dermatology, Boston Medical Center, Boston,
MA, USA
Bradely Glodny, M.D. Department of Dermatology, Mt. Sinai, New York,
NY, USA
Alexandra Golant, M.D. Department of Dermatology, The Mt. Sinai Hospital,
New York, NY, USA
Linda Stein Gold, M.D. Department of Dermatology, Henry Ford Health System,
West Bloomfield, MI, USA
Gary Goldenberg, M.D. Department of Dermatology, The Mount Sinai Hospital,
New York, NY, USA
Kristina Goldenberg, M.D. Department of Dermatology, Mt. Sinai School of
Medicine, New York, NY, USA
Rachel Gordon, M.D. Department of Dermatology, The University of Texas
Medical School at Houston, Houston, TX, USA
Emmy Graber, M.D. Department of Dermatology, Boston Medical Center &
Boston University School of Medicine, Boston, MA, USA
Jeremy B. Green, M.D. Private Practice, Dr. Brandt Dermatology Associates,
Coral Gables, FL, USA
Nicholas Gulati, B.A. Laboratory for Investigative Dermatology, The Rockefeller
University, New York, NY, USA
Cheryl J. Gustafson, M.D. Department of Dermatology, Wake Forest University
Baptist Medical Center, Winston-Salem, NC, USA
Emma Guttman-Yassky, M.D. Department of Dermatology, Mount Sinai NY,
New York, NY, USA
Madelaine Haddican, M.D. Department of Dermatology, Mount Sinai School of
Medicine, New York, NY, USA
Salar Hazany, M.D. Division of Dermatology, Harbor-UCLA Medical Center,
Torrance, CA, USA
Adelaide A. Hebert, M.D. Department of Dermatology, University of Texas
Health Science Center, Houston, Houston, TX, USA
Gillian Heinecke, M.D. Department of Dermatology, Mount Sinai, New York,
NY, USA
Joely Kaufman, M.D. Private Practice, Dr. Brandt Dermatology Associates, Coral
Gables, FL, USA
xviii Contributors

Mark D. Kaufmann, M.D. Department of Dermatology, Icahn School of Medicine

at Mt. Sinai, New York, NY, USA
Jonette Keri, M.D., Ph.D. Department of Dermatology and Cutaneous Surgery,
Veterans Hospital, University of Miami, Miami, FL, USA
Alexa Kimball, M.D., M.P.H. Department of Dermatology, Massachusetts
General Hospital, Boston, MA, USA
Joslyn S. Kirby, M.D. Department of Dermatology, Penn State Hershey, Hershey,
PA, USA
Leon H. Kircik, M.D. Department of Dermatology, Mt. Sinai School of Medicine,
New York, NY, USA
Indiana University School of Medicine, Indianapolis, IN, USA
Mary-Margaret Kober, M.D. Department of Dermatology, SUNY Downstate
Medical Center, Brooklyn, NY, USA
Lauren Kole, M.D. Department of Dermatology, University of Alabama,
Birmingham, Birmingham, AL, USA
John Y.M. Koo, M.D. Psoriasis and Skin Treatment Center, University of
California San Francisco, San Francisco, CA, USA
Angela Lamb, M.D. Department of Dermatology, Mount Sinai Hospital, New
York, NY, USA
Whitney Lapolla, M.D. Department of Dermatology, The University of Texas at
Houston, Houston, TX, USA
Caroline L. LaRosa, B.S. Department of Dermatology and Pediatrics, Penn State/
Milton S. Hershey Medical Center, Hershey, PA, USA
Mark G. Lebwohl, M.D. Department of Dermatology, Mt. Sinai School of
Medicine, New York, NY, USA
Jacquelyn Levin, D.O. Department of Dermatology, Largo Medical Center,
Largo, FL, USA
Moise L. Levy, M.D. Department of Pediatric Dermatology, Dell Children’s
Medical Center, Austin, TX, USA
Rita V. Linkner, M.D. Department of Dermatology, Mount Sinai School of
Medicine, New York, NY, USA
Fan Liu, B.A. Department of Dermatology, University of California, San Francisco,
San Francisco, CA, USA
Adam J. Luber, B.A. Department of Dermatology, Mount Sinai Hospital, New
York, NY, USA
Joy Makdisi, B.S. Department of Medicine, Montefiore – Albert Einstein College
of Medicine, Bronx, NY, USA
Contributors xix

Paula S. Malhotra, B.A., M.D. Department of Dermatology, Northwestern

University, Chicago, IL, USA
Rana Mays, M.D. Department of Dermatology, Baylor College of Medicine,
Houston, TX, USA
Richard Miller, D.O. Nova Southeastern University College of Osteopathic
Medicine, Tampa, FL, USA
Jillian Wong Millsop Department of Dermatology, Psoriasis and Skin Treatment
Center, University of California San Francisco, San Francisco, CA, USA
Maria Elena Miyar, M.D. Department of Dermatology, UT Southwestern, Austin,
TX, USA
Andrea Murina, M.D. Department of Dermatology, Tulane University, New Orleans,
LA, USA
Rajiv I. Nijhawan, M.D. Department of Dermatology, St. Luke’s-Roosevelt
Hospital Center, New York, NY, USA
Oge Onwudiwe, M.D. Callender Dermatology and Cosmetic Center, Glenn Dale,
MD, USA
Omar Pacha, M.D. Department of Dermatology, University of Texas Health
Science Center, Houston, Houston, TX, USA
Kristen Pacific, B.A. Department of Dermatology, Mount Sinai School of
Medicine, New York, NY, USA
Silvina Pugliese, M.D. Department of Dermatology, Loma Linda University,
Loma Linda, CA, USA
Rachel Reynolds, M.D. Department of Dermatology, Beth Israel Deaconess
Medical Center, Brookline, MA, USA
Libby Rhee, D.O., M.S. Department of Dermatology, St. Barnabas Hospital,
Bronx, NY, USA
Sara Risner-Rumhor, M.D. Department of Dermatology, Baylor College of
Medicine, Houston, TX, USA
Ted Rosen, M.D. Department of Dermatology, Baylor College of Medicine,
Houston, TX, USA
Misha Rosenbach, M.D. Department of Dermatology, University of Pennsylvania,
Philadelphia, PA, USA
Aman Samrao, M.D. Division of Dermatology, Harbor-UCLA Medical Center,
Torrance, CA, USA
Bethanee J. Schlosser, M.D., Ph.D. Department of Dermatology, Northwestern
University, Chicago, IL, USA
xx Contributors

Alison Schram, B.S. School of Medicine, University of Pennsylvania, Philadelphia,

PA, USA
Alan R. Shalita, M.D. Department of Dermatology, SUNY Downstate Medical
Center, Brooklyn, NY, USA
Kanade Shinkai, M.D., Ph.D. Department of Dermatology, University of
California, San Francisco, San Francisco, CA, USA
Deanna M. Sikorski, M.D. Department of Dermatology, The Cleveland Clinic
Foundation, Cleveland, OH, USA
Andrea Smith, M.D. Department of Dermatology, Loma Linda University, Loma
Linda, CA, USA
Rebecca L. Smith, M.D. Fort Mill Dermatology, LLC, Fort Mill, SC, USA
James Spencer, M.D. Department of Dermatology, Mt. Sinai School of Medicine,
New York, NY, USA
Ani L. Tajirian, M.D. Fletcher Allen Health Care, University of Vermont College
of Medicine, Burlington, VT, USA
Webster Management Inc., Oakland, CA, USA
Laura Thornsberry, M.D. Department of Internal Medicine, University of
Pittsburgh, UPMC Montefiore Hospital, Pittsburgh, PA, USA
Kenneth J. Tomecki, M.D. Department of Dermatology, The Cleveland Clinic
Foundation, Cleveland, OH, USA
Abel Torres, M.D. Department of Dermatology, Loma Linda University, Loma
Linda, CA, USA
Stephen Tyring, M.D., Ph.D., M.B.A. Department of Dermatology, The
University of Texas at Houston, Houston, TX, USA
Alejandra Vivas, M.D. Department of Dermatology, University of Miami, Miami,
FL, USA
Guy F. Webster, M.D., Ph.D. Department of Dermatology, Jefferson Medical
College, Hockessin, DE, USA
Jonathan S. Weiss, M.D. Department of Dermatology, Emory University, Atlanta,
GA, USA
Elijah B. Wilder, D.O. Philadelphia College of Osteopathic Medicine, Georgia,
Atlanta, GA, USA
Stephen E. Wolverton, M.D. Department of Dermatology, Indiana University
School of Medicine, New York, NY, USA
Gregory N. Yañez, B.A. Icahn School of Medicine at Mount Sinai Class of 2015,
New York, NY, USA
Contributors xxi

Andrea L. Zaenglein, M.D. Department of Dermatology and Pediatrics, Penn

State/Milton S. Hershey Medical Center, Hershey, PA, USA
Joshua A. Zeichner, M.D. Department of Dermatology, Mt. Sinai School of
Medicine, New York, NY, USA
Nick Zilieris, D.O., B.sc., M.D. Department of Internal Medicine, Baptist Hospital,
Miami Beach, FL, USA
 Part I
Acne Vulgaris
Chapter 1
Acne Pathophysiology

Shinjita Das and Rachel Reynolds

1.1 Introduction

Acne vulgaris is the result of multifactorial processes in and around the pilosebaceous
unit. Currently, the major pathogenic factors are thought to be:
1. Androgens [1–3]
2. Sebum [4]
3. Abnormal keratinization [5]
4. Propionibacterium acnes (P. acnes) [6]
5. Innate immune system-mediated inflammation [6, 7]
The traditional notion that these factors contribute independently to acne
development has been replaced by a more nuanced understanding of their complex
interplay. Though the multifactorial nature of acne pathogenesis makes effective
treatment challenging, research has shed light on both the mechanisms of action of
current treatments and discovered new targets for acne therapy.

S. Das, M.D.
Department of Dermatology, Harvard Combined Dermatology
Residency Program, Boston, MA, USA
e-mail: [email protected]
R. Reynolds, M.D. (*)
Department of Dermatology, Beth Israel Deaconess Medical Center,
330 Brookline Avenue, Brookline, MA 02215, USA
e-mail: [email protected]

J.A. Zeichner (ed.), Acneiform Eruptions in Dermatology: A Differential Diagnosis, 3

DOI 10.1007/978-1-4614-8344-1_1, © Springer Science+Business Media New York 2014
4 S. Das and R. Reynolds

1.2 Overview of the Innate Immune System

The immune system consists of both innate (rapid response but no memory to
pathogens) and adaptive (delayed, antigen-specific response forming memory)
mechanisms against pathogens [8]. The skin is a first-line agent of the innate
immune system. As an anatomic barrier, skin physically prevents invasion of exter-
nal toxins and maintains an acidic stratum corneum (from free fatty acids generated
by P. acnes) that limits bacterial colonization [9–11]. It can also generate soluble
immune factors (antimicrobial peptides, complement factors, chemokines, and
cytokines) and express pattern recognition receptors (PRRs) to mediate responses
against pathogen-associated molecular patterns (PAMPs) via effector cells, such
as monocytes/macrophages, natural killer (NK) cells, neutrophils, and dendritic
cells (DCs) [12–15].

1.2.1 Toll-Like Receptors

Toll-like receptors (TLRs), a subtype of PRRs found on immune cells (such as

neutrophils, monocytes/macrophages, and DCs), serve as potent initiators of innate
immune responses. While nearly a dozen TLRs have been identified, TLR2 and
TLR4 seem to play the greatest roles in acne pathogenesis (via P. acnes activation)
[16, 17]. Stimulation of TLRs by microbial ligands activates various pathways that
converge at the level of transcriptional regulation of inflammatory genes via nuclear
factor κB (NF-κB). This results in release of inflammatory molecules (such as IL-1,
IL-6, IL-8, IL-10, IL-12, and TNFα) and destruction of pathogens by effector cells
like neutrophils and NK cells [18, 19].

1.2.2 Inflammation via Innate Immune System

Innate immunity-mediated inflammation is both a precipitating and propagating

factor in acne pathogenesis. The key player appears to be IL-1α. There are multiple
hypotheses about what stimuli promote IL-1α production. IL-1 upregulation may be
mediated by increased sebum production and breakdown of the skin barrier from
decreased linoleic acid in the follicle [20, 21]. P. acnes induction of TLR2 and
oxidized squalene via NFkB-mediated transcription may also drive IL-1 expression.
Damaged keratinocytes stimulate IL-1 production, and in a paracrine manner, lym-
phocytes, selectins, and fibroblasts are summoned to the pilosebaceous unit via IL-1
that also has autocrine function, in that it promotes keratinocyte migration, prolif-
eration, and further production of IL-1. This in turn continues the cycle of hyperke-
ratinization, a driving factor in comedo formation [22, 23]. In vitro studies have
demonstrated increased levels of perifollicular inflammatory markers even before
1 Acne Pathophysiology 5

hyperproliferation of keratinocytes [7, 22]. Furthermore, IL-1α receptor blockade

mitigates hyperkeratinization and comedo formation, suggesting that the process is
IL-1 specific [24]. Furthermore, follicular IL-1α can stimulate endothelial cells of
surrounding vasculature to produce inflammatory vascular markers (E-selectin, vas-
cular cell adhesion molecule-1 VCAM-1, intercellular adhesion molecule-1, ICAM-
1, and human leukocyte antigen-DR HLA-DR) [22].

1.3 Development of Acne Lesions

Acne lesions start as microcomedones, which are present in clinically normal

appearing skin and can mature into visible noninflammatory comedones or inflam-
matory papules. While the multifactorial and synergistic nature of acne pathogene-
sis has long been recognized, in vitro studies have shed light on the extensive cross
talk that occurs among the various factors and the innate immune system. Under
physiologic circumstances, the skin harnesses the innate immune response to pro-
tect the internal environment from extrinsic pathogens. However, collateral damage
to adjacent tissues is an unavoidable consequence of this protective mechanism and
manifests clinically as inflammatory conditions such as acne. It has become clear
that acne is a disease of the innate immune response, as acne lesions have been
shown to express higher levels of inflammatory components compared to normal
skin. Studies have revealed that the initial microcomedo is a product of inflammation
and hyperproliferation of the follicular epithelium [22, 24, 25].

1.3.1 Androgens

Androgens are involved in promoting growth of sebaceous glands and sebum

secretion, inducing keratinocyte proliferation, stimulating hair growth, and inhibit-
ing wound healing [26, 27]. They are produced by adrenal glands and gonads as
well as locally within the sebaceous gland. Androgens from adrenal glands and the
gonads are converted to testosterone and dihydrotestosterone in the skin via type 1
5α-reductase from the infrainfundibulum [28]. The rise in androgens during puberty
stimulates sebum production by binding androgen receptors on pilosebaceous ducts
and sebaceous glands. Acne-prone skin has higher androgen receptor density and
higher 5α-reductase activity [28]. Androgens stimulate keratinocyte differentiation
mediated by growth factors and IL-1α that can result in hyperkeratinization in the
ductal and infundibular regions leading to comedogenesis [7]. Evidence for a
hormonal component to acne stems from clinically higher acne rates seen in patients
with androgen excess states, such as polycystic ovarian syndrome, congenital
adrenal hyperplasia, and tumors [29–31]. In addition, castrated males and those
with androgen insensitivity syndromes (from lack of functional androgen receptors)
do not produce sebum and do not develop acne [32].
6 S. Das and R. Reynolds

1.3.2 Sebum

Sebum is secreted by sebaceous glands through holocrine secretion (extrusion of the

entire cell). The primary components of sebum include squalene, cholesterol,
cholesterol esters, wax esters, and triglycerides [4]. As sebum passes through the
follicular duct, lipases from P. acnes hydrolyze a portion of triglycerides into free
fatty acids and mono- and diglycerides [33].
Androgens and retinoids regulate sebum production by sebaceous glands.
Functional androgen receptors have been identified on the basal layer of sebaceous
glands, and androgens stimulate sebaceous gland growth and secretion [34].
Retinoids (such as isotretinoin, 1-cis retinoic acid), on the other hand, arrest sebo-
cyte differentiation. This causes sebaceous gland shrinkage and inhibits sebum
secretion [35, 36]. Sebocytes are regulated at the transcriptional level by peroxi-
some proliferator-activated proteins (PPARs). PPARs are orphan receptors that
heterodimerize with retinoid receptors to regulate sebum production and keratino-
cyte differentiation [37, 38]. Melanocortins (melanocyte-stimulating hormone,
MSH, and adrenocorticotropic hormone, ACTH) have been found to increase sebum
production by binding to their receptors on sebaceous glands [39–41]. Corticotropin-
releasing hormone (released in response to physiologic stress) and CRH receptors
are expressed by sebaceous glands; in vitro studies have demonstrated increased
sebocyte lipid production in response to CRH exposure [42, 43]. More recently, it
has been found that insulin-like growth factor-1 (IGF-1)-induced sterol response
element-binding protein-1 (SREBP-1) regulates lipogenesis by sebocytes [44].
These findings suggest a role of the sebaceous gland in neuroendocrine function and
the stress response.
In addition to lubricating skin and hair, sebum also plays a role within the innate
immune system through multiple pathways. Increased production of sebum is
necessary but not sufficient for acne pathogenesis; the composition of sebum lipids
also has an impact on inflammation. There are increased free fatty acids, squalene,
and squalene oxidase and decreased linoleic acid, conditions which promote hyper-
cornification of the follicle through direct and indirect modulation of the innate
immune system [38, 45–48]. Sebum lipids activate neutrophil degranulation and
increase leukocyte recruitment. Furthermore, oxidized squalene upregulates
5-lipoxygenase (5-LOX), which catalyzes conversion of arachidonic acid to leukot-
riene B4 (LTB4), a potent recruiter of inflammatory cells via PPARα. 5-LOX is
increased in acne patients and stimulates inflammatory cytokine production.
Oxidized squalene can also stimulate hyperproliferation of keratinocytes via IL-1α
upregulation [49–51]. PPARs also activate T-cell signaling via AP-1- and NFkB-
mediated transcriptional regulation [52]. Lower levels of linoleic acid within
sphingolipids of the follicle may also lead to hyperkeratinization [21, 48].
Sebum-mediated acne pathogenesis occurs in concert with P. acnes. The anaerobic
environment of sebaceous glands and sebum lipids allows proliferation of P. acnes,
which expresses lipases that break down triglycerides into proinflammatory free fatty
acids [9–11]. When stimulated by P. acnes binding to TLR2 and TLR4 on sebaceous
1 Acne Pathophysiology 7

Fig. 1.1 P. acnes promotes acne pathogenesis through multiple pathways involving the innate
immune system

glands, sebocytes also direct innate immunity by producing antimicrobial peptides

(such as HβD1 and HβD2) and inflammatory molecules, such as TNFα, IL-1α, and
IL-8 [53–56]. This complement of findings suggests the important role of sebaceous
glands in pathogen recognition and in regulation of the innate immune system on the
skin surface.

1.3.3 Propionibacterium acnes (P. acnes)

P. acnes is a commensal anaerobic, gram-positive rod whose interaction with the

innate immune systems plays a significant role in acne development. This bacteria
expresses lipases that convert sebum triglycerides into free fatty acids, which
stimulate release of antimicrobial peptides and therefore inflammation and comedo-
genesis [57]. By activating TLR2 (via peptidoglycan as the PAMP) and TLR4 on
keratinocytes and inflammatory cells (e.g., monocytes and macrophages) [16, 53],
P. acnes can stimulate the following (Fig. 1.1):
1. TLR-mediated release of cytokines and chemokines (IL-1β, IL-6, IL-8, and
TNFα), which then recruit neutrophils (via IL-8) and macrophages to the pilose-
baceous unit and promote inflammation and rupture of the follicular wall.
Macrophages propagate the cycle by releasing IL-8 (more neutrophil recruitment)
and IL-12 (promotes Th1 response) [6, 53–55].
2. TLR-mediated release of cytokines and chemokines that also amplifies the AP-1
transcription factor, which induces production of matrix metalloproteinases
(MMPs) [58, 59]. MMPs are involved in tissue destruction and scar formation.
8 S. Das and R. Reynolds

All-trans retinoic acid (ATRA, tretinoin) inhibits P. acnes upregulation of MMPs

and improves acne scarring [58].
3. TLR-mediated expression of antimicrobial peptides (HβD1 and 2, cathelicidin,
and granulysin), which also contribute to inflammation and follicular wall rupture
[55, 56, 60].
P. acnes also promotes differentiation of monocytes to macrophages (expressing
CD209), which then phagocytize microbes, including P. acnes. ATRA has been
shown to promote this same differentiation, which suggests an antimicrobial mech-
anism of action for ATRA [61]. Through integrin and filaggrin induction, P. acnes
can stimulate differentiation and proliferation of keratinocytes [16, 62]. Integrins
are cell adhesion proteins and filaggrin is found in higher concentration in acne-prone
skin (within the sebaceous duct and infundibulum) [63]. This may contribute to the
hyperkeratinization seen in comedones.
P. acnes produces biofilm, a polysaccharide lining around a collection of microbes
that enhances adherence within the follicle. Biofilm can also increase the stickiness
of sebum and impede keratinocyte desquamation, leading to the keratin plug seen in
comedones. Biofilm also enhances P. acnes resistance to antibiotics [64].

1.3.4 Abnormal Keratinization

The microcomedo is the initial lesion of acne development. Previously, abnormal

keratinization was thought to precede inflammation associated with acne. However,
it has become clear that IL-1α-mediated inflammation precedes hyperkeratiniza-
tion. In fact, IL-1α has been localized to open comedones [17, 22]. Hyperkeratinization
is the result of both hyperproliferation and retention of keratinocytes within the
follicle [65]. Factors that promote hyperproliferation include changes in lipid
composition of sebum, response to androgens, inflammation from local cytokines,
and P. acnes. Normally, flow of sebum out of the pilosebaceous duct carries with it
old keratinocytes. However, normal sebum flow is impeded by factors such as P.
acnes biofilm adhering to follicular lining and the “bottleneck” effect of microcom-
edo that limits extrusion of sebaceous material. This, in turn, leads to decreased
ductal keratinocyte desquamation and increased keratinocyte cohesion [22, 64].

1.4 Conclusions

Acne is a disease of inflammation mediated by the innate immune system at the

level of the pilosebaceous unit. Multiple factors share an intertwined and synergistic
dynamic within the greater context of the innate immune responses that underlie
acne pathogenesis. As discussed in this section, the overarching concepts of acne
development are the following (Fig. 1.2):
1 Acne Pathophysiology 9

Fig. 1.2 Abnormal

hyperkeratinization (leading
to microcomedo formation) is
mediated by androgen
stimulation, sebum, and
P. acnes through innate
immune mechanisms

• Androgen production drives sebum secretion.

• Sebum lipids activate the innate immune system.
• Abnormal keratinization is driven by IL-1-mediated inflammation and androgen
production.
• P. acnes activates innate immune response via TLRs, activates MMPs, stimulates
production of AMPs, and stimulates sebum secretion.
Recent insights into the pathogenesis of acne may facilitate development of novel
therapeutics. For example, there may be a role for 5-LOX inhibitors in reducing
inflammatory acne lesions in vivo (zileuton is already approved for asthma). Topical
linoleic acid (a lipid that is decreased in acne lesions) or melanocortin receptor
antagonists may serve as an anti-inflammatory treatment. Blocking physiologic
stress responses may also provide benefit. Further studies will allow us to finesse our
understanding of the immunologic underpinnings of acne pathophysiology and
develop more targeted treatments for acne.

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Chapter 2
Clinical Presentation of Acne

Guy F. Webster

2.1 Introduction

Acne is a disease of the pilosebaceous unit that typically begins on the face and has
a spectrum of lesions and severity (Table 2.1). The classic lesion is a pustule, but
inflammatory papules and nodules are common. The primary lesion, from which all
others develop, is the microcomedo, an impaction and distention of the follicle with
sebum and improperly desquamated keratinocytes from the follicular epithelium.
When microcomedones become visible, they are described as open or closed
comedones. An open comedo has a visible pore that appears as a dark spot (Fig. 2.1).
The pigment is not dirt, but is oxidized lipid and melanin. Closed comedones have
a pore too small to see and appear as white bumps (Fig. 2.2).
In patients who are hypersensitive to Propionibacterium acnes that colonizes
follicles, [1] inflammatory lesions may develop from the microcomedones. Papules
and pustules may be superficial or deep and scarring depending on the vigor of
hypersensitivity (Fig. 2.3). Nodules are inflammatory lesions >0.5–1 cm in size.
Nodules may develop into abscesses, which have incorrectly been termed “cysts”
(Fig. 2.4). The term “nodulocystic acne” is incorrect, but probably too deeply
ensconced to readily fall from use. Conglobate lesions are intensely inflamed
neighboring nodules that merge into a loculated abscess. Secondary lesions such as
scars, keloids, sinus tracts, and true cysts may follow in the most inflammatory
disease.

G.F. Webster, M.D., Ph.D. (*)

Department of Dermatology, Jefferson Medical College, Hockessin, DE, USA

J.A. Zeichner (ed.), Acneiform Eruptions in Dermatology: A Differential Diagnosis, 13

DOI 10.1007/978-1-4614-8344-1_2, © Springer Science+Business Media New York 2014
14 G.F. Webster

Table 2.1 The spectrum of Noninflammatory

acne lesions Microcomedo
Open comedo
Closed comedo
Inflammatory
Papule
Pustule
Nodule/abscess
Conglobate lesions
Secondary lesions
Scars, keloids, hypertrophic scars
True cysts
Sinus tracts

Fig. 2.1 Mixed open

comedones (blackheads)
and closed comedones
(whiteheads) on the
forehead of a teenage girl
(Photo credit: Joshua A.
Zeichner, M.D.)

Fig. 2.2 Closed comedones

(whiteheads) on the
forehead of a teenage boy
(Photo credit: Joshua A.
Zeichner, M.D.)

2.2 The Onset of Acne

Acne usually begins with the onset of puberty [2, 3]. Androgens stimulate sebaceous
secretion and microcomedones inflate with sebum and become visible. Typically initial
lesions are noninflammatory and centrofacial (Fig. 2.5). As maturation progresses
2 Clinical Presentation of Acne 15

Fig. 2.3 Mixed comedonal

acne with inflammatory
papules and scattered
pustules on the forehead of
a teenage girl (Photo credit:
Joshua A. Zeichner, M.D.)

Fig. 2.4 Severe,

inflammatory acne on the
cheeks of an adult woman.
Pustules, papules, nodules,
and scars are clinically
apparent (Photo credit:
Joshua A. Zeichner, M.D.)

inflammatory lesions may appear, and the distribution spreads across the face and
perhaps to the trunk (Fig. 2.6). Severity of acne is clearly correlated with the stage of
puberty. Lucky et al. [4] has shown that early in puberty comedonal acne is common,
but inflammatory acne is rare. In later stages of puberty, inflammatory acne may reach
a 50 % incidence in boys [5]. Mourlatos and colleagues [6] demonstrated that both
sebaceous secretion and follicular P. acnes colonization are elevated early in those
children destined to develop acne.
In some patients, adrenarche is a sufficient stimulus and acne may appear in
7–11-year-olds. Lucky [4] has shown that early acne in girls reflects rising levels of
adrenal dehydroepiandrosterone sulfate (DHEAS). She also found that such patients
tended to have more severe acne as teens, though a sign of difficult acne to come,
such as preadolescent acne, is not a cause for medical concern. However, acne that
occurs between 1 and 7 years, termed mid-childhood acne, is much more unusual
and may reflect an underlying medical condition such as endocrinopathy or tumor.
Work-up by a pediatric endocrinologist is indicated [3].
16 G.F. Webster

Fig. 2.5 Open comedones

(blackheads) on the nose of
an adolescent boy. This acne
was one of the first signs of
puberty (Photo credit:
Joshua A. Zeichner, M.D.)

Fig. 2.6 Truncal acne

characterized by
inflammatory papules
on the back (Photo credit:
Joshua A. Zeichner, M.D.)

2.3 Grading Acne Severity

Grading acne is a surprisingly difficult task. The severity of acne varies widely among
patients and even during the course of disease in a single patient. The traditional grad-
ing method in clinical trials involves counting inflammatory and noninflammatory
2 Clinical Presentation of Acne 17

lesions, but this is confounded by the variable severity of inflammatory lesions.

Papules may be barely visible, or deep, scarring, or just short of a nodule, and still be
counted as equivalent lesions.
Determination of acne severity in clinical trials is problematic. Tan and colleagues
[7] have analyzed the gradable aspects of acne and list lesion type, number of lesions,
extent of lesions, regional involvement, secondary lesions, and patient experiences as
important considerations. Cunliffe and colleagues [8] and more recently Dreno and
coworkers [9] have developed grading systems based on comparison of the patient
with standardized photos of acne of varying severity that in some measure answers
this problem. A limitation of these systems is that they are not as quantifiable as
lesion counting. Clinical trials typically rely on a combination of lesion counting and
severity grading in order to generate both quantifiable and comparable data. The situ-
ation is not yet ideal.
Judging severity in day-to-day practice is much less complex. At the initial visit,
experienced clinicians look at the type and number of lesions, the severity of inflam-
mation, the presence of pigmentary disturbance and scarring, and the distribution of
lesions and quickly have a grasp of the severity and likely response to different
treatments. The presence of deep inflammation, nodules, scarring, and trunk lesions
all point toward more severe acne. A second but important factor in judging acne
severity is the effect of the disease on the patient. If each pimple is a tragedy, then
even mild disease is severe.

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and pathophysiology. Semin Cutan Med Surg. 2010;29:2–4.
3. Mancini AJ, Baldwin HE, Eichenfield LF, Friedlander SF, Yan AC. Acne life cycle: the spec-
trum of pediatric disease. Semin Cutan Med Surg. 2011;30:S2–5.
4. Lucky AW, Biro FM, Simbarti LA, Morrisson JA, Sorg NW. Predictors of severity of acne vul-
garis in young adolescent girls: results of a five year longitudinal study. J Pediatr.
1997;130:30–9.
5. Lucky AW, Biro FM, Huster GA, Morrison JA, Elder N. Acne vulgaris in early adolescent boys.
Correlations wit pubertal maturation and age. Arch Dermatol. 1991;127:210–6.
6. Mourlatos K, Eady EA, Cunliffe WJ. Temporal changes in sebum excretion and propionibacte-
rial colonization in preadolescent children with and without acne. Br J Dermatol. 2007;
156:22–31.
7. Tan J, Wolfe B, Weiss J, Stein-Gold L, Bikowski J, Delrosso J, Webster GF, Lucky A, Thiboutot
D, Wilkin J, Leyden J, Chren MM. Acne severity grading: determining essential clinical
components and features using Delphi consensus. J Am Acad Dermatol. 2012;67:187–93.
8. O’Brien SC, Lewis JB, Cunliffe WJ. The Leeds revised acne grading system. J Dermatol Treat.
1998;9:215–20.
9. Dreno B, Poli F, Pawin H, Beylot C, Faure M, et al. Development and evaluation of a global
acne severity scale (GEA scale) suitable for France and Europe. J Eur Acad Dermato Venereol.
2011;25:43–8.
Chapter 3
Topical Therapies for Acne

Mary-Margaret Kober, Whitney P. Bowe, and Alan R. Shalita

3.1 Introduction

Topical treatment is a key component of acne therapy. Acne treatments target factors
contributing to acne formation and act to normalize follicular keratinization and
decrease sebaceous gland activity and follicular bacterial populations [1]. With early
treatment, acne scarring, post-inflammatory hyperpigmentation, and psychological
distress may be reduced or prevented [2]. Topical therapies for acne come in pre-
scription and over-the-counter formulations. This chapter will focus on prescription
products only.

3.2 Topical Retinoids

Biologically active molecules derived from vitamin A, topical retinoids have

become a mainstay in acne therapy. Retinoids bind retinoic acid receptors (RARs)
and retinoic X receptors (RXRs). Three subgroups of RARs exist: RAR-α (alpha),
RAR-β (beta), and RAR-γ (gamma). RAR-α (alpha) is expressed throughout adult
and embryonic tissue. RAR-β (beta) resides in dermal fibroblasts, and RAR-γ
(gamma), present throughout the epidermis, is likely the receptor responsible for the
positive effects retinoids exert on keratinocytes [3].
Once bound to their receptor, retinoids promote proliferation of basal keratinocytes,
block the terminal stages of epithelial differentiation, and reduce filaggrin expression
and proteolysis of keratins 1 and 14 [4]; these changes normalize keratinization and
prevent the hyperproliferative state associated with comedo formation [5, 6]

M.-M. Kober, M.D. (*) • W.P. Bowe, M.D. • A.R. Shalita, M.D.
Department of Dermatology, SUNY Downstate Medical Center,
450 Clarkson Road, Brooklyn, NY, USA
e-mail: [email protected]; [email protected]; [email protected]

J.A. Zeichner (ed.), Acneiform Eruptions in Dermatology: A Differential Diagnosis, 19

DOI 10.1007/978-1-4614-8344-1_3, © Springer Science+Business Media New York 2014
20 M.-M. Kober et al.

Currently, four topical retinoids are available: tretinoin, isotretinoin, tazarotene,

and adapalene. However, only tretinoin, tazarotene, and adapalene are available in
the United States.

3.2.1 Tretinoin (First-Generation Retinoids)

Tretinoin is the oldest of the retinoids and binds with equal affinity to all RAR
receptors. Tretinoin demonstrates superiority to benzoyl peroxide (BP), sulfur-
resorcinol, and vehicle in the reduction of inflammatory and noninflammatory acne
lesions as well as the global severity of acne [7, 8].
Although there may be some improvement noted after 2–3 weeks, the most
significant reduction in acne lesions is noted after 3–4 months of consistent use [9].
The histopathologic findings seen in skin receiving tretinoin include acanthosis,
parakeratosis, and thinning of the stratum corneum [8], which correlates with the
observation that the tretinoin-induced thinning of the stratum corneum allows for
improved efficacy of topical antimicrobial products [10].
Ultraviolet light and oxidants such as benzoyl peroxide degrade tretinoin upon
exposure [9]. Advances in formulation technology have allowed for the develop-
ment of new tretinoin containing topicals that combat these limitations. One such
example is the development of microsphere formations (Retin-A Micro®) that
significantly decreases degradation [11]. Microsphere formulations also provide a
gradual time release of tretinoin, increasing transdermal penetration and decreasing
the irritation [12].

3.2.2 Tazarotene and Adapalene (Third-Generation Retinoids)

Tazarotene and adapalene only bind to RAR-β (beta) and RAR-γ (gamma) receptor
subtypes, leading to reduced side effects compared to tretinoin.
Although similar in efficacy to tretinoin in the reduction of inflammatory lesions,
tazarotene has proven to be superior to tretinoin in reducing the number of nonin-
flammatory lesions [13]. Tazarotene also shows superiority compared to adapalene
in clearing post-inflammatory hyperpigmentation caused by acne [13].
Adapalene shows similar efficacy to tretinoin in reducing inflammatory and non-
inflammatory lesions and the global severity of acne [14]. However, when compared
to tazarotene, adapalene is less effective in decreasing the number of inflammatory
and noninflammatory lesions [15]. In general, adapalene demonstrates the best
tolerability profile of the topical retinoids [16, 17].
Both tazarotene and adapalene have increased stability in the presence of ultra-
violet light and BP as a result of replacing the labile, light sensitive double bonds
of tretinoin with naphthoic acid rings [18]. This allows for the development of
stable combination products containing third-generation retinoids with other active
ingredients, such as BP.
3 Topical Therapies for Acne 21

Combination products are now available on the market, including adapalene/BP,

tretinoin/clindamycin, and erythromycin/BP or clindamycin/BP. In addition to the
comedolytic effects of retinoids, these products decrease P. acnes counts. Combination
products often have faster results than monotherapy and improved patient compliance
[19, 20].
The most common adverse reactions to topical retinoids include localized dry skin,
erythema, and scaling. Compared to the newer formulations of retinoids, older forms
of tretinoin caused more burning, erythema, and desquamation. Tolerance typically
develops with continued exposure. Unlike systemic retinoids, studies have not dem-
onstrated a teratogenic effect of topical retinoids; however, given the theoretical risk,
many dermatologists advise patients to stop application during pregnancy [21].
Given the chronic nature of acne and its tendency to recur upon cessation of
treatment, maintenance therapy is often required; first-line maintenance therapy is a
topical retinoid. In one study of patients with moderate acne who had initial treat-
ment with a topical retinoid and antimicrobial, those continued on topical retinoid
therapy had significant less rebound and maintained few acne lesions compared to
those who did not receive maintenance therapy [22].

3.3 Topical Antimicrobials

3.3.1 Antibiotics

Clindamycin and erythromycin represent the topical antibiotics most commonly

used for acne treatment, although recent trends suggest that clindamycin is the most
commonly prescribed [23]. Their mechanism of action is based on the reduction of
P. acnes organisms present on the skin, leading to a reduction in inflammatory
pathways and consequently a decrease in the number of inflammatory and nonin-
flammatory acne lesions [24–26].
Several concerns have developed regarding the use of topical antibiotics, specifically
surrounding the emergence of resistant strains of P. acnes. Rates of erythromycin and
clindamycin resistant P. acnes have increased to 40 % globally, leading to a decrease in
treatment efficacy of topical antibiotics [27–29]. Although resistance has emerged to
both erythromycin and clindamycin, the clinical efficacy of clindamycin has been
preserved relative to erythromycin [23].
Perhaps more concerning is the data suggesting pharyngeal colonization with
Streptococcus pyogenes with chronic use of topical antibiotics [14]. Long-term
antibiotic use has also shown the development of bacterial resistance in coagulase-
negative staphylococci [30]. Although coagulase-negative staphylococci are rarely
pathogenic, it may serve as a reservoir of bacterial resistant genes, spreading
resistant genes to other organisms, such as Staphylococcus aureus [31].
Combining BP with a topical antibiotic reduces the emergence of resistant strains
and improves efficacy [32]. Given the occurrence of antibiotic resistance with
monotherapy of topical antibiotics, it is only recommended to use topical antibiotics
22 M.-M. Kober et al.

as part of combination therapy [33]. Several combination products are available that
combine a topical antibiotic with BP into a single product. Combination gels have
reduced antibiotic-resistant strains of P. acnes by 97 % [34] and have shown to
improve patient adherence to treatment regimens [35].
Side effects of topical antibiotics are limited. The most common adverse effects
include reactions at the site of application (erythema, scaling, stinging, or burning);
these reactions have been shown to be at least in part dependent on the vehicle
formulation [23, 24].

3.3.2 Azelaic Acid

The antimicrobial properties of azelaic acid make it another topical treatment option
for acne [33]. Trials comparing azelaic acid to BP or topical clindamycin show
similar reductions in the number or acne lesions [36]. Reduction in the number of
lesions can be seen as early as 4–8 weeks; however, maximum benefit typically
occurs after 16 weeks. Cutaneous side effects of stinging or burning may occur in
10–20 % of patients upon initial use; however, these side effects typically resolve
with continued use and rarely necessitate the cessation of treatment [37, 38].
It should be noted, however, that one of the authors found little or no efficacy with
the original formulation of azelaic acid and one laboratory found no antibacterial
effect on P. acnes.
Topical clindamycin, erythromycin, and azelaic acid appear to be safe during
pregnancy (Category B), with no reports of teratogenicity to date.

3.3.3 Dapsone

Topical dapsone has been approved for the treatment of acne vulgaris, although it
may result in a more modest reduction in acne lesions compared to other therapies.
It has an excellent tolerability profile, but may result in a temporary yellow discol-
oration of the skin when combined with BP [34]. Topical dapsone appears to work
well as an adjuvant to topical retinoids, reducing the irritation and desquamation
commonly associated with topical retinoids as well as significantly increasing their
efficacy [34].

3.4 New Developments in Topical Acne Therapy

Novel topical acne therapies focus on targeting drug delivery to the follicle.
3 Topical Therapies for Acne 23

3.4.1 Liposomes

Liposomes are phospholipid bilayers that create a spherical vesicle with a central
aqueous cavity and possess both hydrophobic and lipophilic properties. Clindamycin
in liposomes has shown a statistically significant decrease in acne lesions compared
to liposome-free clindamycin products [39]; similar efficacy has been seen with
liposome-derived tea tree oil, salicylic acid, retinoids, and BP [40].

3.4.2 Micronization

Smaller particles permit deeper penetration into the pilosebaceous unit. Micronizing
formulations create products of smaller particle sizes, with particles frequently less
than 10 μm. A micronized formulation of tretinoin gel, Atralin®, has demonstrated
enhanced moisture capacity and tolerability with similar lesion reduction compared
to generic tretinoin gel [41].

3.5 Treatment Guidelines

Mild acne responds to treatment with a topical retinoid with possible addition of BP
and/or a topical antibiotic if inflammatory lesions are present. Mild-to-moderate
acne typically requires combination therapy using one of the following regimens:
a topical retinoid combined with BP and an oral antibiotic or a topical retinoid
combined with a topical BP/antibiotic product [42]. Moderate-to-severe acne may
be treated with topical retinoids in combination with BP, topical, and/or oral anti-
biotics; however, acne this severe may require systemic isotretinoin, discussed
elsewhere.

3.6 Conclusion

Acne vulgaris is a chronic disease that requires a patient-centered approach. The

most common topical treatments include retinoids and antibiotics with the addition
of BP to reduce the development of antibiotic resistant strains of P. acnes. New
products and novel formulation of existing drugs continue to expand the arsenal of
available treatments and reduce adverse effects such as irritation and erythema.
Maintenance therapy with topical retinoids is often recommended after initial treat-
ment to prevent relapses.
24 M.-M. Kober et al.

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ate facial acne vulgaris. J Drugs Dermatol. 2009;9(5):549–58.
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different tretinoin formulations. Br J Dermatol. 1998;139 suppl 52:34–40.
17. Caron D, Sorba V, Clucas A, et al. Skin tolerance of adapalene 0.1% gel in combination with
other topical antiacne treatments. J Am Acad Dermatol. 1997;35(6 pt 2):S113–5.
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combined with benzoyl peroxide in presence and in absence of visible light and ultraviolet
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19. Thiboutot DM, Weiss J, Bucko A, Adapalene-BPO Study Group, et al. Adapalene-benzoyl
peroxide, a fixed-dose combination for treatment of acne vulgaris: results of a multicenter,
randomized double-blind, controlled study. J Am Acad Dermatol. 2007;57(5):791–9.
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3 Topical Therapies for Acne 25

21. Loureiro KD, Kao KK, Jones KL, et al. Minor malformations characteristic of the retinoic acid
embryopathy and other birth outcomes in children of women exposed to topical tretinoin
during early pregnancy. Am J Med Genet A. 2005;136(2):117–21.
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and other inflammatory skin disorders: focus on antibiotic resistance. Cutis. 2007;79 suppl
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139:4–8.
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aerobic cutaneous bacterial flora. Antimicrob Agents Chemother. 1996;40:2598–604.
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J Hyg (Lond). 1984;93:59–66.
32. Del Rosso JQ, Leyden JJ, Thiboutot D, et al. Antibiotic use in acne vulgaris and rosacea:
clinical considerations and resistance issues of significance to dermatologist. Cutis. 2008;
82(2S[ii]):5–12.
33. Del Rosso JQ. Topical antibiotics. In: Shalita AR, Del Rosso JQ, Webster GF, editors. Acne
vulgaris. New York, NY: Informa Healthcare; 2011. p. 95–104.
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1(3):97–107.
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and outcomes with topical acne medications: a randomized controlled trial. Cutis. 2010;
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36. Thiboutot D. Versatility of azelaic acid 15% gel in the treatment of inflammatory acne vulgaris.
J Drugs Dermatol. 2008;7:13–6.
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cream for acne. Acta Derm Venereol Suppl (Stockh). 1989;143:45–8.
38. Katsambas A, Graupe K. Azelaic acid for the treatment of acne vulgaris- a clinical comparison
with vehicle and topical tretinoin. Acta Derm Venereol Suppl (Stockh). 1989;143:35–9.
39. Honzak L, Sentjurc M. Development of liposome encapsulated clindamycin for treatment of
acne vulgaris. Pflugers Arch. 2000;440:44–5.
40. Castro GA, Ferreira LA. Novel vesicular and particular drug delivery systems for topical treat-
ment of acne. Expert Opin Drug Deliv. 2008;5:665–79.
41. Torok HM, Pillai R. Safety and efficacy of micronized tretinoin gel (0.05%) in treating adolescent
acne. J Drug Dermatol. 2011;10:647–51.
42. Villasenor J, Berson DS, Kroshinsky D. Combination therapy. In: Shalita AR, Del Rosso JQ,
Webster GF, editors. Acne vulgaris. New York, NY: Informa Healthcare; 2011. p. 105–12.
Chapter 4
Systemic Therapies for Acne

Marisa Kardos Garshick, Alexa Kimball, and Lynn Drake

4.1 Introduction

Individuals with moderate-to-severe inflammatory acne may warrant systemic

therapies, especially if they are unresponsive to topical treatments, or have signifi-
cant quality of life decrements, which is not uncommon in this population. Specific
clinical features, including the type and severity of acne, the presence of scarring,
and the association with abnormal menses, can help guide the appropriate course of
treatment. All dosages mentioned in this section must be adjusted according to the
individual patient.

4.2 Oral Antibiotics

Oral antibiotics used for the treatment of moderate-to-severe inflammatory acne

work by inhibiting the growth of P. acnes, or by anti-inflammatory effects [1]. Due
to the widespread use of antibiotics, there is an increasing concern about antibiotic
resistance. Given this, antibiotics are initially prescribed for a limited course. In the
absence of clinical improvement after 6–8 weeks, a change in the antibiotic or
other treatments may be considered. If partial improvement is observed, response to
therapy should be reassessed after 6–8 weeks [2]. Using topical benzoyl peroxide or
other topicals in combination with antibiotics may decrease the emergence of resis-
tance [3]. Once acne is improved, oral antibiotics are often discontinued and patients
should continue topical therapies for long-term maintenance as acne tends to flare
in the absence of treatment.

M.K. Garshick, B.S. (*) • A. Kimball, M.D., M.P.H. • L. Drake, M.D.

Department of Dermatology, Massachusetts General Hospital, 50 Staniford
Street Suite 240, Boston, MA 02114, USA
e-mail: [email protected]

J.A. Zeichner (ed.), Acneiform Eruptions in Dermatology: A Differential Diagnosis, 27

DOI 10.1007/978-1-4614-8344-1_4, © Springer Science+Business Media New York 2014
28 M.K. Garshick et al.

4.2.1 Macrolides

Erythromycin is not commonly used given the incidence of treatment failure perhaps
due to the development of P. acnes antibiotic resistance or the low level of anti-
inflammatory activity. Erythromycin is usually recommended when tetracycline
derivatives are contraindicated [4]. A common acne dose is 500 mg twice daily. Side
effects may include gastrointestinal (GI) distress, which might be reduced if admin-
istered with food.
Azithromycin has been reported as effective in the treatment of acne, though
there is little consensus for its use and optimum dosing [5–7]. Given its role in the
treatment of respiratory infections and as an alternative treatment for patients
allergic to beta-lactam antibiotics, there is concern with increasing resistance.
Azithromycin does not usually cause GI upset and should be taken on an empty
stomach to enhance GI absorption.

4.2.2 Tetracyclines

The tetracyclines are probably the most commonly used antibiotics, and they have
both antibiotic and anti-inflammatory properties. The newer generation tetracy-
clines (doxycycline and minocycline) are often preferred over tetracycline, due to
decreased rates of resistance and better tolerability [8]. Evidence suggests a reduced
incidence of bacterial resistance with minocycline- and tetracycline-resistant
P. acnes cross-resistant to doxycycline, but sensitive to minocycline [9, 10]. Despite
this, minocycline may be used as first-line therapy due to cost, toxicities, and no
clear evidence of superior efficacy [11, 12].
Tetracycline is typically dosed at 500 mg twice daily, although 250 mg once or
twice daily may also be effective. Patients should be advised to take tetracycline on
an empty stomach as absorption is inhibited by food and with concurrent ingestion
of calcium, magnesium, and aluminum. The absorption of doxycycline and minocy-
cline is not inhibited by food, though concomitant administration with iron supple-
ments may decrease absorption. Doxycycline is commonly prescribed at 50–100 mg
once or twice daily. Although the data is limited, there may be a role for subantimi-
crobial dosing of doxycycline (20 mg twice daily) by which the anti-inflammatory
mechanism is maintained, but the antibacterial properties are lost [13]. Until more
data becomes available, subantimicrobial doses are usually only recommended
when deemed to be in the best interest of the patient. While dosing of minocycline
is usually 50–100 mg twice daily, an extended-release, once daily formulation of
minocycline is FDA-approved at 1 mg/kg/day [14, 15].
The class-related side effects may include GI distress, including esophagitis;
photosensitivity, particularly with doxycycline and tetracycline; and idiopathic
intracranial hypertension (pseudotumor cerebri). To minimize GI side effects, doxy-
cycline and minocycline can be administered with food and water. All tetracyclines
should be avoided in pregnant women and children due to the potential for reduced
4 Systemic Therapies for Acne 29

bone growth and discoloration of developing teeth. Minocycline has been associated
with acute vestibular adverse events; brown, gray, or blue pigmentation of the skin;
lupus-like syndrome; and drug hypersensitivity syndrome [16]. Although it has
been thought that continued use of systemic tetracycline antibiotics results in
colonization with tetracycline-resistant Staphylococcus aureus, this may not be the
case. Evidence suggests that S. aureus may remain sensitive to tetracycline even
after prolonged use [17].

4.2.3 Other Antibiotics

Trimethoprim-sulfamethoxazole has been reported in the treatment of acne [18].

Severe, but rare, adverse effects may include drug hypersensitivity and hematologic
reactions. Given the need to use trimethoprim-sulfamethoxazole in the treatment of
methicillin-resistant S. Aureus infections and the potential side effects, trimethoprim-
sulfamethoxazole should probably be used only in selected cases.

4.3 Isotretinoin

Isotretinoin, a vitamin A analogue, inhibits sebaceous gland activity and promotes

normalization of epidermal differentiation. Additional properties that contribute to its
efficacy include its anti-inflammatory and antibacterial effects. Isotretinoin is FDA-
approved for use in patients with severe, recalcitrant, nodular acne [19] and may also
be used in individuals with acne scarring.
Dosing is 0.5–1 mg/kg/day divided twice daily [19]. It is frequently initiated at
0.5 mg/kg/day to minimize the initial inflammatory response. If after the first
4 weeks, no adverse events occur, the dose may be increased as tolerated to 1 mg/
kg/day to ultimately achieve a cumulative dose of 120–150 mg/kg [20]. A short
course of prednisone may be considered prior to initial treatment or co-administered
with isotretinoin in individuals at risk of a severe inflammatory reaction [21].
Isotretinoin can approach a cure in approximately 40 % of treated patients and
improves many others [22]. Relapses may occur, especially in younger patients,
males, and those with truncal acne. However, they can often be managed with topi-
cal agents or oral antibiotics. If acne remains severe, a repeat course of isotretinoin
may be considered [23].
A number of adverse effects are associated with isotretinoin, some of which are
dose dependent, and many are reversible. Cheilitis and mucocutaneous dryness are
the most common and serve as an indicator of compliance and appropriate dosing.
Dyslipidemia, specifically hypertriglyceridemia, is another common and reversible
side effect [24]. Typically, the alteration in blood lipids occurs during the first
2 months of treatment and then stabilizes. Other less common side effects include
increased transaminase levels, pancytopenia, nausea, diarrhea, idiopathic intracranial
hypertension, arthralgias, and myalgias.
30 M.K. Garshick et al.

Isotretinoin is teratogenic and contraindicated during pregnancy. It poses the

greatest risk in the first trimester and can result in spontaneous abortion, birth
defects, and impaired neurological functioning [25, 26]. To minimize the risk of
pregnancy, all US patients must be enrolled in the iPLEDGE program, which is an
Internet-based registry to ensure that medication is only dispensed after proper
counseling, documentation of two methods of contraception, and negative urinary
pregnancy tests. Patients should not get pregnant for at least 1 month after discon-
tinuing isotretinoin to guarantee clearance [19].
Some controversial side effects may exist for which the evidence is not clear.
These include altered bone mineralization, diffuse idiopathic skeletal hyperostosis
(DISH), the development of inflammatory bowel disease (IBD), and mood distur-
bances [27–29]. Although there is insufficient evidence to prove a causal relation-
ship between isotretinoin and IBD, it may be important to inform patients of this
potential effect [30]. While some studies show no increased risk of depression or
suicidal ideation, physicians and patients may wish to continue to monitor for mood
changes [31–33].

4.4 Hormonal Therapies

Androgens stimulate sebaceous glands to produce sebum and may also affect
follicular hyperkeratinization. As a result, increased levels of serum androgens and
heightened sensitivity of sebaceous glands to circulating androgens may increase
the risk of acne [34]. Even in the absence of androgen excess, hormonal therapies may
be effective through inhibition of androgen action on the pilosebaceous units [35].
Hormonal therapies are typically reserved for adolescent and adult females with
moderate-to-severe acne and should be considered in those with inflammatory
lesions along jaw line and neck that flare prior to menses, concomitant hirsutism, or
menstrual irregularity.

4.4.1 Oral Contraceptives

The estrogen in certain oral contraceptives suppresses ovarian androgen production

and increases sex hormone-binding globulin (SHBG), resulting in an overall decrease
in testosterone bioavailability [36]. The FDA-approved oral contraceptive pills
(OCPs) for the treatment of acne include ethinyl estradiol with different progestins:
norgestimate, norethindrone, and drospirenone [37]. Although a Cochrane review in
2009 concluded that combined OCPs were more effective than placebo in controlling
acne vulgaris, it has yet to be determined which combined OCPs are superior [38].
There was a slightly greater improvement in acne with ethinyl estradiol/drospirenone
4 Systemic Therapies for Acne 31

versus ethinyl estradiol/norgestimate in one clinical trial, perhaps related to the

antiandrogenic progestin [39].
The risks associated with OCPs should be considered prior to initiating therapy.
Individuals with a history of thromboembolic disease should not be placed on an
OCP, and female smokers greater than 35 years of age should be counseled prior to
treatment with an OCP due to the increased risk of thrombosis [40, 41]. Other
reported side effects include nausea, decreased libido, breast tenderness, headache,
breakthrough bleeding, mood disturbances, and potential for weight gain. Due to
the risk of hyperkalemia with drospirenone-containing OCPs, these medications are
contraindicated in patients with renal or adrenal insufficiency and hepatic dysfunc-
tion [40]. Other than for rifampin, there is no definitive evidence to suggest that
antibiotics increase OCP failure rate [42]. Despite this, some individuals have large
decreases in ethinyl estradiol concentrations when they take tetracycline and
penicillin derivatives [43]. If acne does not improve within 6 months of OCP use,
it typically will not improve [44].

4.4.2 Spironolactone

Spironolactone is an antiandrogen that inhibits androgen biosynthesis by inhibiting

5-α(alpha) reductase and blocks the androgen receptor [45]. Spironolactone may be
considered in females with refractory acne or who prefer to avoid isotretinoin.
Although several studies have demonstrated efficacy, a 2009 Cochrane review found
insufficient evidence to confirm the effectiveness of spironolactone versus placebo
in the treatment of acne [46–49]. While benefits may be observed at 25–200 mg/day,
doses ranging from 50 to 100 mg/day are often recommended as lower doses may
reduce the risk of side effects [50, 51]. Doses of 25 mg daily might be sufficient for
some women with sporadic outbreaks or isolated cysts [52]. Absorption may be
increased when administered with food.
Side effects may include hyperkalemia, orthostatic hypotension, menstrual irreg-
ularities, gynecomastia, headaches, fatigue, and GI symptoms. The most concern-
ing is the risk of hyperkalemia, which is greater with higher doses, in older women,
those taking chronic nonsteroidal anti-inflammatory agents and angiotensin-
converting enzyme inhibitors, and those with renal insufficiency or severe cardiac
disease. Potassium levels should be checked in the first month of treatment and
monitored thereafter to determine if any dose adjustments need to be made, and
patients should avoid potassium in their diet. Although breast tumors have been
reported in mice treated with spironolactone, there is no definitive human evidence
[51]. Despite this, some prefer to avoid this medication in women with a personal or
family history of breast cancer. Spironolactone is a pregnancy category C medica-
tion due to the risk of feminization on male fetuses, so co-administration with an
oral contraceptive is recommended.
32 M.K. Garshick et al.

4.4.3 Other Antiandrogens

Other antiandrogens have been used including cyproterone acetate and flutamide but
only in selected cases [2, 52]. Oral corticosteroids may be used at low doses to suppress
adrenal hyperactivity in individuals with adrenal androgen overproduction, seen in
late-onset CAH. Frequently recommended doses are 2.5–5 mg of prednisone daily or
0.25–0.75 mg of dexamethasone [53]. Careful monitoring is always recommended.

4.5 Conclusion

Systemic therapies are an essential part of the management of moderate-to-severe

acne. While systemic medications are effective in the treatment of acne, often they
have associated side effects. As such, it is important to recognize which patients
may benefit and to only use systemic treatment when it is clinically indicated.

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J Dermatolog Treat. 2006;17:217–21.
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treatment of acne vulgaris. Clin Exp Dermatol. 2005;30:215–20.
7. Antonio JR, Pegas JR, Cestari T, Do Nascimento LV. Azithromycin pulses in the treatment of
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19:210–5.
8. Leyden JJ, Del Rosso JQ, Webster GF. Clinical considerations in the treatment of acne vulgaris
and other inflammatory skin disorders: focus on antibiotic resistance. Cutis. 2007;79:9–25.
9. Eady EA, Cove JH, Holland KT, Cunliffe WJ. Superior antibacterial action and reduced
incidence of bacterial resistance in minocycline compared to tetracycline-treated acne patients.
Br J Dermatol. 1990;122:233–44.
10. Eady EA, Jones CE, Gardner KJ, et al. Tetracycline-resistant propionibacteria from acne
patients are cross-resistant to doxycycline but sensitive to minocycline. Br J Dermatol. 1993;
128:556–60.
11. Garner SE, Eady EA, Popescu C, et al. Minocycline for acne vulgaris: efficacy and safety.
Coch Data Syst Rev. 2003; Issue 1: CD002086.
12. McManus P, Iheanacho I. Don’t use minocycline as first line oral antibiotic in acne. BMJ.
2007;334:154.
13. Skidmore R, Kovach R, Walker C, et al. Effects of subantimicrobial-dose doxycycline in the
treatment of moderate acne. Arch Dermatol. 2003;139:459–64.
4 Systemic Therapies for Acne 33

14. Stewart DM, Torok HM, Weiss JS, et al. Dose-ranging efficacy of new once-daily
extended-release minocycline for acne vulgaris. Cutis. 2006;78:11–20.
15. Fleischer Jr AB, Dinehart S, Stough D, et al. Safety and efficacy of a new extended-release
formulation of minocycline for acne vulgaris. Cutis. 2006;78:21–31.
16. Sturkenboom MC, Meier CR, Jick H, Striker BH. Minocycline and lupus-like syndrome in
acne patients. Arch Intern Med. 1999;159:493–7.
17. Fanelli M, Kupperman E, Lautenbach E, Edelstein PH, Margolis DJ. Antibiotics, acne, and
staphylococcus aureus colonization. Arch Dermatol. 2011;147:917–21.
18. Bhambri S, Del Rosso JQ, Desai A. Oral trimethoprim/sulfamethoxazole in the treatment of
acne vulgaris. Cutis. 2007;79(6):430–4.
19. Amnesteem® (Isotretinoin Capsules USP) [package insert]. Morgantown, WV: Mylan
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20. Strauss JS, Rapini RP, Shalita AR, et al. Isotretinoin therapy for acne: results of a multicenter
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21. Ellis CN, Krach KJ. Uses and complications of isotretinoin therapy. J Am Acad Dermatol.
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22. White GM, Chen W, Yao J, Wolde-Tsadik G. Recurrence rates after the first course of
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23. Azoulay L, Oraichi D, Bérard A. Isotretinoin therapy and the incidence of acne relapse: a
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28. Reddy D, Siegel CA, Sands BE, et al. Possible association between isotretinoin and inflamma-
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34 M.K. Garshick et al.

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associated with use of injectable contraception and 20 microg oral contraceptive pills. Am J
Obstet Gynecol. 2008;199:351.e1–e12.
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and reduces sebum excretion. Br J Dermatol. 1984;111:209–14.
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49. Burke BM, Cunliffe WJ. Oral spironolactone therapy for female patients with acne, hirsutism
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50. Shaw JC. Low-dose adjunctive spironolactone in the treatment of acne in women: a retrospec-
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51. Katsambas AD, Dessinioti C. Hormonal therapy for acne: why not as first line therapy? Facts
and controversies. Clin Dermatol. 2010;28:17–23.
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and endocrine effects. Exp Clin Endocrinol Diabetes. 1995;103:241–51.
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Chapter 5
Laser and Light Based Therapies for Acne

Jeremy B. Green, Annelyse Ballin, and Joely Kaufman

5.1 Introduction

Conventional topical and systemic therapeutics are effective for treating acne vulgaris,
but are not perfect solutions. Topical salicylic acid, benzoyl peroxide, and retinoid
preparations can be irritating and present challenges with compliance. Systemic
antibiotics also have issues with tolerability and increasing bacterial resistance, and
isotretinoin has attracted negative attention due to its purported links to inflamma-
tory bowel disease and depression. Laser and light-based treatments can potentially
offer a viable adjunct or even alternative to these conventional options.

5.2 Light/Photodynamic Therapy

Light is thought to treat acne by taking advantage of the endogenous porphyrins

produced by the pathogenic Propionibacterium acnes bacteria in sebaceous skin,
coproporphyrin III and protoporphyrin IX. Porphyrin photoexcitation occurs maxi-
mally within the Soret band, with a peak in the blue light spectrum at approximately
410 nm, and additional smaller absorption peaks in the Q bands (500–635 nm)
[1, 2]. Porphyrin excitation initiates a cascade of events that leads to the production
of reactive oxygen species and destruction of P. acnes. This reaction can be potenti-
ated by the addition of aminolevulinic acid (ALA), an exogenous photosensitizer
that preferentially localizes to sebaceous glands and enhances intracellular porphyrin
synthesis, the so-called photodynamic therapy (PDT).

J.B. Green, M.D. (*) • A. Ballin, M.D. • J. Kaufman, M.D.

Private Practice, Dr. Brandt Dermatology Associates,
4425 Ponce De Leon Blvd, Suite 200, Coral Gables, FL 33146, USA
e-mail: [email protected]

J.A. Zeichner (ed.), Acneiform Eruptions in Dermatology: A Differential Diagnosis, 35

DOI 10.1007/978-1-4614-8344-1_5, © Springer Science+Business Media New York 2014
36 J.B. Green et al.

There is a dearth of large, randomized controlled trials of lasers and lights for
acne [3]. One exception was an industry-sponsored evaluation of 266 severe acne
patients treated with blue light (417 ± 5 nm) and 20 % aminolevulinic acid (ALA)
(BLU-U® and Levulan® Kerastick, DUSA Pharmaceuticals, Inc.) versus blue light
and vehicle alone [4]. In this study, vehicle or ALA was applied for 45 min incuba-
tion followed by 16 min and 40 s of blue light (10 J/cm2 total dose), one treatment
every 3 weeks for four treatments. Interestingly the investigators found a decrease
in inflammatory lesions of 37.5 % for the ALA group versus 41.7 % reduction in the
vehicle group. Noninflammatory lesion counts were not performed. The study
indicates that blue light alone is as effective as blue light plus ALA.
Blue light penetrates to a depth of approximately 90–150 μm. Although it is
unlikely that significant amount of this wavelength reaches the sebaceous gland,
exposure to blue light at a wavelength of 405–420 nm destroys P. acnes. Furthermore,
blue light may inhibit the production of interleukin-1 alpha and intercellular adhesion
molecule-1 [5], as well as tumor necrosis factor alpha and matrix metalloproteinase 2,
all inflammatory mediators implicated in the pathogenesis of acne [6].
Within the visible light spectrum, a longer wavelength of light correlates with
deeper skin penetration, as there is less melanin absorption and less scattering by
connective tissue. Red light penetrates deeper than blue light, to approximately
2 mm of depth. It effectively reaches the sebaceous glands and activates porphyrins
via the Q band at 630 nm. One study evaluated 21 patients treated with 3 h incuba-
tion of 16.8 % methylaminolevulinic acid (Metvix®, Photocure) followed by 9 min
of 630 nm red light (Aktilite® CL 128, Photocure), for a total dose of 37 J/cm2 [7].
After two treatments spaced 2 weeks apart, investigators noted a 68 % reduction in
inflammatory lesions and no change in the 15 control patients. There was no reduc-
tion in noninflammatory lesions in either group. One study found that the combina-
tion of blue and red light was superior to either blue light or 5 % benzoyl peroxide
alone in reduction of the number of inflammatory acne lesions [8].
Limitations of using an exogenous photosensitizer include intra-procedure pain
and post-procedure erythema, edema, and blistering. Of note patients must avoid
direct sunlight exposure for 48 h after the procedure, which can be challenging in
the teenage acne population.
The pulsed dye laser (PDL, 585–595 nm yellow light), potassium titanyl
phosphate (KTP, 532 nm green light), and broadband intense pulsed light (IPL,
500–1,200 nm) with cutoff filters to employ predominately short wavelengths all act
on acne by activating endogenous P. acnes porphyrins and reducing sebaceous
gland function. A 2003 study found a significant reduction of inflammatory acne
lesions (49 %) in 31 patients receiving a single PDL treatment versus 10 patients
receiving “sham” treatment (10 %) [9]. However, a different, split-face trial of 40
patients receiving 1–2 sub-purpuric PDL treatments found no significant difference
in mean papule count versus the untreated control side [10]. A study of the KTP
laser found a 35.9 % reduction in inflammatory lesions 1 month after 4 biweekly
treatments [11]. Anecdotally the authors find these devices to be more useful
for improving the appearance of erythematous “stains” and scars which routinely
appear following the resolution of acne lesions.
5 Laser and Light Based Therapies for Acne 37

Mid-infrared light has also been utilized for acne treatment due to its purported
ability to shrink sebaceous glands and/or alter their secretion [12]. One study of 32
acne patients treated in a split-face fashion with 3 monthly 1,450 nm diode laser
treatments found an equal reduction in inflammatory lesions on both the treatment
and control side [13]. The authors state that this may present evidence of a systemic
anti-inflammatory effect of the laser, though the mechanism is unclear. Another
evaluation of 20 patients treated with a 1,540 nm erbium to glass nonablative
fractional laser monthly for 4 months found that acne lesions improved in 85 % of
patients and 80 % noted a reduction in sebum production [14].

5.3 Photopneumatic Therapy

Improvement of comedonal acne with lasers and lights has been a challenge to
achieve; however the newly developed photopneumatic therapy devices show poten-
tial. Photopneumatic therapy combines vacuum suction to mechanically clear pores
and concomitant broadband pulsed light. Cutoff filters limit the emission spectrum to
500–1,200 nm, wavelengths that activate endogenous porphyrins to destroy P. acnes,
as well as short-wavelength visible light that reduces perilesional erythema.
Published data supporting the efficacy of photopneumatic therapy is limited to
small, uncontrolled trials. A 2008 study of 11 patients receiving photopneumatic
therapy every 3 weeks for four treatments found a statistically significant reduction
in both inflammatory (78.8 %) and noninflammatory (57.8 %) lesions at the 3-month
follow-up visit post-therapy. Nine of the 11 patients were moderately to very satis-
fied with their results [15]. Other similar studies corroborate these findings [16, 17].
In the authors’ experience, photopneumatic therapy is an effective adjunctive
acne treatment.

5.4 Home Devices

Over-the-counter (OTC) handheld laser devices have garnered increasing attention

among mass media and consumers. The potential to improve wrinkles, remove or
grow hair, and treat acne treatment in the comfort and privacy of one’s own home at
a cost generally less than in-office procedures has understandably proven attractive.
However, in order to ensure safety for self-administration, OTC devices are generally
underpowered, require a greater number of treatments, and consequently afford
lesser efficacy than their in-office counterparts.
Despite the fact that dozens of devices are available, few have published data
supporting their efficacy [18] In a prospective, uncontrolled study of one such
device (Omnilux Clear-U®, Photo Therapeutics, Inc, Carlsbad, CA, blue light
415 nm and red light 633 nm), 17 patients with mild to moderate inflammatory
acne self-administered a course of eight light treatments, twice daily over 4 weeks.
38 J.B. Green et al.

Each week, the subject administered two alternate exposures: 20 min for blue and
30 min for red light, with 2–3-day intervals between the alternating light treatments.
Treatment was associated with statistically significant reduction from baseline in
the inflammatory lesion count of 69 % and reduction of 12 % of noninflammatory
lesions [19]. It is important to note that treatment time (20 min for blue light and
30 min for red) for the study covered an area of 5 cm × 6 cm. Consequently, a con-
siderably longer time would be required for full-face treatment. Therefore OTC
acne devices are best suited for spot treatment and are not routinely recommended
by the authors for full-face treatment of acne.

5.5 Future Directions

The future of laser and light therapy for acne is based on the foundation of modern
laser therapy—the principle of selective photothermolysis [20]. None of the afore-
mentioned laser and light sources emit wavelengths of light that are preferentially
absorbed by the sebaceous gland. One approach recently presented involved the
application of gold-coated nanoshells specifically constructed to absorb light at
800 nm. After application to periauricular human skin and subsequent treatment
with an 800 nm diode laser, histologic examination showed partial sebaceous gland
destruction without damage to the surrounding epidermis or dermis [21]. A recent
work investigated the optimal wavelength to target the sebaceous gland found that
sebum preferentially absorbs 1,210 and 1,720 nm light [22]. The investigators also
estimated that the optimal pulse duration of laser light delivered to confine heat to
the target sebaceous gland (thermal relaxation time) to be approximately 100 ms.
With these working parameters devices are in development, and perhaps 1 day laser
practitioners will be able to satisfyingly specifically target acne the way we currently
treat pigmented lesions. Until that day, lasers and lights can provide useful adjuncts
to conventional first-line acne therapy.

References

1. Sakomoto FH, Lopes JD, Anderson RR. Photodynamic therapy for acne vulgaris: a critical
review from basics to clinical practice. Part I. J Am Acad Dermatol. 2010;63:183–93.
2. Sakomoto FH, Torezan L, Anderson RR. Photodynamic therapy for acne vulgaris: a critical
review from basics to clinical practice. Part II. J Am Acad Dermatol. 2010;63:195–211.
3. Hamilton FL, Car J, Lyons M, et al. Laser and other light therapies for the treatment of acne
vulgaris: systematic review. Br J Dermatol. 2009;160:1273–85.
4. http://www.clinicaltrials.gov/ct2/show/results/NCT00706433?term=DUSA+Pharmaceuticals
&rank=1
5. Shnitkind E, Yaping E, Geen S, et al. Anti-inflammatory properties of narrow-band blue light.
J Drugs Dermatol. 2006;5(7):605–10.
6. Fan X, Xing Y-Z, Liu L-H, et al. Effects of 420-nm intense pulsed light in an acne animal
model. J Eur Acad Dermatol Venereol. 2012; doi: 10.1111/j.1468-3083.2012.04487.x
5 Laser and Light Based Therapies for Acne 39

7. Wiegell SR, Wulf HC. Photodynamic therapy of acne vulgaris using methyl aminolevulinic
acid: a blinded, randomized, controlled trial. Br J Dermatol. 2006;154:969–76.
8. Papageorgiou P, Katsambas A, Chu A. Phototherapy with blue (415 nm) and red (660 nm)
light in the treatment of acne vulgaris. Br J Dermatol. 2000;142:973–8.
9. Seaton ED, Charakida A, Mouser PE, et al. Pulsed-dye laser treatment for inflammatory acne
vulgaris: randomised controlled trial. Lancet. 2003;362:1347–52.
10. Orringer JS, Kang S, Hamilton T, et al. Treatment of acne vulgaris with a pulsed dye laser:
a randomized controlled trial. JAMA. 2004;291:2834–9.
11. Bowes L, Manstein D, Anderson R. Effects of 532 nm KTP laser on acne and sebaceous
glands. Laser Med Sci. 2003;18 Suppl 1:S6–7.
12. Perez-Maldonado A, Runger TM, Kreju-Papa N. The 1,450-nm diode laser reduces sebum
production in facial skin: a possible mode of action of its effectiveness for the treatment of
acne vulgaris. Lasers Surg Med. 2007;39:189–92.
13. Darne S, Hiscutt EL, Seukeran DC. Evaluation of the clinical efficacy of the 1450 nm laser in
acne vulgaris: a randomized split-face, investigator-blinded clinical trial. Br J Dermatol. 2011;
165:1256–62.
14. Isarria MJ, Cornejo P, Munos E, et al. Evaluation of clinical improvement in acne scars and
active acne in patients treated with the 1540-nm non-ablative fractional laser. J Drugs Dermatol.
2011;10(8):907–12.
15. Gold M, Biron J. Treatment of acne with pneumatic energy and broadband light. J Drugs
Dermatol. 2008;7(7):639–42.
16. Shamban AT, Enokibori M, Narurkar V, et al. Photopneumatic technology for the treatment of
acne vulgaris. J Drugs Dermatol. 2008;7(2):139–45.
17. Wanitphakdeedcha R, Tanzi E, Alster T. Photopneumatic therapy for the treatment of acne.
J Drugs Dermatol. 2009;8(3):239–41.
18. Metelitsa AI, Green JB. Home-use laser and light devices for the skin—an update. Semin
Cutan Med Surg. 2011;30:144–7.
19. Sadick NS. Handheld LED, array device in the treatment of acne vulgaris. J Drugs Dermatol.
2008;7:347–50.
20. Anderson RR, Parrish JA. Selective photothermolysis: precise microsurgery by selective
absorption of pulsed radiation. Science. 1983;220(4596):524–7.
21. Kauvar A, Lloyd J, Cheung W, et al. Selective photothermolysis of the sebaceous follicle with
gold-coated nanoshells for treatment of acne. Presented at 2012 American Society for Laser
Medicine and Surgery Annual Meeting, Orlando, Florida.
22. Sakamoto FH, Doukas AG, Farinelli WA, et al. Selective photothermolysis to target sebaceous
glands: theoretical estimation of parameters and preliminary results using a free electron laser.
Lasers Surg Med. 2012;44:175–83.
 Part II
Infectious Diseases Mimicking
Acne Vulgaris
Chapter 6
Bacterial Folliculitis

Jessica Gjede and Emmy Graber

6.1 Introduction

Folliculitis is a common disorder characterized by an inflammatory reaction in the

superficial aspect of the hair follicle, involving either the follicular opening or the
perifollicular area [1]. Folliculitis can be classified based on etiology and is divided
into two broad categories: infectious folliculitis and noninfectious folliculitis.
Infectious folliculitis is further classified according to the offending organism and
may include bacterial folliculitis, fungal folliculitis, viral folliculitis, parasitic
folliculitis, and syphilitic folliculitis. Noninfectious etiologies include, but are
not limited to, diagnoses such as drug-induced acneiform folliculitis, acne keloida-
lis nuchae, folliculitis decalvans, and eosinophilic folliculitis. This chapter will
focus on bacterial folliculitis.

6.2 Background

Bacterial folliculitis affects both males and females in children and adults [1–3].
An accurate incidence is difficult to determine as many affected patients in the general
population do not seek medical attention for this condition. Predisposing factors include
occlusion, maceration, hyperhydration, nasal carriage of Staphylococcus aureus
(S. aureus), application of topical steroids, and exposure to oils and certain other chem-
icals, all of which increase bacterial colonization on the skin [1–3]. Environments that
promote occlusion or moisture such as hot or humid weather or prolonged exposure to
heated water (i.e., hot tub, heated swimming pool) are predisposing factors as well.

J. Gjede, M.D. (*) • E. Graber, M.D.

Department of Dermatology, Boston Medical Center, 609 Albany Street,
J-203, Boston, MA 02118, USA
e-mail: [email protected]

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DOI 10.1007/978-1-4614-8344-1_6, © Springer Science+Business Media New York 2014
44 J. Gjede and E. Graber

Manipulation of the follicular unit by plucking, waxing, or shaving, especially when

performed against the normal direction of hair growth, may also be a risk factor. Finally,
patients may have other underlying medical conditions that lead to over-colonization of
the skin surface with bacteria such as diabetes mellitus and atopic dermatitis.
The most common causative agent in bacterial folliculitis is S. aureus; however,
species of Streptococcus, Pseudomonas, Proteus, and other Gram-negative bacteria
have also been implicated [1]. These other forms of folliculitis will be covered
elsewhere in this book.

6.3 Clinical Presentation

The clinical appearance of bacterial folliculitis differs depending on whether

infection occurs in the superficial or deep portion of the follicle. Superficial follicu-
litis, also known as Bockhart impetigo, typically presents with small, folliculocentric
pustules with surrounding erythema that evolve into crusted papules with time [1].
If no pustules are present, a clue to the diagnosis of folliculitis may be an erythema-
tous papule with a collarette of scale, especially when the etiologic agent is
S. aureus (Fig. 6.1) [2, 4]. Associated symptoms include pain, tenderness, and/or
pruritus. Cases of methicillin-resistant S. aureus (MRSA) often follow a more
aggressive course starting with typical erythematous papules and pustules that
progress rapidly to painful nodules, often with purulent drainage.
When bacterial infection progresses to involve the deeper portion of the follicle
beneath the infundibulum or the tissue adjacent the follicle, a furuncle develops [1].
Furuncles begin as small, folliculocentric, painful, inflammatory nodules, often

Fig. 6.1 Follicular-based, erythematous papules where pustules had initially existed and subse-
quently ruptured (Photo credit: Joshua A. Zeichner, M.D.)
6 Bacterial Folliculitis 45

with a central pustule that becomes necrotic within a few days [1]. Furuncles are
more common in young adult males and favor the face, back of neck, axillae, breast,
buttocks, and thighs [1]. Predisposing factors for furunculosis include diabetes
mellitus, HIV infection, malnutrition, crowded living conditions such as incarcera-
tion, and chronic staphylococcus colonization [1].
Bacterial sycosis is another form of deep folliculitis in which a subacute or
chronic staphylococcal infection involves the entire hair follicle [1, 2]. This condi-
tion typically occurs in postpubertal males, often in the third to fourth decade, and
frequently affects the beard region [1, 2]. Early in the clinical course, the condition
presents with an edematous, inflammatory papule or pustule in the beard region
with a burning sensation. This is followed by development of numerous papules and
pustules involving the surrounding follicles that then coalesce into plaques studded
with pustules [1]. In severe or chronic cases persisting for years, the follicles may
be destroyed by scarring or a granulomatous appearance may occur. This has been
termed lupoid sycosis for its morphologic resemblance to lupus vulgaris [1, 2].
The distribution of folliculitis favors hair-bearing areas, especially the scalp and
beard region, but also the upper trunk, buttocks, thighs, axillae, and groin [2]. Areas of
involvement vary among different populations. In infants and children, infection favors
the face, buttocks, and axillae [1]. Folliculitis in adolescent females is commonly
located on the legs, while it affects the flexural areas in adolescent males [1].

6.4 Work-Up

The diagnosis of bacterial folliculitis is typically based on clinical exam. Bacterial

culture and Gram stain obtained from swabs of pustular contents help identify the
causative organism, especially in cases that are recurrent or resistant to treatment
[3]. S. aureus is the causative organism in a majority of cases, but bacterial culture
and Gram stain are particularly helpful in cases caused by less common bacteria.
Correctly identifying the causative pathogen along with culture-directed antibiotic
sensitivity enables treatment with appropriate antibiotic therapy. Cultures should be
performed prior to initiating antibiotic therapy. In chronic cases, nasal culture may
indicate if a patient is a chronic carrier of S. aureus.
Other diagnostic tests may be helpful in differentiating bacterial from nonbacte-
rial infectious folliculitis. For example, scraping of pustular contents can be sent for
fungal culture, and potassium hydroxide preparations can be performed if a fungal
cause is suspected [1]. A Tzanck smear is useful in cases of herpetic folliculitis [1].
Additionally, in some cases of viral folliculitis, polymerase chain reaction (PCR)
can be used to identify the causative virus.
A skin biopsy is rarely needed to confirm the diagnosis of folliculitis. However, if
performed, salient features include a perifollicular or intrafollicular mixed inflamma-
tory infiltrate composed of lymphocytes, histiocytes, or plasma cells, often progressing
to a ruptured follicle surrounded by neutrophils and multinucleated giant cells [5].
Bacteria may be seen within the follicle as well. Older lesions are characterized by
46 J. Gjede and E. Graber

perifollicular fibrosis [5]. A furuncle is characterized histopathologically by similar

features involving the deeper portions of the follicular unit and occasionally, dermal
abscess formation [5].

6.5 Treatment

Treatment in bacterial folliculitis should be targeted at the most common causative

organism or the organism identified by bacterial culture. A majority of the evidence-
based literature focuses on treatment of other superficial skin and skin structure
infections; however, it can be applied to folliculitis because the causative organ-
isms are largely the same. Superficial bacterial folliculitis usually responds to topi-
cal antibacterial treatment, specifically agents that cover S. aureus with consideration
of empiric therapy for MRSA. For culture-negative folliculitis, empiric topical
treatments include benzoyl peroxide, topical antibiotics such as clindamycin, and
antibacterial washes that contain chlorhexidine or triclosan [2, 3]. In addition to
these, mupirocin ointment can be considered for cases of staphylococcal folliculi-
tis, especially those caused by MRSA, although its utility is limited in widespread
disease [1, 3]. Other less common options for staphylococcal folliculitis include
fusidic acid ointment, which is not available in the United States, and topical
retapamulin [1, 6].
When superficial folliculitis becomes widespread or recurrent, oral therapy may
be necessary. Oral antibiotics that have been reported to be effective in folliculitis
include clindamycin, azithromycin, and tetracycline class antibiotics such as
doxycycline and minocycline [2, 6]. Treatment duration of 7–14 days is typically
sufficient, although resistant and complicated cases may require several months of
therapy. For cases caused by MRSA, systemic therapy may include doxycycline or
linezolid in resistant cases, which are both FDA approved for this indication [6].
Additionally, while trimethoprim-sulfamethoxazole is not FDA approved for
MRSA-related skin and soft tissue infections, many reports have shown it to be
efficacious [6]. The recommended treatment duration for MRSA-folliculitis is
10–14 days, although resistant and complicated cases may necessitate a longer
treatment course.
In cases of deep folliculitis or furunculosis, systemic antibiotic therapy is often
necessary. A culture should be performed prior to initiating antibiotic therapy to
identify the causative organism [1]. Typically, oral antibiotics that cover S. aureus
are sufficient; however, in some cases, Gram-negative bacteria may be identified, in
which culture-directed antibiotics should be considered. Ciprofloxacin is often
helpful in these cases [1]. For severe or suppurative folliculitis, intravenous antibi-
otic therapy with linezolid or daptomycin may be indicated [6].
Treatment failure of bacterial folliculitis is rare, but in cases of recurrent or
resistant bacterial folliculitis, eradication of MRSA colonization should be consid-
ered [1, 3]. This can be accomplished by applying mupirocin 2 % ointment to the
nares twice daily for 5 days [3, 6–8]. Some sources also recommend treating the
6 Bacterial Folliculitis 47

axillae, groin, anus, and inframammary areas as well [3], while others recommend
repeating treatment for 5 days each month to reduce recurrence [8]. Topical fusidic
acid and retapamulin can also be used to eradicate MRSA colonization [6, 8].

References

1. Luelmo-Aguilar J, Santandreu MS. Folliculitis: recognition and management. Am J Clin

Dermatol. 2004;5(5):301–10.
2. McMichael A, Sanchez DG, Kelly P. Folliculitis and the follicular occlusion tetrad. In: Bolognia
JL, Jorizzo JL, Rapini RP, editors. Dermatology. 2nd ed. Mosby: Elsevier; 2008. http://www.
expertconsult.com.
3. Halpern AV, Heymann WR. Bacterial diseases. In: Bolognia JL, Jorizzo JL, Rapini RP, editors.
Dermatology. 2nd ed. Mosby: Elsevier; 2008. http://www.expertconsult.com.
4. Levy AL, Simpson G, Skinner RB. Medical pearl: circle of desquamation—a clue to the
diagnosis of folliculitis and furunculosis caused by Staphylococcus aureus. J Am Acad
Dermatol. 2006;55:1079–80.
5. Rapini RP. Practical dermatopathology. Philadelphia, PA: Elsevier; 2005. p. 141.
6. Chon SY, Doan HQ, Mays RM, Singh SM, Gordon RA, Tyring SK. Antibiotic overuse and
resistance in dermatology. Dermatol Ther. 2012;25:55–69.
7. Dryden MS, Dailly S, Crouch M. A randomized, controlled trial regimen for the clearance of
MRSA colonization. J Hosp Infect. 2004;56:283–6.
8. Bernard P. Management of common bacterial skin infections. Curr Opin Infect Dis. 2008;
21(2):122–8.
Chapter 7
Gram-Negative Folliculitis

Ani L. Tajirian and Leon H. Kircik

7.1 Introduction

Gram-negative folliculitis is a complication of treatment of acne or rosaceas with

long-term oral antibiotics, usually tetracyclines. It is caused by the replacement of
the gram-positive flora of the mucous membranes of the nose with gram-negative
bacteria, which is spread to the face. Common causative organisms include
Escherichia coli, Pseudomonas aeruginosa, Serratia marcescens, Klebsiella, and
Proteus mirabilis. Gram-negative folliculitis should be considered in acne patients
who have a flare-up of pustular or cystic lesions while on antibiotics and in patients
who have no significant improvement of acne lesions after 3–6 months of antibiotic
therapy.

7.2 Background

7.2.1 Pathophysiology

Fulton et al. first described gram-negative folliculitis in a group of patients with

long-standing treatment-resistant acne in 1968 [1]. Gram-negative folliculitis is
characterized by the replacement of gram-positive normal flora of the nares and

A.L. Tajirian, M.D. (*)

Fletcher Allen Health Care, University of Vermont College of Medicine, Burlington, VT, USA
Webster Management Inc., 3300 Webster Street, Suite 509, Oakland, CA 94609, USA
e-mail: [email protected]
L.H. Kircik, M.D.
Department of Dermatology, Mt. Sinai School of Medicine, New York, NY, USA
Indiana University School of Medicine, Indianapolis, IN, USA

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50 A.L. Tajirian and L.H. Kircik

adjacent facial skin by gram-negative rods, most commonly Enterobacteriaceae.

In patients with acne who are treated with oral antibiotics, the number of Staphylococcus
aureus and diphtheroids decreases and the number of coagulase-negative staphylo-
coccal and enterobacterial organisms increases in the nares. Gram-negative organisms
require a moist environment to survive and proliferate, so they prosper in areas of
excessive seborrhea. Sebaceous follicles primarily around the nose and mouth become
colonized with these bacteria with subsequent spread to follicles of adjacent skin the
development of recalcitrant papules and pustules. Ordinarily, gram-negative bacteria
constitute less than 1 % of the total bacterial flora in the nose; however, in patients
with gram-negative folliculitis, enterobacteria constitute approximately 4 % of the
total bacterial flora. In addition, tetracyclines impair protein synthesis and the func-
tion of human lymphocytes as well as the chemotaxis of neutrophils thus increasing
the risk of bacterial superinfection [2, 3].
A number of studies have shown changes in the immune defense mechanisms of
acne patients with gram-negative folliculitis. In one study by Neubert et al. [2], a
subset of patients demonstrated a depressed cell-mediated immunity as shown by
weak or absent delayed-type hypersensitivity responses as well as diminished serum
concentrations of IgM. A low IgM concentration might lead to a weakened or absent
response to the O-antigens of enterobacteria thus increasing the likelihood of a
gram-negative rod infection [2]. Alpha-1-antitrypsin deficiency has also been
suggested as a cofactor in the development of gram-negative folliculitis through the
inactivation of granulocyte neutral protease and the intensification of inflammatory
processes [2].
Loofah sponges and exfoliative beauty products might further contribute to the
development of gram-negative folliculitis in patients with acne [4].

7.2.2 Epidemiology

Gram-negative folliculitis is a relatively rare complication of prolonged antibiotic

therapy, occurring in about 4 % of patients with acne vulgaris on oral antibiotics.
It is thought that the frequency of this infection is underreported as it can be mistaken
for an acne exacerbation and is infrequently cultured.
There is no racial or sexual predilection for gram-negative folliculitis. A slightly
increased age of onset has been observed for gram-negative folliculitis as compared
to acne, as most patients who develop gram-negative folliculitis have undergone
treatment of acne with a broad-spectrum antibiotic for many years.

7.3 Clinical Presentation

Typical features of acne patients with gram-negative folliculitis include male

predominance, severe seborrhea with oily skin, perioral and perinasal papules and
pustules, recurrent folliculitis of the scalp, history of prolonged antibacterial
7 Gram-Negative Folliculitis 51

Fig. 7.1 Monomorphic follicular papules in the infranasal area and chin of a teenage boy with
acne who developed gram-negative folliculitis after chronic treatment with doxycycline for acne
(Photo credit: Joshua A. Zeichner, M.D.)

treatment, and isolation of gram-negative rods from pustules of facial skin and
mucous membranes of the nose [2] (Fig. 7.1).
Two main subtypes of gram-negative folliculitis have been described [5]. Type I
is much more common and seen in approximately 80 % of patients. These patients
develop papules and papulopustules flaring out from the nares and involving the
infranasal and perioral skin. In type II, seen in approximately 20 % of patients, deep
fluctuant cystic lesions resembling acne conglobata are the key presenting features.
The distribution of lesions in both types extends from the infranasal area to the chin
and cheeks.
Type I lesions are most commonly associated with a lactose-fermenting, gram-
negative rods including Klebsiella, Escherichia, and Serratia species [5]. However,
cases associated with Citrobacter, which is another organism of the Enterobacteriaceae
family, have been reported [6, 7]. Proteus species is associated with type II lesions;
these organisms are motile granting them the ability to invade more deeply, producing
large suppurative abscesses resulting in deeper cystic lesions [5].
Gram-negative folliculitis has also been described in patients following recurrent
staphylococcal pyoderma [6] as well as after long-term topical antibacterial therapy
[8]. Batholow and Maibach described a patient with acne who was treated with topi-
cal clindamycin followed by benzoyl peroxide and erythromycin and subsequently
developed gram-negative folliculitis secondary to E. coli [8].

7.4 Work-Up

Gram-negative folliculitis is most often diagnosed based on history and physical

examination alone. However, confirmation with gram stain and culture is recom-
mended. Correct sampling is essential for the proper diagnosis of gram-negative
52 A.L. Tajirian and L.H. Kircik

folliculitis. Swabs for bacteriological analysis should be taken from pustules and
from the nasal mucosa. The pustule that is sampled should be fresh and preferably on
an erythematous base. Gram-negative organisms are sensitive to desiccation and thus
samples must be taken rapidly and transported to the laboratory as soon as possible.
It is recommended to culture pustules in any patient with acne who is in their late
teens or older and develops a pustular eruption while on antibiotics. It is important
to note that gram-negative organisms are not recoverable from every pustule.
Selective medium-containing dyes such as methylene blue allow selective growth of
gram-negative organisms while inhibiting the growth of gram-positive organisms.
Inadequate sampling, dried-out swabs, and long delay between culturing the
pustules/nasal mucosa and the arrival of the specimen in the laboratory may lead to
an underestimation of the frequency of gram-negative folliculitis in patients with
acne and/or rosacea [9].

7.5 Treatment

Oral isotretinoin is considered to be first-line therapy for gram-negative folliculitis.

While culture-directed antibiotics may be tried, they are frequently unsuccessful
[9–11]. The effectiveness of isotretinoin has been attributed to its ability to decrease
sebaceous gland secretion by 90 % or more [12]. This dries the skin and mucous
membranes creating a poor environment for gram-negative bacteria growth.
Isotretinoin should be administered at a dose of 0.5–1 mg/kg daily for 4–5 months
[5, 9]. Higher doses in excess of 2.0 mg/kg are not superior to lower doses; in fact,
the most effective dose with the fewest relapses was shown to be 1 mg/kg [2]. In a
subset of patients with recurrent acne lesions and relapses of gram-negative rods,
oral antibiotics may be combined with isotretinoin [13].

References

1. Fulton Jr JE, McGinley K, Leyden J, Marples R. Gram-negative folliculitis in acne vulgaris.

Arch Dermatol. 1968;98:349–53.
2. Neubert U, Jansen T, Plewig G. Bacteriologic and immunologic aspects of gram-negative
folliculitis: a study of 46 patients. Int J Dermatol. 1999;38:270–4.
3. Esterly NB, Koransky JS, Furey NL, Trevisan M. Neutrophil chemotaxis in patients with acne
receiving oral tetracycline therapy. Arch Dermatol. 1984;120:1308–13.
4. Bottone EJ, Perez 2nd AA, Oeser JL. Loofah sponges as reservoirs and vehicles in the
transmission of potentially pathogenic bacterial species to human skin. J Clin Microbiol.
1994;32:469–72.
5. Leyden JJ, Marples RR, Mills Jr OH, Kligman AM. Gram-negative folliculitis—a complication
of antibiotic therapy in acne vulgaris. Br J Dermatol. 1973;88:533–8.
6. Chastain MA. A cycle: recurrent gram-negative folliculitis with Citrobacter diversus (koseri)
following eradication of recurrent staphylococcal pyoderma. Arch Dermatol. 2000;136:803.
7 Gram-Negative Folliculitis 53

7. Mostafa WZ. Citrobacter freundii in gram-negative folliculitis. J Am Acad Dermatol. 1989;

20:504–5.
8. Bartholow P, Maibach HI. Gram-negative folliculitis without systemic antibiotics? Arch
Dermatol. 1979;115:676.
9. Boni R, Nehrhoff B. Treatment of gram-negative folliculitis in patients with acne. Am J Clin
Dermatol. 2003;4:273–6.
10. James WD, Leyden JJ. Treatment of gram-negative folliculitis with isotretinoin: positive
clinical and microbiologic response. J Am Acad Dermatol. 1985;12:319–24.
11. Plewig G, Nikolowski J, Wolff HH. Action of isotretinoin in acne rosacea and gram-negative
folliculitis. J Am Acad Dermatol. 1982;6:766–85.
12. Landthaler M, Kummermehr J, Wagner A, Plewig G. Inhibitory effects of 13-cis-retinoic acid
on human sebaceous glands. Arch Dermatol Res. 1980;269:297–309.
13. Neubert U, Plewig G, Ruhfus A. Treatment of gram-negative folliculitis with isotretinoin.
Arch Dermatol Res. 1986;278:307–13.
Chapter 8
Hot-Tub Folliculitis

Paula S. Malhotra and Joseph F. Fowler Jr.

8.1 Introduction

Hot-tub folliculitis is also known as Pseudomonas aeruginosa (P. aeruginosa)

folliculitis. It is characterized by pruritic maculopapular and pustular lesions that
have follicular accentuation and can manifest anywhere from 1 to 4 days after bath-
ing in a hot tub, whirlpool, or public swimming pool [1–6]. Hot-tub folliculitis is an
infection of the hair follicles that occurs after coming into contact with the bacteria
P. aeruginosa, which thrives in a warm, wet environment. Diving suits have also
been implicated in causing this form of folliculitis as the suits themselves have the
potential to become colonized with P. aeruginosa [7].

8.2 Background

8.2.1 Pathophysiology

Pseudomonas aeruginosa is a ubiquitous gram-negative bacterial organism found in

soil and freshwater that gains its entry through hair follicles or via breaks in the skin.
Exposure to water colonized by P. aeruginosa leads to a follicular skin infection.
Bacterial serotype O:11 is the most commonly reported isolate for water-associated

P.S. Malhotra, B.A., M.D. (*)

Department of Dermatology, Northwestern University, Chicago, IL, USA
e-mail: [email protected]
J.F. Fowler Jr., M.D.
Division of Dermatology, University of Louisville, 501 S Second Street,
Louisville, KY 40202, USA

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DOI 10.1007/978-1-4614-8344-1_8, © Springer Science+Business Media New York 2014
56 P.S. Malhotra and J.F. Fowler Jr.

Pseudomonas folliculitis, but other serotypes have also been reported. Serotype
O:11 is thought to be more invasive and better adapted to survive in halogenated
water than the other serotypes, explaining the prevalence of this serotype in hot-tub
folliculitis [8]. As water temperatures rise, free chlorine levels in the water fall, even
though the total chlorine levels appear adequate. This provides an ideal environment
in which the bacteria can proliferate. Hot water, high pH (>7.8), and low chlorine
level (<0.5 mg/L) all predispose to an increased risk for infection.

8.2.2 Epidemiology

The actual incidence of Pseudomonas folliculitis is difficult to assess because of the

transient nature of the disease [4]. Most cases of Pseudomonas folliculitis resolve
without any adverse reactions or sequelae. There is no known racial or gender
predilection.

8.3 Clinical Presentation

The onset of the rash of hot-tub folliculitis is usually 1–4 days after exposure to
contaminated water. However, skin lesions can develop as early as 8 h after exposure
and as late as 14 days later [9]. Most lesions begin as pruritic, follicular, erythema-
tous macules that progress to papules and pustules. Individual lesions range in size
from 2 to 10 mm in diameter and often demonstrate a central pinpoint vesiculopus-
tule. The rash is most prevalent in the intertriginous areas or under bathing suits
secondary to compression of contaminated water in those areas. It can also be seen
on the trunk and extremities, where the skin is exposed to contaminated water. The
face, neck, palms, and soles are usually spared [10]. Other associated complaints are
minimal and include earache, sore throat, fever, and malaise. Systemic infections
are rare. The rash usually clears spontaneously in 7–14 days without therapy, rarely
recurs, and heals without scarring. Sometimes, it may cause desquamation or leave
behind post inflammatory hyperpigmented macules which can resolve over time.
The rash is not unique in appearance and is most often confused with insect bites.

8.4 Work-Up

The diagnosis of P. aeruginosa folliculitis is usually made clinically by obtaining

the proper history and physical findings. It can be verified by obtaining bacterial
culture results from either a fresh pustule or a sample of contaminated water.
Biopsies of active lesions may show a lymphocytic inflammatory response around
hair follicles.
8 Hot-Tub Folliculitis 57

8.5 Treatment

The folliculitis usually self-resolves within 7–14 days without therapeutic inter-
vention. However, in patients who present with fever, constitutional symptoms, or
prolonged disease, a third-generation cephalosporin or fluoroquinolone like cipro-
floxacin or ofloxacin can be useful [11]. Proper maintenance and chlorination of
pools, hot tubs, whirlpools, and spas are essential to decrease the population of
Pseudomonas species. Showering after exposure to contaminated water does not
seem to prevent Pseudomonas folliculitis.

References

1. Gregory DW, Schaffner W. Pseudomonas infections associated with hot tubs and other
environments. Infect Dis Clin North Am. 1987;1(3):635–48.
2. Highsmith AK, Le PN, Khabbaz RF, Munn VP. Characteristics of Pseudomonas aeruginosa
isolated from whirlpools and bathers. Infect Control. 1985;6(10):407–12.
3. McCausland WJ. Pseudomonas aeruginosa rash associated with whirlpool. JAMA. 1976;
236(22):2490–1.
4. Price D, Ahearn DG. Incidence and persistence of Pseudomonas aeruginosa in whirlpools.
J Clin Microbiol. 1988;26(9):1650–4.
5. Ratnam S, Hogan K, March SB, Butler RW. Whirlpool-associated folliculitis caused
by Pseudomonas aeruginosa: report of an outbreak and review. J Clin Microbiol. 1986;
23(3):655–9.
6. Rose HD, Franson TR, Sheth NK, Chusid MJ, Macher AM, Zeirdt CH. Pseudomonas
pneumonia associated with use of a home whirlpool spa. JAMA. 1983;250(15):2027–9.
7. Lacour JP, el Baze P, Castanet J, Dubois D, Poudenx M, Ortonne JP. Diving suit dermatitis
caused by Pseudomonas aeruginosa: two cases. J Am Acad Dermatol. 1994;31(6):1055–6.
8. Maniatis AN, Karkavitsas C, Maniatis NA, Tsiftsakis E, Genimata V, Legakis NJ. Pseudomonas
aeruginosa folliculitis due to non-O:11 serogroups: acquisition through use of contaminated
synthetic sponges. Clin Infect Dis. 1995;21(2):437–9.
9. Berger RS, Seifert MR. Whirlpool folliculitis: a review of its cause, treatment, and prevention.
Cutis. 1990;45(2):97–8.
10. James W, Berger T, Elston D. Andrews’ clinical dermatology. 9th ed. Elsevier, Philadelphia; 2000.
11. Böni R, Nehrhoff B. Treatment of gram-negative folliculitis in patients with acne. Am J Clin
Dermatol. 2003;4(4):273–6.
Chapter 9
Malassezia Folliculitis

Patricia K. Farris and Andrea Murina

9.1 Introduction

Malassezia folliculitis, also referred to as Pityrosporum folliculitis, is an underdiagnosed

condition that mimics acne vulgaris. This unique type of folliculitis affects the back,
chest, and upper arms in healthy teenagers and young adults and can also be seen in
patients with underlying immunosuppression. Malassezia folliculitis is caused by an
overgrowth of Malassezia yeast that thrives in the sebaceous rich environment of the
hair follicle. Direct microscopic examination with potassium hydroxide and skin biopsy
can be used to identify the presence of yeast within the follicle thus confirming this often
elusive diagnosis.

9.2 Background

The Malassezia genus of yeast is considered to be normal skin flora and is found in
the stratum corneum and hair follicles of up to 90 % of individuals [1]. This lipo-
philic dimorphic yeast can be pathogenic and has been implicated in common skin
disorders such as seborrheic dermatitis and pityriasis versicolor [2]. Malassezia
folliculitis was first described by Weary et al. in 1969 as an acneiform eruption in
the setting of antibiotic therapy with tetracyclines [3]. It is characterized as an
invasion of hair follicles by large numbers of Malassezia yeast. Malassezia furfur,

P.K. Farris, M.D. (*)

Department of Dermatology, Old Metairie Dermatology,
701 Metairie Road, Metairie, LA 70005, USA
e-mail: [email protected]
A. Murina, M.D.
Department of Dermatology, Tulane University, 1430 Tulane Avenue
New Orleans, LA 70112, USA

J.A. Zeichner (ed.), Acneiform Eruptions in Dermatology: A Differential Diagnosis, 59

DOI 10.1007/978-1-4614-8344-1_9, © Springer Science+Business Media New York 2014
60 P.K. Farris and A. Murina

M. pachydermatis, and M. globosa are the predominant causative organisms [4].

This disease is often seen in healthy teens and young adults and is thought to be the
result of follicular occlusion creating the sebaceous rich environment in which
Malassezia thrives [5]. In this regard, the pathogenesis is similar to that of acne
vulgaris. Staphylococcus and Propionibacteria can also be present in the follicles.
Although they are distinct clinical entities, acne vulgaris can occur concomi-
tantly with Malassezia folliculitis. Sweeney et al. reported a series of adolescent
girls who had traditional papules, pustules, and comedones of acne but also
displayed monomorphic papules and pustules that were pruritic and flared during
hot humid weather [6]. Potassium hydroxide examination of the latter showed
Malassezia yeast and all patients responded to topical and systemic antifungal
treatment.
Steroid acne seen after topical or systemic corticosteroid therapy has been
associated with an overgrowth of Malassezia. A study looking at direct microscopic
examination of material gathered using a comedo extractor from lesions of 34
patients with steroid acne demonstrated that 76 % were positive for Malassezia
spores [7]. Treatment with itraconazole resulted in clinical improvement and
reduced spore loads in these patients. The authors suggest that in view of these
results, all patients with steroid acne should have a direct microscopic examination
and/or biopsy to rule out colonization with Malassezia.
Likewise, Malassezia spores have been noted on biopsies of patients with clinical
presentation consistent with eosinophilic pustular folliculitis [8, 9]. Similar to
Malassezia folliculitis, eosinophilic pustular folliculitis (EPF) or Ofuji’s disease is
characterized by an intensely pruritic eruption of erythematous follicular papules.
Histopathology of classic EPF shows a predominance of eosinophils and lack of
organisms [9]. In contrast, biopsy specimens on patients with HIV-associated EPF
may show both eosinophils and Malassezia indicating that Malassezia may play a
role [8].
Malassezia yeasts have also been found in the acneiform eruption that occurs as
a side effect of Cetuximab [10]. Acneiform folliculitis is a class effect of EGFR
inhibitors [11]. It is believed that EGFR inhibition in the skin results in follicular
occlusion by keratinocytes resulting in acneiform folliculitis. Both Staphylococcus
and Malassezia have been reported in patients with this acneiform cutaneous
reaction [10].
Finally, Malassezia folliculitis has a higher incidence in patients who are immu-
nosuppressed [12, 13] as a result of conditions such as HIV [14], Hodgkin’s disease
[15], diabetes [13], and solid organ and bone marrow transplant recipients [16–18].
Patients on broad-spectrum antibiotics may also be more prone to the disease [3].
It is unknown exactly what immune mechanisms lead to the overgrowth of
Malassezia yeast within the follicles. It has been hypothesized that the overgrowth
of Malassezia in the follicles is favored by the lipophilic nature of the yeasts, dimin-
ished T cell function, and the decreased number of Langerhans cells that are present
in the skin in immunocompromised patients [19]. There should be a low threshold
to KOH or biopsy patients with acneiform eruptions and immunosuppression to
evaluate for the presence of Malassezia yeast.
9 Malassezia Folliculitis 61

Fig. 9.1 (a, b) Malassezia folliculitis in a patient following broad-spectrum antibiotics

9.3 Clinical Presentation

Malassezia folliculitis is common in young to middle-age adults. Lesions can be

asymptomatic or pruritic and are distributed on the back, chest, and upper arms [20,
21]. The most common presentation is monomorphic dome-shaped follicular
papules with a central dell although in severe cases pustules, nodules and cysts may
be present (Fig. 9.1). There are no comedones in Malassezia folliculitis which is an
important differentiating point between this condition and chest and back acne.
When the conditions coexist, the acne will usually be present on the face while the
folliculitis occurs on the trunk and upper arms.
Malassezia folliculitis is more frequent in tropical climates due to effects of heat and
humidity with a prevalence reported in the Philippines at 16.5 % [22]. In these environ-
ments, an atypical distribution can occur including spread to the face and cheeks.

9.4 Work-Up

Malassezia folliculitis should be suspected in patients who have papular lesions on the
trunk and upper arms unresponsive to acne treatments, in those who have taken broad-
spectrum antibiotics, or who are immunocompromised. Direct microscopic examina-
tion is preferable to culture since Malassezia is normal skin flora. The organisms can be
seen on direct microscopic examination at high power (40×) when mounted with
10–15 % potassium hydroxide [23]. Examination of the follicular contents after
62 P.K. Farris and A. Murina

Fig. 9.2 Hematoxylin and

Eosin stain showing focal
inflammation surrounding
the follicle

extraction with a comedo extractor may provide superior results to simple skin scrapings
[7]. Biopsy specimens will show abundant round budding yeasts with occasional hyphae
(Fig. 9.2). PAS stain can further highlight the organisms (Fig. 9.3). An inflammatory
infiltrate surrounding the hair follicle consisting of lymphocytes, histiocytes, and
neutrophils is seen on histology [24, 25]. This inflammatory response may be due in part
to the fact that Malassezia yeasts have been shown to hydrolyze triglycerides into free
fatty acids [21, 23, 24]. Hair follicles tend to be dilated, full of keratinous material, and
may have focal rupture. The diagnosis can be made from clinical presentation, a positive
direct microscopic examination, histopathology demonstrating yeast engorged hair
follicles, and a positive response to antifungal treatment.

9.5 Treatment

Treatment of Malassezia folliculitis can be difficult due to the propensity for

recurrence. Topical medications such as 2 % selenium sulfide lotion, 50 % propylene
glycol in water, and 20 % sodium thiosulfate lotion are effective [20]. In a study of
26 cases, the cure rate with topical ketoconazole cream alone, oral ketoconazole
9 Malassezia Folliculitis 63

Fig. 9.3 PAS stain at 40×

showing multiple spores
within the follicle

alone, or topical plus oral ketoconazole was 12 %, 75 %, and 75 %, respectively,

indicating the superior efficacy of systemic therapy [26]. Additionally, there was
high rate of recurrence 3–4 months after therapy was discontinued even in those
who received systemic therapy. Thus, it may be prudent to recommend the use of
topical antifungal preparations periodically to prevent recurrences. Itraconazole,
which is both lipophilic and keratophilic, is also effective in treating Malassezia
folliculitis. In a double-blind placebo-controlled study, short-term itraconazole
therapy (200 mg daily for 7 days) resulted in a negative direct microscopic KOH
examination at 5 weeks in 84.6 % of patients compared to 8.3 % who received
placebo [27]. Fluconazole has also been found to be effective [28].
Isotretinoin has been proposed as a treatment for Malassezia folliculitis in view of
the fact that it reduces sebum secretion [29]. In a case report, 40 mg isotretinoin daily
for 20 weeks (0.65 mg/kg/day) resulted in dramatic improvement of biopsy-proven
Malassezia folliculitis. The authors note that condition reoccurred 10 months after
discontinuation of the isotretinoin. In view of the temporary benefit and potential for
adverse events, isotretinoin is not a favored treatment option in this condition.
For patients who are not candidates for oral antifungal medications or who have
failed treatment, photodynamic therapy may be an option [30]. In a small study, six
patients with recalcitrant Malassezia folliculitis were pretreated with methyl-
5-aminolevulinic acid cream for 3 h followed by noncoherent red light using
light-emitting diodes for 7.5 min. The patients received three treatments at 2-week
intervals. Investigators note that four patients responded well to treatment, one
patient responding slightly, while the other was considered a nonresponder.
Although these results are preliminary, further studies are indicated to determine if
photodynamic therapy might be beneficial for treating Malassezia folliculitis.
64 P.K. Farris and A. Murina

9.6 Conclusion

Malassezia folliculitis is a common and often overlooked condition. Dermatologists

must have a high level of suspicion in order to diagnose this unique type of follicu-
litis which can be confirmed by direct microscopic examination or skin biopsy.
Treatment with oral antifungal medications remains a mainstay of therapy, and it
may be prudent to administer intermittent topical therapy to prevent recurrences.

References

1. Roberts SO. Pityrosporum orbiculare: incidence and distribution on clinically normal skin.
Br J Dermatol. 1969;81:264–9.
2. Gupta AK, Batra R, Bluhm R, Boekhout T, Dawson TL. Skin diseases associated with malas-
sezia species. J Am Acad Dermatol. 2004;51(5):785–98.
3. Weary PE, Russell CM, Butler HK, Hsu YT. Acneiform eruption resulting from antibiotic
administration. Arch Dermatol. 1969;100(2):179–83.
4. Tragiannidis A, Bisping G, Koehler G, Groll AH. Minireview: Malassezia infections in immu-
nocompromised patients. Mycoses. 2009;53:187–95.
5. Hill MK, Goodfield MJ, Rodgers FG, Crowley JL, Saihan EM. Skin surface electron micros-
copy in Pityrosporum folliculitis: the role of follicular occlusion in disease and the response to
oral ketoconazole. Arch Dermatol. 1990;126:1071–4.
6. Sweeney K. Pityrosporum folliculitis: diagnosis and management in 6 female adolescents with
acne vulgaris. Arch Pediatr Adolesc Med. 2005;159(1):64–7.
7. Yu H, Lee S, Son SJ, Kim YS, Yang HY, Kim JH. Steroid acne vs. pityrosporum folliculitis:
the incidence of Pityrosporum ovale and the effect of antifungal drugs in steroid acne. Int
J Dermatol. 1998;37(10):772–7.
8. Ferrandiz C, Ribera M, Barranco JC, Clotet B, Lorenzo JC. Eosinophilic pustular folliculitis
in patients with acquired immunodeficiency syndrome. Int J Dermatol. 1992;31(3):193–5.
9. Nervi SJ, Schwartz RA, Dmochowski M. Eosinophilic pustular folliculitis: a 40 year retrospect.
J Am Acad Dermatol. 2006;855(2):285–9.
10. Cholongitas E, Pipili C, Ioannidou D. Malassezia folliculitis presented as acneiform eruption
after cetuximab administration. J Drugs Dermatol. 2009;8(3):274–5.
11. Duvic M. EGFR inhibitor-associated acneiform folliculitis. Am J Clin Dermatol. 2008;
9(5):285–94.
12. Archer-Dubon C, Icaza-Chivez M, Orozco-Topete R, Reyes E, Baez-Martinez R, de León SP.
An epidemic outbreak of malassezia folliculitis in three adult patients in an intensive care unit:
a previously unrecognized nosocomial infection. Int J Dermatol. 1999;38(6):453–6.
13. Yohn JJ, Lucas J, Camisa C. Malassezia folliculitis in immunocompromised patients. Cutis.
1985;35(6):536–8.
14. Fearfield LA, Rowe A, Francis N, Bunker CB, Staughton RC. Itchy folliculitis and human
immunodeficiency virus infection: clinicopathological and immunological features, pathogen-
esis and treatment. Br J Dermatol. 1999;141(1):3–11.
15. Helm KF, Lookingbill DP. Pityrosporum folliculitis and severe pruritus in two patients with
Hodgkin’s disease. Arch Dermatol. 1993;129(3):380–1.
16. Rhie S, Turcios R, Buckley H, Suh B. Clinical features and treatment of malassezia folliculitis
with fluconazole in orthotopic heart transplant recipients. J Heart Lung Transplant. 2000;
19(2):215–9.
17. Koranda FC, Dehmel EM, Kahn G, Penn I. Cutaneous complications in immunosuppressed
renal homograft recipients. JAMA. 1974;229(4):419–24.
9 Malassezia Folliculitis 65

18. Bufill JA, Lum LG, Caya JG, Chitambar CR, Ritch PS, Anderson T, et al. Pityrosporum
folliculitis after bone marrow transplantation. Ann Intern Med. 1988;108(4):560.
19. Gueho EF, Faegemann J, Lyman C, Anaissie EJ. Malassezia and Trichosporin: two emerging
pathogenic basidiomycetous yeast-like fungi. J Med Vet Mycol. 1994;32:367–78.
20. Bäck O, Faergemann J, Hörnqvist R. Pityrosporum folliculitis: a common disease of the young
and middle-aged. J Am Acad Dermatol. 1985;12(1, Part 1):56–61.
21. Faergemann J, Johansson S, Back O, Scheynius A. An immunologic and cultural study of
pityrosporum folliculitis. J Am Acad Dermatol. 1986;14(3):429–33.
22. Jacinto-Jamora S, Tamesis J, Katigbak ML. Pityrosporum folliculitis in the philippines: diagnosis,
prevalence, and management. J Am Acad Dermatol. 1991;24(5 Pt 1):693–6.
23. Potter BS, Burgoon Jr CF, Johnson WC. Pityrosporum folliculitis: report of seven cases and
review of the pityrosporum organism relative to cutaneous disease. Arch Dermatol. 1973;
107(3):388–91.
24. Faergemann J, Bergbrant I, Dohsé M, Scott A, Westgate G. Seborrhoeic dermatitis and
pityrosporum (malassezia) folliculitis: characterization of inflammatory cells and mediators in
the skin by immunohistochemistry. Br J Dermatol. 2001;144(3):549–56.
25. Sina B, Kauffman CL, Samorodin CS. Intrafollicular mucin deposits in pityrosporum folliculitis.
J Am Acad Dermatol. 1995;32(5 Pt 1):807–9.
26. Levy A, Feuilhade de Chauvin M, Dubertret L, Morel P, Flageul B. Malassezia folliculitis:
characteristics and therapeutic response in 26 patients. Ann Dermatol Venereol. 2007;
134:823–8.
27. Parsad D, Saini R, Negi KS. Short-term treatment of pityrosporum folliculitis: a double blind
placebo-controlled study. J Eur Acad Dermatol Venereol. 1998;11(2):188–90.
28. Faergemann J. Treatment of pityriasis versicolor with a single dose of fluconazole. Acta Derm
Venereol. 1992;72(1):74–5.
29. Friedman SJ. Pityrosporum folliculitis: treatment with isotretinoin. J Am Acad Dermatol.
1987;16:632–3.
30. Lee J, Kim B, Kim M. Photodynamic therapy: new treatment for recalcitrant malassezia
folliculitis. Lasers Surg Med. 2010;42(2):192–6.
Chapter 10
Tinea Barbae

Lauren Kole and Boni Elewski

10.1 Introduction

Tinea barbae is an uncommon dermatophytosis of the beard and moustache areas

with invasion of coarse hairs; thus, it is a condition almost exclusively found in adult
males [1]. Historically, tinea barbae was frequently transmitted by barbers using
contaminated razors before single-use razors became readily available. Currently, in
most cases, the causative organisms are zoophilic ectothrix, namely, Trichophyton
mentagrophytes and Trichophyton verrucosum, acquired from animals. The clinical
presentation is variable and may be severe with intense inflammation or superficial
and less inflammatory, similar to tinea corporis [2]. Diagnosis typically relies on
clinical presentation with confirmatory mycological culture [3]. The treatment of
tinea barbae requires oral antifungal therapy [2].

10.2 Background

Tinea barbae is most frequently seen in tropical countries with high temperatures
and high humidity. The incidence has decreased in recent years due to the increased
availability of disposal razors, as the infection was regularly transmitted by barbers
using unsanitary razors. Today, tinea barbae is more often found among rural
inhabitants exposed to zoophilic dermatophytes from sources such as cattle, horses,
cats, and dogs (Table 10.1). The species commonly isolated include T. mentagrophytes
and T. verrucosum. Microsporum canis and T. mentagrophytes var. erinacei are
less common. In certain geographic regions, other anthropophilic dermatophytes,

L. Kole, M.D. (*) • B. Elewski, M.D.

Department of Dermatology, University of Alabama, Birmingham, 414 CEFH,
1720 2nd Avenue South, Birmingham, AL 35294, USA
e-mail: [email protected]; [email protected]

J.A. Zeichner (ed.), Acneiform Eruptions in Dermatology: A Differential Diagnosis, 67

DOI 10.1007/978-1-4614-8344-1_10, © Springer Science+Business Media New York 2014
68 L. Kole and B. Elewski

Table 10.1 Zoophilic Zoophilic dermatophytes Animal sources

etiologies of tinea barbae
Trichophyton mentagrophytes Rodents
and their animal sources
Trichophyton verrucosum Cattle and horses
Microsporum canis Dogs and cats
Trichophyton mentagrophytes Hedgehogs
var. erinacei

Trichophyton schoenleinii, Trichophyton violaceum, and Trichophyton megninii, are

endemic and can cause tinea barbae [2]. Recently, there have been several case
reports of Trichophyton rubrum infections caused by autoinoculation from onycho-
mycosis and tinea pedis [4, 5].

10.3 Clinical Presentation

Tinea barbae, as the name suggests, is a dermatophyte infection of the bearded areas
of the face and neck of adult males [1]. The clinical presentation maybe either one
of two types: inflammatory or noninflammatory, depending on the infecting fungus
and the patient’s immune response. The zoophilic dermatophyte infections typically
cause severe, deep inflammation, characterized commonly by inflammatory nodules
and multiple follicular pustules [4]. Abscesses, sinus tracts, kerion-like plaques, and
bacterial superinfections may also occur. Furthermore, patients may have constitu-
tional symptoms such as malaise and lymphadenopathy. The involved hairs can
become loose or broken, and this variety of tinea barbae may lead to permanent,
scarring alopecia [2].
The second type of tinea barbae is clinically similar to tinea corporis, as it is
superficial and less inflammatory and is usually caused by T. rubrum. The charac-
teristic lesion is an annular, erythematous plaque with an active, papular border
(Fig. 10.1). Vesicles and overlying crust are other features that are not uncommon.
Reversible alopecia in the center of the lesion may also be present [5].
A third variant of chronic tinea barbae may present similar to sycosis (inflamma-
tion of the hair follicles), with papules and pustules in a follicular distribution [4].
The differential diagnosis of tinea barbae includes bacterial folliculitis, pseudofol-
liculitis barbae, atypical rosacea, periorbital dermatitis, acne vulgaris, cervicofacial
actinomycosis, and viral infections such as herpes simplex or herpes zoster [6].

10.4 Work-up

Tinea barbae is typically diagnosed by a combination of clinical presentation

and confirmatory laboratory tests. In the clinic, a quick potassium hydroxide test
may be performed with direct microscopic fungal element visualization sampled
10 Tinea Barbae 69

Fig. 10.1 Scaly papules affecting the skin within the beard of the anterior neck of a young man.
Fungal culture revealed Trichophyton species (Photo credit: Joshua A. Zeichner, M.D.)

from infected hair and pustules. The dermatophyte Microsporum canis may also be
visualized with Wood’s light, and a biopsy can be diagnostic as well. Fungal culture
is performed on agar with cycloheximide to identify the causative organism [7].

10.5 Treatment

Tinea barbae should be treated with systemic antifungal therapy, as these drugs are
able to penetrate the infected hair shaft, whereas topical therapies cannot.
Debridement and shaving of the affected hairs is also recommended [2]. Griseofulvin
up to 1 g daily, FDA approved for the treatment of tinea capitis, is dosed daily for
6–12 weeks [8]. However, some authors advocate a 4-week course of terbinafine
250 mg daily [7]. Terbinafine should not be the first line of therapy if the causative
organism is unknown, as M. canis is resistant to terbinafine. Treatment with itracon-
azole 200 mg or fluconazole 200 mg daily for 4–6 weeks is also effective [2].
Adjuvant therapy with antifungal shampoos, such as ketoconazole 2 % shampoo
and selenium sulfide 2.5 % shampoo, used at least three times weekly, will decrease
shedding of the infectious fungal elements [9]. Furthermore, elimination of the
source of the infection, whether by treatment of infected animals or treatment of
onychomycosis, is very important [4].
70 L. Kole and B. Elewski

References

1. Burns T, Breathnach S, Cox N, Griffiths C, editors. Rook’s textbook of dermatology. 8th ed. San
Francisco: Wiley-Blackwell; 2010.
2. Bolognia JL, Jorizzo JL, Rapini RP, editors. Dermatology. 2nd ed. St. Louis: Mosby Elsevier;
2008.
3. Drake LA, Dinehart SM, Farmer ER, et al. Guidelines of care for superficial mycotic infections
of the skin: tinea capitis and tinea barbae. Guidelines/Outcomes Committee. American Academy
of Dermatology. J Am Acad Dermatol. 1996;34:290–4.
4. Xavier MH, Torturella DM, Rehfeldt FVS, et al. Sycosiform tinea barbae caused by Trichophyton
rubrum. Dermatol Online J. 2008;14:10.
5. Szepietowski JC, Matusiak L. Trichophyton rubrum autoinoculation from infected nails is not
such a rare phenomenon. Mycoses. 2008;51:345–6.
6. Habif TP. Clinical dermatology. 5th ed. St. Louis: Mosby Elsevier; 2010.
7. Baran W, Szepietowski JC, Schwartz RA. Tinea barbae. Acta Dermatovenerol Alp Panonica
Adriat. 2004;13:91–4.
8. Gupta AK, Dlova N, Taborda P, et al. Once weekly fluconazole is effective in children in the
treatment of tinea capitis: a prospective, multicenter study. Br J Dermatol. 2000;142:965–8.
9. Elewski BE. Treatment of tinea capitis: beyond griseofulvin. J Am Acad Dermatol. 1999;
40:S27–30.
Chapter 11
Flat Warts

Ted Rosen and Sara Risner-Rumohr

11.1 Introduction

Verruca plana, or flat warts, are virally induced papules caused by the human
papillomavirus (HPV) that can mimic a closed comedone or an acneiform papule. This
chapter will discuss the etiology, risk factors, diagnosis, and treatment of flat warts.
Table 11.1 summarizes the similarities and differences between flat warts and acne.

11.2 Background

HPV includes greater than 100 genotypes of a double-stranded DNA virus [1].
Cutaneous HPV types comprise a group of viruses that infect the skin and induce
common warts, palmar and plantar warts, flat warts, and butcher’s warts.
Classification of warts is based upon morphology, anatomic localization, and HPV
typing.
Common warts are hyperkeratotic, exophytic papules, or nodules typically asso-
ciated with HPV-1, HPV-2, or HPV-4 [2]. They are most commonly located on fin-
gers, the dorsal surfaces of hands, and other sites prone to trauma. They typically
spare the face but can occur at any anatomical location. HPV types 2, 27, and 57
caused the majority of palmoplantar warts [2]. Myrmecia are large, deep burrowing
warts on the plantar surface caused by HPV-1. Most commonly, flat warts that have
been analyzed by polymerase chain reaction (PCR) studies contain HPV-3 and, less
often, types 10, 28, 29, and 41 [2–6].

T. Rosen, M.D. (*) • S. Risner-Rumohr, M.D.

Department of Dermatology, Baylor College of Medicine,
1977 Butler Blvd, Suite E6.200, Houston, TX 77030, USA
e-mail: [email protected]; [email protected]

J.A. Zeichner (ed.), Acneiform Eruptions in Dermatology: A Differential Diagnosis, 71

DOI 10.1007/978-1-4614-8344-1_11, © Springer Science+Business Media New York 2014
72 T. Rosen and S. Risner-Rumohr

Table 11.1 Similarities and differences between acne and flat warts
Features Flat warts Acne
Affected age group—childhood and young adult Yes Yes
Koebner phenomenon Yes Occasionallya
Follicular-based papules No Yes
Flat-topped papules Yes No
Virally induced Yes No
Ultraviolet light influenced Yes—worsened Yes—most often improved
Can heal with a scar Occasionallyb Yes
Hormonally influenced No Yes
Cellular immunity related Yes No
Spontaneously resolve Yes Yes
Response to retinoid therapy Yes Yes
a
Acne can be triggered by minor trauma/friction (e.g., acne mechanica)
b
Treatments can lead to permanent scarring

The papillomavirus species-specific life cycle is completed only in fully differen-

tiated human squamous epithelia. The infection and induction of hyperproliferation
are initiated when the virus enters the basal layer [2]. Unlike other viruses, such as
herpes simplex or molluscum contagiosum, HPV does not encode the enzymes
required for the replication of viral DNA. HPV is dependent on the host’s cellular
machinery for replication. HPV proteins can amplify cell replication acting as viral
oncoproteins. However, unlike the high-risk HPV infections located on mucosal
surfaces, flat warts have not been linked to dysplasia and cancer [4].
Nongenital warts occur in 7–10 % of the general population, flat warts being the
least common variant [6]. Children and young adults are primarily affected by flat
warts [5–7]. Sun exposure appears to be a risk factor for flat warts, as the latent
virus has the ability to induce lesions following after ultraviolet exposure [8]. Flat
warts may also develop at sites of trauma (the Koebner phenomenon) as a result of
autoinoculation. This may be clinically manifest as linear configurations. For
example, men who shave their beards and women who shave their legs often exhibit
this pattern [9]. The development of multiple warts has also been reported after tat-
tooing [8, 10].

11.3 Clinical Presentation

Flat warts are 2–4 mm in diameter, slightly elevated, flat-topped, smooth papules
(Fig. 11.1). They can be skin colored or slightly erythematous on pale skin and
hyperpigmented on darker skin. They are generally multiple and grouped. The fore-
head, cheeks, and nose, perioral region, and dorsal hands are classic locations [9].
Hyperpigmented lesions may be confused with lentigines or ephelides. Skin-colored
to erythematous lesions located on the central face may be confused with closed
11 Flat Warts 73

Fig. 11.1 Adolescent woman who presented for treatment of “acne” with typical facial flat warts

comedones or acneiform papules [9]. Filiform warts, a variant of common warts

with characteristic frond-like projections, are often seen on the face but rarely cause
diagnostic confusion [8].

11.4 Work-up

Multiple flat warts are commonly seen in healthy individuals but may also be a sign
of a compromised immune system. When there is extensive involvement in an adult
with no obvious risk factors, or in a treatment-refractory case, the patient’s cellular
immune function should be evaluated. Extensive flat warts have been reported in
patients with human immunodeficiency virus infection (HIV) [11]. Widespread flat
warts have also been reported in immune-reconstitution syndrome in HIV patients
on HAART (Highly Active Anti-Retroviral Treatment) [12]. Similarly, the trans-
plant population and primary immunodeficiency diseases, such as common variable
immunodeficiency, severe combined immunodeficiency, Hyper-IgM, Hyper-
immunoglobulin E syndrome, idiopathic CD4+ T-cell lymphocytopenia [13], and
WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) [14] have
a higher incidence of viral warts.
Epidermodysplasia verruciformis (EDV) is a rare, autosomal recessive disorder
with widespread skin colonization by HPV. The clinical presentation is of dissemi-
nated flat warts or large pityriasis versicolor-like patches induced most commonly by
HPV-3 and HPV-10 [15]. One-third to one-half of patients will develop squamous
cell carcinoma, associated most frequently with HPV subtypes 5, 8, and 47 [2, 15].
74 T. Rosen and S. Risner-Rumohr

A flat wart can be easily discerned from an acneiform lesion with a histological
evaluation. Flat warts show hyperkeratosis and acanthosis, no papillomatosis, only
slight elongation of the rete ridges, and no areas of parakeratosis. In the upper stra-
tum malpighii, including the thickened granular layer, there is diffuse vacuolization
of the cells [16]. The nuclei of the vacuolated cells lie at the centers of the cells, and
some appear deeply basophilic. The dermis appears normal. In spontaneously
regressing warts, there is often a superficial lymphocytic infiltrate in the dermis with
exocytosis and apoptosis of cells in the epidermis [16].

11.5 Treatment

Of all clinical HPV infections, flat warts have the highest rate of spontaneous remis-
sion; they almost universally resolve without treatment over several months to years
[9]. This makes evaluation of any treatment modality difficult [17]. Among immu-
nosuppressed patients, the warts typically persist longer and are more resistant to
treatment [11, 14].
Wart regression is probably the result of cell-mediated immune mechanisms,
although the process is not completely understood [18]. Considerations related to
treatment of flat warts include the patient’s age, immune status, skin integrity, and
potential cosmetic outcome. Despite the fact that a wide range of local treatments
for nongenital cutaneous warts exists, there is only limited reliable evidence regard-
ing the efficacy of various potential interventions [17]. Viral wart survival is based
on evading the immune detection apparatus within the epidermis. Inflammation of
the skin may stimulate a concurrent immunologic response against HPV.
Keratolytics, such as many over-the-counter products containing with salicylic acid
or prescription strength retinoids, are frequently used for flat warts. These cause
chemical irritation and debridement of the wart’s keratotic surface. In reality, topical
salicylic acid products have the highest grade clinical evidence regarding their supe-
riority to placebo [17]. Topical retinoids are potent keratolytics but also assist in the
treatment of warts by the disruption of epidermal growth and differentiation, as well
as via modest immunomodulatory effects. One study investigating tretinoin 0.05 %
cream resulted in an 85 % clearance in a series of children with flat warts compared
to 32 % spontaneous clearance in the controls [19]. Astringent chemicals such as
trichloroacetic acid and cantharidin are also frequently used in the office setting.
Cantharidin is a chemical derived from the blister beetle, Cantharis vesicatoria.
When applied it causes dermal blistering and local necrosis. Responses are variable,
and this material can cause scarring or spread of warts around the index, treated
lesion. Podophyllin, topical 5 % 5-fluorouracil, and intralesional bleomycin are
other topical therapies that have varying degrees of antimitotic effect; however, they
tend to be more beneficial for mucosal lesions and exophytic warts.
Destructive techniques, such as curettage, electrodesiccation, laser therapy, pho-
todynamic therapy, or cryotherapy using liquid nitrogen, have all been utilized with
good results. Nonetheless, destructive techniques are considered second-line
11 Flat Warts 75

therapy as they carry the risk of scar formation and recurrence in or around the treat-
ment site. This is especially true for smaller, less exophytic warts, such as verruca
plana. Prolonged occlusive duct tape treatment followed by periodic manual debride-
ment has been shown to be superior or at least comparable to cryotherapy for com-
mon warts but has not been reported for flat warts [20].
Many laser therapies have been employed. The carbon dioxide (CO2) laser emits
an infrared light emission (10,600 nm) that causes a nonselective thermal tissue
destruction; the lost skin then heals by secondary intent [21]. The erbium:yttrium/
aluminum/garnet (Er:YAG) emits an infrared light emission (2,940 nm) which is
absorbed more efficiently by epidermal water, thus allowing for a more precise
ablation and a smaller zone of thermal damage than the CO2 laser [22]. No random-
ized studies on the efficacy of laser therapy for flat warts have been published.
Infectious hazards have also been demonstrated for both laser and electrocoagula-
tion, as HPV DNA has been identified in the vaporized laser plume [23]. Other laser
therapies such as pulse dye laser have been used to selectively destroy the dilated
capillaries within the warts, producing less pain and scarring than CO2 laser. This
technique has been utilized more for flat warts in children and for facial lesions in
all ages due to a preferable safety profile [24].
Contact immunotherapy can be an effective treatment. Dinitrochlorobenzene
diphenylcyclopropenone or squaric acid have been used as non-mutagenic sensitiz-
ers eliciting a contact allergy that theoretically concomitantly heightens the immune
response against the virus. Intralesional immunotherapy has little role in flat warts
due to their thin nature. A topical immune response modifier, imiquimod, has been
FDA approved for external anogenital warts. Imiquimod has been shown to interact
with Toll-like receptors 7 and 8, resulting in activation of cytokine secretion from
monocytes/macrophages (including α-interferon, interleukin-12, and TNF-α), as
well as stimulation of antigen-presenting dendritic cells [2, 25]. No randomized
controlled studies have been performed with imiquimod cream at any of the avail-
able concentrations (5, 3.75, and 2.5 %) for the management of flat warts.
Nonetheless, imiquimod has been widely utilized in children and for facial flat
warts in all ages as it generally elicits less discomfort compared to many of the other
available treatments. In 2006, the FDA approved an ointment extract of green tea
(Camellia sinensis) containing 15 % sinecatechins for treatment of genital warts.
No studies have been published to date regarding efficacy in flat warts, but it may
well represent a novel topical approach for recalcitrant lesions [26].
Systemic therapies including garlic supplements (Allium sativum) have been
shown to inhibit cellular proliferation of virally infected cells [27]. Oral cimetidine
(20–40 mg/kg/day) and oral zinc sulfate supplementation (10 mg/kg/day) have been
used in an attempt to enhance cell-mediated immunity [28, 29]. Systemic retinoids,
both isotretinoin and acitretin, have been used for extensive flat warts. In immuno-
compromised patients (both EDV and HIV populations), systemic and 1–3 % topical
cidofovir, an antiviral that inhibits DNA synthesis, has been used effectively [30].
A combination of therapies is often pursued due to the frequent resilience of
warts. There is no single gold standard wart treatment. The specific treatment regi-
men should be individualized to the needs and desires of the patient and
76 T. Rosen and S. Risner-Rumohr

subsequently altered or modified based upon the clinical response obtained. With the
exception of topical tretinoin, none of the typical repertoire of topical or systemic
acne interventions would benefit flat warts.

References

1. de Villiers EM, Fauquet C, Broker TR, et al. Classification of papillomaviruses. Virology.

2004;324:17–27.
2. Kirnbauer R, Lenz P, Okun M. Human papillomavirus, Chapter 78. In: Bolognia JL, Jorizzo JL,
Rapini RP, editors. Dermatology. 2nd ed. Philadelphia: Mosby-Elsevier; 2008. p. 1183–98.
3. Harwood CA, Spink PJ, Surentheran T, et al. Degenerate and nested PCR: a highly sensitive
and specific method for detection of human papillomavirus infection in cutaneous warts. J Clin
Microbiol. 1999;37:3545–55.
4. Pfister H. Chapter 8: Human papillomavirus and skin cancer. J Natl Cancer Inst Monogr.
2003;31:52–6.
5. Plasencia JM. Cutaneous warts: diagnosis and treatment. Prim Care. 2000;27:423–34.
6. Brentjens M, Yeung-Yue KA, Lee P, Tyring SK. Human papillomaviruses and warts, Chapter
142. In: Gorbach S, Bartlett J, Blacklow N, editors. Infectious diseases. 3rd ed. Philadelphia:
Lippincott Williams & Wilkins; 2004. p. 1215–20.
7. Lebwohl MG, Rosen T, Stockfleth E. The role of human papillomavirus in common skin
conditions: current viewpoints and therapeutic options. Cutis. 2010;86(5):Suppl 1–11.
8. Brajac I, Loncarek K, Stojnić-Sosa L, Gruber FJ. Delayed onset of warts over tattoo mark
provoked by sunburn. J Eur Acad Dermatol Venereol. 2005;19:247–8.
9. James WD, Elston DM, Berger TG. Viral diseases, Chapter 19. In: Andrews GC, Domonkos
AN, Arnold HL, Odom RB, editors. Andrews’ diseases of the skin: clinical dermatology. 11th
ed. Philadelphia: Saunders-Elsevier; 2011. p. 397–406.
10. Baxter SY, Deck DH. Tattoo-acquired verruca plana. Am Fam Physician. 1993;47:732.
11. Berger TG, Obuch ML, Goldschmidt RH. Dermatologic manifestations of HIV infection. Am
Fam Physician. 1990;41:1729–42.
12. Iarikov D, Duke W, Skiest D. Extensive development of flat warts as cutaneous manifestation
of immune reconstitution syndrome. AIDS Read. 2008;18:524–7.
13. Fischer LA, Norgaard A, Permin H, et al. Multiple flat warts associated with idiopathic CD4-
positive T lymphocytopenia. J Am Acad Dermatol. 2008;58:S37–8.
14. Dotta L, Tassone L, Badolato R. Clinical and genetic features of warts, hypogammaglobu-
linemia, infections and myelokathexis (WHIM) syndrome. Curr Mol Med. 2011;11:317–25.
15. Patel T, Morrison LK, Rady P, Tyring S. Epidermodysplasia verruciformis and susceptibility
to HPV. Dis Markers. 2010;29:199–206.
16. Xu X, Erickson L, Chen L, Elder DE. Diseases caused by viruses, Chapter 25. In: Elder DE,
Elenitsas R, Johnson BL, Murphy GF, editors. Lever’s histopathology of the skin. 10th ed.
Philadelphia: Lippincott Williams & Wilkins; 2004. p. 637–66.
17. Gibbs S, Harvey I. Topical treatments for cutaneous warts. Cochrane Database Syst Rev.
2006;3, CD001781.
18. Aiba S, Rokugo M, Tagami H. Immunohistologic analysis of the phenomenon of spontaneous
regression of numerous flat warts. Cancer. 1986;58:1246–51.
19. Kubeyunje EP. Evaluation of the efficacy and safety of 0.05% tretinoin cream in the treatment
of plane warts in Arab children. J Dermatolog Treat. 1996;7:21–2.
20. Focht III DR, Spicer C, Fairchok MP. The efficacy of duct tape vs. cryotherapy in the treatment
of verruca vulgaris. Arch Pediatr Adolesc Med. 2002;156:971–4.
21. Lauchli S, Kempf W, Dragieva G, et al. CO2 laser treatment of warts in immunosuppressed
patients. Dermatology. 2003;206:148–52.
11 Flat Warts 77

22. Park JH, Hwang ES, Kim SN, Kye YC. Er:YAG laser treatment of verrucous epidermal nevi.
Dermatol Surg. 2004;30:378–81.
23. Sawchuk WS, Weber PJ, Lowy DR, Dzubow LM. Infectious papillomavirus in the vapor of
warts treated with carbon dioxide laser or electrocoagulation: detection and protection. J Am
Acad Dermatol. 1989;21:41–9.
24. Vargas H, Hove CR, Dupree ML, Milliams EF. The treatment of facial verrucae with pulsed
dye laser. Laryngoscope. 2002;112:1573–6.
25. Gaspari A, Tyring SK, Rosen T. Beyond a decade of 5% imiquimod topical therapy. J Drugs
Dermatol. 2009;8:467–74.
26. Viera MH, Amini S, Huo R, et al. Herpes simplex virus and human papillomavirus genital
infections: new and investigational therapeutic options. Int J Dermatol. 2010;49:733–49.
27. Seki R, Tsuji K, Hayato Y, et al. Garlic and onion oils inhibit proliferation and induce differ-
entiation of HL-60 cells. Cancer Lett. 2000;160:29–35.
28. Al-Gurairi FT, Al-Waiz M, Sharquie KE. Oral zinc sulphate in the treatment of recalcitrant
viral warts: randomized placebo-controlled clinical trial. Br J Dermatol. 2002;146:423–31.
29. Rogers CJ, Gibney MD, Siegfried EC, et al. Cimetidine therapy for recalcitrant warts in adults:
is it any better than placebo? J Am Acad Dermatol. 1999;41:123–7.
30. Grone D, Treudler R, de Villiers EM, et al. Intravenous cidofovir treatment for recalcitrant
warts in the setting of a patient with myelodysplastic syndrome. J Eur Acad Dermatol Venereol.
2006;20:202–5.
Chapter 12
Molluscum Contagiosum

Yvonne Clark and Lawrence F. Eichenfield

12.1 Introduction

Molluscum contagiosum is a benign cutaneous and mucosal viral infection

manifested by dome-shaped flat-topped papules with occasional nodules.
Molluscum contagiosum can be seen at any age but predominantly affects chil-
dren. Molluscum lesions are spread by direct skin to skin contact with fomites,
and fomite facilitators can include shaving, tattoos, electrolysis, and bath towels.
The incubation period is quite variable, most commonly ranging from 2 to 7
weeks, while in some cases, the latency period can be as long as 6 months after
exposure. The process of identifying initial infection can be difficult. Molluscum
may be spread through sexual contact as in more commonly seen in young adults
and individuals with decreased immunity, including human immunodeficiency
virus (HIV) or acquired immune deficiency syndrome (AIDS), or those receiving
immunosuppressive therapy. Molluscum contagiosum in neonates and infants is
rare, presumably as a result of maternal antibodies [1, 2].

Y. Clark, MPAS-C
Department of Dermatology, Sharp Rees-Stealy, La Mesa, CA, USA
e-mail: [email protected]
L.F. Eichenfield, M.D. (*)
Division of Pediatric and Adolescent Dermatology, Rady Children’s Hospital, San Diego,
8010 Frost Street, Suite 620, San Diego, CA 92123, USA
e-mail: [email protected]

J.A. Zeichner (ed.), Acneiform Eruptions in Dermatology: A Differential Diagnosis, 79

DOI 10.1007/978-1-4614-8344-1_12, © Springer Science+Business Media New York 2014
80 Y. Clark and L.F. Eichenfield

12.2 Background

Molluscum contagiosum is caused by the molluscum contagiosum virus, the sole

member of the genus Molluscipoxvirus. It is a large double-stranded deoxyribonu-
cleic acid virus constructed of a 190-kbp genome that encodes 163 proteins. Most
of the proteins encoded by the molluscum genome do not illicit a virus–host inter-
action, differentiating it from another virus in the poxvirus family, variola, the caus-
ative agent of smallpox. Research in molluscum–host interactions is needed but has
been hindered by the inability to grow molluscum contagiosum virus in tissue cul-
ture cells or animal models [3, 4].
The transmission through water and swimming pools remains controversial. It is
unclear if transmission is due to swimming in contaminated water versus fomites
used during swimming activities, including toys, kickboards, or towels [1]. The
Center for Disease Control and Prevention recommends children with molluscum to
cover all visible lesions with watertight bandages and to dispose of all bandages at
home. The Center for Disease Control and Prevention also recommends “no sharing
of toys, equipment or kickboards during swimming activities. Individuals with open
sores should not go into swimming pools [5].” The American Academy of Pediatrics
does not restrict children with molluscum contagiosum from attending day care,
school, or swimming in public pools [6].

12.3 Clinical Presentation

Characteristic molluscoid lesions are pearly, flesh- to pink-colored dome-shaped

papules that can be translucent ranging in size from 2 to 8 mm usually with a distinct
white annular area in the center. Lesions can be umbilicated but this finding is not
necessary for diagnosis (Fig. 12.1). Occasionally lesions may be much larger, up to
several centimeters termed “giant molluscum.” Significant erythema is common as
a reactive eczematous dermatitis that is usually local but may generalize similar to
a dermatophytid eruption. Rarely bacterial superinfection can occur with abscess
formation. Most individuals present with more than 15 lesions in common areas like
axilla, groin, popliteal fossa, genitals, and perianal due to rubbing, friction, and
moisture. It is not uncommon to see ill-defined areas of erythematous patches and
plaques surrounding molluscoid lesions known as “molluscum dermatitis.”
Autoinoculation from scratching pruritic skin spreads the virus to other areas of the
body. Lesions can be seen in linear distribution (koebnerization) due to scratching
and trauma [2].
Spontaneous resolution usually occurs but timing can vary. Significant erythema
can be an indication of host immune response. The majority of infections clear
within 6–12 months, but some cases can take years for complete clearance. Children
with atopic dermatitis and those who are immunosuppressed have more widespread
disease and a prolonged course [7].
12 Molluscum Contagiosum 81

Fig. 12.1 Umbilicated,

flesh-colored papules on the
cheek of an adolescent boy.
He presented to the office
with a complaint of acne
(Photo credit: Joshua A.
Zeichner, M.D.)

12.4 Work-Up

Molluscum contagiosum is a clinical diagnosis requiring little to no work-up.

Differential diagnosis includes warts (both flat and common), keratosis pilaris, xan-
thomas, and adnexal tumors [8]. Wright and Giemsa stains of cells from the core
show intracytoplasmic basophilic bodies. Electron microscopy reveals typical pox-
virus particles. Dermoscopy can visualize specific characteristic vascular patterns [9].
Biopsy may be necessary when the diagnosis is unclear, revealing large intracyto-
plasmic basophilic bodies that push the host nucleus to the periphery, giving a signet
ring appearance to the superficial epidermal cells. Real-time polymerase chain reac-
tion is available for homologous p43k and MC080R genes but rarely used [10].
Bacterial cultures may be considered for lesions with signs and symptoms of sec-
ondary bacterial infections.

12.5 Treatment

Treatment options include observation, destructive methods, and immune modulat-

ing modalities. Observation is a reasonable option since spontaneous resolution is
common but due to cosmetic impact, pruritus, and concerns of others, teachers,
school nurses, and other parents, treatment is often requested [1, 2].
Destructive methods include cantharidin, curettage, cryotherapy, tape stripping,
topical tretinoin cream, 5–10 % potassium hydroxide and keratolytics such as
salicylic acid and alpha hydroxyl acid, and pulse dye laser. Immune modulating
therapies include oral cimetidine, intralesional candida antigen, topical imiquimod
5 % cream, and topical cidofovir [11, 12]. With a variety of therapy options
82 Y. Clark and L.F. Eichenfield

Table 12.1 Clinical pearls

Facial lesions Topical tretinoin 0.025 % cream, caution with irritation and sun
sensitivity
Body lesions Cantharidin with 4 h wash off. Do not occlude lesions
Extensive facial and/or body Oral cimetidine 35–40 mg/kg/day for 6–12 weeks. Side effects:
lesions >50 headaches, diarrhea, nausea, inhibitor of cytochrome P450,
intolerable taste (solution formulation)
Adults, older children Cryotherapy (caution post inflammatory pigment changes and
or teenagers scarring) or
Intralesional candida antigen (localized erythema and pain)

available, patient’s age, pain tolerance, and accessibility to clinic should be taken
into consideration when choosing a remedy. Destructive methods can be painful to
younger children but well tolerated in older children and adults. To date there are no
standard treatment protocols or reliable evidence-based recommendations for
treating molluscum contagiosum [13].
The most commonly utilized treatment amongst pediatric dermatologist is can-
tharidin [14]. Cantharidin has been available and used to treat molluscum since 1950.
Cantharidin is derived from the blistering beetle, Cantharis vesicatoria, and causes
vesiculation of the epidermis. Application in office by a physician or other qualified
and well-trained professional is recommended. Side effects include blistering, tem-
porary burning, localized pain, erythema, and pruritus. Occlusion of treated areas is
not recommended and a typical wash-off period can range from 2 to 6 h or sooner if
blistering or discomfort is noted. Cantharidin is a powerful toxin that should not be
ingested or absorbed; therefore application to mucosal areas is not recommended.
Cantharidin generally is not used on the face or on occluded areas such as under a
diaper [15]. Facial lesions may be treated with topical tretinoin cream. Systemic
therapy with oral cimetidine has been advocated by some as monotherapy or in con-
junction with cantharidin for extensive lesions or recalcitrant lesions to cantharidin,
though there is a minimal evidence to support its utility (Table 12.1).

References

1. Braue A, Ross G, Varigos G, Kelly H. Epidemiology and impact of childhood molluscum

contagiosum: a case series and critical review of the literature. Pediatr Dermatol. 2005;22:287–
94. doi:10.1111/j.1525-1470.2005.22401.x.
2. Paller A, Mancini AJ. Molluscum contagiosum. Hurwitz clinical pediatric dermatology: a text-
book of skin disorders of childhood and adolescence. Philadelphia, PA: Elsevier Saunders;
2006. p. 412–5.
3. Senkevich TG, Bugert JJ, Sisler JR, Koonin EV, Darai G, Moss B. Genome sequence of a
human tumorigenic poxvirus: prediction of specific host response-evasion genes. Science.
1996;273(5276):813–6.
4. King AMQ, Adams MJ, Carstens EB, Lefkowitz EJ, editors. Virus taxonomy: classification
and nomenclature of viruses: Ninth Report of the International Committee on Taxonomy of
Viruses. San Diego: Elsevier Academic; 2011.
12 Molluscum Contagiosum 83

5. Homepage | CDC Molluscum Contagiosum. Centers for Disease Control and Prevention.
2011. Web 11 Dec 2011. http://www.cdc.gov/ncidod/dvrd/molluscum/.
6. American Academy of Pediatrics. Summaries of infectious disease. In: Pickering LK, Baker
CJ, Kimberlin DW, Long SS, editors. Red Book: 2009 Report of the committee on infectious
diseases. 28th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2009. p. 466.
7. Dohil M, Lin P, Lee J, Lucky A, Paller A, Eichenfield L. The epidemiology of molluscum
contagiosum in children. J Am Acad Dermatol. 2006;54(1):47–54.
8. Krishnamurthy J, Nagappa DK. The cytology of molluscum contagiosum mimicking skin
adnexal tumor. J Cytol. 2010;27(2):74.
9. Ianhez M, Sda Cestari C, Enokihara MY, Seize MB. Dermoscopic patterns of molluscum
contagiosum: a study of 211 lesions confirmed by histopathology. An Bras Dermatol.
2011;86(1):74–9.
10. Trama JP, Adelson ME, Mordechai E. Identification and genotyping of molluscum contagio-
sum from genital swab samples by real-time PCR and pyrosequencing. J Clin Virol. 2007;
40(4):325–9.
11. Maronn M, Salm C, Lyon V, Galbraith S. One-year experience with Candida antigen
immunotherapy for warts and molluscum. Pediatr Dermatol. 2008;25:189–92. doi:10.1111
/j.1525-1470.2008.00630.x.
12. Enns LL, Evans MS. Intralesional immunotherapy with Candida antigen for the treatment of
molluscum contagiosum in children. Pediatr Dermatol. 2011;28:254–8. doi:10.1111/
j.1525-1470.2011.01492.x.
13. van der Wouden JC, van der Sande R, van Suijlekom-Smit LWA, Berger M, Butler CC, Koning
S. Interventions for cutaneous molluscum contagiosum. Cochrane Database Syst Rev. 2009;4,
CD004767. doi:10.1002/14651858.CD004767.pub3.
14. Coloe J, Morrell DS. Cantharidin use among pediatric dermatologists in the treatment of mol-
luscum contagiosum. Pediatr Dermatol. 2009;26:405–8. doi:10.1111/j.1525-1470.2008.00860.x.
15. Silverberg N, Sidbury R, Mancini AJ. Childhood molluscum contagiosum: experience with
cantharidin therapy in 300 patients. J Am Acad Dermatol. 2000;43(3):503–7.
Chapter 13
Herpes Simplex Virus

Rachel Gordon and Stephen Tyring

13.1 Introduction

Our understanding of human herpes simplex virus (HSV) has increased tremen-
dously since the early descriptions of disease provided by Hippocrates [1, 2].
Notable advances include the correlation of herpetic lesions with genital infections
in the eighteenth century [3] and Vidal’s recognition of human-to-human transmis-
sion in 1893 [2]. Antigenic differences between HSV subtypes, suspected on clini-
cal observations by Lipschitz [4], were confirmed in 1968 [5]. In modern day, there
is successful antiviral treatment available for most HSV infections [6]. Insight into
the viral life cycle and gene expression has been a driving force behind the develop-
ment of antiviral treatment, including new vaccines and gene therapy [4].

13.2 Background

Transmission of HSV occurs when a mucosal surface or abraded skin in a seronega-

tive individual comes into contact with virus. Viral replication at the site of primary
infection is followed by retrograde axonal transportation of a virion to the dorsal
ganglion cells where latency is established by another episode of viral replication
[12]. Recurrent infections occur randomly, but there is a positive correlation with

R. Gordon, M.D. (*)

Department of Dermatology, The University of Texas Medical School at Houston,
6655 Travis Street, Suite 600, Houston, TX 77030, USA
e-mail: [email protected]
S. Tyring, M.D., Ph.D., M.B.A.
Department of Dermatology, The University of Texas at Houston, Houston, TX, USA
e-mail: [email protected]

J.A. Zeichner (ed.), Acneiform Eruptions in Dermatology: A Differential Diagnosis, 85

DOI 10.1007/978-1-4614-8344-1_13, © Springer Science+Business Media New York 2014
86 R. Gordon and S. Tyring

stress, immunosuppression, UV light, fever, and tissue damage [4, 7]. The severity
of the initial infection correlates with the chance of recurrence. Rarely, life-
threatening infections occur in cases of severe immune compromise, pregnancy, and
neonatal disseminated HSV. “Primary infections” are considered first-time events,
but their occurrence in seropositive individuals indicates that latent infection can be
established without prior symptoms [6].
HSV infections are ubiquitous, even in remote areas [8]. More than 57 % of the
US population between the ages of 14 and 49 are seropositive for HSV1 [9].
Incidence correlates with age in a linear fashion, globally reaching 60–90 % in older
adults [10]. HSV1 is most commonly transmitted in childhood and adolescence.
The overall incidence of HSV1 is significantly higher than that of HSV2 [10], which
occurs more commonly in women and in subpopulations with high-risk sexual
behavior [4, 10]. Humans are the only reservoir for HSV infection, and there have
been no reported animal vectors [4].

13.3 Clinical Presentation

13.3.1 Oropharyngeal and Orolabial HSV

Infections around the mouth are the most common sites and reservoirs of HSV.
Primary infection is usually asymptomatic [11]. Symptomatic cases may include
extensive orolabial vesiculo-ulcerative lesions, gingivostomatitis, fever, and local-
ized lymphadenopathy [4]. Adolescents can present with acute pharyngitis and
mononucleosis-like symptoms [12, 13]. Dehydration from poor oral intake is the
most frequent reason for hospitalization [6].
The incubation period for HSV infections is 4 days on average, and clinical
symptoms may persist for 2–3 weeks [4, 14]. Vesicles form within 1–2 days of pro-
dromal symptoms, progress to ulcers in another 1–2 days, and heal within 8–10
days. Pain is most severe with the appearance of lesions [15]. The frequency of
recurrences varies among individuals [4], but is estimated to occur in 20–40 % of
adults [6], most commonly on the vermillion border. Viral shedding increases with
active lesions [16], during episodes of the common cold, oral trauma, and false
prodromes [17]. Shedding persists in the absence of symptoms in an estimated 7 %
of the healthy population [18] (Figs. 13.1 and 13.2).

13.3.2 HSV Keratoconjunctivitis

Keratoconjunctivitis acquired during birth is usually caused by HSV2. Outside the

neonatal period, it is usually caused by HSV1 [4]. These infections result in corneal
scarring and vision loss [19] and are the second most common cause of corneal
blindness in America [4]. Primary infections can be unilateral or bilateral. Presenting
symptoms of pain, tearing, chemosis, and photophobia [6] are associated with
13 Herpes Simplex Virus 87

Fig. 13.1 Herpes labialis in

early stage on the upper
vermillion border

Fig. 13.2 Recurrent herpes

labialis with nearby
cutaneous involvement

periorbital edema and preauricular lymphadenopathy [1]. Corneal lesions with a

branching dendritic pattern are pathognomonic [4]. Even with antiviral therapy,
healing of the cornea can take up to a month [4, 6]. Approximately one-third of
individuals experience a recurrence [1]; when they do occur, they are typically
unilateral [4] and resolve over a period of weeks [4].

13.3.2.1 HSV in Immunocompromised Individuals

The degree of immune suppression correlates with the risk of developing HSV
outbreaks. Organ transplant recipients and individuals with HIV/AIDS are at high
risk for severe infections and frequent recurrences [4, 20]. The most frequent com-
plication is progressive, chronic mucocutaneous infection with subsequent tissue
necrosis [6]. Progressive disease involving the esophagus, respiratory, and gastroin-
testinal tract has been reported [4].
88 R. Gordon and S. Tyring

Fig. 13.3 Eczema herpeticum

13.3.2.2 Neonatal HSV

Neonatal HSV is defined as an HSV infection in a newborn within 28 days of birth.

They are caused by viral exposure during vaginal delivery [21]. The risk of trans-
mission is highest in mothers who acquire genital herpes near term [22].
There are three clinical presentations of neonatal HSV, each with a different
prognosis. Because a rash is absent in 50 % of cases, all infants with CNS or sepsis
symptoms should be evaluated for HSV. First, in 45 % of cases, infection is limited
to the skin, eyes, and mucosa without CNS or visceral organ involvement. The ves-
icles that appear in these areas commonly recur in early childhood. Second, CNS
involvement occurs in 30 % of cases; cutaneous signs are variable. Complications
of CNS involvement include developmental delay, cognitive disabilities, blindness,
and epilepsy. More than 50 % of children with HSV2 CNS infection have neuro-
logic abnormalities. Finally, disseminated HSV occurs in 25 % of cases. It is indis-
tinguishable from sepsis and has a 30 % mortality rate [21].

13.3.2.3 Miscellaneous HSV Infections

Individuals with a damaged epithelial barrier, most commonly from atopic dermati-
tis [23], are susceptible to eczema herpeticum. This presents as a vesiculopustular
eruption in areas of underlying skin disease; lesions may erode and become second-
arily infected. Recurrent episodes are generally less severe [24]. In wrestlers, herpes
gladiatorum occurs in areas of close contact, usually the face and neck [25]. Facial
HSV folliculitis presents as folliculocentric vesiculopapules and is confirmed histo-
pathologically by HSV changes limited to the pilosebaceous unit [26] (Fig. 13.3).
13 Herpes Simplex Virus 89

13.4 Work-Up

Classically, detection is performed by viral culture in media that will show the HSV
cytopathic effect, followed by typing with monoclonal antibodies [27, 28]. Viral
swabs may be obtained from vesicles or other involved sites: oral mucosa, cerebro-
spinal fluid, or conjunctiva [4]. Polymerase chain reaction (PCR) has been the gold
standard for diagnosing CNS infections and may become the standard test to diag-
nose HSV infections in other sites [29]. It has shown greater sensitivity than culture
in detecting virus from oral [30] and genital lesions [31]. Serologic assays using
enzyme-linked immunosorbent assay (ELISA) distinguish between HSV1 and
HSV2 infections and detect infection in the absence of symptoms. Utilization of
Western blot is restricted to research labs [4].
While not as sensitive as PCR [32], Tzanck smears allow for the cytopatho-
logic detection of HSV. They are prepared by scraping the periphery of an ulcer,
smearing the material on a glass slide, fixing immediately in cold ethanol, and
then staining with Giemsa, Papanicolaou, or Wright stain [4]. Herpetic giant cells
have multiple nuclei with molding and a ground-glass appearance, and intranu-
clear inclusion bodies [33]. Intranuclear inclusion bodies are not specific and may
be seen in VZV infections as well [4]. Biopsy samples may show intraepidermal
vesicles containing acantholytic keratinocytes with these cytologic changes [34]
(Fig. 13.4).

Fig. 13.4 HSV-infected cells with ground-glass nuclei, marginated peripheral chromatin, and a
multinucleated giant cell with molding
90 R. Gordon and S. Tyring

13.5 Treatment

Most HSV infections are treated with acyclovir, its prodrug valacyclovir, and
famciclovir (prodrug of penciclovir). These nucleoside analogues are activated by
viral thymidine kinase and selectively inhibit viral DNA production by competing
as substrate for DNA polymerase [6, 35].

13.5.1 Oropharyngeal and Orolabial HSV Infections

In moderate to severe primary disease in children, acyclovir 15 mg/kg five times per
day for 7 days has been shown to decrease the duration of lesions from 10 to 4 days
[11, 36]. Appropriate regimens for treatment of primary infections in adults include
acyclovir 400 mg TID for 7–10 days, valacyclovir 1 g BID for 7–10 days, famciclo-
vir 500 mg BID for 7 days, or 250 mg TID for 7–10 days [11, 37].
The ability to change the course of recurrent disease by administering antiviral
therapy at the onset of symptoms has long been recognized [4, 15, 38]. Beginning
treatment in this narrow therapeutic window is possible with patient-initiated epi-
sodic therapy, which reduces healing time to a greater extent than physician-initiated
therapy [39]. First-line therapy in recurrent herpes labialis consists of famciclovir
1,500 mg once a day or valacyclovir 2 g twice daily for 1 day initiated at the first
prodromal symptom [40, 41]. Suppressive treatment is not frequently practiced
[40], but is effective at reducing recurrences [41, 42]. Valacyclovir 500 mg once
daily is the simplest regimen [4].
Topical therapy includes docosanol 10 % cream (Abreva®) which demonstrated
an 18-h reduced median time to healing in treated patients compared to placebo
[43]. Penciclovir 1 % cream (Denavir®) and acyclovir 5 % cream (Zovirax®) both
demonstrate therapeutic efficacy in early- and late-stage lesions [44].

13.5.2 HSV Keratoconjunctivitis

Trifluridine 1 % ophthalmic solution (Viroptic®) is the treatment of choice for pri-

mary and recurrent disease. Dosing is one drop every 2 h while awake (not to exceed
nine drops per day). Once reepithelialization of the ulcer occurs, dosing continues
at one drop every 4 h while awake for 7 days [4].

13.5.3 Mucocutaneous HSV in Immunocompromised

Individuals

Acyclovir is effective in the prevention and treatment of HSV infections [4, 45]. For
adults intravenous dosing is 5 mg/kg over 1 h, every 8 h for 7 days. In children, the
13 Herpes Simplex Virus 91

dose is 250 mg/m2 with the same schedule. For limited disease, topical 5 % acyclovir
ointment can be used every 3 h for 7 days [4]. One recent review found no evidence
that valacyclovir is more efficacious than acyclovir [45]. In patients with HIV, epi-
sodic treatment with famciclovir 500 mg BID for 7 days or valacyclovir 500 mg to
1 g BID for 7 days is appropriate. The same regimen can be used off-label for
chronic suppressive therapy [4].
Antiviral-resistant herpes virus, usually secondary to mutations in viral thymi-
dine kinase, is a special concern in this population as suppressive therapy has
become standard. In such cases, treatment with the pyrophosphate analogue foscar-
net and the nucleotide analogue cidofovir are appropriate [46]. Standard drug-
sensitivity tests take more than 10 days for a result, but newer, faster methods are
being developed [47].

13.5.4 Neonatal HSV

Intravenous acyclovir 20 mg/kg every 8 h for 14 days is recommended for disease

restricted to the skin and mucosa. The same regimen is extended to 21 days for
disseminated and CNS disease. The 14-day regimen is considered appropriate
therapy for asymptomatic infants born to mothers who acquired HSV infection
near term [21].

13.5.5 Miscellaneous HSV Infections

Without controlled studies, it is intuitive that primary and recurrent cutaneous infec-
tions may be treated with valacyclovir or famciclovir at doses used to treat primary
and recurrent herpes genitalis [4]. Prophylactic use of valacyclovir (500 mg or 1 g
once or twice daily) is effective at preventing recurrences of herpes gladiatorum
during the wrestling season [48].

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dents in eastern China. BMC Infect Dis. 2011;11:69.
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LE. Trends in herpes simplex virus type 1 and type 2 seroprevalence in the United States.
JAMA. 2006;296(8):964–73.
10. Smith JS, Robinson NJ. Age-specific prevalence of infection with herpes simplex virus types
2 and 1: a global review. J Infect Dis. 2002;186 Suppl 1:S3–28.
11. Wheeler Jr CE. The herpes simplex problem. J Am Acad Dermatol. 1988;18:163–8.
12. Glezen WP, Fernald GW, Lohr JA. Acute respiratory disease of university students with special
reference to the etiologic role of Herpesvirus hominis. Am J Epidemiol. 1975;101(2):111–21.
13. McMillan JA, Weiner LB, Higgins AM, Lamparella VJ. Pharyngitis associated with herpes
simplex virus in college students. Pediatr Infect Dis J. 1993;12(4):280–4.
14. Young SK, Rowe NH, Buchanan RA. A clinical study for the control of facial mucocutaneous
herpes virus infections. I. Characterization of natural history in a professional school popula-
tion. Oral Surg Oral Med Oral Pathol. 1976;41:498–507.
15. Spruance SL, Overall Jr JC, Kern ER, Krueger GG, Pliam V, Miller W. The natural history of
recurrent herpes simplex labialis: implications for antiviral therapy. N Engl J Med. 1977;
297:69–75.
16. Daniels CA, LeGoff SG. Shedding of infectious virus/antibody complexes from vesicular
lesions of patients with recurrent herpes labialis. Lancet. 1975;2:524–8.
17. Spruance SL. Pathogenesis of herpes simplex labialis: excretion of virus in the oral cavity.
J Clin Microbiol. 1984;19(5):675–9.
18. Buddingh GJ, Schrum DI, Lanier JC, Guidry DJ. Studies of the natural history of herpes sim-
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19. Simmons A. Clinical manifestations and treatment considerations of herpes simplex virus
infection. J Infect Dis. 2002;186 Suppl 1:S71–7.
20. Shiley K, Blumberg E. Herpes viruses in transplant recipients: HSV, VZV, human herpes
viruses, and EBV. Infect Dis Clin North Am. 2010;24:373–93.
21. Corey L, Wald A. Maternal and neonatal herpes simplex virus infections. N Engl J Med.
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22. Brown ZA, Selke S, Zeh J, Kopelman J, Maslow A, Ashley RL, et al. The acquisition of herpes
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23. Mooney MA, Janniger CK, Schwartz RA. Kaposi’s varicelliform eruption. Cutis. 1994;53:
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24. Kramer SC, Thomas CJ, Tyler WB, Elston DM. Kaposi’s varicelliform eruption: a case report
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saliva from 1,000 oral surgery outpatients by the polymerase chain reaction (PCR) and virus
isolation. J Oral Pathol Med. 1994;23:80–4.
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13 Herpes Simplex Virus 93

32. Nahass GT, Goldstein BA, Zhu WY, Serfling U, Penneys NS, Leonardi CL. Comparison of
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Press; 2002.
34. Weedon D. Skin pathology. Edinburgh: Churchill Livingstone; 2002.
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herpes simplex virus-induced DNA polymerases by 9-(2-hydroxyethoxymethyl)guanine
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36. Amir J, Harel L, Smetana Z, Varsano I. Treatment of herpes simplex gingivostomatitis with
aciclovir in children: a randomised double blind placebo controlled study. BMJ. 1997;
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37. Thomas Kreig DRB, Miyachi Y, editors. Therapy of skin diseases: a worldwide perspective on
therapeutic approaches and their molecular basis. London: Springer; 2010.
38. Spruance SL, Schnipper LE, Overall Jr JC, Kern ER, Wester B, Modlin J, et al. Treatment of her-
pes simplex labialis with topical acyclovir in polyethylene glycol. J Infect Dis. 1982;146:85–90.
39. Reichman RC, Badger GJ, Mertz GJ, Corey L, Richman DD, Connor JD, Redfield D, Savoia
MC, Oxman MN, Bryson Y, et al. Treatment of recurrent genital herpes simplex infections
with oral acyclovir. A controlled trial. Treatment of recurrent genital herpes simplex infections
with oral acyclovir. JAMA. 1984;251(16):2103–7.
40. Modi S, Van L, Gewirtzman A, Mendoza N, Bartlett B, Tremaine AM, Tyring S. Single-day
treatment for orolabial and genital herpes: a brief review of pathogenesis and pharmacology.
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41. Rooney JF, Straus S, Mannix ML, Wohlenberg CR, Alling DW, Dumois JA, Notkins AL. Oral
acyclovir to suppress frequently recurrent herpes labialis. A double-blind, placebo-controlled
trial. Ann Intern Med. 1993;118(4):268–72.
42. Baker D, Eisen D. Valacyclovir for prevention of recurrent herpes labialis: 2 double-blind,
placebo-controlled studies. Cutis. 2003;71(3):239–42.
43. Sacks SL, Thisted RA, Jones TM, Barbarash RA, Mikolich DJ, Ruoff GE, Jorizzo JL, Gunnill
LB, Katz DH, Khalil MH, Morrow PR, Yakatan GJ, Pope LE, Berg JE, Docosanol 10% Cream
Study Group. Clinical efficacy of topical docosanol 10% cream for herpes simplex labialis: a
multicenter, randomized, placebo-controlled trial. J Am Acad Dermatol. 2001;45(2):222–30.
44. Spruance SL, Nett R, Marbury T, Wolff R, Johnson J, Spaulding T. Acyclovir cream for treat-
ment of herpes simplex labialis: results of two randomized, double-blind, vehicle-controlled,
multicenter clinical trials. Antimicrob Agents Chemother. 2002;46(7):2238–43.
45. Glenny AM, Fernandez Mauleffinch LM, Pavitt S, Walsh T. Interventions for the prevention
and treatment of herpes simplex virus in patients being treated for cancer. Cochrane Database
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46. Piret J, Boivin G. Resistance of herpes simplex viruses to nucleoside analogues: mechanisms,
prevalence, and management. Antimicrob Agents Chemother. 2011;55:459–72.
47. Shiota T, Lixin W, Takayama-Ito M, Iizuka I, Ogata M, Tsuji M, et al. Expression of herpes
simplex virus type 1 recombinant thymidine kinase and its application to a rapid antiviral
sensitivity assay. Antiviral Res. 2011;91:142–9.
48. Anderson BJ. The effectiveness of valacyclovir in preventing reactivation of herpes gladiatorum
in wrestlers. Clin J Sport Med. 1999;9:86–90.
Chapter 14
Varicella Zoster Virus

Rachel Gordon, Stephen Tyring, Whitney Lapolla, and Rana Mays

14.1 Introduction

Varicella zoster virus causes two clinical syndromes. Chicken pox, or varicella, is a
self-limiting disease of childhood characterized by a highly pruritic rash. Shingles,
or herpes zoster, is a reactivation of the virus typically seen in adults. Heberden first
distinguished these illness as separate entities in 1767 [1], and Osler emphasized the
distinction in his book on clinical medicine [2]. Their relation was suggested by von
Bokay in 1892 when he noted that children developed varicella after coming into
contact with herpes zoster patients [3]. Weller et al. proved a common etiological
agent [3–5], and Garland and Hope-Simpson were the first to propose a reactivation
of latent varicella as the cause of herpes zoster [3]. In 1995, the FDA approved the
first vaccine for the prevention of varicella, significantly changing the epidemiology
of this disease [6].

R. Gordon, M.D. (*)

Department of Dermatology, The University of Texas Medical School at Houston,
6655 Travis Street, Suite 600, Houston, TX 77030, USA
e-mail: [email protected]
S. Tyring, M.D., Ph.D., M.B.A. • W. Lapolla, M.D.
Department of Dermatology, The University of Texas at Houston, Houston, TX, USA
R. Mays, M.D.
Department of Dermatology, Baylor College of Medicine, Houston, TX, USA

J.A. Zeichner (ed.), Acneiform Eruptions in Dermatology: A Differential Diagnosis, 95

DOI 10.1007/978-1-4614-8344-1_14, © Springer Science+Business Media New York 2014
96 R. Gordon et al.

14.2 Background

Varicella virus is transmitted both by direct contact and through airborne spread
when a patient breathes or sneezes. Transmission may occur more easily in temper-
ate environments as compared to tropical climates, though seasonal peaks are seen
in both climates [2]. In the United States, April has the highest incidence of VZV
infection [7]. Before the advent of vaccination, primary varicella was commonplace
and approximately 11,000 hospitalizations per year in the United States resulted
from complications of the illness in otherwise healthy children [2]. Vaccination
decreased the incidence of disease in all age groups with the greatest decline in
children aged 12 months to 4 years [8]. By 2004, mortality associated with varicella
had decreased 82 % from the pre-vaccine era [9].
While the incidence of varicella has decreased by 76–90 % as a result of vaccina-
tion [10, 11], roughly 90–95 % of adults in the United States are seropositive for
varicella [12, 13]. Therefore, most people are susceptible to herpes zoster, the life-
time risk of which has been estimated to be 10–30 % [10, 14]. Age is a major risk
factor for herpes zoster, and its prevalence increases dramatically every 5 years; the
sharpest spike is between 50 and 60 years of age [15]. Other risk factors include
HIV [16], malignancy (especially lymphoproliferative cancers), immunosuppres-
sive therapy, history of organ transplant [17], and possibly trauma [18]. Genetics
may also be a risk factor as 39 % of herpes zoster patients recall a blood relative
with a history of shingles compared to 11 % of control patients without herpes
zoster who report shingles in a blood relative [19]. Recurrent zoster is rare, but may
occur in 1.7–6 % of patients [15, 20].
VZV is a DNA alpha-herpesvirus that adheres to respiratory mucosa with the
glycoproteins on its outer lipid-containing envelope. Viral replication occurs in
regional lymph nodes and the reticuloendothelial system, followed respectively by
viremia at 4–6 and again at 14 days [21]. Involvement of the skin is due to transmis-
sion of the virus from infected CD4+ T cells expressing skin-homing factors to
dermal fibroblasts and keratinocytes [22]. During primary infection, the virus
spreads to the cranial or dorsal root ganglia, possibly by retrograde transport, infects
ganglia tissue, and then enters a latent state [23]. VZV resides in both neurons and
satellite cells, unlike herpes simplex virus, which is restricted to neurons [24].
Primary infection occurs typically in childhood when susceptible individuals
inhale airborne virus or directly contact the rash of primary varicella or herpes zos-
ter. VZV is highly contagious and 61–100 % of contacts develop clinical infection
after exposure. Transmission by airborne respiratory droplets occurs 1–2 days before
the development of lesions. Virus can be transmitted from the rash up to a week after
lesions appear [2]. Once lesions are crusted, they are no longer contagious [21].
Herpes zoster results from VZV reactivation following an unknown trigger, pos-
sibly when cell-mediated immunity decreases below a crucial level [15]. Replication
in affected ganglia and anterograde spread via secondary afferent sensory neurons
are associated with inflammation and necrosis of neuronal and non-neuronal cells
[2, 3]. The neuropathic pain associated with shingles is caused by damage to neu-
rons and altered central nervous system (CNS) signal processing [2, 25].
14 Varicella Zoster Virus 97

14.3 Clinical Presentation

14.3.1 Primary Varicella (Chicken Pox)

Primary varicella infection presents with fever and a rash starting on the head and
extending to the trunk and extremities. Adults and adolescents may have a pro-
drome of fever, malaise, and headache 1–2 days before the rash, while in children
the fever and rash develop at the same time. The rash begins as macules and then
evolves through stages of papules, vesicles, and pustules before forming scabs [2].
Pruritus is universal [26]. A unique characteristic is that new lesions appear as older
ones crust; thus lesions will be at different stages [27]. Lesions may involve muco-
sal surfaces [28], and scarring is unusual [2].
Varicella is usually a self-limiting disease, but complications exist and morbidity
and mortality are significantly higher in adults. In 1990–1994, adults had a risk of
dying from varicella 25 times greater than children 1–4 years old, and most people
who died were previously healthy [29]. One severe complication, varicella pneumo-
nia, develops within 6 days of rash onset [2]. In a study of adult men, the mortality
rate was 10 % or 30 % in immunocompetent and immunocompromised people,
respectively [30]. The most common complication is bacterial superinfection (usu-
ally with staphylococcus or streptococcus), which frequently scars, but rarely leads
to septicemia. CNS complications occur in less than 1 out of 1,000 cases and include
encephalitis, meningoencephalitis, acute cerebellar ataxia, and Guillain-Barre
syndrome [2]. Since introduction of the vaccine, the most common neurological
complication is meningitis [31].
If primary varicella is acquired during pregnancy, there is a 10 % risk of devel-
oping pneumonia [32]. Risk to the fetus is highest in the first trimester with a 2.2 %
chance of embryopathy [33]. Defects include hypoplastic limbs, cortical atrophy,
ocular abnormalities, psychomotor retardation, and low birth weight (37). It is
recommended that susceptible women be vaccinated before pregnancy [32]
(Figs. 14.1 and 14.2).

14.3.2 Herpes Zoster (Shingles)

Herpes zoster is characterized by a prodrome with acute stinging, itching, tingling,

burning, paresthesias, and hyperesthesia in a single dermatome 1–5 days before the
rash [2]. Patients may also have constitutional symptoms of headache, malaise, and
fever and present with dependent lymphadenopathy [15]. Pain in a dermatome pre-
ceding cutaneous manifestations can cause misdiagnoses such as myocardial
infarction, peptic ulcer, and appendicitis [28]. A unilateral rash of erythematous
macules and papules evolves into vesicles, with new vesicles forming up to 7 days.
Vesicles evolve into pustules and ultimately scabs which fall off within 4 weeks.
Most commonly, the midthoracic to upper lumbar (T3-L2) and ophthalmic (V1)
regions are involved [34]. Classically, the rash is unilateral and does not cross the
98 R. Gordon et al.

Fig. 14.1 Primary varicella (chickenpox) in an adult

Fig. 14.2 Primary varicella (chickenpox) in an adult

midline, but bilateral zoster has been reported in both immunocompromised and
immunosuppressed patients [2]. Symptoms of zoster along with its serologic or
virologic evidence presenting without cutaneous signs are called zoster sine herpete;
it rarely occurs.
14 Varicella Zoster Virus 99

Fig. 14.3 Herpes zoster in V1 distribution of the trigeminal nerve with contralateral edema

The neuralgia of herpes zoster usually resolves as the lesion crusts fall off [2].
However, 20 % of all patients will experience the most common complication of
herpes zoster post-herpetic neuralgia (PHN) [15]. Under the age of 40, PHN is
uncommon [2], but more than one third of patients over 60 years [2, 34], and 75 %
of those over 75 years will develop PHN [35]. In addition to age, risk factors include
female sex, immunosuppression, and severity of rash and acute pain [36]. The inten-
sity of PHN typically lessens in 1–6 months, but the duration varies [2] (Fig. 14.3).
Reactivation in the ophthalmic division of the trigeminal nerve (V1) occurs in
10–20 % of zoster cases and is known as herpes zoster ophthalmicus (HZO) [37].
The development of ocular disease occurs in 20–70 % of these cases [2], validating
referral to an ophthalmologist [15]. Ocular complications include scleritis, acute
epithelial keratitis, uveitis, chorioretinitis, oculomotor palsies, optic neuritis, and
panophthalmitis secondary to bacterial infection [2, 38]. Impaired corneal sensation
may result in ulceration. Involvement of the second or third divisions of the trigemi-
nal nerve may result in lesions in the mouth, pharynx, larynx, or ears. In Ramsay-
Hunt syndrome, involvement of the facial or auditory nerves may cause symptoms
of vertigo, loss of taste, tinnitus, and otalgia [2]. Cutaneous and visceral dissemina-
tion is rare in immunocompetent individuals (Figs. 14.4, 14.5, and 14.6).

14.4 Work-Up

Most cases of varicella and herpes zoster can be diagnosed on the basis of clinical
history and exam. However, herpes simplex virus (HSV) can be a very good imita-
tor of VZV, especially when it occurs outside of its typical distribution. Differentiation
100 R. Gordon et al.

Fig. 14.4 Herpes zoster in V2 distribution of the trigeminal nerve

Fig. 14.5 Herpes zoster in V2 distribution of the trigeminal nerve in a child

of VZV from HSV with viral culture is most specific, but it takes 1–2 weeks for
results and the sensitivity is 60–75 % [2, 15]. Serologic testing is limited by possible
preexistence of antibodies to VZV as well as to HSV 1 or 2. In addition, commercial
ELISA tests are usually not sufficiently sensitive to identify the level of immunity
that develops in vaccines [10]. PCR is the most sensitive and specific test [15] and
has been used to detect VZV from skin lesions, peripheral blood, CSF, and other
14 Varicella Zoster Virus 101

Fig. 14.6 Disseminated herpes zoster on the back

tissues from infected patients. Because of their rapid results and high sensitivity,
direct immunofluorescence and PCR are currently the preferred methods of diagno-
sis. Histopathology and cytopathology are not clinically useful in the differentiation
of varicella from herpes zoster or VZV [2].

14.5 Treatment

Primary prevention is preferred over treatment of an outbreak. For the prevention of

varicella in infants and children, two vaccines are available: a monovalent varicella
vaccine and a quadrivalent (measles, mumps, rubella, and varicella – MMRV) vac-
cine. MMRV is associated with a twofold increase in febrile seizures when com-
pared with MMR and varicella given separately. A two-dose schedule is currently
recommended to reduce breakthrough varicella [39]. Some pregnant women have
received the vaccine inadvertently, and there have been no reported varicella syn-
dromes from these instances [2]. Zostavax® was developed to boost VZV-specific
cell-mediated immunity and has been approved for use in adults older than 50 years.
It has greater efficacy in preventing zoster in the age group 60–69, and it prevents
PHN to a greater extent in those over 70 [40].
Treatment for primary varicella often uses antiviral therapy. Oral acyclovir has
been shown to significantly reduce the severity and duration of illness and is approved
for the treatment of primary varicella after the age of 2. The dose is 20 mg/kg QID for
5 days, or 800 mg five times a day for 7 days in children over 40 kg and adults. The
same regimens of valacyclovir and famciclovir used in treating zoster are also com-
monly used to treat primary varicella, though it is not specifically FDA approved [2].
102 R. Gordon et al.

In cases of herpes zoster, treatment within 72 h of vesicle formation with antiviral

medications has been found to reduce the duration of the rash and zoster-related pain
by nearly half. If patients present outside 72 h, they still may benefit from antiviral
therapy [15]. First-line treatment in immunocompetent patients is valacyclovir 1 g
every 8 h or famciclovir 500 mg every 8 h for 7 days [2, 15, 41]. Novel anti-VZV
drugs, including the bicyclic nucleoside analog FV-100, the helicase-primase
inhibitor ASP2151, and valomaciclovir, have recently been evaluated in clinical
trials. To date, it seems these drugs should be as safe as, and possibly more effective
than, valacyclovir [42].
Immunocompromised patients with primary varicella or herpes zoster are at high
risk for disseminated VZV. Hospitalization for treatment with IV acyclovir 10 mg/
kg Q8H for 7 days, or until the infection is controlled, should be considered. After
this point, oral medication may be used to complete a course of 7–10 days [2, 15].
Acyclovir resistance is rare, but should be considered if there is vesicle formation
beyond 7 days. In such cases, IV foscarnet and cidofovir are appropriate [15].
Controlling acute pain and PHN is a challenge in zoster patients; however there
is poor evidence to recommend a specific regimen. Evidence of antiviral treatment
reducing the incidence and duration of PHN is conflicting [41], but early, concomi-
tant use of valacyclovir and gabapentin has been effective at reducing the incidence
of PHN [43]. Management of PHN is palliative, and topical lidocaine 5 % plus
gabapentin or pregabalin is first-line treatment [15]. Pregabalin offers a more rapid
clinical effect than gabapentin [41]. Alternative agents include opioid analgesics,
NSAIDS, tricyclic antidepressants (amitriptyline), and capsaicin cream [15, 41].
Systemic corticosteroids administered within 72 h of rash onset have a clinically
significant benefit on acute pain, but no demonstrable effect on PHN [41].

14.6 Conclusion

In an age of vaccinations, primary prevention of both varicella and zoster is

increasing. While not as rampant an infection as it was several decades ago, correct
diagnosis and treatment is extremely important when cases arrive. An acute onset of
herpes zoster on the face is clinically distinguishable from acne, but such a diagno-
sis may not be clear to patients. Prompt antiviral therapy for these patients can clear
the infection while minimizing any cutaneous or neurological sequelae.

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 Part III
Variants of Acne Vulgaris
Chapter 15
Acne Conglobata

Jonathan S. Weiss and Elijah Wilder

15.1 Introduction

The term acne conglobata is reserved for the most severe form of inflammatory
acne. While uncommon, the condition presents as a highly inflammatory, extensive
nodulocystic eruption. Acne conglobata is differentiated from acne fulminans by
the former’s lack of systemic symptoms, including fever [1]. Severe disfigurement
and scarring are a common result leading to potential psychological impairment,
including anxiety and depression. Acne conglobata comprises one part of the
follicular occlusion triad, along with perifolliculitis capitis abscedens et suffodiens
(dissecting cellulitis of the scalp) and hidradenitis suppurativa [2].

15.2 Background

The primary cause of acne conglobata remains unknown. Distinctly uncommon, it

has a predilection for males over females with an age of onset most often between
18 and 30 years. The condition is seen rarely, if ever, in infants and children [3].
Certainly the pathophysiologic factors of acne vulgaris play a role, including
Propionibacterium acnes (P. acnes), release of inflammatory mediators, and hor-
monal influences. Anabolic/androgenic steroid use, androgen-producing tumors,
and testosterone therapy have all been associated with the development of acne
conglobata [4]. Environmental factors that lead to acne vulgaris have been present

J.S. Weiss, M.D., F.A.A.D. (*)

Department of Dermatology, Emory University, Atlanta, GA 30322, USA
e-mail: [email protected]
E. Wilder, D.O.
Philadelphia College of Osteopathic Medicine, Georgia, Atlanta, GA USA

J.A. Zeichner (ed.), Acneiform Eruptions in Dermatology: A Differential Diagnosis, 107

DOI 10.1007/978-1-4614-8344-1_15, © Springer Science+Business Media New York 2014
108 J.S. Weiss and E. Wilder

in some patients with this most severe form of inflammatory acne, including expo-
sure to halogenated hydrocarbons or ingestion of halogens [3]. Chromosomal
defects have been found in some patients with acne conglobata, namely, an XXY
karyotype in individuals that do not exhibit Klinefelter’s syndrome [5]. PAPA
syndrome, consisting of pyoderma gangrenosum, acne conglobata, and pyogenic
aseptic arthritis, has been mapped to a locus on the long arm of chromosome 15 and
may be associated with mutations CD 2 binding protein 1 (CD2BP1) [6, 7].

15.3 Clinical Presentation

Acne conglobata may arise in preexisting acne vulgaris or as an acute onset

eruption. Areas of involvement include the chest, shoulders, back, buttocks, and
face [8, 9]. Lesion types include extensive nodules, cysts, sinus tracts, along with
papules, pustules, and severe double comedones. As inflammation progresses,
interconnecting/communicating abscesses form and foul-smelling purulent drain-
age ensues. Crusts may form over healing erosions and ulcers. Active lesions are
often tender. Atrophic and hypertrophic scars are common following resolution of
the inflammation (Fig. 15.1). Patients who exhibit acne conglobata along with
sacroiliitis have also been found to have anterior uveitis [10]. Renal amyloidosis
and musculoskeletal syndrome have also been associated [11]. Cutaneous associa-
tions include hidradenitis suppurativa, dissecting cellulitis of the scalp and

Fig. 15.1 Hypertrophic scars on the chest of a young man with acne conglobata (Photo credit:
Joshua A. Zeichner, M.D.)
15 Acne Conglobata 109

pyoderma gangrenosum [12]. The differential diagnosis of acne conglobata

includes acne fulminans, severe acne vulgaris, other acneiform eruptions/drug-
induced acne, and sporotrichosis [3].

15.4 Work-Up

Acne conglobata is generally a clinical diagnosis. A good history and physical to

rule out acne fulminans is indicated. While uncommon in women, the presence of
acne conglobata may indicate the need for an endocrinologic work-up to include
total and free testosterone, DHEAS, prolactin, LH, and FSH [2]. Concerns of abnor-
malities should prompt referral to an endocrinologist or general internist, either of
whom might feel it prudent to perform a glucose tolerance test and/or lipid profile.
Depending on therapeutic considerations, such as isotretinoin, a CBC, liver function
studies, and lipid profile may be indicated, along with serum or urine pregnancy tests
in women. Draining cysts and sinus tracts should be cultured to ensure they are not
superinfected with gram-negative bacteria or coagulase-positive Staphylococcus.

15.5 Treatment

Isotretinoin in a dosage of 0.5–1 mg/kg per day is the treatment of choice for fully
developed acne conglobata [3]. Its effects on remission of nodulocystic lesions are
unparalleled in acne therapeutics. Because isotretinoin can increase inflammation
early in the course of therapy, in the absence of contraindications, the prudent prac-
titioner may also add systemic corticosteroids (prednisone/prednisolone) 40–60 mg
daily with taper over the first 2–4 weeks of therapy. By reducing the overall inflam-
mation and severity of nodules and cysts, corticosteroids may alleviate discomfort
and reduce ultimate scarring. If cultures are positive for pathogenic organisms, anti-
biotics are also indicated, the choice being guided by sensitivity testing. During
isotretinoin therapy, tetracycline antibiotics are relatively contraindicated due to
risks of pseudotumor cerebri. If isotretinoin is contraindicated or refused by the
patient, less optimal therapeutic options include oral antibiotics. Tetracycline, doxy-
cycline, minocycline, clarithromycin, and sulfamethoxazole/trimethoprim would be
good initial choices. Dapsone in dosages of 50–150 mg daily can be used as adjuvant
therapy in patients showing suboptimal responses to either isotretinoin or antibiot-
ics [13]. For patients on antibiotic therapy, topical retinoid treatment may help with
comedonal and microinflammatory lesions.
Procedures that may be indicated to assist with resolution of acne conglobata
include aspiration of cysts/sinuses and injection of intralesional corticosteroids.
Both may be performed in association with either isotretinoin or systemic antibiotic
therapy, either alone or together. Triamcinolone 2.5–3 mg/ml is the authors’ agent
of choice for intralesional injection. Incision and drainage of cysts or excision of
110 J.S. Weiss and E. Wilder

nodules have been previously advocated but should be avoided during isotretinoin
treatment due to poor healing tendencies under the influence of systemic retinoids
[14]. Cryotherapy of nodules has also been advocated by some authors [15]. After
resolution, fractional laser resurfacing, CO2 laser, dermabrasion, and chemical
peeling have been utilized to reduce the appearance of scarring [16].
Psychological implications of acne conglobata cannot be overlooked. Depression,
feelings of shame, and anxiety over one’s appearance all contribute to a decreased
quality of life. Depression can also be a rare but highly publicized side effect of
isotretinoin therapy. At the very least, the treating practitioner should question
patients and/or their family members regarding their psychological state and the
effects that the condition and therapies are having on their lives. Referral to appro-
priate mental health professionals should always be considered.

References

1. Bolognia J, Jorizzo J, Rapini R, editors. Dermatology. 2nd ed. Philadelphia: Mosby-Elsevier;

2008.
2. Habif T. Clinical dermatology. 5th ed. Philadelphia: Mosby-Elsevier; 2010.
3. Schwartz R. Acne conglobata. Medscape Reference. http://emedicine.medscape.com/
article/1072716-overview. Accessed 12 Dec 2011.
4. Melnik B, Jansen T, Grabbe S. Abuse of anabolic-androgenic steroids and bodybuilding acne:
an underestimated health problem. J Dtsch Dermatol Ges. 2007;5(2):110–7.
5. Wollenberg A, Wolff H, Jansen T, Schmid MH, Rocken M, Plewig G. Acne conglobata and
Klinefelter’s syndrome. Br J Dermatol. 1997;136(3):421–3.
6. Ziff M, Maliakkal J. Acne conglobata and arthritis. Ann Intern Med. 1983;98(3):417.
7. Yeon HB, Lindor NM, Seidman JG, Seidman CE. Pyogenic arthritis, pyoderma gangrenosum,
and acne syndrome maps to chromosome 15q. Am J Hum Genet. 2000;66(4):1443–8.
8. Patterson WM, Stibich AS, Dobke M, Schwartz RA. Mutilating facial acne conglobata. Cutis.
2000;66(2):139–40.
9. Shimomura Y, Nomoto S, Yamada S, Ito A, Ito K, Ito M. Chronic glomerulonephritis
remarkably improved after surgery for acne conglobata of the buttocks. Br J Dermatol. 2001;
145(2):363–4.
10. Leybishkis B, Fasseas P, Ryan KF, Roy R. Hidradenitis suppurativa and acne conglobata
associated with spondyloarthropathy. Am J Med Sci. 2001;321(3):195–7.
11. Perez-Villa F, Campistol JM, Ferrando J, Botey A. Renal amyloidosis secondary to acne
conglobata. Int J Dermatol. 1989;28(2):132–3.
12. Velez A, Alcala J, Fernandez-Roldan JC. Pyoderma gangrenosum associated with acne
conglobata. Clin Exp Dermatol. 1995;20(6):496–8.
13. Tan BB, Lear JT, Smith AG. Acne fulminans and erythema nodosum during isotretinoin
therapy responding to dapsone. Clin Exp Dermatol. 1997;22(1):26–7.
14. Weinrauch L, Peled I, Hacham-Zadeh S, Wexler MR. Surgical treatment of severe acne
conglobata. J Dermatol Surg Oncol. 1981;7(6):492–4.
15. Leyden JJ, Mills OH, Kligman AM. Cryoprobe treatment of acne conglobata. Br J Dermatol.
1974;90(3):335–41.
16. Hasegawa T, Matsukura T, Suga Y, et al. Case of acne conglobata successfully treated by
CO(2) laser combined with topical tretinoin therapy. J Dermatol. 2007;34(8):583–5.
Chapter 16
Acne Excoriée

Jillian Wong Millsop and John Y.M. Koo

16.1 Introduction

There are a variety of psychiatric problems that relate to dermatological conditions.

Psychiatric and psychosocial factors are reportedly significant in at least 25–33 %
of dermatology patients [1]. Acne can have a negative impact physically and
psychologically, resulting in social isolation and even more severe secondary
consequences on the psyche. Moreover, acne itself can be aggravated by underlying
psychopathology. Acne excoriée is one such condition, resulting from the relation-
ship between acne and a psychiatric disorder.

16.2 Background

Acne excoriée is a psychodermatological condition that refers to the behavior of

picking acne lesions (Fig. 16.1) [2]. The primary pathophysiologic source is in the
psyche and not in the skin [3]. Acne excoriée is characterized by picking or scratch-
ing at acne or skin with minor epidermal abnormalities [4]. This subtype of excori-
ating behavior in acne patients is also referred to by various other names, including
neurotic excoriation, psychogenic excoriation, pathological or compulsive skin
picking, and dermatillomania.
Though the patient has a skin condition, there is a primary psychiatric distur-
bance that focuses on acne. The disturbance can simply be the habit of picking;
however, there can also be a more serious source for the behavior. Patients with acne

J.W. Millsop, M.D., M.S. (*) • J.Y.M. Koo, M.D.

Department of Dermatology, University of California San Francisco, Psoriasis and Skin
Treatment Center, 515 Spruce Street, San Francisco, CA 94118, USA
e-mail: [email protected]

J.A. Zeichner (ed.), Acneiform Eruptions in Dermatology: A Differential Diagnosis, 111

DOI 10.1007/978-1-4614-8344-1_16, © Springer Science+Business Media New York 2014
112 J.W. Millsop and J.Y.M. Koo

Fig. 16.1 Facial acne

excoriation

Fig. 16.2 Acne excoriation

over the back with scarring

excoriée can have a variety of underlying psychopathology, but depression and

anxiety appear to be the two most common underlying psychiatric conditions [3].
Many patients also report the compulsion for picking the skin associated with poor
self-image [5]. Scar formation as a result of excoriation (Fig. 16.2) has a further
negative psychosocial impact, exacerbating the patient’s social isolation, depres-
sion, and anxiety. This continues in a vicious cycle.
Approximately 2 % of all dermatology clinic patients are found to have some
form of psychogenic excoriation [4]. The age of onset of the condition typically
ranges from 15 to 45 years, and the duration of symptoms has a range of 5 and 21
years [4]. Though onset of this condition generally occurs in adulthood, acne
excoriée is one of the most common presentations of psychodermatology in the
pediatric age group [5]. More females than males are affected with acne excoriée,
while the female to male ratio for all psychogenic excoriations is 8:1 [4, 6]. Case
studies reporting Caucasian patients with acne excoriée are more common than
those of African Americans or other racial groups, but no confirmatory studies of
racial distribution in the general population exist. In addition, the lifetime preva-
lence of the condition is unknown.
16 Acne Excoriée 113

16.3 Clinical Presentation

A patient with acne excoriée most commonly presents as a young, Caucasian female
with excoriated acne and scars. As a result of the self-inflicting nature of the condi-
tion, patients tend to pick at skin regions most easily accessible. Therefore, the
distribution of scars or excoriations over the body can provide a useful clue to clini-
cians. The patient with acne excoriée can have a distribution of lesions resembling
the shape of butterfly wings on the back, referred to as the “butterfly sign” [3]. In the
butterfly sign, there is sparing of the upper, lateral sides of the back bilaterally
resulting from the fact that the patient cannot reach these areas. Similarly, there
tends to be more involvement of the extensor arm as compared to the medial arm
and more involvement of the anterior thigh as compared to the posterior thigh.
Often, patients report a sense of tension immediately prior to picking at their skin
and a sense of relief after the behavior is complete [6].
Patients can present with severe psychosocial impairment. Comorbidities of acne
excoriée include mood and anxiety disorders. Mood disorders are found in 48–68 %
of patients, which include major depression, dysthymia, and bipolar disorders [7, 8].
Anxiety disorders are found in 41–65 % of patients and include generalized anxiety
disorder, agoraphobia, panic disorder, social and more specific phobia, obsessive-
compulsive disorder, and post-traumatic stress disorder [7, 8]. Additionally, if a
patient has a mood or anxiety disorder, he or she frequently has comorbid psychiatric
disorders related to the mood or anxiety disorder, particularly a compulsive-impulsive
spectrum disorder [9], including body dysmorphic disorder, eating disorder, sub-
stance use disorder, or an impulse control disorder, which includes kleptomania,
compulsive buying, and trichotillomania [7, 8, 10]. For very rare patients, acne
excoriée may even present as a manifestation of a delusional disorder [2].
Significant functional impairment is a common occurrence. Patients are often
embarrassed to admit their behavior to a physician. Many report impairment in social
functioning including avoidance of activities that expose their skin to the public, such
as sexual activity, going to the beach, and attending sports and community events [4,
11]. Patients often use cosmetics, bandages, and clothing to hide their excoriations.

16.4 Work-Up

As a result of the psychiatric nature of the condition, there are no laboratory

measures to make the diagnosis of acne excoriée. Instead, diagnosis is based on
clinical presentation.
The approach that the authors recommend includes taking a thorough history,
conducting a detailed physical examination, and assessing the patient for an under-
lying psychiatric disorder that may be related to the condition. In particular, evaluat-
ing the patient for the exact nature of the underlying psychopathology such as
depression, anxiety, and obsessive-compulsive disorder (OCD) is key.
114 J.W. Millsop and J.Y.M. Koo

In order to evaluate the patient for major depression or depression-related

disorder, one should ask the patient about subjective and physiological symptoms
of depression. Subjective symptoms include depressed mood, excessive guilt,
anhedonia, feelings of worthlessness, hopelessness, helplessness, and crying
spells. Physiological symptoms of depression include loss of appetite, hyperpha-
gia, insomnia, hypersomnia, fatigue, memory loss, poor concentration, and psy-
chomotor agitation or retardation [3]. In order to assess the patient for anxiety,
ask the patient about feeling tense or restless, becoming easily fatigued, difficulty
concentrating, irritability, significant muscle tension, and difficulty sleeping [12].
In order to evaluate the patient for OCD, inquire about repugnant thoughts and
compulsive behaviors. OCD patients can be distinguished from delusional
patients by retention of insight that their behavior is destructive. OCD patients
believe their behavior is damaging in contrast to delusional patients who have no
insight and believe that what they are doing to the skin is justified no matter how
destructive the behavior [2].

16.5 Treatment

Due to the nature of the disorder, therapy targeting the psyche can help decrease
destructive behavior involved in acne excoriée. For a patient with depression as the
underlying cause of the acne excoriée, an antidepressant with psychotherapy can be
provided [1, 13, 14]. A patient with anxiety as the underlying source for acne
excoriée can use an anti-anxiolytic medication combined with psychotherapy.
Patients with obsessive thoughts and compulsive urges to damage the skin may find
relief through an anti-OCD medication such as paroxetine (Paxil®) and fluoxetine
(Prozac®) along with behavioral therapy to reduce the obsessions and compulsions
[4, 15]. Behavioral therapy is generally thought to be more efficacious for the treat-
ment of OCD than insight-oriented psychotherapy [16]. For mixed depression-OCD
patients, selective serotonin reuptake inhibitors (SSRIs) are the preferred choice of
therapy because of their dual antidepressant and anti-OCD properties [2]. In gen-
eral, SSRIs are commonly used to treat patients in dermatology with psychiatric
comorbidity, especially major depressive disorder [1, 11]. It is important to under-
stand that pharmacologic therapy alone may not be effective if the patient is not
motivated to control the compulsive urges such as a case in which a teenager is
brought in by his/her parents. If the clinician perceives a “power struggle” between
the teenager and the parent over the issue of excoriation, it is often helpful to see the
teenager alone and first try to build therapeutic rapport with the teenage patient.
In this situation, it is important to establish rapport so that the dermatologist is not
seen as another “authority figure” to rebel against.
Case reports have also documented efficacy of pulsed dye laser irradiation along
with cognitive psychotherapy. Treatment of hypertrophic scars and acne lesions
with laser was first introduced with argon laser [17]. In a case series, 585-nm
flashlamp-pumped pulsed dye with concomitant cognitive psychodynamic therapy
16 Acne Excoriée 115

was used to stop skin picking and scar formation in two OCD patients with acne
excoriée [18]. In the cases, practical behavior modification techniques, including
removal of mirrors in the home and avoidance of situations that would induce stress
or conflict, were helpful.
Finally, biofeedback techniques and hypnosis have also been documented to
improve acne excoriée and other dermatoses with a psychological component [19].
Posthypnotic suggestion has also been used to treat the condition. In two case
reports, patients were instructed to remember the word “scar” when they felt the
urge to pick at the face and to say “scar” to refrain from picking. In both cases, acne
excoriée resolved [19]. Aversion therapy techniques and habit reversal have been
noted in case reports as successful strategies for cognitive-behavioral therapy [20–22].
Aversion therapy occurs when self-destructive behavior is linked to an aversive
stimulus. Habit reversal treatment involves making the patient aware of the scratch-
ing behavior, teaching the patient about the negative social impact of the habit, and
developing competing response of isometric exercise using fist clenching to prevent
scratching.
It is important to recognize the clinical presentation and work-up of acne
excoriée, as the underlying source of the condition can be found in the psychopa-
thology rather than in the skin itself. Working closely with the patient to serve his or
her specific needs and establishing a solid therapeutic alliance can significantly
improve outcomes with all treatments.

Acknowledgements Figures 16.1 and 16.2 are courtesy of Joseph Bikowski, M.D.

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30:934–8.
19. Shenefelt PD. Biofeedback, cognitive-behavioral methods, and hypnosis in dermatology: is it
all in your mind? Dermatol Ther. 2003;16:114–22.
20. Ratliffe R, Stein N. Treatment of neurodermatitis by behavior therapy: a case study. Behav Res
Ther. 1968;6:397–9.
21. Rosenbaum MS, Ayllon T. The behavioral treatment of neurodermatitis through habit reversal.
Behav Res Ther. 1981;19:313–8.
22. Kent A, Drummond LM. Acne excoriée- a case report of treatment using habit reversal. Clin
Exp Dermatol. 1989;14:163–4.
Chapter 17
Acne Fulminans

Alison Schram and Misha Rosenbach

17.1 Introduction

Acne fulminans is a rare, severe form of acne vulgaris associated with the acute
onset of systemic symptoms. This entity was first described in 1959 when Burns
and Colville reported a case of acne conglobata with septicemia in a 16-year-old
boy with an acute febrile illness [1]. In 1971, Kelly and Burns described two patients
with a syndrome they termed “acute febrile ulcerative conglobate acne with polyar-
thralgia.” The features of this syndrome included the sudden onset of severe ulcer-
ative acne conglobata without cyst formation, fever, polyarthralgia, failure to
respond to usual antibiotic therapy, and a favorable response to debridement in com-
bination with steroid therapy [2]. In 1975, Plewig and Kligman named this disease
acne fulminans [3]. This rare entity may occur in isolation or as part of the SAPHO
syndrome (synovitis, acne, pustulosis, hyperostosis, and osteitis).

17.2 Background

The etiology of acne fulminans remains unclear, although infection, exogenous

drug reaction, immunologic abnormalities, and genetic causes have all been pro-
posed. Bacterial cultures reveal no unusual organisms and systemic antibiotics are
ineffective when used as monotherapy, suggesting bacterial infection in isolation is

A. Schram, B.S.
School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
M. Rosenbach, M.D. (*)
Department of Dermatology, University of Pennsylvania, 3600 Spruce Street,
2nd Floor, Maloney Building, Philadelphia, PA 19014, USA
e-mail: [email protected]

J.A. Zeichner (ed.), Acneiform Eruptions in Dermatology: A Differential Diagnosis, 117

DOI 10.1007/978-1-4614-8344-1_17, © Springer Science+Business Media New York 2014
118 A. Schram and M. Rosenbach

unlikely to be the causative mechanism. One theory suggests that acne fulminans is
the manifestation of a severe immunologically mediated hypersensitivity reaction to
Propionibacterium acnes (P. acnes) antigens. Cases of acne fulminans precipitated
by isotretinoin therapy have been described, leading some to postulate that
isotretinoin-induced fragility of the pilosebaceous unit increases the immune
system’s contact with P. acnes antigens [4, 5]. This theory is consistent with data
suggesting that isotretinoin may initially increase superoxide ion and myeloperoxi-
dase release from neutrophils in the early stages of acne treatment [6]. Genetically
determined changes in neutrophil activity may put some individuals at increased
risk for this aberrant immune response. Interestingly, a pair of siblings has been
reported in whom one developed isotretinoin-induced eruptive pyogenic granulo-
mas and the other isotretinoin-induced acne fulminans [5]. There have been reports
of monozygotic twins and HLA-matched siblings who presented at the same age
with similar clinical features, lending support to the role of hereditary factors in the
pathogenesis of this entity [7–9].
Circulating immune complexes have been documented in patients with acne
fulminans, causing some to postulate that the mechanism is that of an autoimmune
disease. Other factors that favor the autoimmune hypothesis include the increase in
γ-globulins and decrease in complement (C3) levels seen in some patients [10–12].
Additionally, patients often respond rapidly to systemic steroids.
Acne fulminans develops almost exclusively in adolescent boys, raising the
question of whether hormonal factors are relevant in the pathogenesis of this condi-
tion. One report describes acne fulminans in three boys treated with testosterone for
excessively tall stature [13]. Additionally, a 21-year-old body builder developed
acne fulminans after taking 4 weeks of testosterone and anabolic steroids; however,
on measurement his serum testosterone levels were found to be within normal limits [14].
Androgenic steroids augment sebum excretion in postpubertal men, leading to an
increase in P. acnes. In some individuals, this may lead to an immunological reac-
tion that manifests as acne fulminans.
The precise etiopathogenesis of this rare entity is uncertain and may involve a
combination of factors including genetic susceptibility (potentially with abnormal
hormone levels or immune response) and a vigorous reaction to bacterial antigens.
Acne fulminans occurs primarily in adolescent, Caucasian males, aged 13–19
years old. While it may occur in women, it is exceptionally rare. The disease usually
begins as mild cystic acne that becomes fulminant after 1–2 years on average,
although de novo presentations with acne fulminans as the initial presentation of
acne have been reported [15].

17.3 Clinical Presentation

Patients usually present with a history of mild to moderate acne that suddenly
erupts into spreading, ulcerative acne lesions with intense inflammation and necro-
sis. The lesions most often occur on the chest, and back, or face, and rarely the
17 Acne Fulminans 119

Fig. 17.1 Severe depressed scarring and post-inflammatory erythema in a patient with resolving
acne fulminans

scalp and thighs [15]. The face is usually less severely affected than the trunk, and
isolated lesions on the face are uncommon [4]. The highly inflammatory lesions
initially resemble acne conglobata; however, they quickly form hemorrhagic
nodules and plaques that undergo suppurative degeneration. The resultant lesions
appear as ragged ulcerations with gelatinous, necrotic debris at their bases [10]
(Figs. 17.1, 17.2, and 17.3). In contrast to acne vulgaris, open and closed comedo-
nes are uncommon. These fulminant eruptions are extremely tender and painful.
A broad spectrum of systemic reactions can be seen in patients with acne fulmi-
nans. The majority of cases are accompanied by systemic signs and symptoms, such
as fever, fatigue, malaise, arthralgias, and myalgias. Other systemic findings of
arthritis, myositis, erythema nodosum, hepatosplenomegaly, and aseptic bone
lesions are less common [11, 15–17]. Musculoskeletal pain is often located in the
chest, shoulder girdle, lower back, and large joints [15]. Patients may experience
painful joint swelling in the iliosacral, iliac, and knee joints, resulting in a bent-over
posture when walking. If present, erythema nodosum usually occurs on the shins
[11, 16, 17]. Additionally, a patient has been reported with concurrent posterior
scleritis and pyoderma gangrenosum-like eruptions on the lower legs [18].

17.4 Work-Up

Laboratory findings in acne fulminans are not consistent and may include leukocy-
tosis, thrombocytosis, anemia, proteinuria, microscopic hematuria, and elevated
erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and liver enzymes.
Occasionally, a leukemoid reaction is present with an increased percentage of
120 A. Schram and M. Rosenbach

Fig. 17.2 Extensive areas of

broad erosion with
granulation and scattered
inflammatory pustules and
comedones

Fig. 17.3 Close up view of

comedones, inflammatory
pustules, and broad areas of
erosion with scattered
resolving lesions leaving
depressed atrophic scars
17 Acne Fulminans 121

myeloblasts, promyelocytes, and myelocytes in the peripheral blood [19]. Serum

proteins may show decreased albumin or increased α-globulin and γ-globulin.
Circulating immune complexes have been reported, as well as low C3 levels
[10–12]. Rheumatoid factor and antinuclear antibody (ANA) tests have been
negative, and there is no known association with HLA-B27 [4]. In contrast to
patients with acne vulgaris, those with acne fulminans have shown depressed
delayed hypersensitivity to various antigens on skin testing [20].
Bone involvement in acne fulminans is rare but well described. Lesions are
initially osteolytic but become sclerotic with periosteal formation of new bone.
Radiographs may demonstrate lytic bone lesions, and bone scans often show
increased uptake of technetium “hot spots” [4, 21].
Histologically, early pustules show an intense dermal infiltrate of granulocytes
with the destruction of follicles and sebaceous glands. The epidermis necroses sec-
ondary to hyalinized thrombotic vessels and profuses bleeding into the skin. The
hemorrhagic skin becomes surrounded by a mixed granulocytic and lymphocytic
infiltrate [10]. Some follicles distend with accumulating keratinized cells but do not
form comedones. Late nodules show a regenerating acanthotic epidermis with a
dense dermal mixed cellular infiltrate, vascular hyperplasia, and numerous stellate
fibroblastic cells [4]. Direct immunofluorescence testing can rarely reveal a linear
immunoglobulin M and fibrin band at the dermo-epidermal junction, in addition to
fibrin deposition around the sebaceous glands [10].
Bone lesions in acne fulminans have historically been biopsied to rule out malig-
nancy or infection. These specimens show benign, reactive changes. The inflamma-
tory infiltrate and granulation tissue observed can mimic osteomyelitis; however,
there is no evidence of microorganisms [22, 23].
Bacterial cultures from blood, joint fluid, skin, and bone lesions are usually nega-
tive. In addition to the usual organisms cultured from skin, Staphylococcus aureus
can occasionally be seen. Antistaphylococcal and antistreptococcal antibody levels
are usually normal [10]. P. acnes has been isolated from bone lesions of patients
with acne fulminans, although the clinical significance of this finding is unclear, and
contamination from the skin puncture site was not ruled out [22].

17.5 Treatment

The mainstay of treatment in patients with acne fulminans includes local wound
care, supportive systemic care, and systemic corticosteroids. Patients often feel sick
and require bed rest or hospitalization. The first step in management is gentle surgi-
cal debridement and frequent application of warm compresses with 20–40 % urea
solutions to prevent the accumulation of crusts. Urea is also beneficial for its deodor-
ant and antiseptic properties. Other topical treatments, including local antimicrobial
agents, may be used as well. High-potency topical corticosteroids can effectively
decrease inflammation when applied to the ulcerated nodules twice daily for 7–10
days [10]. Pulsed laser has also been reported to improve local control [24].
122 A. Schram and M. Rosenbach

Systemic corticosteroids (0.5–1.0 mg/kg prednisolone) are indicated in patients

with acne fulminans to manage the skin lesions, reduce fever, and improve muscu-
loskeletal symptoms. Oral therapy should be gradually reduced to avoid the adverse
effects of prolonged treatment with systemic steroids; however, relapse can occur
2–8 weeks after the acute attack when corticosteroid therapy is decreased [15]. The
required duration of treatment seems to be 2–5 months to avoid relapse. Patients
should be counseled about the anticipated long course of steroids and monitored
closely for steroid-related side effects.
The use of isotretinoin in combination with oral corticosteroids is controversial.
Systemic isotretinoin has been used in the successful treatment of acne fulminans;
however, it has also been reported to precipitate the condition [4, 5, 15]. Isotretinoin
should be started 2–4 weeks after corticosteroid therapy. It is recommended that
physicians initiate isotretinoin at low doses (e.g., 0.1 mg/kg/day) initially to avoid
exacerbation of lesions in patients with crusting. The final recommended dosage is
0.5–2.0 mg/kg/day, treated to a minimum total dose of 120 mg/kg. Occasionally, a
repeat course of isotretinoin may be required. Although the utility of dapsone is
unclear in acne fulminans, it may be used if isotretinoin is contraindicated [4].
Additional treatment may be useful in controlling the symptoms of acne
fulminans. The myalgia, arthritis, and fever often respond to nonsteroidal anti-
inflammatory drugs. Antibiotic therapy is indicated if there are signs of secondary
bacterial infection. Other therapies have been tried with variable results, including
intra-articular corticosteroids, methotrexate, sulfasalazine, cyclosporine A, bisphos-
phonates, and infliximab [4]. Regular measurement of ESR and white blood cell
count provide an objective measure of treatment response and may correlate with
the clinical course [10].
The long-term prognosis for patients with acne fulminans is good. Although relapse
can occur when steroid treatment is reduced quickly, the risk of relapse is small after
1 year. The cutaneous lesions may result in significant scarring. Residual bone changes,
including sclerosis and hyperostosis, remain visible radiographically [4].

References

1. Burns RE, Colville JM. Acne conglobata with septicemia. Arch Dermatol. 1959;79:361–3.
2. Kelly AP, Burns RE. Acute febrile ulcerative conglobate acne with polyarthralgia. Arch
Dermatol. 1971;104:182–7.
3. Plewig G, Kligman AM. Acne: morphogenesis and treatment. Berlin: Springer; 1975. p. 196.
4. Zaba R, Schwartz RA, Jarmuda S, Czarnecka-Operacz M, Silny W. Acne fulminans: explosive
systemic form of acne. J Eur Acad Dermatol Venereol. 2011;25(5):501–7.
5. Blanc D, Zultak M, Wendling D, et al. Eruptive pyogenic granulomas and acne fulminans in
two siblings treated with isotretinoin: a possible common pathogenesis. Dermatologica.
1988;177(1):16–8.
6. Perkins W, Crocket KV, Hodgins MB, Mackie RM, Lackie JM. The effect of treatment with
13-cis-retinoic acid on the metabolic burst of peripheral blood neutrophils from patients with
acne. Br J Dermatol. 1991;124:429–32.
7. Darley CR, Currey HL, Baker H. Acne fulminans with arthritis in identical twins treated with
isotretinoin. J R Soc Med. 1984;77:328–30.
17 Acne Fulminans 123

8. Gonzales T, Gantes M, Bustabad S, et al. Acne fulminans associated with arthritis in

monozygotic twins. J Rheumatol. 1985;12:389–90.
9. Wong SS, Pritchard MH, Holt PJA. Familial acne fulminans. Clin Exp Dermatol. 1992;
17:351–3.
10. Jansen T, Plewig G. Acne fulminans: review. Int J Dermatol. 1998;37:254–7.
11. Kellett J, Beck MH, Chalmers RJG. Erythema nodosum and circulating immune complexes in
acne fulminans after treatment with isotretinoin. Br Med J. 1985;290:820.
12. Woolfson H. Acne fulminans with circulating immune complexes and leukaemoid reaction
treated with steroids and azathioprine. Clin Exp Dermatol. 1986;12:463–6.
13. Traupe H, von Muhlendahl KE, Bramswig J, et al. Acne of the fulminans type following tes-
tosterone therapy in three excessively tall boys. Arch Dermatol. 1988;124:414–7.
14. Heydenreich G. Testosterone and anabolic steroids and acne fulminans. Arch Dermatol.
1989;125:571–2.
15. Karvonen SL. Acne fulminans: report of clinical findings and treatment of twenty-four
patients. J Am Acad Dermatol. 1993;28:572–9.
16. Reizis Z, Trattner A, Hodak E, et al. Acne fulminans with hepatosplenomegaly and erythema
nodosum migrans. J Am Acad Dermatol. 1991;24:886–8.
17. Williamson DM, Cunliffe WJ, Gatecliff M, Scott FG. Acute ulcerate acne conglobata (acne
fulminans) with erythema nodosum. Clin Exp Dermatol. 1977;2:351–4.
18. Kurokawa S, Tokura Y, Nham NX, et al. Acne fulminans coexisting with pyoderma
gangrenosum-like eruptions and posterior scleritis. J Dermatol. 1996;23:37–41.
19. Strom S, Thyresson N, Bostrom H. Acute febrile ulcerative conglobate acne with leukemoid
reaction. Acta Derm Venereol. 1973;53:306–12.
20. Palatsi R. Delayed hypersensitivity and febrile acne conglobata. Acta Derm Venereol.
1977;57:51–3.
21. Jemec GBE, Rasmussen I. Bone lesions of acne fulminans: case report and review of the
literature. J Am Acad Dermatol. 1989;20:353–7.
22. Nault P, Lassonde M. Acne fulminans with osteolytic lesions. Arch Dermatol. 1985;121:662–4.
23. Hunter LY, Hensinger RN. Destructive arthritis associated with acne fulminans: a case report.
Ann Rheum Dis. 1980;39:403–5.
24. Friedlander SF. Effective treatment of acne fulminans-associated granulation tissue with the
pulsed dye laser. Pediatr Dermatol. 1998;15:396–8.
Chapter 18
Acne Mechanica

Zoe Diana Draelos

18.1 Introduction

Acne mechanica is a term used to describe the presence of inflammatory papules

and pustules caused by friction from repetitive rubbing, stretching, or squeezing of
the skin accompanied by heat, pressure, and occlusion.
It can be observed under many different circumstances, which will be discussed
in this chapter [1]. Most of the references to acne mechanica in the modern literature
come from sports-associated dermatoses [2], but Albert Kligman was present at an
NIOSH workshop held in Cincinnati, Ohio, on April 6–8, 1983, that discussed the
chronic effects of repeated mechanical trauma to the skin where acne mechanica
was discussed in detail [3]. He likened acne mechanica to a category of contact
dermatitis only provoked by physical stressors. The goal of the workshop was to
define the various categories of superficial skin injuries resulting from repetitive
trauma, which led to a clearer understanding of acne mechanica.

18.2 Background

An understanding of acne mechanica demands a discussion of the surface skin

architecture. While many might view the skin as a smooth even surface, it is actually
a series of mountains and valleys that give rise to skin dermatoglyphics. The moun-
tains are created by the pilosebaceous apparatus sitting higher than the surrounding
skin creating the intervening valleys. When the skin is rubbed, the follicular ostia

Z.D. Draelos, M.D. (*)

Department of Dermatology, Duke University School of Medicine,
2444 North Main Street, High Point, NC 27262, USA
e-mail: [email protected]

J.A. Zeichner (ed.), Acneiform Eruptions in Dermatology: A Differential Diagnosis, 125

DOI 10.1007/978-1-4614-8344-1_18, © Springer Science+Business Media New York 2014
126 Z.D. Draelos

are preferentially mechanically damaged. This chronic irritation is thought to

account for acne mechanica; however, several addition factors can worsen the
disease. If the skin surface is covered in sweat, the moisture decreases the mechani-
cal resistance of the skin to shear forces and worsens the inflammation. Since the
skin is more hydrated when heat is applied, this enhances the susceptibility of the
skin to shear forces from rubbing. Finally, if occlusion is present, this hyperhydrates
the skin causing further problems in resisting the shear force. Thus, acne mechanica
is due to a combination of follicular ostia prominence and skin hydration.
Mills and Kligman developed a model for studying acne mechanica where they
sealed acne-bearing skin with adhesive tape for 2 weeks and documented new
inflammatory lesions. They believed that the increase in acne resulted from the rup-
ture of microcomedones that were not visible to the human eye [4].

18.3 Clinical Presentation

Acne mechanica can occur in several settings. The most commonly recognized
cause of acne mechanica is use of a chinstrap in football [5]. The sweat that accu-
mulates beneath the plastic chin cup macerates the skin that is then subject to con-
tinuous rubbing from speaking, mastication, and facial movement. However, acne
mechanica can be seen on all body areas where football pads are worn, including the
upper back and shoulders [6]. The fact that the pads contacting the skin are caus-
ative has been proven by the initiation of acne mechanica with football activities
and its spontaneous resolution at the end of the season. Acne mechanica needs to be
separated from hormonally induced acne; however, the presentation is similar and
both may occur simultaneously. It should be recognized that acne mechanica can
occur in the absence of traditional acne.
Another common setting for acne mechanica is under the chinstrap in persons
who wear a helmet for equestrian activities [7]. Any helmet or hat that has a chin-
strap could potentially cause problems. Acne mechanica is even seen under the chin
in violin players from rubbing on the chin rest, a condition known as fiddler’s neck
[8]. A variety of acne mechanica has been reported from the repeated trauma of a
comb and brush on the face [9]. Other causes include rubbing from a backpack or
riding in a vehicle for prolonged periods.

18.4 Work-Up

The diagnosis of acne mechanica is primarily made based on clinical appearance

and distribution. Moreover, a detailed personal history from the patient should be
taken, with particular attention paid to lifestyle factors such as use of products that
occlude or mechanically apply trauma to the skin.
18 Acne Mechanica 127

18.5 Treatment

The primary treatment for acne mechanica is discontinuation of the trauma to

the skin, which may result in spontaneous resolution. However, situations may
arise where additional treatment is necessary. Acne mechanica is treated like
acne vulgaris with topical and oral therapies. Topical agents useful in treatment
include benzoyl peroxide alone or in combination with clindamycin. Benzoyl
peroxide possesses antibacterial, anti-inflammatory, and comedolytic effects, all
of which may be valuable in the treatment of acne mechanica [10]. When ben-
zoyl peroxide touches the skin, it breaks down into benzoic acid and oxygen.
Benzoyl peroxide acts as an anti-inflammatory agent by reducing oxygen radi-
cals. Further, its ability to reduce the Propionibacterium acnes (P. acnes) popu-
lation also reduces inflammation due to lessened bacterial induced monocytes
producing tumor necrosis factor-alpha, interleukin-1beta, and interleukin-8 [11].
This anti-inflammatory effect is perceived by the patient as reduced redness and
pain. Combining benzoyl peroxide with clindamycin also increases antibacterial
efficacy. Finally, topical retinoids, such as adapalene, tretinoin, or tazarotene,
may be helpful as both anti-inflammatories and comedolytics [12].
Oral antibiotics are appropriate in patients with more painful and inflammatory
acne mechanica. The same antibiotics used in traditional acne treatment may be
employed here. These include oral tetracycline, doxycycline, minocycline, trime-
thoprim/sulfamethoxazole, and ciprofloxacin [13]. One treatment regimen is to use
the oral antibiotic along with a topical benzoyl peroxide/clindamycin preparation
until control is achieved and then discontinue the oral medication while continuing
the topical treatment until the activity causing the acne mechanica has been
discontinued. Perhaps the most important aspect of acne mechanica treatment is the
identification of the source of friction, heat, pressure, and occlusion that is inciting
the disease. The patient will then be reassured of the diagnosis and can vary activi-
ties to assist in prevention.
A variety of ancillary over-the-counter preparations can also be used for the
treatment of acne mechanica. These include triclosan-containing antibacterial soaps
and salicylic acid containing cleansers. Removing bacteria and sweat from the skin
afflicted with acne mechanica is important. Immediate removal of the sweat-soaked
clothing from the body and elimination of the acne causing athletic device as soon
as possible may be helpful. Special clothing made of a non-water retaining fabrics,
such as polyester, should be selected over cotton to avoid keeping sweat in contact
with the skin.
In summary, acne mechanica is a term used to describe the presence of inflam-
matory papules and pustules caused by friction from repetitive rubbing, stretching,
or squeezing of the skin accompanied by heat, pressure, and occlusion. Eliminating
the inciting factors is the key to treatment and preventions.
128 Z.D. Draelos

References

1. Basler RSW. Skin injuries in sports medicine. J Am Acad Dermatol. 1989;21(6):1257–62.

2. Levine N. Dermatologic aspects of sports medicine. J Am Acad Dermatol. 1980;3(4):
415–24.
3. Kligman AM. The chronic effects of repeated mechanical trauma to the skin. Am J Ind Med.
1985;8:257–64.
4. Mills OH, Kligman A. Acne mechanica. Arch Dermatol. 1975;111(4):481–3.
5. Farber GA, Burks JW, Hegre AM, Brown GR. Football acne—an acneiform eruption. Cutis.
1977;20(3):356–60.
6. Kirkland R, Adams BB. Dermatologic problems in the football player. Int J Dermatol. 2006;
4(8):927–32.
7. Freiman A, Barakin B, Elpern DJ. Sports dermatology part 1: common dermatoses. Can Med
Assoc J. 2004;7(8):851–3.
8. Peachey RDG, Matthews CAN. Fiddler’s neck. Br J Dermatol. 2006;98(6):669–74.
9. Petrozzi W. Comb and brush acne. Cutis. 1980;26(6):568–71.
10. Tanghetti E. The evolution of benzoyl peroxide therapy. Cutis. 2008;82(5):5–11.
11. Kim J, Ochoa M, Krutzik S, Takeuchi O, Uematsu S, Legaspi A, et al. Activation of toll-like
receptor 2 in acne triggers inflammatory cytokine responses. J Immunol. 2002;169:1535–41.
12. Pharis DB, Teller C, Wolf JE. Cutaneous manifestations of sports participation. J Am Acad
Dermatol. 1997;36(3):448–59.
13. Shalita A. Clinical aspects of acne. Dermatology. 1998;196(1):93–4.
Chapter 19
Cushing’s Syndrome

Nick Zilieris, Cheryl J. Gustafson, and Steven R. Feldman

19.1 Introduction

Cushing’s syndrome is a constellation of signs and symptoms due to chronic gluco-

corticoid excess. Glucocorticoids have far-reaching effects that are not only seen
within the body but also seen externally affecting the integumentary system. This
chapter will review the pathophysiology, epidemiology, clinical cutaneous manifes-
tations, diagnosis, and treatment of Cushing’s syndrome.
Harvey Williams Cushing, M.D., an American Neurosurgeon, first described
Cushing’s syndrome in 1912 as an endocrinological syndrome caused by a mal-
function of the pituitary gland, which he termed “polyglandular syndrome” [1].
Today, Cushing’s syndrome is defined as a constellation of signs and symptoms due
to chronic glucocorticoid excess. The etiology of hypercortisolism can be classified
as exogenous or endogenous. Exogenous hypercortisolism typically results from
the administration of corticosteroids prescribed by physicians to manage chronic
diseases, whereas endogenous hypercortisolism results from an imbalance in the
body’s regulation of serum cortisol levels. Endogenous forms of Cushing’s syn-
drome can be further subcategorized into adrenocorticotropin (ACTH)-dependent
and adrenocorticotropin (ACTH)-independent conditions. ACTH-dependent

N. Zilieris, D.O.
Department of Internal Medicine, Baptist Hospital, Miami Beach, FL, USA
C.J. Gustafson, M.D. (*)
Department of Dermatology, Wake Forest University Baptist Medical Center,
4618 Country Club Road, Winston-Salem, NC 27104, USA
e-mail: [email protected]
S.R. Feldman, M.D., Ph.D.
Department of Dermatology, Pathology, and Public Health Sciences, Wake Forest University
Baptist Medical Center, Winston-Salem, NC, USA

J.A. Zeichner (ed.), Acneiform Eruptions in Dermatology: A Differential Diagnosis, 129

DOI 10.1007/978-1-4614-8344-1_19, © Springer Science+Business Media New York 2014
130 N. Zilieris et al.

conditions are characterized by high or inappropriately normal ACTH levels, which

result in excess production and secretion of cortisol from the adrenal glands. There
are three main types of ACTH-dependent conditions: (1) ACTH-secreting pituitary
adenomas (i.e., Cushing’s disease), (2) ectopic ACTH-secreting tumors (typically
bronchogenic or neuroendocrine in origin), and (3) ectopic corticotropin-releasing
hormone (CRH). ACTH-independent conditions are characterized by excessive
cortisol secretion by the adrenal glands despite a suppressed ACTH level. These
conditions include (1) adrenal adenomas, (2) bilateral adrenal hyperplasia, and (3)
adrenal carcinoma [2].

19.2 Background

Cushing’s syndrome follows a complex pathway within the pituitary–hypotha-

lamic–adrenal axis. The paraventricular nucleus (PVN) of the hypothalamus
releases CRH, which stimulates the release of ACTH from the pituitary gland.
ACTH travels hematogenously to the adrenal gland to stimulate the release of cor-
tisol and other steroids from the zona fasciculata and reticularis of the adrenal cor-
tex. Elevated levels of cortisol exert negative feedback on the pituitary gland,
thereby decreasing the release of ACTH [3].
Cushing’s disease refers specifically to hypercortisolism secondary to excess
production of ACTH from a corticotrophic pituitary adenoma. The tumor renders
the pituitary gland unresponsive to the negative feedback effect of elevated cortisol
levels. As a result, Cushing’s disease is characterized by elevated levels of ACTH
and cortisol.
In adrenal sources of Cushing’s syndrome, excess cortisol is produced by
adrenal gland tumors, hyperplastic adrenal glands, or adrenal glands with nodular
adrenal hyperplasia. As a result, the serum ACTH level is low and serum cortisol
is high. Additionally, ectopic tumors, which are located outside the normal
pituitary-adrenal system, can produce ACTH, thereby stimulating excess secretion
of cortisol from the adrenal glands. This results in elevated serum levels of ACTH
and cortisol.
In all forms of Cushing’s syndrome, the effects of excess glucocorticoids may be
mixed with the effects of excess mineralocorticoids and androgenic steroids. These
effects are seen in many body systems because cortisol is part of the pituitary–
hypothalamic–adrenal axis, which affects the higher functioning central nervous
system, as well as lower functioning organ systems. Hence, cutaneous manifesta-
tions of Cushing’s syndrome result from the effects of excess cortisol on the
epidermis and dermis. More specifically, hypercortisolism inhibits epidermal cell
division and impairs the synthesis of collagen and mucopolysaccharides [4]. As a
result, the epidermis becomes thin, shiny, and even scaly.
Cushing’s syndrome affects 1–2 individuals per 100,000 each year [3]. Women
are affected four times more than men. The disease occurs primarily between the
ages 25 and 40, with peak onset during the second and third decades. No ethnic
19 Cushing’s Syndrome 131

disparities have been identified [5, 6]. Cushing syndrome occurs in 30 % of people
with Carney complex, a familial form of micronodular hyperplasia of the adrenal
gland that results in an ACTH-independent form of Cushing’s syndrome [7].
Iatrogenic Cushing’s syndrome, due to the exogenous administration of
glucocorticoids, accounts for the majority of Cushing’s syndrome cases. However,
traditional estimates regarding the prevalence of different forms of Cushing’s
syndrome do not include iatrogenic cases. This is largely due to the lack of a uni-
formly accepted definition and/or gold standard diagnostic tests. Despite this fact,
exogenous hypercortisolism accounts for more causes of Cushing’s syndrome than
all causes of endogenous hypercortisolism combined. Although there is no widely
accepted definition, most clinicians agree that exogenous Cushing’s syndrome is
present when symptoms of Cushing’s syndrome develop in individuals treated with
supraphysiological doses of glucocorticoids [8].
Endogenous Cushing’s syndrome results from excessive production of cortisol.
Overproduction of cortisol may occur in three ways: (1) Excess production of
ACTH from the pituitary (Cushing’s disease) accounts for 70 % of these cases.
Although pituitary microadenomas are one of the main sources of excess ACTH
from the pituitary, 40–60 % of patients with Cushing’s disease have no identified
tumor [8]. (2) Ectopic corticotropin-producing tumors (typically bronchogenic or
pancreatic cancer) are the underlying etiology in 15 % of Cushing’s syndrome
patients. However, in infants, adrenal carcinoma is the leading cause of Cushing’s
syndrome [9]. (3) Primary adrenal sources of excess cortisol production (e.g., adre-
nal hyperplasia, adrenal adenomas) account for the remaining 15 % of endogenous
Cushing’s syndrome cases.

19.3 Clinical Presentation

Cushing’s syndrome, like many endocrine disorders, induces changes in multiple

body systems, the extent to which depends on the adrenocortical hormone involved,
as well as the duration of exposure [5]. Glucocorticoid excess induces striking
changes in body habitus. Central obesity is the most common feature, occurring in
97 % of patients. Fat deposition occurs in the face (“moon” facies), retro-orbital
fossa, neck, supraclavicular fossa (“supraclavicular fat pads”), trunk, upper back
(“buffalo” hump), and abdomen with loss of subcutaneous fat in the extremities
[10]. The exact cause of adipose deposition in Cushing’s syndrome remains
unknown; however, it is theorized to be secondary to insulin resistance [9]. Central
obesity is accompanied by wasting of the extremities. Additionally, increased pro-
tein catabolism occurs in peripheral supportive tissue resulting in muscle weakness,
fatigability, and osteoporosis.
A variety of cutaneous manifestations are seen in Cushing’s syndrome.
Violaceous, atrophic striae on the abdomen and thighs is a classic finding. Striae and
easy bruisability result from rupture of weakened collagen fibers in the dermis [9].
Thinning of the epidermis is another common skin manifestation. It is often
132 N. Zilieris et al.

Fig. 19.1 The back of a man

diagnosed with Cushing’s
disease. The patient presented
with acne on his back. On
close examination, he showed
signs of a small prominence
of fat on the upper back, the
so-called buffalo hump. After
his primary care doctor
discovered he suffered from
osteoporosis, a work-up
revealed an ACTH-secreting
pituitary adenoma leading to
hypercortisolism. The tumor
was subsequently surgically
removed (Photo credit:
Joshua A. Zeichner, M.D.)

described as a fine “cigarette paper” wrinkling and primarily involves the dorsal
surfaces of the hands and elbows [11]. In severe cases, the epidermis can peel off
after being covered with adhesive tape, a finding referred to as the Liddle sign [12].
Likewise, the dermis becomes thin and loose in areas of reduced subcutaneous fat
[13]. Overall, the skin becomes friable and easily damageable with markedly
impaired wound healing. Subsequently, other complications may result, such as
infections (e.g., dermatophyte, bacterial, fungal, and opportunistic) and ulcerations
[14]. Another common cutaneous manifestation of Cushing’s syndrome is plethora
of the face, neck, and chest, which is not accompanied by an increase in red blood
cell concentration.
Acneiform eruptions occur with Cushing’s syndrome because sebaceous gland
activity and sebum production are intricately involved acne formation and are hor-
monally regulated (Fig. 19.1). The hormones specifically related to Cushing’s syn-
drome that affect the sebaceous glands include androgens, CRH, ACTH, and
glucocorticoids [15]. Androgen receptors have been localized to the basal layer of
the sebaceous gland and the outer root sheath of the hair follicle. When activated,
these receptors stimulate the sebaceous gland to secrete sebum, which can poten-
tially clog the follicle and result in pimples [15]. When glucocorticoid excess is
accompanied by androgen excess, acne and oily skin can develop. In Cushing’s
syndrome, acneiform eruptions are typically monomorphic, perifollicular papules
produced by hyperkeratosis of follicular openings typically on the face, chest, and
back. Mild pustule formation can be seen; however, deep cystic lesions and comedo
19 Cushing’s Syndrome 133

formation, which are features characteristic of adolescent acne, are uncommon in

Cushing’s syndrome [15]. Additionally, the pimples of steroid acne are usually
more uniform in size unlike acne vulgaris [16].
CRH’s main effect on the skin is at the level of the sebaceous gland where it
inhibits sebaceous proliferation, promotes sebaceous differentiation, and induces
sebaceous gland lipogenesis by enhancing androgen bioavailability. Clinical and
experiment evidence implicates the involvement of CRH in the development of acne
[17]. Other skins changes include cutis xerosis, purpura, ecchymoses, livedo
reticularis, and poikiloderma-like changes [9]. Hyperpigmentation may be seen
secondary to the production of ACTH and related peptides, such as melanocyte-
stimulating hormone (MSH). MSH is derived from the same prohormone,
pro-opiomelanocortin, as is ACTH [14].
In addition to the classical cutaneous manifestations, Cushing’s syndrome is
characterized by a diversity of systemic manifestations. In regard to the endocrine
system, hypercortisolism induces increased hepatic gluconeogenesis and insulin
resistance, which can subsequently lead to impaired glucose tolerance [18].
Ultimately, less than 20 % of patients develop diabetes mellitus type II. In associa-
tion with impaired glucose tolerance, acanthosis nigricans can be seen in patients
with Cushing’s syndrome [19]. Hypertension is a common cardiovascular manifes-
tation of Cushing’s syndrome and occurs in 82 % of patients due to sodium and
water retention. Interestingly, in people diagnosed with primary hypertension,
0.5–1 % have Cushing’s syndrome [9]. Other common systemic manifestations of
Cushing’s syndrome include proximal myopathy, oligomenorrhea/amenorrhea,
personality changes, osteoporosis, and edema [9].

19.4 Work-Up

The overnight dexamethasone suppression test is the initial screening test of choice
as it has a sensitivity of 97 % and a specificity of 80 %, if the cortisol level is >3 μg/
dl [3]. A 24-h urine free cortisol level can be used as an alternative screening test. A
level >140 nmol is suggestive of Cushing’s syndrome with 90–95 % specificity and
sensitivity [18]. Definitive diagnosis is confirmed with a standard low-dose dexa-
methasone suppression test done over 48 h. The test is positive when urinary corti-
sol stays >25 nmol/L or plasma cortisol remains >140 nmol/L.
Determining the etiology of Cushing’s syndrome is complicated secondary to the
fact that tests lack specificity. Additionally, tumors producing this syndrome are
prone to spontaneous and often dramatic changes in hormone secretion (periodic
hormonogenesis) [3]. Hence, a combination of laboratory and imaging tests is often
needed to determine the specific cause.
Plasma ACTH levels can be useful in determining the specific etiology of
Cushing’s syndrome, particularly in regard to differentiating ACTH-dependent from
ACTH-independent causes. Evaluating the response of cortisol output upon admin-
istration of high-dose dexamethasone can help distinguish ACTH-secreting pituitary
134 N. Zilieris et al.

microadenomas or hypothalamic–pituitary dysfunction from other etiologies of

Cushing’s syndrome. The metyrapone and CRH infusion tests function under the
rationale that the hypothalamic–pituitary axis will be suppressed by steroid hyperse-
cretion by an adrenal tumor or ectopic production of ACTH, thereby resulting in
inhibition of ACTH release by the pituitary. As a result, patients with pituitary–
hypothalamic dysfunction and/or a microadenoma have an increase in steroid or
ACTH secretion in response to metyrapone or CRH administration.
The diagnosis of adrenal carcinoma is suggested by a palpable abdominal mass
and by markedly elevated baseline values of both urine 17-ketosteroids and plasma
DHEA sulfate. Plasma and urine cortisol levels are variably elevated. Adrenal carci-
noma is usually resistant to both ACTH stimulation and dexamethasone suppression.
Imaging modalities include brain MRI to evaluate the pituitary, high-resolution chest
CT to evaluate ectopic ACTH, and abdominal CT to evaluate the adrenals [9].

19.5 Treatment

Treatment is directed at correcting the source of the hypercortisolism, thus restoring

hormone balance. The gold standard for Cushing’s disease is transsphenoidal
surgery with an initial cure rate of 70–80 % [9]. For adrenal tumors, the treatment is
typically surgical resection of the tumor. Once the tumor causing the hypercorti-
solism is removed, the HPA axis typically remains suppressed. Therefore, hydro-
cortisone replacement therapy is needed postsurgery until there is physiologic
adaptation to normal cortisol levels, which may require many months or even years
of therapy [9].
In some cases adjuvant therapy, such as radiation therapy, chemotherapy, and/or
drug therapy, is required to suppress cortisol synthesis [7]. Oral agents with estab-
lished efficacy in regard to inhibition of steroid synthesis in Cushing’s syndrome
include metyrapone, ketoconazole, and mitotane.

References

1. Deacon SP. Pituitary-dependent Cushing’s disease. BMJ. 1977;1:1409.

2. Boscaro M et al. Cushing’s syndrome. Lancet. 2001;357:783.
3. Arlt Wiebke. Disorders of the adrenal cortex (chapter 342). In: Fauci AS, Braunwald E, Kasper
DL, Hauser SL, Longo DL, Jameson JL, Loscalzo J, editors. Harrison’s principles of internal
medicine, 18th ed. http://www.accessmedicine.com/content.aspx?aID=9140931.
4. Fisher LB, Maibach HI. The effect of corticosteroids on human epidermal mitotic activity.
Arch Dermatol. 1971;103:39–44.
5. Wilkins L. Professional guide to diseases. 9th ed. 2009;11:631–37.
6. Humes H, et al. Kelley’s textbook of internal medicine, 4th edn. 2000;407:2721–27.
7. James W, Berger T, Elston D. Andrews’ Diseases of the skin: clinical dermatology, vol. 24.
10th ed. London: Saunders; 2005. p. 500–1.
8. Carroll TB, Findling JW.Curr Opin Endocrinol Diabetes Obes. 2009;16(4):308–15. Review
Erratum in: Curr Opin Endocrinol Diabetes Obes. 2010;17(5):492.
19 Cushing’s Syndrome 135

9. Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, Loscalzo J.In:
Disorders of the adrenal cortex (chapter 336). Fauci AS, Braunwald E, Kasper DL, Hauser SL,
Longo DL, Jameson JL, Loscalzo J, editors. Harrison’s Principles of internal medicine, 17th ed.
10. Freinkel RK. Cutaneous manifestations of endocrine diseases. In: Fitzpatrick TB, Eisen AZ,
Wolff K, et al., editors. Dermatology in general medicine. 4th ed. New York: McGraw-Hill;
1993. p. 2113–31.
11. Yanovski JA, Cutler GB. Glucocorticoid action and the clinical features of Cushing’s
syndrome. Endocrinol Metab Clin North Am. 1994;23(3):487–509.
12. Orth DN, Kovacs WJ. The adrenal cortex. In: Wilson JD, Foster DW, Kronenberg HM, et al.,
editors. William’s textbook of endocrinology. 9th ed. Philadelphia: Saunders; 1998. p. 565–9.
13. Rokowski K, Sheehy J, Cutroneo KR. Glucocorticoid-mediated selective reduction of func-
tioning collagen messenger ribonucleic acid. Arch Biochem Biophys. 1981;210:74–81.
14. Findling JW, Raff H. Diagnosis and differential diagnosis of Cushing’s syndrome. Endocrinol
Metab Clin North Am. 2001;30(3):729–47.
15. Lolis MS, Bowe WP, Shalita AR. Acne and systemic disease. Med Clin N Am. 2009;93:
1161–81.
16. Ross EJ, Linch DC. Cushing’s syndrome-killing disease: discriminatory value of signs and
symptoms aiding early diagnosis. Lancet. 1982;2:646–9.
17. Shome B, Saffran M. Peptides of the hypothalamus. J Neurochem. 1966;13(5):433–48.
18. Meier CA, Biller BM. Clinical and biochemical evaluation of Cushing’s syndrome. Endocrinol
Metab Clin North Am. 1997;26:741–62.
19. Winkelmann RK, Scheen RS, Underhal LO. Acanthosis nigricans and endocrine disease.
JAMA. 1960;174(9):1145–52.
Chapter 20
PAPA Syndrome

Fan Liu and Kanade Shinkai

Abbreviations

ASC Apoptosis-associated speck-like protein with a caspase recruitment

domain
C3 Complement component 3
CAPS Cryopyrin-associated periodic syndromes
CD2BP1 CD2-binding protein 1
DMARDs Disease-modifying antirheumatic drugs
FMA Familial Mediterranean fever
IgM Immunoglobulin M
IL Interleukin
IL-1β Interleukin-1-beta
kD Kilodalton
NLRP3 Nucleotide oligomerization domain-like receptor family pyrin domain
containing 3
NSAIDs Nonsteroidal anti-inflammatory drugs
PAPA Pyogenic sterile arthritis, pyoderma gangrenosum, and acne
PSTPIP1 Proline-serine-threonine phosphatase interacting protein 1
PTP-PEST Proline-glutamic acid-serine-threonine-rich family of protein tyrosine
phosphatases
TNFα Tumor necrosis factor alpha

F. Liu, B.A., M.D. • K. Shinkai, M.D., Ph.D. (*)

Department of Dermatology, University of California, San Francisco, 1701 Divisadero Street,
3rd Floor, San Francisco, CA 94115, USA
e-mail: [email protected]

J.A. Zeichner (ed.), Acneiform Eruptions in Dermatology: A Differential Diagnosis, 137

DOI 10.1007/978-1-4614-8344-1_20, © Springer Science+Business Media New York 2014
138 F. Liu and K. Shinkai

20.1 Introduction

The pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome
was first recognized in 1997 when ten family members in three generations mani-
fested with variable expression of juvenile-onset arthritis and subsequent presenta-
tion of pyoderma gangrenosum and cystic acne in adolescence and adulthood [1].
This inherited disorder stems from dysregulation of the innate immune system,
presenting with symptoms of seemingly unprovoked episodes of synovial tissue
and skin inflammation [1]. Recurrent inflammation seen in PAPA syndrome
typifies that classically seen in autoinflammatory disorders. Autoinflammatory
disorders, though lacking clear diagnostic criteria, are marked by chronic and
intermittent episodes of fever, cytokine dysregulation, and organ inflammation;
skin and joint involvement is a prominent feature [2, 3]. Unlike autoimmune
diseases, autoinflammatory disorders lack high-titer autoantibodies and autoreac-
tive T lymphocytes [2]. Genes associated with inherited syndromes of autoinflam-
mation encode for protein mediators of apoptosis, inflammation, and cytokine
processing (Table 20.1) [3].

Table 20.1 Inherited autoinflammatory disorders

Inherited autoinflammatory disorders Associated genetic mutation OMIM#
Familial Mediterranean fever (FMF) Pyrin (MEFV) 249100
Cryopyrin-associated periodic syndromes Nucleotide oligomerization domain-like 191900,
[Muckle-Wells syndrome (MWS), receptor family, pyrin domain 120100,
familial cold autoimmune syndrome containing 3 (NLRP3, also known as 607115
(FCAS), neonatal-onset multisystem Nalp3 or cryopyrin)
inflammatory disease (NOMID)]
Tumor necrosis factor receptor-associated Tumor necrosis factor receptor superfamily 142680
periodic syndrome (TRAPS) member 1A (TNFRSF1A)
Hyper-immunoglobulin D Mevalonate kinase (MVK) 260920
syndrome (HIDS)
Blau syndrome Caspase recruitment domain family, 186580
member 15/nucleotide-binding
oligomerization domain protein 2
(CARD15/NOD2)
Deficiency of interleukin 1 receptor Interleukin 1 receptor antagonist (IL1RN) 612852
antagonist (DIRA)
Generalized pustular psoriasis (GPP) Interleukin 36 receptor antagonist 614204
(IL-36RN)
Crohn’s disease Caspase recruitment domain family, 266600
member 15/nucleotide-binding
oligomerization domain protein 2
(CARD15/NOD2)
Japanese autoinflammatory syndrome Proteasome subunit, β type 8 (PSMB8) 256040
with lipodystrophy (JASL)
20 PAPA Syndrome 139

20.2 Background

Five years after the first cases of PAPA was described, a gene mutation associated
with this syndrome was localized to the CD2-binding protein 1 (CD2BP1) gene on
chromosome 15q. CD2BP1 and its murine ortholog, proline-serine-threonine phos-
phatase interacting protein 1(PSTPIP1), are cellular signaling adaptors known to
play integral roles in cellular distribution of proteins, including actin reorganization
[2]. Indeed, cultured macrophages from patients with PAPA syndrome demonstrate
abnormal podosome structures and focal adhesion complexes, leading to defects in
chemotaxis and migration [4].
CD2BP1 also activates innate immune responses by regulating inflammatory cyto-
kine production, especially interleukin-1-beta (IL-1β). Key members of the signaling
cascade upstream of IL-1β activation include pyrin (the susceptibility gene for
Familial Mediterranean fever, FMF) and the Nalp3 inflammasome, a multi-protein
signaling complex comprised of cryopyrin (also known as nucleotide oligomerization
domain-like receptor family pyrin domain containing 3, NLRP3), apoptosis-associ-
ated speck-like protein with a caspase recruitment domain (ASC) and caspase 1[4, 5].
Mutations in CD2BP1 seen in association with PAPA syndrome result in
enhanced IL-1β production through its effects on critical upstream regulatory path-
ways. Specifically, known mutations of CD2BP1 abrogate binding to proline-
glutamic acid-serine-threonine-rich family of protein tyrosine phosphatases
(PTP-PEST), an interaction essential for CD2BP1 dephosphorylation [3, 6].
Hyperphosphorylation of CD2BP1 in turn augments its interaction with pyrin,
downregulating the inhibitory effect of pyrin on activation of the Nalp3 inflamma-
some, the multi-protein signaling complex that mediates the catalytic cleavage of
pro-IL-1β to its active form [4, 7]. While the direct mechanism by which pyrin
interacts with the inflammasome remains unclear, mutations in CD2BP1 associated
with PAPA syndrome may enhance recruitment of CD2BP1 to ASC aggregates,
potentially augmenting inflammasome signaling [8]. An alternative hypothesis pos-
tulates that mutations in CD2BP1 activate pathways leading to cell death and cyto-
kine release, including IL-1β [4, 9]. Taken in sum, mutations in CD2BP1 impact
many important aspects of immunity: immune cell adhesion, migration, activation,
signaling, cytokine production, and apoptosis.
The importance of the IL-1 regulatory pathway in inflammation is highlighted by
the emerging knowledge that several inherited autoinflammatory syndromes are asso-
ciated with IL-1 dysregulation, including FMF, cryopyrin-associated periodic syn-
dromes (CAPS), and deficiency of IL-1 receptor antagonist (DIRA). It is unknown
whether enhanced IL-1 production seen in autoinflammatory diseases results from
aberrant activation (i.e., activation of the pathway in the absence of physiologic trig-
gers such as infection) or an inability to turn off normal inflammatory responses due
to mutations in key signaling or regulatory components [10]. The aforementioned
IL-1 signaling cascade is highly expressed in both skin and synovial tissue, possibly
explaining the common involvement of these tissues in autoinflammatory disorders.
140 F. Liu and K. Shinkai

20.3 Clinical Presentation

To date there are eight families with PAPA syndrome reported in the literature,
with a total of 37 affected family members (Table 20.2) [1, 11–17]. The syndrome
is inherited in an autosomal dominant pattern, with clinical manifestations
typically presenting in childhood. The most common clinical feature of PAPA
syndrome is chronic, recurrent, sterile arthritis with prominent neutrophilic syno-
vial infiltrate with onset in childhood. Skin involvement is variable and presents in
adolescence or adulthood after joint signs have resolved or subsided; cutaneous
manifestations include pyoderma gangrenosum, severe acne, and ulcerations
(Figs. 20.1 and 20.2) [1, 16].

20.3.1 Joint Manifestations of PAPA Syndrome

Patients with PAPA syndrome present with asymmetric, destructive, and inflamma-
tory poly-arthropathy with onset usually by 5 years of age. The natural history of
this arthritis is chronic and intermittent. Some patients recall an initiating monoar-
ticular traumatic event [1, 13–17]. Recurrent episodes of synovial inflammation
fluctuate with periods of inactivity and eventually enter remission by late adoles-
cence. While the most commonly affected joints are the ankle, knee, and elbow,
cases of jaw and axial involvement, specifically the cervical spine, have been
reported [14]. Diagnostic imaging often reveals diffuse joint space narrowing,
osteophyte formation, subchondral sclerosis, cyst formation, periosteal prolifera-
tion, and ankylosis (Fig. 20.3) [1, 14].

20.3.2 Cutaneous Manifestations of PAPA Syndrome

Skin manifestations of PAPA syndrome present in adolescence, as the inflammatory

joint disease subsides. A majority of patients with PAPA syndrome develop acne,
usually severe. The acne seen in these individuals has been described in the literature
as cystic in morphology, early in onset (including infancy), and persistent into adult-
hood (oldest reported age was 63 years) [1, 11]. The anatomic distribution resembles
that commonly seen in patients with acne vulgaris, with predominant facial and trun-
cal involvement. Acne associated with PAPA syndrome is often scarring. Other
acneiform eruptions, including hidradenitis suppurativa, pustulosis, and pustular
rosacea, have also been reported in patients with PAPA syndrome [1, 14, 17].
Pyoderma gangrenosum was observed in a total of 11 of 37 reported patients
with PAPA syndrome. Sites most commonly affected include the upper and lower
extremities, face, and neck. Several cases of pyoderma gangrenosum have been
 20

Table 20.2 Clinical features of 37 patients with PAPA syndrome reported in the literature
Family
Family member Arthritis Pyoderma gangrenosum Acne Other
PAPA Syndrome

Age of onset Age of onset Clinical

(years) Joints involved (years) Site Age of onset (years) Clinical description description
Family 1 [1] 1 4 Elbow, hand, 19 Legs 13 Severe, cystic Sterile abscess at
hip, knee injection site,
hidradenitis
suppurativa
a
2 16 Elbow 52 Legs 12 None
a
3 2 Elbow, hand, None None 12 Sterile abscess at
knee injection site
a
4 3 Elbow, knee, None None 12 Sterile abscess at
ankle injection site
a
5 1.5 Wrist, hip, ankle 11 Face, cesarean 11 Sterile abscess at
section scar injection site
a
6 None None None None 11 None
a
7 1.5 Elbow, knee 12 Face 11 None
8 5 Elbow, knee None None None None None
9 1 Shoulder, elbow, None None None None None
ankle
10 8 Knee, ankle None None None None None
(continued)
141
 142

Table 20.2 (continued)

Family
Family member Arthritis Pyoderma gangrenosum Acne Other
Age of onset Age of onset Clinical
(years) Joints involved (years) Site Age of onset (years) Clinical description description
Family 2 [11] 1 Infancy Elbow, knee, 8 Arms, legs Infancy Cystic None
ankle
a a
2 Infancy Elbow, knee, None None None
ankle
a a
3 Infancy Elbow, knee, None None None
ankle
a
4 Between None None Yes Severe None
3 months and
5 years of age
a a a
5 None None None
a a a
6 None None None
a a a
7 None None None
a a a
8 None None None
a a a
9 None None None
a a
Family 3 [12] 1 2 Shoulder, wrist, 2 Arm None
hand, hip,
knee, ankle
a a a a
2 Adolescence Severe, necrotic; face, None
trunk
a a a a
F. Liu and K. Shinkai

3 Childhood Multiple None

 Family
Family member Arthritis Pyoderma gangrenosum Acne Other
Age of onset Age of onset Clinical
(years) Joints involved (years) Site Age of onset (years) Clinical description description
20

a a
Family 4 [13] 1 16 Knee, ankle Yes Mild; peri-nasal None
a a a
2 Yes Yes Mild; peri-nasal None
a a a
3 Yes Yes Mild; peri-nasal None
a a a
4 Yes Yes Mild; peri-nasal None
a a a
5 Yes Yes Mild; peri-nasal None
Family 5 [14] 1 5 Cervical spine, Probable Legs Yes Mild Psoriasis
PAPA Syndrome

jaw, hip,
knee, ankle
2 5 Jaw, shoulder, None None Yes Severe Pustular rosacea
hip, knee,
foot
a
3 2 Cervical spine, Yes Yes Severe None
jaw, elbow,
hand, hip,
knee
a
4 Before age 5 Jaw, shoulder, Probable Yes Mild, cystic None
elbow, wrist,
hand, hip,
knee, ankle
5 Before age 5 Jaw, elbow, None None Yes Mild None
wrist, hand,
knee, ankle,
foot
Family 6 [15] 1 Adolescence Elbow, knee, Before age 42 Neck, leg Adolescence Severe; face, upper None
ankle back
a
Family 7 [16] 1 22 Knee 12 Legs 16 Nodulocystic; face
Family 8 [17] 1 3 Ankle None None None None Pustulosis
a
2 33 Ankle None None 18 Abscess,
hidradenitis
suppurativa
a a
3 26 None None 16 Abscess
143

a
Data not reported
144 F. Liu and K. Shinkai

Fig. 20.1 Biopsy-confirmed

lesions of pyoderma
gangrenosum on bilateral
lower extremities of a patient
with PAPA syndrome [1]

Fig. 20.2 Scarring,

papulopustular, and
nodulocystic acne on the face
of a patient with PAPA
syndrome [16]

reported to develop after a pathergy-like reaction to mild trauma. In some cases,

lesions begin as erythematous or violaceous sterile papules or pustules with subse-
quent evolution to persistent, deep inflammatory ulcerations [1, 11, 14, 15].

20.4 Work-Up

The unique constellation of clinical features and natural history of PAPA syndrome
often make it a clinical diagnosis. However, fever, arthralgias, elevated markers of
systemic inflammation, acneiform or neutrophilic dermatoses, and ulcers may be
20 PAPA Syndrome 145

Fig. 20.3 X-ray of the hands of a patient with PAPA syndrome demonstrating advanced arthritis
with joint space narrowing, osteophyte formation, and subchondral sclerosis [14]

seen in a broad spectrum of conditions; the differential diagnosis of PAPA syndrome

with distinguishing clinical features is presented in Table 20.3. Commercially avail-
able genetic testing for common CD2BP1 coding mutations associated with PAPA
syndrome is helpful in confirming the diagnosis and is currently the only specific
diagnostic test [4]. Of note, there is one reported patient with all of the classical
clinical features of PAPA syndrome without an identifiable mutation in the CD2BP1
gene [16].
Common laboratory findings include elevated serum markers of general sys-
temic inflammation, such as erythrocyte sedimentation rate (ESR) and C-reactive
protein (CRD). More specifically, elevated IL-1β and tumor necrosis factor alpha
(TNFα) have also been observed [1, 11]. A 160 kD yet-unidentified streaking leu-
kocyte factor is also seen; it is so named for its ability to enhance migration of
mononuclear cells [4]. In vitro stimulation of patients’ peripheral blood mononu-
clear cells with lipopolysaccharide showed increased IL-1α, IL-1β, TNFα, and
IL-10 production [17].
Synovial biopsies typically reveal a nonspecific pattern of neutrophilic infiltrate.
Skin biopsies of ulcerations or pyoderma gangrenosum lesions also reveal dense
neutrophilic infiltrates with dermal inflammation, hemorrhage, and signs of wound
healing [1, 11, 16]. Immunofluorescence of both skin and synovium lack immuno-
globulin M (IgM), complement component 3 (C3), or fibrinogen deposition.
Cultures of synovial fluid are sterile. Serum rheumatoid factor and antinuclear anti-
bodies are also absent [11, 14].
146 F. Liu and K. Shinkai

Table 20.3 Differential diagnoses of PAPA syndrome

Associated
Bone and joint genetic OMIM
Disease Age of onset Skin involvement involvement mutation #
PAPA (pyogenic Childhood Acne, pyoderma Pyogenic sterile CD2BP1 604416
sterile arthritis, gangrenosum arthritis (autosomal
pyoderma dominant)
gangrenosum,
and acne)
DIRA (deficiency of Infancy Pustulosis Periostitis, IL1RN 612852
the interleukin- osteomyelitis (autosomal
1-receptor recessive)
antagonist)
SAPHO (synovitis, Childhood or Acne, pustulosis Synovitis, unknown
acne, pustulosis, adulthood hyperostosis,
hyperostosis, osteomyelitis
and osteitis)
Majeed syndrome Childhood Acne, Sweet’s Recurrent LPIN2 609628
syndrome multifocal (autosomal
osteomyelitis recessive)
Acne inversa Adolescence Acne, cysts, sinus Arthralgias NCSTN, 142690
(hidradenitis tracts, PSENEN,
suppurativa) pyoderma and PSEN1
gangrenosum (familial
form)
PASH (pyoderma Adolescence Acne, pyoderma None unknown
gangrenosum, gangrenosum,
acne, and suppurative
suppurative hidradenitis
hidradenitis)
PAPASH (Pyogenic Adulthood Acne, pyoderma Pyogenic PSTPIP1 None
arthritis, gangrenosum, arthritis
pyoderma suppurative
gangrenosum, hidradenitis
acne, and
hidradenitis
suppurativa
CD2BP1 CD2-binding protein 1, IL1RN interleukin-1 receptor antagonist, LPIN2 lipin 2, NCSTN
nicastrin, PSENEN presenilins, PSEN1 presenilin 1

20.5 Treatment

Given PAPA syndrome is so rare, there is limited evidence supporting the efficacy
of treatments for this condition. Treatments for pyogenic arthritis have been reported
in the literature with variable success. These therapies include aspirin, ibuprofen,
methotrexate, leflunomide, sulfasalazine, hydroxychloroquine, antibiotics, osteot-
omy, and bone grafting. High-dose intra-articular and systemic corticosteroids may
be effective in controlling arthritic flares [1, 11, 13]. Disease-modifying antirheu-
matic drugs (DMARDs) have also been used early in the treatment course in an
attempt to prevent full expression of the PAPA syndrome with inconclusive results.
Patients with aggressive joint disease may require joint replacements [14].
20 PAPA Syndrome 147

Fig. 20.4 Patient with PAPA syndrome and pyoderma gangrenosum of the neck before (a) and
1 month after (b) anakinra therapy [15]

For the treatment of pyoderma gangrenosum, a combination of topical steroids

and systemic DMARDs such as azathioprine, methotrexate, and hydroxychloroquine
have been shown to be effective in some patients with PAPA [1, 11, 14, 17]. Because
IL-1β and TNFα levels are elevated in patients with PAPA, and because of important
role of TNFα in the pathogenesis of pyoderma gangrenosum, these cytokines have
emerged as new therapeutic targets. Anakinra, a recombinant IL-1 receptor antago-
nist requiring daily subcutaneous injection, has been reported to be effective in treat-
ing three patients with PAPA syndrome, improving active arthritic flares, severe
cystic acneiform eruptions, and chronic pyoderma gangrenosum lesions (Fig. 20.4)
[13, 15, 17, 18]. The duration of anakinra treatment for these patients ranged from
1 week to 8 months in reported cases. Anti-TNFα blockade, including infliximab and
etanercept, have also been reported to be effective in treating some of the symptoms
of PAPA syndrome, with dramatic resolution of pyoderma gangrenosum in one
patient [4, 12, 19]. While the impact of these biologic therapies on acne is not well
148 F. Liu and K. Shinkai

documented in the literature, the available reports suggest that these agents are less
consistently efficacious for acne. There are reports of successful treatment of severe
nodulocystic acne in patients with PAPA with systemic isotretinoin [16, 17].

References

1. Lindor NM, Arsenault TM, Solomon H, Seidman CE, McEvoy MT. A new autosomal domi-
nant disorder of pyogenic sterile arthritis, pyoderma gangrenosum, and acne: PAPA syndrome.
Mayo Clin Proc. 1997;72(7):611–5.
2. Wise CA, Gillum JD, Seidman CE, Lindor NM, Veile R, Bashiardes S, Lovett M. Mutations in
CD2BP1 disrupt binding to PTP PEST and are responsible for PAPA syndrome, an autoinflam-
matory disorder. Hum Mol Genet. 2002;11(8):961–9.
3. Hull KM, Shoham N, Chae JJ, Aksentijevich I, Kastner DL. The expanding spectrum of sys-
temic autoinflammatory disorders and their rheumatic manifestations. Curr Opin Rheumatol.
2003;15(1):61–9.
4. Smith EJ, Allantaz F, Bennett L, Zhang D, Gao X, Wood G, Kastner DL, Punaro M,
Aksentijevich I, Pascual V, Wise CA. Clinical, molecular, and genetic characteristics of PAPA
syndrome: a review. Curr Genomics. 2010;11(7):519–27.
5. McDermott MF. A common pathway in periodic fever syndromes. Trends Immunol. 2004;
25(9):457–60.
6. Veillette A, Rhee I, Souza CM, Davidson D. PEST family phosphatases in immunity, autoim-
munity, and autoinflammatory disorders. Immunol Rev. 2009;228(1):312–24.
7. Goldfinger S. The inherited autoinflammatory syndrome: a decade of discovery. Trans Am
Clin Climatol Assoc. 2009;120:413–8.
8. Waite AL, Schaner P, Richards N, Balci-Peynircioglu B, Masters SL, Brydges SD, Fox M,
Hong A, Yilmaz E, Kastner DL, Reinherz EL, Gumucio DL. Pyrin modulates the intracellular
distribution of PSTPIP1. PLoS One. 2009;4(7):e6147.
9. Yu JW, Fernandes-Alnemri T, Datta P, Wu J, Juliana C, Solorzano L, McCormick M, Zhang Z,
Alnemri ES. Pyrin activates the ASC pyroptosome in response to engagement by autoinflam-
matory PSTPIP1 mutants. Mol Cell. 2007;28(2):214–27.
10. Shinkai K, McCalmont TH, Leslie KS. Cryopyrin-associated periodic syndromes and autoin-
flammation. Clin Exp Dermatol. 2008;33(1):1–9.
11. Wise CA, Bennett LB, Pascual V, Gillum JD, Bowcock AM. Localization of a gene for familial
recurrent arthritis. Arthritis Rheum. 2000;43(19):2041–5.
12. Cortis E, De Benedetti F, Insalaco A, Cioschi S, Muratori F, D’Urbano LE, Ugazio AG.
Abnormal production of tumor necrosis factor (TNF) alpha and clinical efficacy of the TNF
inhibitor etanercept in a patient with PAPA syndrome. J Pediatr. 2004;145(6):851–5.
13. Dierselhuis MP, Frenkel J, Wulffraat NM, Boelens JJ. Anakinra for flares of pyogenic arthritis
in PAPA syndrome. Rheumatology. 2005;44(3):406–8.
14. Tallon B, Corkill M. Peculiarities of PAPA syndrome. Rheumatology. 2006;45(9):1140–3.
15. Brenner M, Ruzicka T, Plewig G, Thomas P, Herzer P. Targeted treatment of pyoderma gangreno-
sum in PAPA (pyogenic arthritis, pyoderma gangrenosum and acne) syndrome with the recombi-
nant human interleukin-1 receptor antagonist anakinra. Br J Dermatol. 2009;161(5):1199–201.
16. Hong JB, Su YN, Chiu HC. Pyogenic arthritis, pyoderma gangrenosum, and acne syndrome
(PAPA syndrome): report of a sporadic case without an identifiable mutation in the CD2BP1
gene. J Am Acad Dermatol. 2009;61(3):533–5.
17. Schellevis MA, Stoffels M, Hoppenreijs EP, Bodar E, Simon A, van der Meer JW. Variable
expression and treatment of PAPA syndrome. Ann Rheum Dis. 2011;70(6):1168–70.
18. Lolis MS, Bowe WP, Shalita AR. Acne and systemic diseases. Med Clin North Am. 2009;
93(6):1161–81.
19. Stichweh DS, Punaro M, Pascual V. Dramatic improvement of pyoderma gangrenosum with
infliximab in a patient with PAPA syndrome. Pediatr Dermatol. 2005;22(3):262–5.
Chapter 21
Polycystic Ovary Syndrome

Joslyn Kirby

21.1 Introduction

Polycystic ovary syndrome (PCOS) was first described in 1935 by Stein and
Leventhal [1]. They described several women with amenorrhea, hirsutism, obesity,
and polycystic ovaries. Today, PCOS is one of the most common endocrine
diseases in women. It is also one of the most common causes of infertility and
menstrual irregularity. Acne is common in women with PCOS and may be the
initial reason women with occult PCOS seek medical attention. Inquiring about
menstrual irregularity and/or hirsutism in women with acne may facilitate referral
to a gynecologist or endocrinologist for early intervention on fertility issues and
medical comorbidities.

21.2 Background

PCOS is one of the most common endocrine disorders in women. In a study of

unselected black and white women, the prevalence was 6–12 % [2]. The prevalence
is higher in women with obesity, diabetes mellitus (type 1, type 2, or gestational),
and those with first-degree family members with PCOS [3]. The variability in the
reported prevalence is in part due to the inherent variability among patient popula-
tions (black, Caucasian, Latina, etc.) and the method of diagnosis (which diagnostic
criteria are used) [4].

J. Kirby, M.D. (*)

Department of Dermatology, Penn State Hershey, 500 University Drive,
Hershey, PA 17033, USA
e-mail: [email protected]

J.A. Zeichner (ed.), Acneiform Eruptions in Dermatology: A Differential Diagnosis, 149

DOI 10.1007/978-1-4614-8344-1_21, © Springer Science+Business Media New York 2014
150 J. Kirby

The principle characteristics of PCOS are anovulation, polycystic ovaries, and

hyperandrogenism. PCOS is likely a multifactorial condition with genetic as well as
environmental contributions. Studies have shown women with PCOS have abnor-
mal function of the hypothalamic–pituitary–ovary endocrine axis as well as other
tissues and organs. The hypothalamus in women with PCOS secretes gonadotropin-
secreting hormone (GnRH) at an elevated frequency. It is not known what factor(s)
incites the abnormal pulse frequency, be it an intrinsic abnormality in the hypothala-
mus or faulty feedback mechanisms at the ovary [5]. This increased frequency
favors the production of lutenizing hormone (LH) over follicle-stimulating hormone
(FSH). This results in an elevated LH to FSH ratio and excess LH results in the
overproduction of androgens by the ovarian theca cells.
Acne has been shown to be more common in women with high levels of andro-
gens. Androgen overproduction in PCOS likely contributes to acne by triggering
excessive sebum production. Conversely, acne is less common in women with ele-
vated levels of sex-hormone binding globulin (SHBG) [6]. This protein binds the
hormones and reduces the amount of free androgens available in the serum. Oral
contraceptive pills have been shown to increase levels of SHBG, partially explain-
ing their efficacy in treating acne [7]. In addition to overproduction of androgens,
acne may be more common in these patients due to the influence of 5-α-reductase.
This enzyme is found in facial hair follicles and converts testosterone to dihydrotes-
tosterone (DHT), a more potent androgen. DHT production via 5-α-reductase is
stimulated by excess androgens, insulin, and insulin-like growth factor, which are
all elevated in women with PCOS [8, 9].

21.3 Clinical Presentation

PCOS is a spectrum disorder due to hyperandrogenism with a variety of possible

symptoms and signs, some of which may be absent and others expressed with vari-
able severity. Menstrual irregularity, hirsutism (Fig. 21.1), and polycystic ovaries
are common features; however the diagnosis does not hinge on any single feature
[10, 11]. Though not strictly a feature of the cutaneous exam, women with PCOS
are frequently at least overweight or more frequently obese; obesity is found in
30–75 % of women with PCOS [12]. The most common cutaneous features of
PCOS are hirsutism, acne, and androgenetic alopecia [5].
Acne affects an estimated 10–34 % of women with PCOS (Fig. 21.2) [13].
Compared to age-matched controls, acne has been shown to be at least three times
more prevalent in women with PCOS [14]. Facial acne is most common, but 50 %
of women with PCOS also have involvement of their chest and back [8]. In one
study, 37 % (19/51) of women presenting with acne met criteria for PCOS [15]. The
diagnosis of PCOS was based on menstrual disturbances, cutaneous signs of hyper-
androgenism (acne, hirsutism, seborrhea), presence of ovarian cysts, and elevated
LH to FSH ratio. This study supports the practice of asking women presenting with
acne about their menstrual cycles. This may facilitate referral of appropriate patients
to a gynecologist or endocrinologist for work-up and diagnosis.
21 Polycystic Ovary Syndrome 151

Fig. 21.1 Hirsutism in the

sideburn and neck of a
woman with polycystic ovary
syndrome. She also suffered
from mild acne along the
lower 1/3 of the face (Photo
credit: Joshua A. Zeichner,
M.D.)

Fig. 21.2 Typical appearance of acne along the chin of the a woman with polycystic ovary syndrome
(Photo credit: Joshua A. Zeichner, M.D.)

Given the high prevalence of obesity, it is not surprising women with PCOS have
an elevated prevalence of other systemic metabolic diseases. Impaired glucose
tolerance is found in 30–40 % [16]. Women are also more likely to develop endo-
metrial hyperplasia and carcinoma [17], lipid abnormalities (including hypertri-
glyceridemia, elevated LDL, and low HDL) [18], obstructive sleep apnea [19], and
cardiovascular disease [20].
152 J. Kirby

21.4 Work-Up

The differential diagnosis of PCOS includes hyperprolactinemia, acromegaly,

congenital adrenal hyperplasia, Cushing’s syndrome, and an androgen-secreting
neoplasm. Of these, congenital adrenal hyperplasia, Cushing’s syndrome, and an
androgen-secreting neoplasm are the most likely to present with acne and/or
hirsutism in addition to menstrual irregularity or infertility [5]. The most recent
diagnostic criteria require the exclusion of these conditions before PCOS can be
diagnosed [10].
There are multiple published diagnostic criteria for PCOS [4, 11, 21]. In 2006,
the Androgen Excess Society suggested that PCOS be diagnosed based on (1) signs
of hyperandrogenism including hirsutism and hyperandrogenemia, (2) signs of
ovarian dysfunction including oligo-anovulation or polycystic ovaries, and finally
(3) exclusion of other states of androgen excess [21]. If the practitioner is suspicious
a patient has the condition, it is prudent to refer the patient to a gynecologist or
endocrinologist. Laboratory tests can be ordered in anticipation of this consultation.
LH is elevated out of proportion to FHS, resulting in an elevated LH to FSH ratio.
It is elevated in about 50 % of patients with PCOS [5]. LH and FSH should be tested
during the early follicular phase of the menstrual cycle, before the midcycle LH
surge. The presence of hyperandrogenism is best confirmed by assessing serum
total and free testosterone. These are best assessed in the morning and early in the
menstrual cycle. Most women with PCOS will have total testosterone levels below
150 ng/dl [22]. Levels above 200 ng/dl are concerning for a virilizing tumor.
Ultrasonography of the ovaries is not a specific test, since about 20 % of a general
adult population and about 50 % of women with regular menses can have polycystic
ovaries [23]. Imaging is best reserved for women with physical exam and laboratory
findings suggestive of PCOS.

21.5 Treatment

Typical therapies such as topical retinoids, benzoyl peroxide, and topical antibiotics
(singly or fixed-combination products), as well as oral antibiotics, are utilized to
treat acne for women with PCOS. In addition, due to the hyperandrogenism under-
lying the cutaneous findings of PCOS (namely, acne, androgenetic alopecia, and
hirsutism), therapy is aimed at reducing androgen production and the efficacy of
their hormones at their targets (e.g., hair follicle, sebaceous glands) [13].
One of the most common treatments is hormonal birth control. Combination
hormonal birth control, containing both an estrogen and progestin, has been shown
to decrease ovarian production of androgens and increase levels of sex-hormone-
binding globulin [24]. Oral contraceptives with 30–35 mcg of ethinyl estradiol and
a progestin with minimal androgenicity such as norethindrone norgestimate,
desogestrel, or drospirenone are favored [25].
21 Polycystic Ovary Syndrome 153

Spironolactone can be an effective therapy alone or in combination with hor-

monal contraceptives [26, 27]. Spironolactone is an aldosterone antagonist with
antiandrogenic properties. It has been commonly used to treat hirsutism. The mech-
anism of action includes competition for the androgen receptor, suppression of
cytochrome P450, and inhibition of steroidogenesis, as well as reduction in
5-α-reductase activity. In an open-label study, 27 women with severe facial acne
were treated with a hormonal birth control containing drospirenone and spironolac-
tone 100 mg daily. 85 % of subjects were entirely clear of acne lesions or had excel-
lent improvement. In another study, 35 women with acne of various severities
received spironolactone 100 mg daily for 16 days per month for 3 months. Twenty-
four patients (85.71 %) had significant improvement. The patients with clinical
response also had a decrease in their mean DHEAS level; however, there was no
change in the mean total testosterone levels [28].
Other therapies with androgen-mitigating effects include flutamide, an androgen-
receptor antagonist, and 5-α-reductase inhibitor, a 5-α-reductase inhibitor. Both
have demonstrated efficacy for therapy of acne but fewer studies have been done
with these agents in comparison to spironolactone [29, 30].
Metformin is an insulin-sensitizing agent commonly used to treat PCOS. Along
with other insulin-sensitizing agents (e.g., thiazolidinediones), metformin has been
shown to decreased androgen production. One study demonstrated improvement of
mild acne after 12 months of metformin therapy [31]. More research is needed
before these drugs can be recommended to treat acne in the PCOS population.

References

1. Stein I. Amenorrhea associated with bilateral polycystic ovaries. Am J Obstet Gynecol.

1935;29:181.
2. Knochenhauer ES, Key TJ, Kahsar-Miller M, Waggoner W, Boots LR, Azziz R. Prevalence of
the polycystic ovary syndrome in unselected black and white women of the southeastern
United States: a prospective study. J Clin Endocrinol Metab. 1998;83(9):3078–82.
3. Yildiz BO, Knochenhauer ES, Azziz R. Impact of obesity on the risk for polycystic ovary
syndrome. J Clin Endocrinol Metab. 2008;93(1):162–8.
4. Broekmans FJ, Knauff EA, Valkenburg O, Laven JS, Eijkemans MJ, Fauser BC. PCOS accord-
ing to the Rotterdam consensus criteria: change in prevalence among WHO-II anovulation and
association with metabolic factors. BJOG. 2006;113(10):1210–7.
5. Ehrmann DA. Polycystic ovary syndrome. N Engl J Med. 2005;352(12):1223–36.
6. Karrer-Voegeli S, Rey F, Reymond MJ, Meuwly JY, Gaillard RC, Gomez F. Androgen
dependence of hirsutism, acne, and alopecia in women: retrospective analysis of 228 patients
investigated for hyperandrogenism. Medicine (Baltimore). 2009;88(1):32–45.
7. Walton S, Cunliffe WJ, Keczkes K, et al. Clinical, ultrasound and hormonal markers of
androgenicity in acne vulgaris. Br J Dermatol. 1995;133(2):249–53.
8. Archer JS, Chang RJ. Hirsutism and acne in polycystic ovary syndrome. Best Pract Res Clin
Obstet Gynaecol. 2004;18(5):737–54.
9. Falsetti L, Gambera A, Andrico S, Sartori E. Acne and hirsutism in polycystic ovary syndrome:
clinical, endocrine-metabolic and ultrasonographic differences. Gynecol Endocrinol. 2002;
16(4):275–84.
154 J. Kirby

10. Azziz R, Carmina E, Dewailly D, et al. The Androgen Excess and PCOS Society criteria for the
polycystic ovary syndrome: the complete task force report. Fertil Steril. 2009;91(2):456–88.
11. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic
ovary syndrome (PCOS). Hum Reprod. 2004;19(1):41–7.
12. Azziz R, Ehrmann D, Legro RS, et al. Troglitazone improves ovulation and hirsutism in the
polycystic ovary syndrome: a multicenter, double blind, placebo-controlled trial. J Clin
Endocrinol Metab. 2001;86(4):1626–32.
13. Chuan SS, Chang RJ. Polycystic ovary syndrome and acne. Skin Therapy Lett. 2010;
15(10):1–4.
14. Kelekci KH, Kelekci S, Incki K, Ozdemir O, Yilmaz B. Ovarian morphology and prevalence
of polycystic ovary syndrome in reproductive aged women with or without mild acne. Int
J Dermatol. 2010;49(7):775–9.
15. Timpatanapong P, Rojanasakul A. Hormonal profiles and prevalence of polycystic ovary syn-
drome in women with acne. J Dermatol. 1997;24(4):223–9.
16. Legro RS, Kunselman AR, Dodson WC, Dunaif A. Prevalence and predictors of risk for type
2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospec-
tive, controlled study in 254 affected women. J Clin Endocrinol Metab. 1999;84(1):165–9.
17. Hardiman P, Pillay OC, Atiomo W. Polycystic ovary syndrome and endometrial carcinoma.
Lancet. 2003;361(9371):1810–2.
18. Talbott E, Guzick D, Clerici A, et al. Coronary heart disease risk factors in women with
polycystic ovary syndrome. Arterioscler Thromb Vasc Biol. 1995;15(7):821–6.
19. Gopal M, Duntley S, Uhles M, Attarian H. The role of obesity in the increased prevalence of
obstructive sleep apnea syndrome in patients with polycystic ovarian syndrome. Sleep Med.
2002;3(5):401–4.
20. Orio Jr F, Palomba S, Spinelli L, et al. The cardiovascular risk of young women with polycystic
ovary syndrome: an observational, analytical, prospective case-control study. J Clin Endocrinol
Metab. 2004;89(8):3696–701.
21. Azziz R, Carmina E, Dewailly D, et al. Positions statement: criteria for defining polycystic
ovary syndrome as a predominantly hyperandrogenic syndrome: an Androgen Excess Society
guideline. J Clin Endocrinol Metab. 2006;91(11):4237–45.
22. Derksen J, Nagesser SK, Meinders AE, Haak HR, van de Velde CJ. Identification of virilizing
adrenal tumors in hirsute women. N Engl J Med. 1994;331(15):968–73.
23. Codner E, Villarroel C, Eyzaguirre FC, et al. Polycystic ovarian morphology in postmenarchal
adolescents. Fertil Steril. 2011;95(2):702–6. e701-702.
24. Azzizz R. The evaluation and management of hirsutism. Obstet Gynecol. 2003;101(5):
995–1007.
25. Arowojolu AO, Gallo MF, Lopez LM, Grimes DA, Garner SE. Combined oral contraceptive
pills for treatment of acne. Cochrane Database Syst Rev. 2009;3, CD004425.
26. Goodfellow A, Alaghband-Zadeh J, Carter G, et al. Oral spironolactone improves acne
vulgaris and reduces sebum excretion. Br J Dermatol. 1984;111(2):209–14.
27. Krunic A, Ciurea A, Scheman A. Efficacy and tolerance of acne treatment using both spirono-
lactone and a combined contraceptive containing drospirenone. J Am Acad Dermatol. 2008;
58(1):60–2.
28. Yemisci A, Gorgulu A, Piskin S. Effects and side-effects of spironolactone therapy in women
with acne. J Eur Acad Dermatol Venereol. 2005;19(2):163–6.
29. Cusan L, Dupont A, Gomez JL, Tremblay RR, Labrie F. Comparison of flutamide and spirono-
lactone in the treatment of hirsutism: a randomized controlled trial. Fertil Steril. 1994;
61(2):281–7.
30. Carmina E, Lobo RA. A comparison of the relative efficacy of antiandrogens for the treatment
of acne in hyperandrogenic women. Clin Endocrinol (Oxf). 2002;57(2):231–4.
31. Harborne L, Fleming R, Lyall H, Sattar N, Norman J. Metformin or antiandrogen in the
treatment of hirsutism in polycystic ovary syndrome. J Clin Endocrinol Metab. 2003;
88(9):4116–23.
Chapter 22
Pomade Acne

Oge Onwudiwe and Valerie D. Callender

22.1 Introduction

Pomade acne (aka acne venenata) is considered a clinically distinct entity from the
more common acne vulgaris. It is caused by the use of pomades applied to the hair
and scalp in individuals of African descent with tight curly hair. Pomades are oil- or
ointment-based hair care products used to lubricate the scalp and improve manage-
ability of the hair. Pomade acne consists mainly of uniform, closely set comedones
predominantly of the forehead and temple region. Involvement of the cheeks and
ears has been documented as well [1]. It is said to be associated with little to no
inflammation [2] which is in stark contrast with the comedones of acne vulgaris in
which Halder et al. histologically found a marked inflammatory response in indi-
viduals with skin of color [3]. These lesions are primarily follicular and considered
to be of very slow onset. Characteristically, pomade acne is limited to the come-
donal stage but inflammatory papules, pustules, miliary cyst, and an erythematous
and edematous phase have all been documented [1, 2].

22.2 Background

In 1954, Berlin described an acneiform eruption of predominantly the cheeks and

secondly the forehead which was seen in children who applied paraffin oil to their
scalp. The eruption consisted of uniform pinhead-sized papules, confined to the fol-
licles. Some showed black points in the center while others a perifollicular inflam-
matory process. Few cysts and pitted scars were also seen. The disease was readily

O. Onwudiwe, M.D. (*) • V.D. Callender, M.D.

Callender Dermatology and Cosmetic Center, 12200 Annapolis Road,
Ste 315, Glenn Dale, MD 20769, USA
e-mail: [email protected]

J.A. Zeichner (ed.), Acneiform Eruptions in Dermatology: A Differential Diagnosis, 155

DOI 10.1007/978-1-4614-8344-1_22, © Springer Science+Business Media New York 2014
156 O. Onwudiwe and V.D. Callender

distinguished from the adolescent type of acne by the age of onset, the uniformity
of the eruption, the overwhelming predominance of comedones, and finally the lack
of seborrhea and lack of involvement of back and chest. Improvement was seen
upon discontinuation of the use of paraffin oil to the scalp as well as the use of a
comedo extractor and benzine to dissolve the oil [1].
In 1970, Plewig et al. described a similar eruption. This was seen in African
American men who applied various grooming substances to the face and scalp. The
observations in this study were confined to Negro male prisoners. The mean age
was 30 but ranged from 21 to 53 years of age. Six products were found to be in com-
mon use among them: Noxzema, Wildroot, Dixie Peach, Royal Crown, and mineral
oil. Common to these are high melting hydrocarbons. In the small study conducted,
five of these pomades were applied to the backs of three African Americans and
three Caucasian subjects for a period of 8 weeks. The formulation was applied every
other day to a 4 cm square area. Occlusion was primarily maintained via the use of
a polyethylene film. The control site consisted of a similar occlusive dressing with-
out application of any agents or vehicles. After 8 weeks, 6 mm full thickness punch
biopsies were obtained. Clinically, only two of the six subjects displayed follicular
papules. The observed lesions were not dense in number and a few were mildly
inflammatory. In decreasing order, Dixie Peach, Wildroot, and Noxzema had the
highest frequency of pomade acne occurrence. Not surprisingly, histologic accumu-
lation of horny material in the follicular lumen was most evident in the three afore-
mentioned formulations [2].
Plewig et al. showed that a number of chemicals can induce an acneiform
eruption upon contact with human skin [2]. Some of these agents contain various
mixtures of petrolatum; lanolin; and vegetable, mineral, or animal oils [2, 4–6].
It has been shown that cultural practices play a role in the development of pomade
acne. Due to the tight and curly nature of the hair of some individuals of skin of
color, hair pomades or “hair grease” and other products are placed on the scalp and
hair regularly for more manageability. These agents are usually rubbed into the
scalp, hair shaft, and at times directly applied to the face. In addition, the many
artistic hairstyles being worn by the same population, requires gels and other prod-
ucts to help keep such styles in place. In one study, skin manifestations related to
cultural practices were seen in more than 20 % of patients and most prevalent were
alopecia and hypertrophic scars followed by pomade acne [7].
The underlying etiopathogenesis is believed to be occlusion of sebaceous and fol-
licular openings [7]. Pomades which have been implicated are usually thought to be
cheaper products in which the acneigenic components are impurities [2]. The question
remains whether other factors such as differences in gland size, sebaceous activity, or
follicular hyperkeratinization among races are predisposing factors. The true etiology
is likely multifactorial. The pomades that typically cause pomade acne are weak
acneigens as it generally takes a year or more of daily use to produce the eruption
clinically [2]. In addition, human skin is not considered conducive or the optimal host
for testing comedogenecity. Plewig et al. were able to produce clinically significant
comedones with all six agents in the ear canal of rabbits [2].
22 Pomade Acne 157

The true prevalence of pomade acne is not known. It is, however, less common
than acne vulgaris and typically limited to patients of skin of color. The eruption
occurs in all age groups and is not restricted to the adolescent or young adult [2].
A survey conducted by Taylor et al. showed that 46.2 % of black individuals admit-
ted to hair pomade use. Of them, 70.3 % presented with lesions clinically consistent
with pomade acne [8]. Likewise, Arfan-aul bari et al. reported pomade acne in 103
South African patients or 3.4 % of their study population [7].

22.3 Clinical Presentation

Pomade acne occurs characteristically in African American adults who apply vari-
ous grooming substances to the scalp and hair. The lesions are typically uniform
follicular-based comedones that are in close proximity to one another (Fig. 22.1).
Expression of the contents of lesions with an acne extractor yields a firm material
with a cheesy consistency [2]. Some comedonal lesions show inflammatory changes.
The main ingredients are thought to be materials/hydrocarbons with a high melting
point. These pomades are considered to be weak acneigens as a clinically apparent
eruption isn’t evident after limited use. It generally takes a year or more of daily use
to produce the eruption [2] and this may be in part due to the fact that the finished
products using comedogenic ingredients are not necessarily comedogenic [7].
In addition, human skin is not a very suitable host for testing comedogenicity [2].
The disease is considered to be relatively mild and typically leaves no scars [2]. On
the contrary, due to the inflammatory nature of some of the comedones, pigmentary
alterations have been identified.

Fig. 22.1 While most

common on the face,
especially around the hair
line and forehead, pomade
acne may occur in other areas
where pomades were used.
This middle aged woman
developed this monomorphic
acneiform eruption on the
chest after starting to use a
new pomade body
moisturizer (Photo credit:
Joshua A. Zeichner, M.D.)
158 O. Onwudiwe and V.D. Callender

The histologic picture of pomade acne is indistinguishable from acne vulgaris.

Plewig et al. showed that the comedones contained numerous gram-positive diph-
theroids, marked thinning of the surrounding epithelium, and partial involution of
the sebaceous glands. Few comedones showed inflammatory changes [2]. It is
important to note that comedones in skin of color, when compared to clinical pho-
tographs, the histological inflammatory reaction can be out of proportion from what
is seen clinically. Halder et al. and Davis et al. showed that there was always some
degree of inflammation around simple comedones which were not clinically
inflamed [3, 4].

22.4 Treatment

Discontinuation of the offending agent can lead to resolution in 4–6 months [2]. So
therefore, a discussion of the use of current hair and skin care products should be
done to determine if these practices are involved in the etiology of pomade acne and
should be avoided [4]. Lighter hair moisturizing agents that are less occlusive, such
as silicone-based products (dimethacone) should replace the thicker pomades [4,
9–12]. In addition, hair mositurizers should be applied to the hair shaft only, avoid
scalp application and the hair should be kept off of the face.
For patients with skin of color, optimal treatment for comedones should include
an agent with anti-inflammatory effects to help combat possible pigmentary altera-
tions. As mentioned earlier, in a study conducted by Halder et al., marked inflam-
mation with infiltrates of polymorphonuclear leukocytes was noted in comedonal
lesions of African Americans. Of note, these findings were not seen in the Caucasian
group that was studied [3]. Topical retinoids are seemingly the drug of choice as it
combats follicular hyperkeratosis and concurrently treats post-inflammatory hyper-
pigmentation (PIH). Other topical regimens solo or in combination with retinoids
include azelaic acid, topical dapsone, salicylic acid, benzoyl peroxide, and topical
antibiotics. Hydroquinone-containing medications should also be considered in the
treatment of acne-induced PIH [10, 12].
Comedone extraction and superficial chemical peels, in particular salicylic acid
peels, are useful adjunctive methods of treating open and closed comedones in
patients with pomade acne [13].

References

1. Berlin C. Acne comedo in children due to paraffin oil applied on the head. AMA Arch Derm
Syphilol. 1954;69(6):683–7.
2. Plewig G, Fulton JE, Kligman AM. Pomade acne. Arch Dermatol. 1970;101(5):580–4.
3. Halder RM, Holmes YC, Bridgeman-Shah S, Kligman AM. A clinicohistopathologic study of
acne vulgaris in black females (abstract). J Invest Dermatol. 1996;106:888.
4. Draelos ZD. Black individuals require special products for hair care. Cosmet Dermatol. 1993;
6:19–20.
22 Pomade Acne 159

5. Goode ST. Hair pomades. Cosmet Toil. 1979;94:71–4.

6. Wilborn WS. Disorders in hair growth in African Americans. In: Olsen EA, editor. Disorders
of hair growth. New York: McGraw-Hill Inc.; 1994. p. 389–407.
7. Arfan-ul-Bari, Khan MB. Dermatological disorders related to cultural practices in black
Africans of Sierra Leone. J Coll Physicians Surg Pak. 2007;17(5):249–52
8. Taylor SC, Cook-Bolden F, Rahman Z, et al. Acne vulgaris in skin of color. J Am Acad
Dermatol. 2002;46 Suppl 2:S98–106.
9. Draelos ZD, DiNardo JC. A re-evaluation of the comedogenicity concept. J Am Acad
Dermatol. 2006;54(3):507–12.
10. Davis EC, Callender VD. A review of acne in ethnic skin: pathogenesis, clinical manifesta-
tions, and management strategies. J Clin Aesthetic Dermatol. 2010;3(4):24–38.
11. Callender VD, Davis EC. Cosmetic applicatins. In: Taylor SC, Badreshia-Bansal S, Callender
VD, Cochran-Gathers R, Rodriquez DA, editors. Treatments for skin of color. New York:
Elsevier Saunders; 2011. p. 289–308.
12. Callender VD. Acne in ethnic skin: special considerations for therapy. Dermatol Ther.
2004;17:184–95.
13. Grimes PE, Rendon MI, Pellerano J. Superficial chemical peels. In: Grimes PE, editor.
Aesthetics and cosmetic surgery for darker skin types. Philadelphia, PA: Lippincott Williams
& Wilkins; 2008. p. 154–69.
Chapter 23
Post-adolescent Female Acne

Gillian Heinecke and Diane Berson

23.1 Introduction

While acne has been traditionally considered an adolescent disorder, recent studies
show a significant prevalence among adults. The mean age of presentation for acne
treatment is 24 years with 21 % of acne office visits by patients 25–34 years old and
15 % of these visits by patients 35 years and older [1]. In adults, acne occurs more
frequently among women than men [2]. The characteristic clinical picture is mild to
moderate deep-seated inflammatory papules and nodules on the face, especially the
chin, jawline, and neck. Most commonly, this is “persistent” acne, which began in
adolescence and has continued to adulthood, although a “late-onset” form also
occurs. Recognizing acne in this population and providing treatment is essential
since acne scarring can be correlated with duration of disease [3].

23.2 Background

Community-based clinical examination of adults found that 54 % of women over

25 years have physiological acne and 12 % have clinical acne [2]. The prevalence of
clinical acne in adults does not substantially decrease until after age 45 [2, 4]. While
most adults report that the severity of their acne actually improved after teenage
years, 13.3 % of women report worsening of their acne in adulthood, and for 9.8 % of
women, the acne severity stayed the same [5]. Among the adults with post-adolescent
acne, 50 % had a first-degree relative who also had post-adolescent acne [6].

G. Heinecke B.S. (*)

Department of Dermatology, Mount Sinai, New York, NY, USA
e-mail: [email protected]
D. Berson, M.D.
Department of Dermatology, Weill Cornell Medical College, New York, NY, USA

J.A. Zeichner (ed.), Acneiform Eruptions in Dermatology: A Differential Diagnosis, 161

DOI 10.1007/978-1-4614-8344-1_23, © Springer Science+Business Media New York 2014
162 G. Heinecke and D. Berson

23.3 Pathophysiology

The reason acne persists into adulthood is multifactorial. The most common form of
adult acne is persistence of acne that began in adolescence, and this form appears to
share the same pathogenic features of increased sebum production, follicular hyper-
keratinization, inflammation, and increased Propionibacterium acnes colonization
as seen in adolescent acne [7]. Women with post-adolescent acne have significantly
higher sebum excretion rate compared to women without acne [8]. Since androgens
play a role in stimulating the sebaceous gland, the roles of both systemic and local
tissue-derived androgens have been explored. While most women with post-
adolescent acne have androgen levels in the normal range, several studies report
lower levels of sex hormone-binding globulin (SHBG) and higher levels of free
testosterone and dehydroepiandrosterone sulfate (DHEA-S) in adult female acne
patients compared to controls [9–11]. However, the severity of the acne is not
positively correlated with these levels [9–12]. In patients with signs of hyperan-
drogenism, the presence of an underlying endocrine disorder such as polycystic
ovarian syndrome or late-onset adrenal hyperplasia should be explored.
The skin and sebaceous gland can produce and metabolize androgens. The
presence of several key steroidogenic enzymes, 3β-hydroxysteroid dehydroge-
nase (3β-HSD), 17β-HSD, and 5α-reductase, enables the conversion of inactive
adrenal precursors to potent androgens in the sebaceous gland. Excess local tissue
androgens produced through increased sebaceous steroidogenic enzyme activity
and therefore increased androgen synthesis has been proposed as a cause of the
elevated sebum production seen in adult acne patients [13–15].
Other etiological factors include genetic predisposition, smoking, and stress. The
role of heredity in acne vulgaris is well established by several twin and cross-
sectional studies [16, 17]. The post-adolescent variant also appears to have a genetic
component since 50 % of patients were found to have a first-degree relative also
with post-adolescent acne [6]. While the correlation between smoking and acne in
the general population remains controversial [18, 19], there appears to be a strong
correlation between smoking and the comedonal post-adolescent (CPAA) variant of
acne in adult females [20]. Nicotine has been shown to have a hyperkeratizing effect
by stimulating the acetylcholine receptors on epidermal keratinocytes while also
being anti-inflammatory and vasoconstrictive. This correlates with the clinical pic-
ture of CPAA, a predominance of micro- and macrocomedones with few inflamma-
tory lesions [21]. Chronic stress activating the hypothalamic-pituitary-adrenal
(HPA) axis has also been purported to exacerbate acne. Activation of HPA axis
leads to both enhanced secretion of adrenal androgens and neuropeptides such as
corticotrophin-releasing hormone (CRH). Recent studies demonstrate that CRH
promotes lipid synthesis in the sebaceous gland and that the CRH system is abun-
dantly expressed in acne-involved skin [22].
While antibacterial resistance of P. acnes and use of cosmetics were initially pro-
posed as potential etiological factors, the current evidence suggests that they do
not play a significant role in the pathophysiology of post-adolescent female acne.
23 Post-adolescent Female Acne 163

When the cutaneous microbiology and serum P. acne antibody levels of patients with
either persistent or late-onset post-adolescent acne were compared to adolescent acne
patients, no differences were found between the acne variants [23]. Initially the use of
cosmetics was the attributed etiological factor in the majority of adult females pre-
senting with a mild acneiform eruption, leading Kligman to coin the condition “acne
cosmestica” [24]. While a variety of cosmetic ingredients are known to be comedo-
genic including lanolin, petrolatum, types of vegetable oils, butyl stearate, lauryl
alcohol, and oleic acid, many cosmetic companies now replace these ingredients with
non-comedogenic alternatives [24, 25]. Recent studies suggest that external factors
such as cosmetics, drugs, and occupation are less important etiological factors [6].

23.4 Clinical Features

Classically post-adolescent acne has been divided into two clinical types: persistent
and late onset. Persistent acne represents a continuation of adolescent acne into
adulthood. It is the more prevalent of the two types occurring in 82 % of cases [2].
Late-onset acne occurs for the first time after age 25. The characteristic clinical
picture for both types is mild to moderate deep-seated, tender inflammatory papules
predominantly involving the lower third of the face, jaw line and neck. The shoul-
ders and back may also be affected. Comedonal lesions may occur on the forehead
or lateral margins of the face but they are not prominent. Acne flares that occur
premenstrually or at times of increased psychological stress are common.
Several clinical variants have been described. Comedonal post-adolescent acne
(CPAA) has been documented in darker skin types (type III and IV) and is charac-
terized by the predominance of retention lesions and micro- and macrocomedones,
with fewer than 5 % inflammatory lesions. The comedones are homogenously dis-
tributed over the entire face [20]. While acne scarring is usually attributed to inflam-
matory lesions [26], ice pick scars occur in CPAA patients, and in severe cases
numerous ice pick scars can coalesce into carters [20]. “Chin acne” is a clinical
variant in mature females, which is characterized by premenstrual flares of inflam-
matory papules on the chin and perioral region (see Fig. 23.1). “Sporadic acne”
consists of unpredictable sudden outbreaks of inflammatory papules and pustules in
usually one but sometimes several locations in middle aged and older adults. These
outbreaks usually coincide with a systemic illness or surgical operation, although
inciting events are not always found [27].

23.5 Work-Up

While routine endocrinologic evaluation is not indicated for the majority of acne
patients, this evaluation can be helpful in adult women with recalcitrant or late-
onset acne or those with symptoms of hyperandrogenism including irregular
164 G. Heinecke and D. Berson

Fig. 23.1 Pustules and inflammatory papules on the cheeks and chin of an adult woman. She has
been suffering from acne since her teenage years

menses, hirsutism, alopecia, infertility, deepening of voice, increased libido, acan-

thosis nigricans, and truncal obesity [28]. Features of hyperandrogenism are not
uncommon in adult female acne patients, occurring in 37 % [6] of patients, and
should be sought out by a focused medical history and physical examination.
Polycystic ovarian syndrome (PCOS) is the most common cause of hyperandrogen-
ism in women and is important to be identified since it may impart an increased risk
for type 2 diabetes mellitus and cardiovascular disease [29]. The screening labora-
tory tests for an underlying endocrine disorder consist of serum DHEA-S, total
testosterone, free testosterone, and luteinizing hormone/follicle-stimulating hor-
mone (LH/FSH) ratio (Table 23.1) [31]. Since the hormone surge that occurs with
ovulation can cause an inaccurate assessment, these tests should be drawn either
just before or during the menstrual period. Oral contraceptives may mask underly-
ing hyperandrogenism, therefore the oral contraceptives should be discontinued 4–6
weeks prior to laboratory assessment [31].

23.6 Treatment

The general principles of treating female post-adolescent acne are not significantly
different from treating other acne populations, though there are some subtle differ-
ences that should be considered. Older skin tends to be more sensitive to the poten-
tial irritant effects of topical retinoids but more resistant to the irritant effects of
benzoyl peroxide [27]. Acne is a chronic condition for many of these patients with
81 % of women reporting failures with systemic antibiotics and 15–30 % having
23 Post-adolescent Female Acne 165

Table 23.1 Typical results of screening laboratory tests in women with endocrine abnormalities
[30–32, 35]
Endocrine abnormality Typical screening test abnormalities
Polycystic ovarian syndrome LH/FSH ratio greater than 2–3
Serum total testosterone 70–120 ng/dL
Androstenedione 3–5 ng/mL
50 % of women also have elevation in DHEA-S
Late-onset congenital adrenal DHEAS 4,000–8,000 ng/mL
hyperplasia 17-Hydroxyprogesterone greater than 200 ng/dL
Cushing’s syndrome Overnight dexamethasone suppression test >5 μg/100 mL
Ovarian tumor Serum total testosterone greater than 150–200 ng/dL
Normal serum DHEAS
Adrenal tumor DHEAS >8,000 ng/mL
Serum total testosterone greater than 150–200 ng/dL

Table 23.2 Hormonal modifying treatments of acne [30, 31, 35]

Drug Standard dose Side effects
Androgen receptor blockers
Spironolactone 50–200 mg daily Menstrual irregularities, breast tenderness,
hyperkalemia, birth defects, hypotension,
headache, dizziness, downiness, confusion,
nausea, vomiting, anorexia, diarrhea
Cyproterone acetate 50–100 mg daily Breast tenderness, headache, nausea,
or breakthrough bleeding, fatal hepatotoxicity
2 mg with 35 μg Birth defects
of ethinyl
estradiol
Flutamide 62.5–500 mg daily Breast tenderness, gastrointestinal upset, hot
flashes, decreased libido, fatal hepatitis,
birth defects
Ovarian androgen production blocker
Oral contraceptives Varies depending Menstrual irregularities, breast tenderness,
on specific pill gastrointestinal upset, weight gain,
(see Table 23.3) thromboembolic events, myocardial
infarction
Adrenal androgen production blocker
Glucocorticoids— 2.5–5 mg daily Adrenal suppression (higher risk with
preferably prednisone (at bedtime) dexamethasone)

had recurrence after isotretinoin treatment [30]. Hormonal therapies can be a useful
therapeutic approach and can be effective even in patients with normal serum andro-
gen levels [31]. These include androgen receptor blockers, which block the effect of
the androgens on the sebaceous gland, and inhibitors of androgen production either
by oral contraceptives which block ovarian production or glucocorticoids which
block adrenal production (Table 23.2). Glucocorticoids are most commonly used to
treat patients with late-onset adrenal hyperplasia.
166 G. Heinecke and D. Berson

Table 23.3 Oral contraceptives used in treatment of female acne

Ethinyl
Trade name estradiol (μg) Progesterone (mg)
FDA approved
Estrostep 20/30/35 Norethindrone 1
(Warner Chilcott Company Inc., Fajardo, Puerto Rico)
Ortho Tri-Cyclen 35 Norgestimate
(Ortho-McNeil Pharmaceutical Inc., Raritan, NJ) 0.18/0.215/0.25
Yaz 30 Drospirenone 3
(Bayer Healthcare Pharmaceuticals Inc., Wayne, NJ)
Non-FDA approved
Alesse 20 Levonorgestrel 0.1
(Wyeth Pharmaceuticals Inc. A Wyeth-Ayerst Company
Philadelphia, PA)
Desogen 30 Desogestrel 0.15
(N.V. Organon, Oss, Holland or Organon (Ireland) Ltd.,
*Swords, Co. Dublin, Ireland)
Diane-35 35 Cyproterone 2
(Bayer Schering Pharma, Berlin, Germany)
Femodene/Femovan 30 Gestodene .75
(Bayer HealthCare Pharmaceuticals Inc. Wayne, NJ)
Mircette 20/10 Desogestrel 0.15
(Duramed Pharmaceuticals Inc., subsidiary of Barr
Pharmaceutical, Inc., Pomona, NY)
Nordette/Microgynon/Levlen 30 Levonorgestrel 0.15
(Duramed Pharmaceuticals Inc., subsidiary of Barr
Pharmaceutical, Inc., Pomona, NY)
Ortho Cyclen 35 Norgestimate 0.25
(Ortho-McNeil Pharmaceutical Inc. Raritan, NJ)
Triphasil 30/40/30 Levonorgestrel
(Wyeth Laboratories, A Wyeth-Ayerst Company 0.5/0.75/0.125
Philadelphia, PA)
Yasmin 30 Drospirenone 3
(Bayer Healthcare Pharmaceuticals Inc., Wayne, NJ)

The class of androgen receptor blockers includes spironolactone, cyproterone

acetate, and flutamide. In the United States, none of these agents are FDA approved
for the treatment of acne, and cyproterone acetate is not available [31]. Spironolactone
is the most commonly used and has been shown to effectively control female acne
at dosages of 25–200 mg daily [33, 34]. Side effects are dose dependent with the
most common in women being menstrual irregularities and breast tenderness/
enlargement. Hyperkalemia can occur and it is generally recommended to check
potassium levels in older patients with comorbidities or 1 month into therapy when
high doses are utilized [30]. Spironolactone is contraindicated in pregnancy due to
the risk of hypospadias and feminization of the male fetus with prenatal exposure.
Due to the risk of birth defects and to minimize side effects spironolactone is usu-
ally used in combination with an oral contraceptive pill [35].
23 Post-adolescent Female Acne 167

Combination estrogen and progestin oral contraceptives reduce the production of

ovarian androgens and sebum through the inhibition of LH and FSH. They are
particularly useful in women with acne who also desire the contraceptive benefits.
While several oral contraceptives have been studied specifically for the treatment of
acne (Table 23.3), only four (Ortho Tri-Cyclen®, Estrostep®, Yaz®, and Beyaz®) are
FDA approved for this purpose [35]. While the use of oral contraceptives is gener-
ally considered safe, potential adverse events must be considered before prescrib-
ing. The most serious potential side effects are thromboembolic events and
myocardial infarction, however in healthy nonsmokers under 35 years of age the
risk is low. Contraindications to oral contraceptives include pregnancy, history of
thromboembolic or heart disease, smoking, liver disease, hypertension, diabetes,
migraine, breast feeding and certain malignancies including current breast and liver
cancer [36]. Oral contraceptives are usually used in combination with other modali-
ties for the treatment of female acne.

23.7 Conclusion

Acne vulgaris is a disease that affects not only teenagers but also adults. It can be a
source of significant psychological impairment and interfere with interpersonal and
professional activities. A full work-up is important in evaluating these patients to
rule out potential endocrine abnormalities. While many of the same treatments can
be used in adult women as other patients with acne, an additional option includes
the use of hormonal and anti-androgen therapies.

References

1. McConnell RC, Fleischer Jr AB, Willford PM, Feldman SR. Most topical tretinoin treatment
is for acne vulgaris through the age of 44 years: an analysis of the national ambulatory medical
care survey, 1990–1994. J Am Acad Dermatol. 1998;38:221–6.
2. Goulden V, Stables GI, Cunliffe WJ. Prevalence of facial acne in adults. J Am Acad Dermatol.
1999;41:577–80.
3. Layton AM, Henderson K, Cunliffe WJ. A clinical assessment of acne scarring. Clin Exp
Dermatol. 1994;4:303–8.
4. Cunliffe WJ, Gould DJ. Prevalence of facial acne vulgaris in late adolescence and in adults. Br
Med J. 1979;1:1109–10.
5. Collier CN, Harper JC, Cafardi JA, et al. The prevalence of acne in adults 20 years and older.
J Am Acad Dermatol. 2008;58:56–9.
6. Goulden V, Clark SM, Cunliffe WJ. Post-adolescent acne: a review of clinical features. Br
J Dermatol. 1997;136:66–70.
7. Gollnick H, Cunliffe W, Berson D, et al. Management of acne: a report from a global alliance
to improve outcomes in acne. J Am Acad Dermatol. 2003;49:S1–37.
8. McGeown CH, Goulden V, Holland DB, et al. Sebum excretion rate in post-adolescent acne
compared to controls and adolescence acne. J Invest Dermatol. 1997;108:386.
9. Aizawa H, Niimura M. Adrenal androgen abnormalities in women with late onset and persis-
tent acne. Arch Dermatol Res. 1993;284:451–5.
168 G. Heinecke and D. Berson

10. Darley CR, Kirby JD, Besser GM et al. Circulating testosterone, sex hormone binding globulin
and prolactin in women with late onset or persistent acne vulgaris
11. Seirafi H, Farnaghi F, Vasheghani-Farahani A, et al. Assessment of androgens in women with
adult-onset acne. Int J Dermatol. 2007;46:1188–91.
12. Cibula D, Hill M, Vohradnikova O, Kuzel D, Fanta M, Zivny J. The role of androgens in
determining acne severity in adult women. Br J Dermatol. 2000;143:399–404.
13. Lookingbill DP, Horton R, Demers LM, Egan N, Marks Jr JG, Santen RJ. Tissue production of
androgens in women with acne. J Am Acad Dermatol. 1985;12:481–7.
14. Carmina E, Lobo RA. Evidence for increased androsterone metabolism in some normandro-
genic women with acne. J Clin Endocrinol Metab. 1993;76:1111–4.
15. Carmina E, Godwin AJ, Stanczyk FZ, Lippman JS, Lobo RA. The association of serum
androsterone glucuronide with inflammatory lesions in women with adult acne. J Endocrinol
Invest. 2002;25:765–8.
16. Cunliffe WJ. Natural history of acne. In: Plewig G, Marks R, editors. Acne and related
disorders. London: Martin Dunitz; 1989. p. 4–6.
17. Ballanger F, Baudry P, N’Guyen JM, Khammari A, Dréno B. Heredity: a prognostic factor for
acne. Dermatology. 2006;212:145–9.
18. Schäfer T, Nienhaus A, Vieluf D, Berger J, Ring J. Epidemiology of acne in the general
population: the risk of smoking. Br J Dermatol. 2001;145:100–4.
19. Mills CM, Peters TJ, Finlay AY. Does smoking influence acne? Clin Exp Dermatol.
1993;18:100–1.
20. Capitanio B, Sinagra JL, Bordignon V, Cordiali Fei P, Picardo M, Zouboulis CC. Underestimated
clinical features of post-adolescent acne. J Am Acad Dermatol. 2010;63:782–8.
21. Misery L. Nicotine effects on the skin: are they positive or negative? Exp Dermatol. 2004;
13:665–70.
22. Ganceviciene R, Graziene V, Fimmel S, Zouboulis CC. Involvement of the corticotropin-releasing
hormone system in the pathogenesis of acne vulgaris. Br J Dermatol. 2009;160:345–52.
23. Till AE, Goulden V, Cunliffe WJ, Holland KT. The cutaneous microflora of adolescence,
persistent and late-onset acne patients does not differ. Br J Dermatol. 2000;142:885–92.
24. Kligman AM, Mills Jr OH. Acne Cosmetica. Arch Dermatol. 1975;106:843–50.
25. Nelson FP, Rumsfield J. Cosmetics. Content and function. Int J Dermatol. 1988;27:665–72.
26. Rivera AE. Acne scarring: a review and current treatment modalities. J Am Acad Dermatol.
2008;59:659–76.
27. Marks R. Acne and its management beyond the age of 35 years. Am J Clin Dermatol. 2004;
5:459–62.
28. Strauss JS, Krowchuk DP, Leyden JJ, et al. Guidelines of care for acne vulgaris management.
J Am Acad Dermatol. 2007;56:651–63.
29. Goudas VT, Dumesic DA. Polycystic ovary syndrome. Endocrinol Metab Clin North Am.
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Dermatol. 2009;2:16–22.
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33. Goodfellow A, Alaghband-Zadeh J, Carter G, et al. Oral spironolactone improves acne vulgaris
and reduces sebum excretion. Br J Dermatol. 1984;111:209–14.
34. Saint-Jean M, Ballanger F, Nguyen JM, Khammari A, Dreno B. Importance of spironolactone
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Chapter 24
SAPHO Syndrome

Caroline L. LaRosa and Andrea L. Zaenglein

24.1 Introduction

SAPHO syndrome is a chronic rheumatologic disorder that involves the skin, bone,
and joints. The name SAPHO is an acronym for the primary manifestations
associated with this disorder: synovitis, acne, pustulosis, hyperostosis, and osteitis.
It is listed by the National Institutes of Health as a rare disease, but it is an important
one for physicians to include in their differential diagnosis for acne as it is often
misdiagnosed and under-recognized.

24.2 Background

As a result of the lack of awareness and difficulty in diagnosing SAPHO syndrome,

it may be unrecognized or misdiagnosed, and therefore, the exact prevalence is
unknown [1, 2]. SAPHO typically affects children and young to middle-aged adults
[3]. There is no sexual predilection. Familial cases have been reported but are rare.
The etiology of SAPHO syndrome is still largely unknown, but it is likely the
result of a complex interaction between various genetic and immunologic factors.
Inflammation, particularly abnormal neutrophil function and response, affects the
skin and bones.
Genetic predisposition plays a prominent role in patients with SAPHO syn-
drome. Certain genes have been suspected as having a role in SAPHO due to their
association with other inflammatory disorders. These candidate genes include the
proline-serine-threonine phosphatase-interacting protein 2 gene (PSTPIP2), which

C.L. LaRosa, B.S. • A.L. Zaenglein, M.D. (*)

Department of Dermatology and Pediatrics, Penn State/Milton S. Hershey Medical Center,
500 University Drive, Hershey, PA 17033, USA

J.A. Zeichner (ed.), Acneiform Eruptions in Dermatology: A Differential Diagnosis, 169

DOI 10.1007/978-1-4614-8344-1_24, © Springer Science+Business Media New York 2014
170 C.L. LaRosa and A.L. Zaenglein

encodes a protein expressed on macrophages and is involved in macrophage motility.

In addition, the LPIN2 gene may be involved, as it encodes a protein involved in
lipid metabolism and inflammation [4]. Mutations of the LPIN2 gene also play a
role in Majeed syndrome, which shares the SAPHO feature of chronic recurrent
multifocal osteomyelitis. Finally, the NOD2 gene is also a candidate, as it is involved
in the development of bacterial recognition and inflammation. NOD2 is also strongly
associated with Crohn’s disease. While no variants in any of these genes have been
found consistently in SAPHO patients, two rare variants of LPIN2 have been asso-
ciated in SAPHO patients with psoriasis. The LPIN2 locus is weakly associated
with the psoriasis susceptibility locus, PSORS10, and therefore may account for the
psoriasis component of SAPHO in some patients. While there is similarity between
psoriasis and SAPHO, affected individuals do not show a predominance of class II
HLA genes (HLA-B27, HLA-Cw6, or HLA-DR) typical for psoriasis [3]. Evidence
for the genetic basis of a SAPHO-like phenotype was found in the observance of
neutrophil defects in patients with SAPHO [5]. A significant reduction in oxidant
production in neutrophils was observed in one patient with SAPHO syndrome, and
the same reduced internal oxidative burst was observed in neutrophils isolated from
the patient’s mother, who had a similar SAPHO-like phenotype. This example of
familial SAPHO-like syndrome showed a response to anti-inflammatory medica-
tions, suggestive of an autoinflammatory disorder.
Due to the association between acne and SAPHO syndrome, Propionibacterium
acnes (P. acnes), a follicular gram-positive anaerobic bacterium that plays a substan-
tial role in the pathogenesis of acne, is being investigated as a causative agent. P. acnes
can be strong inducer of innate immunity through the Toll-like receptor 2 pathway. To
what extent its role is in SAPHO is unclear. Bone biopsies performed on six patients
with SAPHO only found P. acnes in one specimen, indicating that it is not often found
in bone lesions of patients with SAPHO [6]. It is thought that P. acnes may be a trigger
for global neutrophil activation and a widespread inflammatory response [7]. Two
immunomodulators, interleukin (IL)-8 and tumor necrosis factor (TNF)-α, were
found at higher levels in patients with SAPHO syndrome. Yet P. acnes-induced pro-
duction of IL-8 and TNF-α in polymorphonuclear neutrophils was impaired in patients
with SAPHO as compared to those with rheumatoid arthritis and psoriatic arthritis [7].
Taken together, this evidence suggests that SAPHO syndrome may be triggered by the
effects of P. acnes in initiating a strong cellular inflammatory response.

24.3 Clinical Presentation

The clinical course of the SAPHO syndrome has great variability between patients.
Proposed diagnostic criteria require one of the three following criteria [8]:
1. Chronic recurrent multifocal osteomyelitis
(a) Usually sterile
(b) Spine may be involved
(c) With or without skin condition
24 SAPHO Syndrome 171

Table 24.1 Cutaneous Commonly associated Less commonly associated

presentations of SAPHO
Palmoplantar pustulosis Sneddon-Wilkinson disease
syndrome
Acne fulminans Linear IgA bullous dermatosis
Acne conglobata Behçet’s disease
Psoriasis Sweet’s syndrome
Pustular psoriasis Pyoderma gangrenosum
Hidradenitis suppurativa

2. Acute, subacute or chronic arthritis associated with any of the following:

(a) Palmoplantar pustulosis
(b) Pustular psoriasis
(c) Severe acne
3. Any sterile (or P. acnes-positive) osteitis associated with any of the following:
(a) Palmoplantar pustulosis
(b) Pustular psoriasis
(c) Psoriasis vulgaris
(d) Severe acne
The main dermatologic findings of SAPHO syndrome include severe acne and
neutrophilic, pustular dermatoses. Palmoplantar pustulosis (PPP), the most com-
mon skin manifestation, presents as chronic, yellowish intradermal sterile pustules
on the palms and soles. Acne is generally more severe, such as acne fulminans or
acne conglobata, but can be mild in some cases. Hidradenitis suppurativa and
dissecting cellulitis of the scalp have also been reported. Psoriasis, especially
pustular psoriasis, is also associated with SAPHO syndrome. Sweet’s syndrome and
pyoderma gangrenosum has also been described in a patient with SAPHO syndrome
highlighting the overlap of neutrophilic disorders [9]. Table 24.1 lists the cutaneous
disorders associated with SAPHO syndrome.
Skin lesions do not always present at the time of the osteoarticular manifesta-
tions. They may precede, occur simultaneously, or follow the bone and joint
symptoms. Skin lesions usually appear within a 2-year time period, though some
report onset 20 years following initial diagnosis [10], a study of 120 patients
revealed 66 % with PPP, 31 % with psoriasis, and 25 % with severe acne [3].
Approximately 16 % of patients did not exhibit any cutaneous manifestations.
Musculoskeletal findings associated with SAPHO syndrome are characterized by
osteitic and hyperostotic bone lesions [8, 11]. Most patients experience pain, soft
tissue swelling, and limitations in mobility of the involved area. The osteoarticular
findings often display an age-dependent pattern. In adults, synovitis affects the
joints of the anterior chest wall, sacroiliac joins, and, to a lesser extent, the periph-
eral joints. Other typical osteoarthritic manifestations include hyperostosis and oste-
itis, both symptoms of a chronic inflammatory reaction. Hyperostosis sometimes,
172 C.L. LaRosa and A.L. Zaenglein

though rarely, involves the pelvis and the long bones. In children and young adults,
osteomyelitis has a preference for the anterior chest wall, particularly the clavicle,
and often displays multiple, symmetric lesions along the metaphyses of long bones.
Chronic recurrent multifocal osteomyelitis (CRMO), a chronic nonbacterial
osteomyelitis, manifests as recurrent flares of inflammatory bone pain, typically
involving the metaphyses of long bones, and may present with or without fever.
Some consider CRMO to be the pediatric equivalent of SAPHO syndrome or at
least in the same spectrum of disease [11, 12].
Though usually confined to the skin, bone, and joints, systemic symptoms such
as fever sometimes occur [13]. Inflammatory bowel disease, both Crohn’s disease
and ulcerative colitis, have been associated [3, 14].

24.4 Work-Up

Laboratory blood tests are often useful but rarely diagnostic in SAPHO syndrome.
The erythrocyte sedimentation rate (ESR) is usually elevated, indirectly indicative
of the inflammation associated with synovitis, acne, pustulosis, and osteitis. The
ESR is a screening test and cannot be used to diagnose SAPHO syndrome but may
be used for monitoring the degree of inflammation in patients. Similarly, elevated
C-reactive protein (CRP) values may also indicate degree of inflammation in the
condition.
Definitive diagnosis is difficult and often requires confirmation by scintigraphy
or histopathology of bony lesions. Bone metastasis cannot completely be ruled out
by scintigraphy alone, and fluorodeoxyglucose positron emission tomography
(FDG-PET) is used for definitive exclusion of metastatic bone tumors [15, 16].
Bone scans, CT scans, and even full-body MRI are also helpful diagnostically in
establishing sites of bone involvement. Radiological features of SAPHO syndrome
are mainly hyperostosis and osteitis. Multiple skeletal sites may be involved and the
lesions can occur simultaneously or successively. Hyperostosis is characterized by
a chronic periosteal reaction and cortical thickening that results in narrowing of the
medullary canal and leads to hypertrophy.
Bone biopsy may be performed to confirm a diagnosis of CRMO or to distin-
guish unifocal CRMO from a tumor or infection. Histopathological analysis of the
biopsy specimen may show Paget-like hyperostosis and inflammatory cell infiltra-
tion. Inflammation characterizes the acute phase, which shows polymorphonuclear
leukocytes, plasma cells, edema, and prominent periostitis. The later phase has less
evident inflammation but displays enlarged and sclerotic trabeculae and increased
marrow fibrosis.
Skin biopsy will reveal the histopathologic findings characteristic of the associ-
ated skin finding such as acne or pustular psoriasis. Polymorphonuclear leukocytes
characteristically predominate the various skin lesions associated with SAPHO
syndrome.
24 SAPHO Syndrome 173

24.5 Treatment

Treatment for SAPHO syndrome is based on the severity of presentation and gener-
ally aimed at reducing the associated inflammation in the affected organ system,
bone, or skin. Treatment options and effects are listed in Table 24.2.
If severe acne is seen, prompt and aggressive systemic treatment with oral tetra-
cyclines or isotretinoin should be started to prevent scarring. The addition of oral
corticosteroids may be necessary to control inflammation when starting isotretinoin.
Etanercept has been used in severe refractory cases.
For the psoriatic manifestations (palmoplantar pustulosis, pustular psoriasis, or
pustular psoriasis), topical corticosteroids may be used to control mild and limited
presentations. The addition of phototherapy with narrowband UVB is typically con-
sidered second-line therapy for most patients with psoriatic skin lesions. For exten-
sive, severe, or refractory disease, oral retinoids, methotrexate, or anti-TNF-α agents
or PUVA could be employed depending on the age of the patient and comorbid
factors as well as the severity of joint disease. Combinations of these therapies may
be required in those patients unresponsive to monotherapy.

Table 24.2 Treatment of SAPHO syndrome

Treatment of skin manifestations
Disorder Treatment
Acne conglobata Oral tetracyclines (tetracycline, doxycycline,
Acne fulminans minocycline)
Isotretinoin
Oral corticosteroids
Palmoplantar pustulosis Mid to high potency topical corticosteroids
Pustular psoriasis Methotrexate
Psoriasis Etanercept or other anti-TNF-α agents
Phototherapy
Hidradenitis suppurativa Oral tetracyclines (tetracycline, doxycycline,
minocycline)
Isotretinoin
Etanercept or other anti-TNF-α agents
Treatment of joint manifestations
Medication Effect
NSAIDs Pain relief and anti-inflammatory
Corticosteroids (intralesional or oral) Anti-inflammatory
Methotrexate Anti-inflammatory
Oral antibiotics (doxycycline, azithromycin, Antibiotic (in P. acnes-positive joint
clindamycin) cultures)
Etanercept or other anti-TNF-α agents Anti-inflammatory
Pamidronate or other bisphosphonates To prevent bone loss
Colchicine Anti-inflammatory
Sulfasalazine Anti-inflammatory
174 C.L. LaRosa and A.L. Zaenglein

For the joint disease, a variety of standard therapies are used. Nonsteroidal
anti-inflammatory drugs (NSAIDs), such as aspirin, ibuprofen, and naproxen are
first-line drugs used to provide relief from bone pain. Corticosteroids, including oral
or intralesional injection, as well as topical cold applications, are also used to treat
the inflammatory symptoms. Successful prolonged antibiotic therapy has also been
reported for cases where bone biopsy is positive for P. acnes, but flaring occurs with
discontinuation [17]. Sulfasalazine and methotrexate are used for more severe cases
or for patients with persistent joint pain. Etanercept, an anti-TNF-α biological agent,
has shown success in several case reports as well [18, 19]. Of note, life-threatening
disseminated tuberculosis was observed as a complication of TNF-α blockade in a
17-year-old female with SAPHO, highlighting the need for careful screening of
patients prior to initiating systemic biologic therapies [20]. Combination therapy is
often required to control the disease. Pamidronate or other bisphosphonates have
demonstrated success in some uncontrolled series and case reports in preventing
bone loss [21].

24.6 Conclusion

Dermatologists should be familiar with the association between cutaneous neutro-

philic disorders and sterile arthritis. An understanding of SAPHO syndrome is use-
ful in providing a link between several idiopathic disorders that share clinical,
radiological, and pathologic characteristics. Proper identification of patients with
SAPHO will help by unifying the diagnosis and establishing a cohesive treatment
plan for affected individuals.

References

1. Karadag-Saygi E, et al. SAPHO syndrome: misdiagnosed and operated. Acta Reumatol Port.
2008;33(4):460–3.
2. Van Doornum S, et al. SAPHO: rare or just not recognized? Semin Arthritis Rheum.
2000;30(1):70–7.
3. Hayem G, et al. SAPHO syndrome: a long-term follow-up study of 120 cases. Semin Arthritis
Rheum. 1999;29(3):159–71.
4. Hurtado-Nedelec M et al. Genetic susceptibility factors in a cohort of 38 patients with SAPHO
syndrome: a study of PSTPIP2, NOD2, and LPIN2 genes. J Rheumatol. 2010;37(2):401–9.
5. Ferguson PJ, et al. Neutrophil dysfunction in a family with a SAPHO syndrome-like pheno-
type. Arthritis Rheum. 2008;58(10):3264–9.
6. Colina M, et al. Propionibacterium acnes and SAPHO syndrome: a case report and literature
review. Clin Exp Rheumatol. 2007;25(3):457–60.
7. Hurtado-Nedelec M, et al. Characterization of the immune response in the synovitis, acne,
pustulosis, hyperostosis, osteitis (SAPHO) syndrome. Rheumatology. 2008;47(8):1160–7.
8. Kahn M-F, Khan MA. The SAPHO syndrome. Baillière's Clin Rheumatol. 1994;8(2):333–62.
9. Bachmeyer C, et al. Overlapping neutrophilic dermatosis in a patient with SAPHO syndrome.
Arch Dermatol. 2007;143(2):275–6.
24 SAPHO Syndrome 175

10. Davies AM, et al. SAPHO syndrome: 20-year follow-up. Skeletal Radiol. 1999;28(3):159–62.
11. Earwaker JW, et al. SAPHO: syndrome or concept? Imaging findings. Skeletal Radiol. 2003;
32(6):311–27.
12. Tlougan BE, et al. Chronic recurrent multifocal osteomyelitis (CRMO) and synovitis, acne,
pustulosis, hyperostosis, and osteitis (SAPHO) syndrome with associated neutrophilic dermato-
ses: a report of seven cases and review of the literature. Pediatr Dermatol. 2009;26(5):497–505.
13. Beretta-Piccoli BC, et al. Synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome
in childhood: a report of ten cases and review of the literature. Eur J Pediatr. 2000; 159(8):
594–601.
14. Colina M, et al. Clinical and radiologic evolution of synovitis, acne, pustulosis, hyperostosis,
and osteitis syndrome: a single center study of a cohort of 71 subjects. Arthritis Rheum.
2009;61(6):813–21.
15. Quirico Rodriguez M et al. The importance of bone scintigraphy in the diagnosis of SAPHO
syndrome. Rev Esp Med Nucl. 2010;29(3):127–30.
16. Salles M et al. The SAPHO syndrome: a clinical and imaging study. Clin Rheumatol.
2011;30(2):245–9.
17. Assmann G, et al. Efficacy of antibiotic therapy for SAPHO syndrome is lost after its
discontinuation: an interventional study. Arthritis Res Ther. 2009;11(5):R140.
18. Vilar-Alejo J et al. SAPHO syndrome with unusual cutaneous manifestations treated success-
fully with etanercept. Acta Derm Venereol. 2010;90(5):531–2.
19. Ben Abdelghani K et al. Tumor necrosis factor-alpha blockers in SAPHO syndrome.
J Rheumatol. 2010;37(8):1699–704.
20. Hess S et al. Life-threatening disseminated tuberculosis as a complication of TNF-α blockade
in an adolescent. Eur J Pediatr. 2011;170(10):1337–42.
21. Ichikawa J, et al. Successful treatment of SAPHO syndrome with an oral bisphosphonate.
Rheumatol Int. 2009;29(6):713–5.
 Part IV
Genetic Syndromes Mimicking
Acne Vulgaris
Chapter 25
Apert Syndrome

Yasser Albahrani and Joshua A. Zeichner

25.1 Introduction

Apert syndrome is a condition characterized by skeletal abnormalities as well as

acne. It was first described in two cases by Wheaton in 1894 [1, 2] and by renowned
French pediatrician Eugène Charles Apert, who in 1906 reported several individuals
with congenital malformations of the skull and syndactyly of the hands and feet [3].

25.2 Background

Also known as acrocephalosyndactyly type I (ACS1), Apert syndrome is a rare

congenital disorder that affects males and females equally. While generally consid-
ered to have an autosomal dominant inheritance pattern, the majority of cases are
due to sporadic mutations. Apert syndrome incidence ranges from 1 in 160,000 to
1 in 2,000,000 live births [4, 5].
A missense germ-line mutation in the fibroblast growth factor receptor 2 (FGFR2)
gene mapped to chromosome 10q25-10q26 has been identified in Apert syndrome.
This gain-of-function mutation leads to increased FGF binding, upregulation of
PI3K⁄Akt, and a resulting reduction of FoxO1, a transcription factor suggested to
play an important role in sebaceous gland activity [6–11]. Thus, patients with Apert
syndrome may have an atypical sensitivity to normal levels of circulating androgens
rather than an excess number of androgen receptors [12].

Y. Albahrani M.D. • J.A. Zeichner, M.D. (*)

Department of Dermatology, Mt. Sinai School of Medicine, New York, NY, USA

J.A. Zeichner (ed.), Acneiform Eruptions in Dermatology: A Differential Diagnosis, 179

DOI 10.1007/978-1-4614-8344-1_25, © Springer Science+Business Media New York 2014
180 Y. Albahrani and J.A. Zeichner

25.3 Clinical Presentation

Apert syndrome is part of the acrocephalosyndactyly spectrum, which is classified

into five subtypes:
Type I Apert syndrome
Type II Vogt Cephalosyndactyly
Type III Saethre-Chotzen syndrome
Type IV Waardenburg syndrome
Type V Pfeiffer syndrome
Cutaneous manifestations of Apert syndrome include moderate to severe resistant
acne, oily skin, hyperhidrosis, interrupted eyebrows, excessive forehead wrinkling,
lateral plantar hyperkeratosis, skin dimpling over joints, and oculocutaneous
hypopigmentation [13–15].
Acne in Apert syndrome typically begins in early puberty in the form of
comedones, papules, pustules, nodules, and cysts. Patients suffer from extensive
post-inflammatory pigment alteration and scarring of varying severity. The dis-
tribution is usually widespread affecting face, chest, back, arms, buttocks, and
thighs [1, 16, 17].
The severity of the clinical features of Apert syndrome is varied. Patients suffer
from bony abnormalities of the head including craniosynostosis (premature fusion
of one or more of the skull fibrous sutures), midfacial hypoplasia, broad nasal
bridge, micrognathia, and a cleft palate. In addition, they have a prominent fore-
head, proptosis, and low-set ears. Other bony changes include vertebral fusion,
severe symmetric syndactyly (fusion of digits), and symphalangism (fusion of pha-
langes to the digits). Craniosynostosis often leads to elevated cranial pressure and
variable degrees of mental impairment [1].

25.4 Work-Up

Diagnosis of Apert syndrome is made based on the clinical constellation of find-

ings. A thorough history should be obtained with a complete list of medications
that can cause acneiform eruptions. A laboratory work-up should be performed to
evaluate endocrine function. Skin cultures may be performed to evaluate pustular
lesions.

25.5 Treatment

Management of Apert syndrome is shared among different medical specialties.

Surgical interventions may be necessary to address bony abnormalities of the skull
and face. Evaluation for chronic infections of airways and ears with possible
25 Apert Syndrome 181

continuous positive airway pressure (CPAP) machines and placement of ear tubes
must be performed. Finally behavioral and psychological interventions may be
necessary for social and intellectual impairments.
For cutaneous disease, topical therapy may suffice in mild to moderate cases of
acne. In resistant or more severe patients, oral therapies may be added. Oral isotreti-
noin has been reported to be successful in treating severe, nodulocystic acne in
patients with Apert syndrome [18–22]. One published report describes a female
patient with Apert syndrome put on an oral contraceptive pill to treat a large ovarian
cyst, who experienced a significant improvement of her acne [23].

References

1. Cunningham ML, Seto ML, Ratisoontorn C, Heike CL, Hing AV. Syndromic craniosynostosis:
from history to hydrogen bonds. Orthod Craniofac Res. 2007;10(2):67–81.
2. Wheaton SW. Two specimens of congenital cranial deformity in infants associated with fusion
of the fingers and toes. Trans Pathol Soc Lond. 1894;45:238.
3. Steffen C. The man behind the eponym. Eugene Apert (1868–1940). Am J Dermatopathol.
1984;6:223–4.
4. Boulet SL, Rasmussen SA, Honein MA. A population-based study of craniosynostosis in
metropolitan Atlanta, 1989–2003. Am J Med Genet A. 2008;146A:984–91.
5. Blank CE. Apert’s syndrome (a type of acrocephalosyndactyly)—observations on British
series of 39 cases. Ann Hum Genet. 1950;24:151–63.
6. Melnik BC. Role of FGFR2-signaling in the pathogenesis of acne. Dermatoendocrinol.
2009;1(3):141–56.
7. Melnik BC. FoxO1- the key for the pathogenesis and therapy of acne? J Dtsch Dermatol Ges.
2010;8:105–14.
8. Melnik BC. Is nuclear deficiency of FoxO1 due to increased growth factor⁄PI3K⁄Akt-signalling
in acne vulgaris reversed by isotretinoin treatment? Br J Dermatol. 2010;162:1398–400.
9. Wilkie AO, Slaney SF, Oldridge M, et al. Apert syndrome results from localized mutations of
FGFR2 and is allelic with Crouzon syndrome. Nat Genet. 1995;9:165–72.
10. Melnik BC, Schmitz G, Zouboulis CC. Anti-acne agents attenuate FGFR2 signal transduction
in acne. J Investig Dermatol. 2009;129:1868–77.
11. Chen W, Obermayer-Pietsch B, Hong JB, et al. Acne-associated syndromes; models for better
understanding of acne pathogenesis. J Eur Acad Dermatol Venereol. 2011;25:637–46.
12. Henderson CA, Knaggs H, Clark A, Highet AS, Cunliffe WJ. Apert’s syndrome and androgen
receptor staining of the basal cells of sebaceous glands. Br J Dermatol. 1995;132:139–43.
13. Freiman A, Tessler O, Barankin B. Apert syndrome. Int J Dermatol. 2006;45:1341–3.
14. Cohen MM, Kreiborg S. Cutaneous manifestations of Apert syndrome. Am J Med Genet.
1995;58:94–6.
15. Cohen Jr MM, Kreiborg S. Visceral anomalies in the Apert syndrome. Am J Med Genet.
1993;45:758–60.
16. Solomon LM, Fretzin D, Pruzansky S. Pilosebaceous abnormalities in Apert’s syndrome. Arch
Dermatol. 1970;102:381–5.
17. Atherton DJ, Rebello T, Wells RS. Apert’s syndrome with severe acne vulgaris. Proc Roy Soc
Med. 1976;69:517–8.
18. Downs AMR, Condon CA, Tan R. Isotretinoin therapy for antibiotic-refractory acne in Apert’s
syndrome. Clin Exp Dermatol. 1999;24:461–3.
19. Robinson D, Wilms NA. Successful treatment of the acne of Apert syndrome with isotretinoin.
J Am Acad Dermatol. 1989;21:315–6.
182 Y. Albahrani and J.A. Zeichner

20. Campanati A, Marconi B, Penna L, Paolinelli M, Offidani A. Pronounced and early acne in
Apert’s syndrome: a case successfully treated with oral isotretinoin. Eur J Dermatol. 2002;
12:496–8.
21. Gilaberte M, Puig L, Alomar A. Isotretinoin treatment of acne in a patient with Apert
syndrome. Pediatr Dermatol. 2003;20:443–6.
22. Parker TL, Roth JG, Esterly NB. Isotretinoin for acne in Apert syndrome. Pediatr Dermatol.
1992;9:298–300.
23. Hsieh T, Ho N. Resolution of acne following therapy with an oral contraceptive in a patient
with Apert syndrome. J Am Dermatol. 2005;53(1):173–4.
Chapter 26
Birt-Hogg-Dubé Syndrome

Kristina Goldenberg and Gary Goldenberg

26.1 Introduction

Birt-Hogg-Dubé syndrome (BHD), also known as fibrofolliculomas with trichodiscomas

and acrochordons syndrome, is an autosomal dominant genodermatosis [1]. Internal
tumors, such colonic polyps and renal carcinomas, have also been described in
these patients. This condition was originally described in 1977, when Birt, Hogg,
and Dubé described a family in which 15 of 70 members over three generations
exhibited multiple, skin-colored, dome-shaped papules distributed over the face,
neck, and upper trunk [2, 3]. It has been shown that BHD is caused by a germline
mutation in the FLCN (folliculin) gene (Online Mendelian Inheritance in Man
#135150) [4].

26.2 Background

The gene locus for BHD was identified in 2001, localized to chromosome 17p11.2
by linkage analysis [5, 6]. Nickerson and colleagues later described a truncating
germline mutation in a novel gene, the FLCN (BHD) gene, coding for a protein of
unknown function called folliculin (FLCN) [7]. Chromosome 17p11.2 contains 14
exons and encodes folliculin. This evolutionary conserved protein of 579 amino
acids that has no major homology to any other human protein and its function is
unknown. Tumor suppressor function for FLCN was noted in BHD-associated
renal tumors, consistent with somatic second-hit mutations [8], and loss of FLCN

K. Goldenberg, M.D. (*)

Department of Dermatology, Mt. Sinai School of Medicine, New York, NY, USA
G. Goldenberg, M.D. (*)
Department of Dermatology, The Mount Sinai Hospital, New York, NY, USA

J.A. Zeichner (ed.), Acneiform Eruptions in Dermatology: A Differential Diagnosis, 183

DOI 10.1007/978-1-4614-8344-1_26, © Springer Science+Business Media New York 2014
184 K. Goldenberg and G. Goldenberg

mRNA expression was found in renal tumors from patients with BHD [9].
Interestingly, Van Steensel and colleagues did not detect loss of FLCN mRNA in
fibrofolliculomas, suggesting that mechanisms of tumorigenesis might differ in
renal and skin tumors [10].
Pathogenesis of Birt-Hogg-Dubé syndrome has also been associated with the
energy-sensing mammalian target of rapamycin (mTOR) pathway [11, 12]. A 130-
kDa FLCN-interacting protein, FNIP1, interacts with 5′AMP-activated protein
kinase (AMPK), a protein involved in the mTOR pathway [13]. Hasumi and col-
leagues and Tagaki and colleagues showed an interaction between an FNIP homo-
logue, FNIP2, with FLCN and AMPK [14, 15].
Some clinical overlap between BHD and tuberous sclerosis exists, such as skin
hamartomas, pulmonary cysts, pneumothorax, and renal tumors [4]. The tuberous
sclerosis complex genes TSC1 and TSC2 encode proteins that regulate the mTOR
pathway. It has been shown that downregulation of FLCN leads to mTOR inhibition
and downregulation of TSC proteins leads to mTOR activation [16]. Therefore, it
seems likely that folliculin has several functions and its role in the mTOR pathway
is still under investigation [4].
Birt-Hogg-Dubé is a rare condition and its epidemiology is largely unknown.
Some authors suggest that it may be underdiagnosed [17].

26.3 Clinical Presentation

26.3.1 Dermatologic Manifestation

The original description by Birt, Hogg, and Dubé included fibrofolliculomas,

trichodiscomas, and acrochordons as a triad of skin lesions that characterize BHD
syndrome [3]. The lesions usually appear in the late teens or early twenties. These
are usually flesh-colored to reddish dome-shaped papules on the face, with nose and
cheeks being the most common locations (see Fig. 26.1) [4]. Lesions can also be
seen on the neck, upper trunk, and ears. The lesions are typically 2–4 mm in size
and have been described as waxy, white, opaque, and smooth [18]. Acrochordon-
like papillomatous lesions have also been described in this syndrome and are usually
seen on the eyelids, around the eyes, neck, and skin folds.
Histopathology of lesions found in BHD syndrome ranges from fibrofolliculo-
mas and trichodiscomas to fibroepithelial polyps with or without cystic features.
While the diagnosis of fibrofolliculoma or trichodiscoma is not specific to BHD,
presence of multiple biopsy-proven lesions in a single patient should alert the clini-
cian to this possibility. Therefore, multiple biopsies are usually needed.
Histopathology of fibrofolliculoma shows a central distorted hair follicle from
which numerous thin, anastomosing, basaloid bands of follicular epithelium extend
into the surrounding stroma. The surrounding stroma is fibrous and somewhat baso-
philic. The central hair follicle may be dilated or cystic and a connection to the
epidermis is not seen in every case.
26 Birt-Hogg-Dubé Syndrome 185

Fig. 26.1 Monomorphic, flesh-colored to white, dome-shaped papules on the face of a patient
with Birt-Hogg-Dubé syndrome. Histologically these lesions reveal fibrofolliculomas and
trichodiscomas, which can be difficult to distinguish clinically

Trichodiscomas are thought to represent hamartomas of the mesodermal compo-

nent of hair disk. Histopathology of trichodiscomas shows area of fine, eosinophilic,
fibrilar connective tissue stroma with dilated blood vessels. The overlying epidermis
is usually attenuated and a collarette surrounding the central fibrilar stroma may be
seen. A follicular structure is usually found at the edge of the lesion, although mul-
tiple step sections may be required to find it. Some authors, including authors of this
chapter, consider fibrofolliculomas and trichodiscomas to be lesions on the same
spectrum. In fact, oftentimes features of both lesions can be seen in different areas
of the same biopsy specimen.
The clinical differential diagnosis of BHD syndrome is broad. It includes other
adnexal tumors, such as syringomas, trichoepitheliomas, and trichoblastomas; vas-
cular tumors, such as angiofibromas and capillary hemangiomas; acne vulgaris;
rosacea; vellus hair cysts; and milia. Other familial cancer syndromes are also on
the differential diagnosis, including Cowden syndrome, Brooke-Spiegler syndrome,
and Basal cell nevus (Gorlin’s) syndrome [18, 19].

26.3.2 Renal Manifestations

The risk of a renal neoplasm in patients with BHD syndrome ranges from 20 to
30 %, with equal male and female distribution [20, 21]. This differs from general
population, where renal cell carcinoma is more prevalent in men. The average age
of presentation is around 50 year old, which is younger than patients with spontane-
ous renal cell carcinoma usually present [22]. Multiple renal cysts have also been
reported in patients with BHD and these are usually seen after the age of 40 [23].
186 K. Goldenberg and G. Goldenberg

FLCN is thought to be a tumor suppressor gene in the kidneys [18]. Somatic mutations
or loss of heterozygosity of the FLCN gene causes different renal tumors in patients with
BHD [8]. Therefore, BHD differs from other hereditary renal cancer syndromes in the
diversity of histological subtypes of renal cell tumors these patients develop.
The most common and characteristic tumor types in BHD syndrome are hybrid
chromophobe/oncocytic (50 %) and chromophobe (33 %) renal cancer, clear cell
carcinomas (9 %), oncocytoma (5 %), and papillary carcinomas [24]. These tumors
can be solitary and unilateral or multifocal and bilateral.

26.3.3 Pulmonary Manifestations

Spontaneous pneumothorax is common in patients with BHD syndrome, with preva-

lence of 25 %, occurring most commonly during the fifth decade of life [25]. Lung
cysts are another common (90 %) findings in patients with BHD syndrome.
Pulmonary manifestations may be seen in absence of dermatologic or renal disease.
The differential diagnosis of cystic lung disease in BHD includes lymphangioleio-
myomatosis; pulmonary Langerhans’ cell histiocytosis, lymphocytic interstitial pneu-
monitis, and pneumocystis pneumonia; smoking-related interstitial lung disease; and
rarely metastatic neoplasms, such as adenocarcinomas and low-grade sarcomas [18].

26.4 Work-Up

Diagnosis of BHD is based on the presence of the following criteria [4]:

Major Criteria
At least five fibrofolliculomas or trichodiscomas, at least one histologically
confirmed, of adult onset
Pathogenic FLCN germline mutation
Minor Criteria
Multiple lung cysts with or without spontaneous primary pneumothorax
Renal cancer: early onset (<50 years) or multifocal or bilateral renal cancer, or renal
cancer of mixed chromophobe and oncocytic histology
A first-degree relative with BHD
Several laboratory and radiologic tests aid in the diagnosis of BHD syndrome.
DNA-based testing for FLCN gene is recommended for patients with a clinical diagno-
sis of BHD syndrome [4]. Counseling and testing the relative of patients with positive
test should also be considered. Ultrasound, computated tomography (CT), and mag-
netic resonance imaging (MRI) can all be used to evaluate and diagnose renal tumors in
patients with BHD. Chest X-ray, CT, and MRI can be used to evaluate lung disease.
26 Birt-Hogg-Dubé Syndrome 187

26.5 Treatment

26.5.1 Dermatologic Manifestations

The treatment options for patients with fibrofolliculomas and trichodiscomas are
limited. Treatment is largely surgical, with excision, shave and cautery, electrodes-
sication, and curettage reported [4]. Laser ablation with erbium-YAG or fractional
CO2 laser has also been reported [26, 27]. Although the treatment is not curative, the
psychological burden of multiple facial lesions should be conserved and treatment
offered to the patients.

26.5.2 Renal Manifestations

Patients with known BHD syndrome should undergo an annual renal MRI, with
renal ultrasound also an option [18]. Surveillance for renal tumors is also indi-
cated for carriers of FLCN germline mutations and for relatives of patients with
known BHD syndrome. Once renal cancer is diagnosed, staging and treatment
should follow standard procedure [28]. It has also been suggested that rapamycin
and its derivatives can be used, since FLCN mutation can result in deregulation on
mTOR [18].

26.5.3 Pulmonary Manifestations

The treatment of pneumothorax in patients with BDH is the same as spontaneous

pneumothorax. Smoking should be strongly discouraged in these patients. Patients
should also be counseled regarding changes in ambient pressure, flying, and deep-
sea diving [18].

26.6 Conclusion

Skin changes may be the first manifestation of the Birt-Hogg-Dubé syndrome. This
condition affects several organ systems in the body, and recognition of the unique
presenting skin changes can lead to early diagnosis and work-up. Given the poten-
tially severe renal and pulmonary manifestations, full work-ups should be per-
formed for patients in which this condition is suspected. Referral to the appropriate
specialists, including genetic counselors, is important to properly manage this
syndrome.
188 K. Goldenberg and G. Goldenberg

References

1. Toro JR, Glenn G, Duray P, Darling T, Weirich G, Zbar B, Linehan M, Turner ML. Birt-Hogg-
Dubé syndrome: a novel marker of kidney neoplasia. Arch Dermatol. 1999;135(10):1195–202.
2. Warwick G, Izatt L, Sawicka E. Renal cancer associated with recurrent spontaneous pneumo-
thorax in Birt-Hogg-Dubé syndrome: a case report and review of the literature. J Med Case
Rep. 2010;4:106.
3. Birt AR, Hogg GR, Dube WJ. Hereditary multiple fibrofolliculomas with trichodiscomas and
acrochordons. Arch Dermatol. 1977;113:1674–7.
4. Menko FH, van Steensel MA, Giraud S, Friis-Hansen L, Richard S, Ungari S, Nordenskjöld
M, Hansen TV, Solly J, Maher ER, European BHD Consortium. Birt-Hogg-Dubé syndrome:
diagnosis and management. Lancet Oncol. 2009;10(12):1199–206.
5. Khoo SK, Bradley M, Wong FK, Hedblad M-AM, Nordenskjöld BT. The Birt-Hogg-Dubé
syndrome: mapping of a novel hereditary neoplasia gene to chromosome 17p12–q11.2.
Oncogene. 2001;20:5239–42.
6. Schmidt LS, Warren MB, Nickerson ML, et al. Birt-Hogg-Dubé syndrome, a genodermatosis
associated with spontaneous pneumothorax and kidney neoplasia, maps to chromosome
17p11.2. Am J Hum Genet. 2001;69:876–82.
7. Nickerson ML, Warren MB, Toro JR, et al. Mutations in a novel gene lead to kidney tumors,
lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dubé
syndrome. Cancer Cell. 2002;2:157–64.
8. Vocke CD, Yang Y, Pavlovich CP, et al. High frequency of somatic frameshift BHD gene muta-
tions in Birt-Hogg-Dubé-associated renal tumors. J Natl Cancer Inst. 2005;97:931–5.
9. Warren MB, Torres-Cabala CA, Turner ML, et al. Expression of Birt-Hogg-Dubé gene mRNA
in normal and neoplastic human tissues. Mod Pathol. 2004;17:998–1011.
10. van Steensel MA, Verstraeten VL, Frank J, et al. Novel mutations in the BHD gene and absence
of loss of heterozygosity in fibrofolliculomas of Birt-Hogg-Dubé patients. J Invest Dermatol.
2007;127:588–93.
11. Inoki K, Corradetti MN, Guan K-L. Dysregulation of the TSC-mTOR pathway in human dis-
ease. Nat Genet. 2005;37:19–24.
12. van Steensel MA, van Geel M, Badeloe S, Poblete-Gutiérrez P, Frank J. Molecular pathways
involved in hair follicle tumor formation: all about mammalian target of rapamycin. Exp
Dermatol. 2009;18:185–91.
13. Baba M, Hong S-B, Sharma N, et al. Folliculin encoded by the BHD gene interacts with a
binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling. Proc Natl
Acad Sci U S A. 2006;103:15552–7.
14. Hasumi H, Baba M, Hong SB, et al. Identification and characterization of a novel folliculin-
interacting protein FNIP2. Gene. 2008;415:60–7.
15. Takagi Y, Kobayashi T, Shiono M, et al. Interaction of folliculin (Birt-Hogg-Dubé gene prod-
uct) with a novel Fnip1-like (FnipL/Fnip2) protein. Oncogene. 2008;27:5339–47.
16. Hartman TR, Nicolas E, Klein-Szanto A, et al. The role of the Birt-Hogg-Dubé protein in
mTOR activation and renal tumorigenesis. Oncogene. 2009;28:1594–604.
17. Lindor NM, et al. Birt-Hogg-Dube syndrome: an autosomal dominant disorder with predispo-
sition to cancers of the kidney, fibrofolliculomas, and focal cutaneous mucinosis. Int
J Dermatol. 2001;40(10):653–6.
18. Reese E, Sluzevich J, Kluijt I, Teertstra HJ, De Jong D, Horenblas S, Ryu J. Birt-Hogg-Dubé
syndrome. In: Riegert-Johnson DL, Boardman LA, Hefferon T, Roberts M, editors. Cancer syn-
dromes [Internet]. Bethesda, MD: National Center for Biotechnology Information (US); 2009.
19. Vincent A, et al. Birt-Hogg-Dube syndrome: a review of the literature and the differential
diagnosis of firm facial papules. J Am Acad Dermatol. 2003;49(4):698–705.
20. Pavlovich CP, et al. Renal tumors in the Birt-Hogg-Dube syndrome. Am J Surg Pathol.
2002;26(12):1542–52.
26 Birt-Hogg-Dubé Syndrome 189

21. Toro JR, et al. BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-
Dube syndrome: a new series of 50 families and a review of published reports. J Med Genet.
2008;45(6):321–31.
22. Schmidt LS, et al. Germline BHD-mutation spectrum and phenotype analysis of a large cohort
of families with Birt-Hogg-Dube syndrome. Am J Hum Genet. 2005;76(6):1023–33.
23. Gupta P, et al. Radiological findings in Birt-Hogg-Dube syndrome: a rare differential for
pulmonary cysts and renal tumors. Clin Imaging. 2007;31(1):40–3.
24. Linehan WM, et al. Identification of the genes for kidney cancer: opportunity for disease-
specific targeted therapeutics. Clin Cancer Res. 2007;13(2 Pt 2):671s–9.
25. Ayo DS, et al. Cystic lung disease in Birt-Hogg-Dube syndrome. Chest. 2007;132(2):679–84.
26. Gambichler T, Wolter M, Altmeyer P, Hoffman K. Treatment of Birt-Hogg-Dubé syndrome
with erbium: YAG laser. J Am Acad Dermatol. 2000;43:856–8.
27. Kahle B, Hellwig S, Schulz T. Multiple mantelome bei Birt-Hogg-Dubé-Syndrom.
Erfolchreiche therapie mit dem CO2-laser. Hautarzt. 2001;52:43–6.
28. Ng CS, Wood CG, Silverman PM, Tannir NM, Tamboli P, Sandler CM. Renal cell carcinoma:
diagnosis, staging, and surveillance. Am J Roentgenol. 2008;191:1220–32.
Chapter 27
Brooke-Spiegler Syndrome

Bradley Glodny and Joshua A. Zeichner

27.1 Introduction

Brooke-Spiegler syndrome (BSS) is an autosomal dominant (AD) inherited

syndrome predisposing those affected, to the development of multiple hamartomas/
neoplasms derived from skin appendage structures. These tumors include cylindro-
mas, trichoepitheliomas, and spiradenomas. In the setting of BSS, these lesions
most often appear as multiple papules or nodules on the head and neck region dur-
ing adolescence or early adulthood. BSS may be mistaken for the eruption of acne
vulgaris [1, 2]. While BSS was initially described as a unique entity, it is now
thought to exist as part of a spectrum of AD appendage tumor syndromes allelic for
germline mutations within the Cylindromatosis (CYLD) gene. This group includes
two other syndromes: familial cylindromatosis (FC) and multiple familial trichoepi-
thelioma (MFT) [2]. As indicated by their name, MFT is characterized by trichoepi-
theliomas, while FC is characterized by cylindromas [3]. Therefore, MFT and FC
represent two ends of a spectrum with BSS falling within the middle [4].

27.2 Background

BSS is a rare AD syndrome, occurring secondary to a germline mutation in the tumor

suppressor gene CYLD, located on chromosome 16q12-q13 [4]. To date, 73 families
have been identified with CYLD mutations without an identifiable racial or ethnic predi-
lection [4]. These CYLD mutations have been associated with BSS, MFT, as well as FC.

B. Glodny, M.D. (*)

Department of Dermatology, Mt. Sinai, New York, NY, USA
e-mail: [email protected]
J.A. Zeichner, M.D.
Department of Dermatology, Mt. Sinai School of Medicine, New York, NY, USA

J.A. Zeichner (ed.), Acneiform Eruptions in Dermatology: A Differential Diagnosis, 191

DOI 10.1007/978-1-4614-8344-1_27, © Springer Science+Business Media New York 2014
192 B. Glodny and J.A. Zeichner

More than 50 mutations have been described within exons 9–20 of the CYLD
gene. The CYLD tumor suppressor protein product functions by negatively regulating
the nuclear factor (NF)-kB and c-Jun N-terminal kinase pathways [1, 4]. Approximately
86 % of these mutations lead to a truncated CYLD protein, while the remaining 14 %
are missense mutations leading to a dysfunctional CYLD protein [4]. CYLD is
thought to be involved in regulating many cellular functions, including cell prolifera-
tion [4]. CYLD expression has found to be exceptionally high in the outer root sheath
of human scalp hair follicles [5]. Recently, animal models have been developed to
study the effects of the CYLD gene mutation, including those in “immunity, lipid
metabolism, spermatogenesis, antimicrobial defense, and inflammation” [4].
Dysfunction of the CYLD gene in BSS is limited to the skin adnexa, with resulting
appendageal tumors. Cylindromas and spiradenomas are thought to develop from the
secretory portion of the sweat gland, while trichoepitheliomas from hair follicles [2].

27.3 Clinical Presentation

Neoplasms in BSS include cylindromas, trichoepitheliomas, and less often spirad-

enomas. These tumors may develop individually in sporadic cases. However, when
many of these neoplasms occur in the same patient, a syndrome like BSS, FC, or
MFT should be considered. However, given the common folliculosebaceous-
apocrine lineage, even patients without BSS have been found to develop individual
cylindromas, trichoepitheliomas, and spiradenomas [6].
In the setting of BSS, these tumors commonly present on the head and neck dur-
ing childhood or early adulthood and continue to develop later in life [4]. Patients
may confuse these lesions with acne, but there is a lack of comedones or acne pap-
ules or pustules. Rarely, cylindromas many coalesce to form a large plaque covering
the scalp, referred to as a “turban tumor” [7]. Trichoepitheliomas present as papules
on the nasolabial folds, nose, and upper lips, but can cover large surface areas of the
face [1, 2]. Spiradenomas are clinically indistinct papules affecting non-glabrous
skin. Patient may experience spontaneous pain, which can be a clue to its diagnosis.
Additionally, spiradenomas may have a blue hue [1]. While these are the most com-
mon cutaneous neoplasms of BSS, these patients also can develop syringomas and
basal cell cancers (BCC) [8]. These neoplasms are frequently numerous, becoming
aesthetically bothersome to the patient.
While most tumors in BSS are benign, malignant transformation is a risk. More
than 25 cases of cylindrocarcinomas developing from cylindromas have been
reported [9–11]. Likewise, trichoepithelioma must be followed as they may degen-
erate into BCC [12]. Over 35 cases of carcinomatous or sarcomatous transformation
from spiradenomas have also been described [13]. Both cylindrocarcinomas and
malignant spiradenomas have been found to be more aggressive compared to
BCC’s, posing a great risk for both local destruction and metastasis [9, 14]. In addi-
tion to cutaneous neoplasms, patients with BSS are at risk for neoplasms of the sali-
vary and parotid glands [9, 15]
27 Brooke-Spiegler Syndrome 193

27.4 Work-Up

All patients with multiple, fixed facial papules of unclear etiology should be worked
up, as definite diagnosis by clinical inspection is difficult. While dermoscopic
evaluation may provide a consistent appearance with telangiectasia and blue struc-
tures [16], histopathology is often necessary [2]. Trichoepitheliomas represent an
over proliferation of follicular germinative, basaloid cells organized in a cribriform
pattern surrounded by a coarse, fibrous stroma [1, 17, 18]. As opposed to BCCs,
there is no clefting between basaloid cells and the stroma [19]. Cylindromas are
well-circumscribed nodules in the dermis or subcutis comprised of compact lobules
of basaloid cells that form a “jigsaw puzzle” arrangement [1]. Spiradenomas appear
as dermal or subcutaneous multinodular growths with pale-staining cells in
trabecular pattern, with basophilic cells at the periphery. A clue to the diagnosis is
the presence of lymphocytes scattered throughout the lesion [1].
Patients with multiple trichoepitheliomas, spiradenomas, and/or cylindromas
should be referred to genetics to be screened for CYLD gene mutations. The
differential diagnosis for trichoepitheliomas and trichoepitheliomas includes
Bazex and Rombo syndromes, but the patients also develop epidermoid cysts,
milia, hypotrichosis, BCCs, atrophoderma vermiculatum, and peripheral
cyanosis [1]. Patients should also be referred to otolaryngology for evaluation
for salivary or parotid tumors.

27.5 Treatment

Most of the cutaneous neoplasm in BSS are benign in nature and pose more of a
cosmetic challenge than medical necessity. However, close monitoring for malig-
nant transformation is prudent. Biopsies should be performed lesions that are
growing or ulcerating [1, 9]. When lesions grow so large that they cause functional
derangements, they may require treatment. Individual lesions may be surgically
excised, but surgery may not be a realistic option for BSS patients with large num-
bers of lesions [1, 20], Alternative therapies include electrosurgery, cryosurgery,
photodynamic therapy, imiquimod, or laser ablation that can be used alone or in
combination [20].

27.6 Conclusion

Brooke-Spiegler syndrome is a condition characterized by the development of many

adnexal neoplasms. While cosmesis is usually the primary concern for these
patients, functional impairments from large growing lesions must be addressed.
Moreover, these patients must be continually monitored because of the risk for
malignant transformation.
194 B. Glodny and J.A. Zeichner

References

1. Bolognia JL, Jorizzo JL, Schaffer JV. Dermatology. 3rd ed. Saunders; June 4, 2012. Ch 111;
1834–1835.
2. Lee DA, Grossman ME, Schneiderman P, Celebi JT. Genetics of skin appendage neoplasms
and related syndromes. JMEd Genet. 2005;42:811–9.
3. Welch JP, Wells RS, Kerr CB. Ancell-Spiegler cylindromas (turban tumors) and Brooke-
Fordyce trichoepitheliomas: evidence for a single genetic entity. J Med Genet. 1968;5:29–35.
4. Blake PW, Toro JR. Update of cylindromatosis gene (CYLD) Mutations in Brooke-Spiegler
syndrome: novel insights into the role of deubiquitination in cell signaling. Hum Mutat.
2009;30(7):1025–36.
5. Massoumi R, Podda M, Fassler R, Paus R. Cylindroma as tumor of hair follicle origin. J Invest
Dermatol. 2006;126:1182–4.
6. Michal M, Lamovec J, Mukensnabl P, Pizinger K. Spiradenocylindromas of the skin: tumors
with morphological features of spiradenoma and cylindroma in the same lesion: report of 12
cases. Pathol Int. 1999;49:419–25.
7. Nerad JA, Folberg R. Multiple cylindromas. “The turban tumor”. Arch Opthalmol. 1987;105:1137.
8. Uede K, Yamamoto Y, Furukawa F. Brooke-Spiegler syndrome associated with cylindroma,
trichoepithelioma, spiradenoma, and syringoma. J Dermatol. 2004;31:32–8.
9. Gerretsen A, van der Putte S, Deenstra W. Cutaneous cylindroma with malignant transforma-
tion. Cancer. 1993;72:1618–23.
10. Durani BK, Kurzen H, Jaeckel A, Kuner N, Naeher H, Hartschuh W. Malignant transformation
of multiple dermal cylindromas. Br J Dermatol. 2001;145(4):653–6.
11. Pizinger K, Michal M. Malignant cylindroma in Brooke-Spiegler Syndrome. Dermatology.
2000;201(3):255–7.
12. Ayhan M, Adanali G, Senen D, Gorgu M, Erdogan B. Rarely seen cutaneous lesions in an
elderly patient: malignant transformation of multiple trichoepithelioma. Ann Plast Surg. 2001;
47:98–9.
13. Ishikawa M, Nakanishi Y, Yamazaki N, Yamamoto A. Malignant eccrine spiradenoma: a case
report and review of the literature. Dermatol Surg. 2001;27:67–70.
14. Lo JS, Snow SN, Reizner GT, Mohs FE, Larson PO, Hruza GJ. Metastatic basal cell carcinoma:
report of twelve cases with a review of the literature. J Am Acad Dermatol. 1991;24: 715–9.
15. Jungehulsing M, Wagner M, Damm M. Turban tumor with involvement of the parotid gland.
J Laryngol Otol. 1999;113:779–83.
16. Jarret R, Walker L, Bowling J. Dermoscopy of Brooke-Spiegler syndrome. Arch Dermatol.
2009;145(7):854.
17. Ackerman AB, Reddy VB, Soyer HP. Neoplasms with follicular differentiation. 2nd ed. New
York: Ardor Scribendi; 2001. p. 1109.
18. Elston D, Ferringer T, Ko C, Peckham S, High W, DiCaudo D, Bhuta S. Requisites in
dermatology: dermatopathology. New York, Saunders Elsevier; 2008. p. 70–1.
19. Bettencourt MS, Preito VG, Shea CR. Trichoepithelioma: a 19-year clinicopathologic
re-evaluation. J Cutan Pathol. 1999;26:398–404.
20. LoPiccolo M, Sage R, Kouba D. Comparing ablative fractionated resurfacing, photodynamic
therapy, and topical imiquimod in the treatment of trichoblastomas of Brooke-Spiegler
syndrome: a case study. Dermatol Surg. 2011;37:1047–50.
Chapter 28
Cowden Syndrome

Rita V. Linkner and Joshua A. Zeichner

28.1 Introduction

Cowden syndrome (CS) is an autosomal dominant genodermatosis and represents one

of the clinical disorders on the spectrum linked to the germline mutation in the phos-
phatase and tensin homolog gene (PTEN). Located on chromosome 10, the PTEN
gene is a dual specificity phosphatase which plays various roles in cell migration,
apoptosis, and all processes that are important in the regulation of normal cellular
growth [1]. Mutations in PTEN have been associated with various other disorders
including Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, adult L’hermitte-
Duclos disease, and autism-like disorders associated with macrocephaly [2].
Cowden syndrome was first described by in the 1960s in a case report involving
a patient named Rachel Cowden who presented with multiple hamartomas, unusual
cutaneous findings, abnormal CNS findings, and fibrocystic breast disease [3].
Years later, Weary et al further reported the existence of this disorder with the first
case series involving five subjects with similar clinical findings [4]. The PTEN
mutation was finally found to be the cause in 1996. Currently, the clinical definition
of CS has not only been widened to include multiple hamartomas involving any and
sometimes all of the three embryonic germ cell layers but also now incorporates the
significant risk of developing breast and/or non-medullary thyroid malignancy [5].

28.2 Background

With identification of the PTEN mutation, the estimated incidence of CS is between

1 in 200,000 and 1 in 250,000 [6]. Studies report a Caucasian female predominance.
The age of diagnosis is variable, ranging from 13 to 65 years of age [7].

R.V. Linkner, M.D. (*) • J.A. Zeichner, M.D.

Department of Dermatology, Mount Sinai School of Medicine, New York, NY, USA
e-mail: [email protected]

J.A. Zeichner (ed.), Acneiform Eruptions in Dermatology: A Differential Diagnosis, 195

DOI 10.1007/978-1-4614-8344-1_28, © Springer Science+Business Media New York 2014
196 R.V. Linkner and J.A. Zeichner

Cowden syndrome is inherited autosomal dominantly with incomplete penetrance

and variable expressivity. The PTEN gene was localized to chromosome 10q22-23
by an extensive linkage family study involving 12 separate families [5]. PTEN is a
9-exon tumor suppressor gene that acts as a lipid phosphatase to negatively regulate
the mTOR pathway [8]. Studies have shown the involvement of PTEN in a large
number of sporadic tumors such as glioblastomas, prostate cancer, melanoma,
thyroid, and endometrial tumors. Germline coding sequence mutation in PTEN is
reported in 80 % of those with CS [9].

28.3 Clinical Presentation

Cowden syndrome affects various organs and increases the risk for overgrowth of
different tissues. Mucocutaneous lesions are found in nearly all cases of CS [10].
While the age of onset of these characteristic lesions is quite variable, the lesions most
commonly associated with CS include trichilemmomas, oral papillomas, and acral
keratoses. Trichilemmomas are benign hamartomatous lesions of the follicle outer
root sheath that end to be slow growing and skin colored and most commonly found
on the face or neck (Fig. 28.1) [11]. Oral papillomas are benign lesions that can occur
on the oral mucosa, primarily on the tongue (Fig. 28.2) [12]. Acral keratoses are clini-
cally seen as verrucous papules on the dorsal surfaces of the hands and feet (Fig. 28.3).

Fig. 28.1 Flesh-colored

papules on the face, which
histologically were revealed
to be trichilemmomas. In
addition, he also suffered
from comedones (Photo
credit: Joshua A. Zeichner,
M.D.)
28 Cowden Syndrome 197

Fig. 28.2 Flesh-colored

papules along the border of
the tongue, consistent with
the oral papillomas observed
in Cowden syndrome (Photo
credit: Joshua A. Zeichner,
M.D.)

Fig. 28.3 Acral keratoses on the dorsal hands, which clinically appear as warty, stuck on papules
(Photo credit: Joshua A. Zeichner, M.D.)

Strict mucosal involvement, which typically occurs after cutaneous involvement, is

seen in over 80 % of cases and is described when either the gingival or buccal mucosa
is developing a “cobblestone” appearance [13].
The most common malignancy associated with CS is breast cancer, with a
lifetime risk of 25–50 % and an average age of diagnosis of 36–46 years old [14].
Similar to what is observed in the general population, ductal adenocarcinoma is
most commonly diagnosed in patients with CS [15]. Other benign breast disorders
are increased in CS, including fibroadenomas, apocrine metaplasia, and mammary
hamartomas. These benign entities have not been associated with malignant trans-
formation these patients [16].
198 R.V. Linkner and J.A. Zeichner

Other cancers observed in CS include follicular thyroid carcinoma, malignant

testicular seminoma, mixed germ cell tumors, and endometrial cancers [17].
Melanoma, renal cell carcinoma, and colon cancer have also been reported as well
[18]. L’hermitte-Duclos disease is pathognomonic for CS. This indolent, benign
hamartomatous overgrowth of the cerebellum leads to headaches, ataxia, and visual
disturbances. The diagnosis may be made through MRI and surgical excision can be
curative [19].
Patients with CS commonly suffer from periodontitis, dental caries, skeletal
abnormalities, and a high arched palate. Additionally, mental retardation occurs in
up to 20 % of patients [20–23].

28.4 Work-Up

Patients with fixed facial papules or oral lesions of unclear diagnosis should be
evaluated with a biopsy for histologic evaluation, as they may be a presenting sign
of CS. The United States National Comprehensive Cancer Network (NCCN) has
published screening criteria, outlined in Table 28.1. Clinical diagnostic criteria for
CS are met if the patient has adult L’hermitte-Duclos disease or a requisite number
of mucocutaneous lesions, macrocephaly plus one other major criterion, one major
and three minor criteria, or four minor criteria. Any patient who fits the screening
criteria, should be referred to genetics for PTEN gene testing [24]. Patients should
also be evaluated for the presence of internal malignancies, including breast and
thyroid disease.

Table 28.1 Cowden syndrome NCCN guidelines, 2009 [24]

Pathognomonic criteria Adult L’hermitte-Duclos disease
Mucocutaneous lesions
Facial trichilemmomas
Acral keratoses
Papillomatous papules
Major criteria Breast carcinoma
Non-medullary thyroid carcinoma
Macrocephaly
Endometrial carcinoma
Minor criteria Other thyroid lesions
Mental retardation (IQ < 75)
GI hamartomas
Fibrocystic disease of the breast
Lipomas
Fibromas
Genitourinary tumors (especially renal cell carcinoma)
Genitourinary structural abnormalities
Uterine fibroids
28 Cowden Syndrome 199

28.5 Treatment

A multidisciplinary approach must be employed in treating CS. These patients

require the resources of dermatology, endocrinology, gynecology, and genetics.
Women should conduct monthly self breast examinations, starting at 18 years old.
A physician clinical breast examination should be initiated at age 25 or 10 years
prior to the earliest known breast cancer in the family, whichever occurs first.
Mammography along with breast MRI should commence at 30 years old or 5 years
prior to the earliest known breast cancer in the family, whichever occurs first.
Prophylactic mastectomy should be discussed on a case by case basis with familial
history being taken into account [24].
For both males and females, a full physical examination should be started at the
age of 18 or 5 years before to the diagnosis of a component cancer in the family,
whichever occurs first. At the age of 18, thyroid ultrasounds should be initiated
annually. A dermatologist conducting a total body skin check should also be
recommended. Genetic counseling is another important topic to be broached with
the patient and those relatives whom are deemed to be at high risk [24].
Treatment of cutaneous lesions is largely cosmetic in nature, as these lesions are
benign. However, larger lesions affecting the mouth or acral areas may lead to functional
impairment requiring intervention. Physical modalities such as surgical excision or
laser ablation may be of use.

28.6 Conclusion

It is important for the dermatologist to be familiar with Cowden syndrome, considering

the malignant potential of this disorder. The various unique skin manifestations poten-
tially offer early clues to screen, properly diagnose, and treat patients early in the course
of the disease to improve patients’ quality of life.

References

1. Tamguney T, Stokoe D. New insights into PTEN. J Cell Sci. 2007;120(23):4071–9.

2. Pilarski R. Cowden syndrome: a critical review of the literature. J Genet Counsel. 2009;
18:13–27.
3. Lloyd KM, Denis M. Cowden disease: a possible new symptom complex with multiple
symptom involvement. Ann Inten Med. 1963;58:136–42.
4. Weary PE, Gorlin RJ, Gentry WC, Comer JE, Greer KE. Multiple hematoma syndrome
(Cowden disease). Arch Dermatol. 1972;106(5):682–90.
5. Nelen MR, Kremer H, Konigns IBM, Schoute F, van Essen AJ, Koch R, et al. Novel PTEN
mutations in patients with Cowden disease: absence of clear genotype phenotype correlations.
Eur J Human Genet. 1999;7:267–73.
200 R.V. Linkner and J.A. Zeichner

6. Starlink T, Cander Veen J, Artwert F, Erikson AW. The Cowden syndrome: a clinical and
genetic study in 21 patients. Clin Genet. 1986;29:222–33.
7. Salem OS, Steck WD. Cowden’s disease. A case report and review of the English literature.
J Am Acad Dermatol. 1983;8(5):686–96.
8. Pilarski R, Eng C. Will the real Cowden syndrome please stand up (again)? Expanding muta-
tional and clinical spectra of the PTEN hamartoma tumour syndrome. J Med Genet. 2004;
41(5):323–6.
9. Guldberg P, Thor Straten P, Birck A, Ahrenkiel V, Kirkin AF, Zeuthen J. Disruption of the
MMAC1/PTEN gene by deletion of mutation is a frequent event in malignant melanoma.
Cancer Res. 1997;57(17):3660–3.
10. Fistarol SK, Marc D, Anliker MS, Peter H. Cowden disease or multiple hamartoma syndrome—
cutaneous clue to internal malignancy. Eur J Dermatol. 2002;12(5):411–21.
11. Brownstein MH, Mehregan AH, Bilowski JB. Trichilemmomas on Cowden’s disease. J Am
Med Assoc. 1977;238(1):26.
12. Devlin MF, Barrie R, Ward-Booth RP. Cowden’s disease: a rare but important manifestation of
oral papillomatosis. Br J Oral Maxillofacial Surg. 1992;30:335–6.
13. Blumenthal GM, Dennis PA. PTEN hamartoma tumor syndromes. Eur J Human Genet.
2008;16:1289–300.
14. Nusbaum R, Vogel JK, Ready K. Susceptibility to breast cancer: hereditary syndromes and low
penetrance genes. Breast Dus. 2007;27:21–50.
15. Schrager CA, Schneider D, Gruener AC. Clinical and pathological features of breast disease in
Cowden’s syndrome: an under-recognized syndrome with an increased risk of breast cancer.
Human Pathol. 1998;29:47–53.
16. Brownstein MH, Wolf M, Bikowski JB. Cowden’s disease: a cutaneous marker of breast
cancer. Cancer. 1978;41:2393–8.
17. Farooq A, Walker LJ, Bowling J, Audisio RA. Cowden syndrome. Cancer Treat Rev. 2010;8:
577–83.
18. Pilariski R. Cowden syndrome: a critical review. J Genet Counsel. 2009;18:13–27.
19. Lok C, Viseux V, Avril MF, Richard MA, Gondry-Jouet C, Deramond H, et al. Brain magnetic
resonance imaging in patients with Cowden syndrome. Medicine. 2005;84(2):129–36.
doi:10.1097/01.md.0000158792.24888.d2.
20. Bagan JV, Penarrocha M, Vera-Sempere F. Cowden syndrome: clinical and pathological
considerations in two new cases. J Oral Maxillofacial Surg. 1989;47(3):291–4. doi:10.1016/
0278-2391(89)90234-6.
21. Starink TM. Cowden’s disease: analysis of fourteen new cases. J Am Acad Dermatol.
1984;11(6):1127–41. doi:10.1016/S0190-9622(84)70270-2.
22. Salem OS, Steck WD (1983) Cowden’s disease (multiple hamartoma and neoplasia syndrome).
A case report and review of the English literature. J Am Acad Dermatol. 8(5):686–96.aa
23. Parisi M, Dinulos MB, Leppid KA, Sybert VP, Eng C, Hudgins L. The spectrum and evolution of
phenotypic findings in PTEN mutation positive cases of Bannayan-Riley-Ruvalcaba syndrome.
J Med Genet. 2001;38:52–7.
24. The NCCN 1.2009 Cowden syndrome clinical practice guidelines in oncology. National
Comprehensive Cancer Network, 2009. Available from: http://www.nccn.org. Adapted with
permission from NCCN [accessed 10.06.09]. (To view the most recent and complete version
of the guideline, go online to www.nccn.org).
Chapter 29
Gardner Syndrome

Alexandra Golant and Joshua A. Zeichner

29.1 Introduction

Gardner syndrome (GS) is a phenotypic variant of familial adenomatous polyposis

(FAP). The syndrome is characterized by premalignant intestinal polyposis and distinct
extraintestinal features, such as multiple epidermoid cysts, osteomas, and desmoid or
fibrous tumors of the skin and soft tissue [1].

29.2 Background

FAP and GS are caused by mutations in the adenomatous polyposis coli (APC)
tumor suppressor gene on chromosome 5q21–22 [2]. There is a correlation between
the site of the mutation on the APC gene and the clinical phenotype [3]. Specifically,
APC mutations between codon 1395 and 1493 are frequently associated with
features of GS [4]. APC gene mutations result in accumulation of β-catenin which
bypasses the growth-regulating effects of Wnt signaling resulting in important
implications for cell differentiation, proliferation, and adhesion [5, 6]. GS is inherited
as an autosomal dominant disorder with high penetrance and variable expressivity,
though approximately 25 % of patients have de novo mutations and no family
history [6]. The estimate of incidence of GS ranges from approximately 1 in 6,850 to
1 in 31,250 births [7–9].

A. Golant, M.D. (*)

Department of Dermatology, The Mt. Sinai Hospital, New York, NY, USA
e-mail: [email protected]
J. A. Zeichner, M.D.
Department of Dermatology, Mt. Sinai School of Medicine, New York, NY, USA

J.A. Zeichner (ed.), Acneiform Eruptions in Dermatology: A Differential Diagnosis, 201

DOI 10.1007/978-1-4614-8344-1_29, © Springer Science+Business Media New York 2014
202 A. Golant and J.A. Zeichner

29.3 Clinical Features

In addition to the intestinal manifestations of FAP, patients with GS have characteristic

extraintestinal manifestations—both cutaneous and extracutaneous.

29.3.1 Cutaneous Findings

Cutaneous lesions and bony abnormalities in GS often appear during childhood and
adolescence, frequently before polyposis develops. Epidermoid cysts are the most
common cutaneous finding in GS, affecting approximately one-third of patients [10].
Epidermoid cysts are firm, well-circumscribed dermal nodules that contain soft
keratin secretions. They may be present at birth but often occur at puberty, occur in
multiplicity in more than 50 % of patients, and tend to occur in unusual locations
such as the face, scalp, and extremities [10]. Cysts in GS typically occur earlier than
ordinary cysts, as seen in patient with acne. Though the majority of cysts are asymp-
tomatic, they can be pruritic, inflamed, or ruptured [10]. Cutaneous cysts showing
unusual histological features—namely, a mixture of epidermoid, trichilemmal, and/
or pilomatricoma-like features—are considered a hallmark of GS [6].
Desmoid tumors are benign fibrous mesenchymal neoplasms that result from the
proliferation of well-differentiated fibroblasts seen in 3–30 % of patients with GS
[2, 6, 11], with average onset around age 30 and a marked female predominance
(70–85 %) [6, 11, 12]. Desmoid tumors in GS are associated with mutations occurring
downstream of codon 1400 of the APC gene [6, 12] and can be located in the abdomi-
nal region (intra-abdominally or within the abdominal wall) or extra-abdominally in
the shoulder girdle, chest well, and inguinal regions [12, 13]. Physical exam may
reveal a well-circumscribed, firm, flesh-colored tumor [13]. These tumors may occur
spontaneously or at incision sites, commonly developing after colectomy which is a
leading cause of morbidity in GS [12]. Although cytologically benign and non-meta-
static, desmoid tumors are locally aggressive and can be invasive, recur after excision,
and even lead to death [11].
Fibromas are another feature of GS and may occur in the skin, subcutaneous
tissues, mesentery, or even retroperitoneum [11]. Nuchal fibromas classically
present with diffuse swelling and induration of the back of the neck [2, 6]. “Gardner
fibromas” arise in the first decade of life, favor the trunk or paraspinal region, and
can serve as a desmoid precursor [11]. Lipomas, leiomyomas, trichoepitheliomas,
and neurofibromas are other skin findings less commonly observed in GS [2, 6, 11].
None of the cutaneous lesions in GS have been reported to progress to malignancy.

29.3.2 Extracutaneous Findings

Osteomas occur in approximately 20 % of patients with GS and favor the mandible

and maxilla. Less frequently, they can develop in long bones or the skull and are
commonly associated with cutaneous cysts [2, 6]. Osteomas can present as early as
29 Gardner Syndrome 203

childhood and often predate intestinal polyposis. These tumors are benign and
painless but may be multiple or grow to reach significant enough size to be detected
on physical exam [11]. Other skeletal abnormalities in GS include exostoses,
endostoses, and cortical thickening of the long bones [11].
Dental anomalies are well described in GS and are seen in approximately 20 %
of patients. These include odontomas and odontogenic cysts; absent, supernumer-
ary, or rudimentary teeth; and multiple dental caries [2, 6].
Congenital hypertrophy of the retinal pigment epithelium (CHRPE) affects
approximately two-thirds of patients with GS and can be an early sign of the syn-
drome [14]. CHRPE is a patch of darkly pigmented retinal epithelium that can be
detected on ophthalmologic exam at birth [13]. While unilateral solitary CHRPE is
not specific for FAP, multiple or bilateral lesions are considered highly specific for
FAP [2, 6, 15]. In GS, CHRPE is associated with mutations between codons 767
and 1513 [16].
Importantly, patients with GS are at increased risk for the development of several
extracolonic malignancies. These include duodenal cancer, papillary thyroid carcinoma
(mostly in females), brain tumors (glioblastoma, astrocytoma, medulloblastoma), hepa-
toblastoma (mostly in children), pancreatic and biliary tract carcinomas, adrenal ade-
noma, and various sarcomas (including fibrosarcoma and osteosarcoma) [2, 5, 6, 11, 17].

29.3.3 Gastrointestinal Manifestations

FAP is characterized by the development of hundreds of adenomatous polyps of the

colorectum that typically appear in the second decade [2]. These polyps invariably
undergo malignant transformation resulting in colorectal carcinoma (CRC) at a
mean age of 39 years if undetected or untreated [18]. Polyps occur primarily in the
colon (typically bilaterally, but may initially be right sided) [13], but can also be
found in the small intestine and stomach in over 50 % of patients [6]. Consideration
of FAP or GS is often made when a patient presents with GI symptoms including
bleeding, anemia, abdominal pain, diarrhea, constipation, or weight loss.

29.4 Work-Up

Patients suspected of having FAP/GS should be managed by a multidisciplinary

medial team, including dermatologists, gastroenterologists, geneticists, and surgeons.
The diagnosis of FAP should be suspected in any patient found to have multiple
colorectal adenomas with any of the manifestations described above or in first-degree
relatives of affected family members. In a patient who has cysts with an atypical
histology, along with a history of jaw cysts, the diagnosis of GS should be considered.
These may present prior to gastrointestinal signs in some patients.
Genetic testing for APC mutations is required for a definitive diagnosis of FAP.
Molecular testing for APC mutations is commercially available and recommended
for all patients suspected of having FAP/GS and their first-degree relatives.
204 A. Golant and J.A. Zeichner

Cutaneous cysts in patients with GS usually demonstrate the same microscopic

changes as ordinary epidermoid cysts (lining of keratinizing epithelium including a
granular layer containing loose lamellar keratin within the cyst) but also classically
demonstrate cysts with pilomatrical differentiation (containing areas of ghost cell
keratinization) [19]. “Gardner fibromas” appear as sheets of thick, haphazardly
arranged collagen bundles with interspersed bland fibroblasts [20]. Intestinal polyps
of GS show adenomatous hyperplasia of the mucosa [21].

29.5 Treatment

Management of the extraintestinal and intestinal manifestations of GS necessitates

involvement of a multidisciplinary medical team. Symptomatic epidermoid cysts can
be managed by intralesional steroid injection or surgical excision [1]. Desmoid
tumors can be managed by surgical excision, though there is a high rate of recurrence
and recurring tumors may be more aggressive [6]. If wide surgical excision of
desmoid tumors fails, hormonal therapy (e.g., tamoxifen, raloxifene), and/or
anthracycline-containing chemotherapy can be tried [22]. Some osteomas in GS may
be amenable to surgical intervention [6, 11]. Medications that affect prostaglandin
metabolism, such as nonsteroidal anti-inflammatory drugs, have been reported to
reduce the risk of colorectal cancer and desmoids tumors [23].
Because of the significant risk of malignancy, strict screening regimens are
crucial for patients with FAP/GS. Due to the inevitability of developing CRC,
patients with FAP/GS should undergo annual sigmoidoscopy starting at age 10–15
and prophylactic colectomy is typically recommended when polyps are identified or
by the end of the 2nd or 3rd decade [5, 6, 18]. Chemoprevention with cyclooxygen-
ase inhibitors (i.e., celecoxib) has been associated with some level of polyp regres-
sion, but is not adequate to control the cancer risk [24].
Other recommended screening includes upper GI endoscopy every 1–3 years
(depending on polyp burden) along with annual thyroid exam due to risk of
malignancy [18, 25]. Annual abdominal ultrasounds and monitoring of serum
α-fetoprotein levels during the first 5 years of life are recommended due to risk of
hepatoblastoma in this age group [1]. Ophthalmologic exam should be performed
upon consideration of the diagnosis of FAP/GS to evaluate for the presence of
CHRPE. Panoramic dental radiographs can detect osteomas, odontomas, and
supernumerary teeth, and long-bone x-rays can be used to detect osteomas [2].
No consensus exists for routine screening for the detection of desmoid tumors,
but palpable masses or symptoms should be explored using computerized tomog-
raphy [1].
Genetic counseling is an extremely important consideration and all family
members should be offered genetic testing and be evaluated for evidence of GS.
29 Gardner Syndrome 205

29.6 Conclusion

Gardner syndrome affects multiple body systems, including the skin, soft tissue, bone,
gastrointestinal system, as well as other solid organs. Recognition of cutaneous signs
may provide an early diagnosis and can be lifesaving with proper management.

References

1. Juhn E, Khachemoune A. Gardner syndrome: skin manifestations, differential diagnosis and

management. Am J Clin Dermatol. 2010;11(2):117–22.
2. Ponti G, Pellacani G, Seidenari S, Pollio A, Muscatello U, Tomasi A. Cancer-associated geno-
dermatoses: skin neoplasms as clues to hereditary tumor syndromes. Crit Rev Oncol Hematol.
2012;85(3):239–56.
3. Nieuwenhuis MH, Vasen HF. Correlations between mutation site in APC and phenotype of
familial adenomatous polyposis (FAP): a review of the literature. Crit Rev Oncol Hematol.
2007;61(2):153–61.
4. Wallis YL, Morton DG, McKeown CM, Macdonald F. Molecular analysis of the APC gene
in 205 families: extended genotype-phenotype correlations in FAP and evidence for the role
of APC amino acid changes in colorectal cancer predisposition. J Med Genet. 1999; 36(1):
14–20.
5. Doxey BW, Kuwada SK, Burt RW. Inherited polyposis syndromes: molecular mechanisms,
clinicopathology, and genetic testing. Clin Gastroenterol Hepatol. 2005;3(7):633–64.
6. Kanitakis J. Adnexal tumours of the skin as markers of cancer-prone syndromes. J Eur Acad
Dermatol Venereol. 2010;24(4):379–87.
7. Bussey HJR. Familial polyposis coli: Family studies, histopathology, differential diagnosis,
and results of treatment. Baltimore: Johns Hopkins University Press; 1975
8. Järvinen HJ. Epidemiology of familial adenomatous polyposis in Finland: impact of family
screening on the colorectal cancer rate and survival. Gut. 1992;33(3):357–60.
9. Bülow S, Faurschou Nielsen T, Bülow C, Bisgaard ML, Karlsen L, Moesgaard F. The inci-
dence rate of familial adenomatous polyposis. Results from the Danish Polyposis Register. Int
J Colorectal Dis. 1996;11(2):88–91.
10. Shen Z, Hoffman JD, Hao F, Pier E. More than just skin deep: faciocutaneous clues to genetic
syndromes with malignancies. Oncologist. 2012;17(7):930–6.
11. Bayliss SJ, Berk DR, Burton BK, Cohen BA, Bree AF, Sybert VP. Other genodermatoses. In:
Bolognia JL, Jorizzo JL, Schaffer JV, editors. Dermatology. St. Louis, MO: Mosby/Elsevier; 2012.
12. Leal RF, Silva PV, Ayrizono Mde L, Fagundes JJ, Amstalden EM, Coy CS. Desmoid tumor in
patients with familial adenomatous polyposis. Arq Gastroenterol. 2010;47(4):373–8.
13. Shah KR, Boland CR, Patel M, Thrash B, Menter A. Cutaneous manifestations of gastrointestinal
disease: part I. J Am Acad Dermatol. 2013;68(2):189.e1–189.e21.
14. Shields JA, Shields CL, Shah PG, et al. Lack of association among typical congenital
hypertrophy of the retinal pigment epithelium, adenomatous polyposis and Gardner syndrome.
Ophthalmology. 1992;99(11):1709–13.
15. Baker RH, Heinemann MH, Miller HH, DeCosse JJ. Hyperpigmented lesions of the retinal
pigment epithelium in familial adenomatous polyposis. Am J Med Genet. 1988;31(2):
427–35.
16. Bisgaard ML, Bülow S. Familial adenomatous polyposis (FAP): genotype correlation to FAP
phenotype with osteomas and sebaceous cysts. Am J Med Genet A. 2006;140(3):200–4.
206 A. Golant and J.A. Zeichner

17. Tsao H. Update on familial cancer syndromes and the skin. J Am Acad Dermatol. 2000;
42(6):939–69.
18. Jasperson KW, Tuohy TM, Neklason DW, Burt RW. Hereditary and familial colon cancer.
Gastroenterology. 2010;138(6):2044–58.
19. Pujol RM, Casanova JM, Egido R, Pujol J, de Moragas JM. Multiple familial pilomatricomas:
a cutaneous marker for Gardner syndrome? Pediatr Dermatol. 1995;12(4):331–5.
20. Coffin CM, Hornick JL, Zhou H, Fletcher CD. Gardner fibroma: a clinicopathologic and
immunohistochemical analysis of 45 patients with 57 fibromas. Am J Surg Pathol. 2007;
31(3):410–6.
21. Naylor EW, Lebenthal E. Early detection of adenomatous polyposis coli in the Gardner’s
syndrome. Pediatrics. 1979;63(2):222–7.
22. de Camargo VP, et al. Clinical outcomes of systemic therapy for patients with deep fibromatosis
(desmoid tumor). Cancer. 2010;116(9):2258–65.
23. Hughes-Fulford M, Boman B. Growth regulation of Gardner’s syndrome colorectal cancer
cells by NSAIDs. Adv Exp Med Biol. 1997;407:433–41.
24. Boardman LA. Heritable colorectal cancer syndromes: recognition and preventive management.
Gastroenterol Clin North Am. 2002;31(4):1107–31.
25. Gallagher MC, Phillips RK, Bulow S. Surveillance and management of upper gastrointestinal
disease in familial adenomatous polyposis. Fam Cancer. 2006;5(3):263–73.
Chapter 30
Gorlin Syndrome

Madelaine Haddican and James Spencer

30.1 Introduction

Basal cell nevus syndrome (BCNS) is an autosomal dominantly inherited condition

first described in 1960 by Dr. Gorlin and Dr. Goltz [1]. BCNS is known by several other
names including nevoid basal cell carcinoma syndrome, basal cell carcinoma nevus
syndrome, Gorlin syndrome, and Gorlin-Goltz syndrome. Although BCNS demon-
strates a high degree of penetrance, the diagnosis can be challenging due to its variable
expressivity even within families [2, 3] and the age-dependent appearance of certain
traits associated with this disorder. Some of the more frequent and characteristic fea-
tures of BCNS include multiple basal cell carcinomas (BCCs), odontogenic kerato-
cysts, skeletal abnormalities, palmar and/or plantar pits, calcified falx cerebri, and facial
dysmorphism [1]. Other clinical features found in association with BCNS include neo-
plasms such as medulloblastoma, ovarian fibroma, and cardiac fibromas [4–7].

30.2 Background

BCNS results from mutations in the PTCH1 tumor suppressor gene which is found
on chromosome 9q22.3-q31 [8]. The product of the PTCH1 gene normally represses
gene transcription in the Hedgehog signaling pathway by acting as a transmem-
brane receptor for the Sonic Hedgehog (SHH) ligand [9]. The Hedgehog signaling
pathway was first described as a developmental pathway during research on the fruit
fly, Drosophila melanogaster [10]. Post-developmentally in humans, the Hedgehog
signaling pathway is typically only active in hair follicles and skin cells [11].

M. Haddican, M.D. (*) • J. Spencer, M.D.

Department of Dermatology, Mount Sinai School of Medicine, New York, NY, USA
e-mail: [email protected]

J.A. Zeichner (ed.), Acneiform Eruptions in Dermatology: A Differential Diagnosis, 207

DOI 10.1007/978-1-4614-8344-1_30, © Springer Science+Business Media New York 2014
208 M. Haddican and J. Spencer

The neoplasms of the syndrome require two hits to the PTCH1 gene, with a muta-
tion in the second normal allele [12]. However, some clinical features of BCNS,
such as palmar pits, bifid rib, and macrocephaly, only require the inherited defective
allele [3].
Women and men appear to be equally affected by BCNS. However, the prevalence
of BCNS ranges from 1/57,000 to 1/256,000 depending on the studied population
[13, 14]. It should be noted that certain clinical manifestations of BCNS, mainly
BCCs, are less prevalent in darker skin individuals [15].

30.3 Clinical Presentation

More than 100 different clinical features have been found in association with BCNS
[16]. The most frequent and characteristic features of BCNS have been listed chron-
ologically by age of presentation.
Facial Dysmorphism: Most individuals with BCNS have one or more of the
following “coarse” facial features: macrocephaly, frontal bossing, broad nasal
bridge, prognathism, high arched eyebrows and/or palate, and cleft lip/palate [4,
17]. Patients with BCNS sometimes have a history of being delivered by cesarean
section due to macrocephaly which is the most common facial dysmorphism asso-
ciated with BCNS [18].
Skeletal Abnormalities: In addition to abnormal skull findings, other skeletal
abnormalities typically present at birth include bifid ribs, vertebral abnormalities,
Sprengel shoulder, pectus deformity, short 4th metacarpal, and syndactyly of the
digits [7].
Ocular Abnormalities: Other congenital abnormalities associated with BCNS
include severe eye defects such as strabismus, hypertelorism, telecanthus, cataracts,
glaucoma, microphthalmia, orbital cyst, and coloboma [6, 14, 17].
Cardiac Fibromas: Less than 5 % of patients with BCNS develop cardiac fibromas
which typically appear in the first year of life [6]. The detection of this benign tumor
qualifies as one of the minor criteria for the diagnosis. In general, cardiac fibromas
are asymptomatic, but they can cause conduction defects (arrhythmias) and ven-
tricular outflow obstruction [19].
Medulloblastoma: Less than 5 % of patients with BCNS also present with medul-
loblastomas. Compared to sporadic medulloblastomas which usually occur between
the ages of 6 and 10, medulloblastomas in association with BCNS are more common
in male patients and typically present by 2 years of age [13, 20].
Odontogenic (Jaw) Keratocysts: Approximately 90 % of patients with BCNS
develop multiple jaw keratocysts which occur mostly in the mandible [14]. These
keratocysts have been reported as early as 4 years old, but typically occur during
30 Gorlin Syndrome 209

Fig. 30.1 2 mm pearly

papules on the face. Biopsies
revealed these lesions to be
basal cell carcinomas (Photo
credit: Joshua A. Zeichner,
M.D.)

the second and third decade of life [21]. The presentation of these keratocysts
ranges from asymptomatic to painless jaw swelling, tooth disruption, and rarely jaw
fracture [22].
BCCs: BCCs in patients with BCNS occur in more than 75 % of Caucasians
(Fig. 30.1) but less often in African American and Asian patients [15, 23]. BCCS in
BCNS has been reported as early as 3 years of age, but the peak incidence occurs
at 20 years of age [6]. They typically occur in sun-exposed area. While only a small
percentage are locally invasive, they are challenging to treat and surgical manage-
ment is potentially disfiguring [17].
Palmoplantar Pitting: Approximately 80 % of patients with BCNS develop
palmoplantar pitting typically beginning in the second decade of life [24] (Fig. 30.2).
Intracranial Calcification: In a study of 105 individuals with BCNS (mean age of
32.5 years), approximately 65 % of these patients had intracranial calcification,
particularly of the falx cerebri [4].
Ovarian Fibromas: Approximately 15–25 % of female patients with BCNS have
ovarian fibroma which is often bilateral and calcified [4, 6]. Most are asymptomatic
and are usually discovered incidentally, but some can undergo torsion [3].
Lymphomesenteric Cysts: The exact incidence and age of presentation for lympho-
mesenteric cysts is unknown. They are also usually asymptomatic [23].
210 M. Haddican and J. Spencer

Fig. 30.2 1–2 mm depressed papules on the palms (Photo credit: Joshua A. Zeichner, M.D.)

30.4 Work-Up

The diagnosis of BCNS is typically based on the constellation of clinical manifesta-

tions [25]. Depending on the age of the patient, the following criteria can be used to
establish the diagnosis:
• Physical examination for facial dysmorphism [26].
• X-rays to detect skeletal abnormalities [7].
• Ophthalmologic evaluation [3].
• Measurement of head circumference to evaluate for macrocephaly [25].
• Echocardiography to evaluate for the presence of a cardiac fibroma [25].
• Brain MRI for the detection of a medulloblastoma [25].
• Panoramic jaw X-rays to evaluate for odontogenic keratocysts [27]
• Skin examination (including biopsies of suspected lesions) for BCCs [25].
• Pelvic ultrasound examination to evaluate for ovarian fibromas in females [25].
There have been no formal studies to help clarify the best combination of clinical
features which most accurately leads to a diagnosis of BCNS. The diagnostic crite-
ria for BCNS generally include either two major criteria or one major and two
minor criteria. The major criteria include BCC before 20 years old or excessive
numbers of BCCs, odontogenic (jaw) keratocyst before 20 years old, palmar and/or
plantar pitting, calcification of the falx cerebri, medulloblastoma, and family history
of BCNS. The minor criteria include rib abnormalities, other skeletal malforma-
tions, macrocephaly, cleft/lip palate, ovarian/cardiac fibroma, lymphomesenteric
cysts, and ocular abnormalities [25].
30 Gorlin Syndrome 211

30.5 Treatment

There is no cure for BCNS and patients are managed based on syndrome-related
findings [3]. The different clinical manifestations are treated similarly in patients
without the disorder. However, surveillance guidelines for the detection of different
tumors and odontogenic cysts are important; and thus, patients with BCNS need to
be treated under the care of several specialists including medical geneticists, derma-
tologists, oral surgeons, and plastic surgeons [25]. Fortunately, the life span of
patient with BCNS is not significantly different from the average [3], but exposure
to ionizing and UV radiation should be minimized to reduce the total number of
BCCs [28].
For the management of BCCs, a regular complete skin examination by a
dermatologist every 2–4 months is recommended for patients with BCNS [3, 25].
Due to the increased number of BCCs typically present during a lifetime, there is a
tendency to reserve surgical treatment for aggressive or invasive tumors in order to
prevent disfigurement [3, 29]. Although the majority of BCCs are nodular in BCNS,
topical application of 0.1 % tretinoin cream, 5-fluorouracil cream, and imiquimod
5 % cream is effective for treating superficial BCCs and has been used for these
BCCs as well [3, 29, 30]. One of the more novel therapeutic approaches for BCC
involves photodynamic therapy (PDT) which is the topical application of an agent,
such as 5-aminolevulinic acid (ALA, Levulan®, DUSA Pharmaceuticals, Inc.,
Wilmington, MA, USA) or methyl ester form, methyl 5-aminolevulinate (MAL,
Metvixia TM, Galderma, Princeton, NJ, USA) [31, 32]. Both ALA and MAL are
converted to a photosensitizer protoporphyrin IX in tumor cells. MAL-PDT is
unique in not only demonstrating a high efficacy in the treatment of superficial
BCC; it has also been shown to be effective in the treatment of nodular BCC [33].
Vismodegib, an oral Hedgehog pathway inhibitor, has also been shown to be an
important option in the treatment of BCCs. However, the side effects of oral vismo-
degib, including muscle spasms, hair loss, altered taste sensation, weight loss,
fatigue, nausea, decreased appetite, and diarrhea, may not be well tolerated in some
patients [34, 35]. Additionally, a topical inhibitor of the Hedgehog pathway has
shown promising results in a randomized trial for patients with BCNS [36].
While great care is taken to treat BCC’s, prophylactic therapy may be used to
prevent growth of new cancers. Given these patients’ high risk for continually
developing BCCs, therapy to prevent them can save disfiguring treatments. Acitretin
has been shown to reduce the size of clinically apparent skin cancers and may been
used as chemoprevention [37]. While the efficacy of acitretin has been described for
squamous cell carcinomas (SCCs), the drug may be used for patients with BCNS.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are also used as chemoprevention
for SCCs. Oral celecoxib has been shown to be effective in suppression BCCs in
both mice and humans with PTCH1 gene mutations [38].
For the detection of odontogenic keratocysts, annual dental panoramic X-rays are
recommended beginning at the age of eight [27]. These cysts are typically removed
by wide excision/enucleation with curettage but have a high rate of recurrence [23,
212 M. Haddican and J. Spencer

39]. There is some evidence that oral vismodegib is also an important treatment
option for keratocysts; however, more studies are needed in patients with BCNS [40].
Notably in pediatric patients, surveillance for the development of medulloblas-
toma and cardiac fibroma is important. An annual cranial MRI is recommended
until 8 years of age for the detection of a medulloblastoma [25]. For the treatment of
a medulloblastoma, radiation therapy should be avoided because it causes multiple
BCCs to develop in the field of radiation [28]. To monitor for the presence of a car-
diac fibroma, an echocardiogram should be completed in the first year of life.
Asymptomatic patients with a cardiac fibroma should be closely followed by a
pediatric cardiologist [25].

30.6 Conclusion

Gorlin syndrome is an autosomal dominant condition characterized by countless

number of basal cell carcinomas, in combination with various other findings such as
odontogenic (jaw) keratocysts and palmar and/or palmar pits, and medulloblastoma.
Treatment requires a multidisciplinary approach to monitor the various organ
systems involved. Dermatologists play a crucial role not only in treating skin cancers
but also in preventing the onset of new malignancies.

References

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2. Anderson D, Taylor W, Falls H, Davidson R. The nevoid basal cell carcinoma syndrome. Am
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3. Lo Muzio L. Nevoid basal cell carcinoma syndrome (Gorlin syndrome). Orphanet J Rare Dis.
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4. Kimonis VE, et al. Clinical manifestations in 105 persons with nevoid basal cell carcinoma
syndrome. Am J Med Gen. 1997;69:300.
5. Shanley S, et al. Nevoid basal cell carcinoma syndrome: review of 118 affected individuals.
Am J Med Genet. 1994;50:282.
6. Evans DG, Ladusans EJ, Rimmer S, Burnell LD, Thakker N, Farndon PA. Complications of
the naevoid basal cell carcinoma syndrome: results of a population based study. J Med Genet.
1993;30:460–4.
7. Ratcliffe JF, Shanley S, Chenevix-Trench G. The prevalence of cervical and thoracic congeni-
tal skeletal abnormalities in basal cell naevus syndrome; a review of cervical and chest radio-
graphs in 80 patients with BCNS. Br J Radiol. 1995;68:596–9.
8. Farndon PA, Del Mastro RG, Evans DG, Kilpatrick MW. Location of gene for Gorlin
syndrome. Lancet. 1992;339:581–2.
9. Booth DR. The hedgehog signaling pathway and its role in basal cell carcinoma. Cancer
Metastasis Rev. 1999;18:261.
10. Hahn H, Wicking C, Zaphiropoulous PG, Gailani MR, Shanley S, Chidambaram A,
Vorechovsky I, Holmberg E, Unden AB, Gillies S, et al. Mutations of the human homolog of
Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell. 1996;85:841–51.
30 Gorlin Syndrome 213

11. Gailani M, Bale A. Developmental genes and cancer: role of patched in basal cell carcinoma
of the skin. J Natl Cancer Inst. 1997;89:1103.
12. Levanat S, Gorlin R, Fallet S, et al. A two-hit model for developmental defects in Gorlin
syndrome. Nat Genet. 1996;12:85.
13. Evans DG, Farndon PA, Burnell LD, Gattamaneni HR, Birch JM. The incidence of Gorlin
syndrome in 173 consecutive cases of medulloblastoma. Br J Cancer. 1991;64:959–61.
14. Lo Muzio L, Nocini PF, Savoia A, Consolo U, Procaccini M, Zelante L, Pannone G, Bucci P,
Dolci M, Bambini F, et al. Nevoid basal cell carcinoma syndrome. Clinical findings in 37
Italian affected individuals. Clin Genet. 1999;55:34–40.
15. Goldstein AM, Pastakia B, DiGiovanna JJ, Poliak S, Santucci S, Kase R, Bale AE, Bale SJ.
Clinical findings in two African-American families with the nevoid basal cell carcinoma
syndrome (NBCC). Am J Med Genet. 1994;50:272–81.
16. Farndon PA. Gorlin (naevoid basal cell carcinoma) syndrome. In: Eeles R, Easton DF, Ponder
BAJ, Eng C, editors. Genetic predisposition to cancer. London: Hodder Arnold; 2004.
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17. Gorlin RJ. Nevoid basal-cell carcinoma syndrome. Medicine (Baltimore). 1987;66:98.
18. Hogge WA, Blank C, Roochvarg LB, Hogge JS, Wulfsberg EA, Raffel LJ. Gorlin syndrome
(naevoid basal cell carcinoma syndrome): prenatal detection in a fetus with macrocephaly and
ventriculomegaly. Prenat Diagn. 1994;14:725–7.
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associated with cardiac tumor. Am Heart J. 1986;111:1013.
20. Lacombe D, Chateil JF, Fontan D, Battin J. Medulloblastoma in the nevoid basal-cell carcinoma
syndrome: case reports and review of the literature. Genet Couns. 1990;1:273.
21. Woolgar JA, Rippin JW, Browne RM. The odontogenic keratocyst and its occurrence in the
nevoid basal cell carcinoma syndrome. Oral Surg Oral Med Oral Pathol. 1987;64:727–30.
22. Myoung H, Hong SP, Hong SD, et al. Odontogenic keratocyst: review of 256 cases for recur-
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30. Gollnick H, Barona CG, Frank RG, et al. Recurrence rate of superficial basal cell carcinoma
following treatment with imiquimod 5 % cream: conclusion of a 5-year long-term follow-up
study in Europe. Eur J Dermatol. 2008;18:677–82.
31. Hsi RA, Rosenthal DI, Glatstein E. Photodynamic therapy in the treatment of cancer:current
state of the art. Drugs. 1999;57:725–34.
32. Morton CA, MacKie RM, Whitehurst C, Moore JV, McColl JH. Photodynamic therapy for
basal cell carcinoma: effect of tumor thickness and duration of photosensitizer application on
response. Arch Dermatol. 1998;134:248–9.
33. Horn M, Wolf P, Wulf HC, et al. Topical methyl aminolaevulinate photodynamic therapy in
patients with basal cell carcinoma prone to complications and poor cosmetic outcome with
conventional treatment. Br J Dermatol. 2003;149:1242–9.
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34. LoRusso PM, Rudin CM, Reddy JC, Tibes R, Weiss GJ, Borad MJ, Hann CL, Brahmer JR,
Chang I, Darbonne WC, Graham RA, Zerivitz KL, Low JA, Von Hoff DD. Phase I trial of
hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with refractory, locally
advanced or metastatic solid tumors. Clin Cancer Res. 2011;17:2502–11.
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36. Skvara H, Kalthoff F, Meingassner JG, et al. Topical treatment of Basal cell carcinomas in
nevoid basal cell carcinoma syndrome with a smoothened inhibitor. J Invest Dermatol. 2011;
131:1735.
37. Lebwohl M, Tannis C, Carrasco D. Acitretin suppression of squamous cell carcinoma: case
report and literature review. J Dermatolog Treat. 2003;14 Suppl 2:3–6. Review.
38. Tang JY, Aszterbaum M, Athar M, et al. Basal cell carcinoma chemoprevention with nonste-
roidal anti-inflammatory drugs in genetically predisposed PTCH1+/− humans and mice.
Cancer Prev Res (Phila). 2010 Jan;3(1):25–34.
39. Dominguez FV, Keszler A. Comparative study of keratocysts, associated and non-associated
with nevoid basal cell carcinoma syndrome. J Oral Pathol. 1988;17:39–42.
40. Goldberg LH, Landau JM, Moody MN, et al. Resolution of odontogenic keratocysts of the jaw
in basal cell nevus syndrome with GDC-0449. Arch Dermatol. 2011;147:839.
Chapter 31
Muir-Torre Syndrome

Adam J. Luber and Joshua A. Zeichner

31.1 Introduction

Muir-Torre syndrome (MTS) is a rare, autosomal dominant genodermatosis

characterized by sebaceous neoplasms, keratoacanthomas, and visceral malignan-
cies [1, 2]. MTS is a phenotypic subset of hereditary nonpolyposis colorectal cancer
(HNPCC) caused by mutations in mismatch repair genes associated with microsat-
ellite instability [3]. Due to the increased risk in developing visceral malignancies,
it is important that the proper diagnosis to be made as early as possible and family
members be evaluated for MTS and its associated cancers.
MTS was first described separately by Muir [4] and Torre [5] in 1967 and 1968,
respectively. Muir first reported a patient with a sebaceous adenoma, multiple kerato-
acanthomas of the face, and multiple carcinomas of the gastrointestinal tract [4]. Torre
described a case of multiple sebaceous neoplasms in a patient with a history of two
gastrointestinal malignancies [5]. The combined name of the syndrome was created in
1982 when Fahmy et al. reported 20 cases with a similar constellation of findings [6].

31.2 Background

MTS is inherited as an autosomal dominant disorder with variable penetrance and

expressivity [3]. The syndrome has a slight male predilection, with a male to female
ratio of 3:2 and a mean age of 53 (ranging from the 30s to 80s) at the time of diag-
nosis [7, 8]. A 2004 study reported that more than 200 cases of MTS have been
described in the literature since 1982 [3]. There is limited data on an ethnic or
ancestral predisposition to MTS; however, the majority of cases are reported in

A.J. Luber, B.A. (*)

Department of Dermatology, Mt Sinai Hospital, New York, NY, USA
J.A. Zeichner, M.D.
Department of Dermatology, Mt. Sinai School of Medicine, New York, NY, USA

J.A. Zeichner (ed.), Acneiform Eruptions in Dermatology: A Differential Diagnosis, 215

DOI 10.1007/978-1-4614-8344-1_31, © Springer Science+Business Media New York 2014
216 A.J. Luber and J.A. Zeichner

Caucasian patients residing in the developed world [2]. MTS is observed in 28 % of

families and 9 % of individuals with HNPCC [9]. The two disorders share similar
genetic mechanisms—both are caused by mutations in mismatch repair genes, which
produce enzymes involved in maintaining accurate DNA replication in cells [10].
MTS is caused by heterozygous germline mutations in one of the following
mismatch repair genes: MutS homolog 2 (MSH2), MutL homolog 1 (MLH1), or
MutS homolog 6 (MSH6). The mismatch repair mechanism prevents errors in the
short, repeat sequences of DNA, called microsatellites. Ninety percent of mutations
in MTS occur in MSH2 on chromosome 2 [11, 12]. Mismatch repair deficiency
results from an inherited germline mutation combined with a somatic loss-of-function
mutation in the contralateral wild-type allele. Ensuing errors in DNA replication at
multiple loci begin to accumulate and are termed microsatellite instability (MSI),
which promote tumor formation [13].
In HNPCC, approximately 75 % of germline mutations are seen in either MSH2
or MLH1, with the remainder of mutations in MSH6 and postmeiotic segregation
increased 2 (PMS2) [3, 9]. Mutations in MSH2 disrupt the MSH2-MSH6 heterodi-
mer, ultimately causing a lack of expression of the MSH6 protein in both MTS and
HNPCC [14].

31.3 Clinical Presentation

A diagnosis of MTS is made by the presence of at least one sebaceous gland

neoplasm and at least one visceral malignancy, in the absence of any known predis-
posing factors [15]. While sebaceous adenomas are the most common sebaceous
neoplasms found in MTS (68 %), sebaceous carcinomas (30 %), sebaceous epithe-
liomas (sebaceoma), keratoacanthomas with sebaceous differentiation (seboacan-
thoma), or basal cell carcinomas with sebaceous differentiation are included in the
diagnostic criteria (sebaceous hyperplasia and nevus sebaceous of Jadassohn are
excluded) [13]. Alternatively, when no sebaceous tumor is present, a patient can
be diagnosed with MTS based on a personal history of multiple keratoacanthomas
and visceral malignancies in the setting of a family history of MTS [1, 10, 16].
Sebaceous neoplasms are yellow papules or nodules that are typically found on
the head, neck, or trunk; sporadic cases are almost exclusively on the head and neck
[10, 16, 17]. Keratoacanthomas are rapidly appearing, erythematous papules or
nodules that are seen in 25 % of patients with MTS [15]. While some patients with
MTS present with a solitary sebaceous neoplasm, it is more common to see several
and sometimes hundreds of tumors [1]. Excluding sebaceous carcinomas, the seba-
ceous neoplasms associated with MTS have low malignant potential and rarely
metastasize. Sebaceous carcinomas, particularly when located in periocular regions,
are aggressive tumors that invade angiolymphatic space [7].
Cutaneous manifestations can present prior to (30 % of cases), concurrently with
(10 %), or after (60 %) the diagnosis of internal malignancy [15]. Reports have
documented skin lesions preceding internal malignancy by 25 years or developing
37 years after [8]. Sixty-one percent of internal malignancies associated with MTS
31 Muir-Torre Syndrome 217

arise from the alimentary system, with colorectal carcinoma being the most common
[3, 18]. MTS-associated colorectal carcinoma usually develops proximal to the
splenic flexure and typically appears by age 50. In contrast, colorectal carcinoma in
the general population is diagnosed, on average, 10 years later (age range 55–65)
and is commonly located in the distal colon [7, 13]. Other visceral malignancies
linked to MTS include genitourinary, breast, hematologic, head and neck, small
intestine, and stomach [19].
While MTS-associated malignancies are usually less aggressive than their
sporadic counterparts, approximately 60 % of patients affected by the syndrome
will develop metastatic disease [20]. Few studies have examined survival rates
among individuals with MTS, however, MTS-associated neoplasms may be more
surgically responsive compared to sporadic carcinomas [2].

31.4 Work-Up

Laboratory evaluation for MTS can be conducted by peripheral blood samples to

detect germline mutations at commercial laboratories. Many pathologists suggest that
any sebaceous neoplasm that is difficult to classify should be investigated as a MTS
lesion [13]. In general, histopathological examination of sebaceous neoplasms in MTS
reveals the equivalent findings as the same lesion in non-MTS individuals [10, 16].
Immunohistochemical (IHC) analysis of the tumor specimens has become a
popular method to differentiate MTS-associated neoplasms. The IHC assays are
highly sensitive and specific since the antibodies target the DNA mismatch repair
enzymes known to be linked to MTS—MLH1, MSH2, and MSH6. The absence of
these enzymes on IHC analysis (i.e., loss of expression) is consistent with a MTS-
associated neoplasm [10]. Polymerase chain reaction (PCR) assays can detect MSI
in tissue specimens of MTS-associated malignancies [14].
MTS is diagnosed based on specific criteria, including the presence of multiple
sebaceous neoplasms, skin lesions located outside of the head and neck region,
and sebaceous neoplasms with high specificity for MTS (such as seboacanthoma).
In addition, a personal or family history of colorectal cancer before the age of 50 or
other HNPCC-related malignancy (small bowel, gastric, endometrial, bladder, ureteral,
renal, biliary, pancreatic, or glioblastoma) increases the probability of MTS [15].

31.5 Treatment

Benign sebaceous neoplasms can be treated with cryotherapy, curettage, or simple

excision depending on the size and location of the lesion. Wide, local excision with
5–6 mm margins or Mohs micrographic surgery is the recommended treatments for
sebaceous carcinomas [1, 7]. Radiotherapy has been successful in treating surgi-
cally difficult sebaceous carcinomas located on the orbit or ocular adnexa [21, 22].
Oral isotretinoin, alone or in combination with interferon-alpha, is used to limit
the growth of existing sebaceous tumors and to prevent new tumor development.
218 A.J. Luber and J.A. Zeichner

Additionally, topical fluorouracil and imiquimod are employed as chemoprophylaxis

therapies in reducing the burden of keratoacanthomas and basal cell carcinomas that
may be associated with MTS [7, 23, 24]. Lymphadenopathy warrants fine needle
aspiration for further inspection, followed by regional lymphadenectomy if lymph
node involvement is present [2]. Patients with a visceral malignancy require proper
oncologic management beyond the scope of this chapter.
Managing patients and families affected by MTS requires a multidisciplinary
approach including primary care physicians, dermatologists, gastroenterologists,
oncologists, surgeons, and geneticists [2, 25]. Because of the syndrome’s inheri-
tance pattern, family members who acquire the DNA mismatch repair defect have a
considerably increased risk of developing visceral malignancies and should commit
to routine cancer surveillance [13].
Patients with MTS, as well as asymptomatic carriers of mutations, require annual
physical examinations by a primary care physician and dermatologist. Beginning at
ages 25–30, individuals should undergo colonoscopy or evaluation with barium
enema every 3–5 years. Regular chest radiographs and serial renal ultrasounds are
also useful screening tests. Females should have annual breast exams, mammograms,
and Pap smears. Annual laboratory studies include urinalysis, complete blood count,
carcinoembryonic antigen, and erythrocyte sedimentation rate [2, 15, 25].

31.6 Conclusion

Muir-Torre Syndrome is a disease characterized by both cutaneous and systemic

changes. Patients diagnosed with sebaceous gland tumors, especially multiple
tumors, should be offered genetic tests to detect mutations in mismatch repair genes
associated with MTS [2, 3, 25]. These skin lesions often serve as a herald sign to a
potentially life-threatening internal malignancy. Regular and strict dermatology
follow-up is critical for affected individuals and their family members.

References

1. Schwartz RA, Torre DP. The Muir-Torre syndrome: a 25-year retrospect. J Am Acad Dermatol.
1995;33(1):90–104.
2. Ponti G, Ponz de Leon M. Muir-Torre syndrome. Lancet Oncol. 2005;6(12):980–7.
3. Curry ML, Eng W, Lund K, Paek D, Cockerell CJ. Muir-Torre syndrome: role of the dermato-
pathologist in diagnosis. Am J Dermatopathol. 2004;26(3):217–21.
4. Muir EG, Bell AJ, Barlow KA. Multiple primary carcinomata of the colon, duodenum, and
larynx associated with kerato-acanthomata of the face. Br J Surg. 1967;54(3):191–5.
5. Torre D. Multiple sebaceous tumors. Arch Dermatol. 1968;98(5):549–51.
6. Fahmy A, Burgdorf WH, Schosser RH, Pitha J. Muir-Torre syndrome: report of a case and
reevaluation of the dermatopathologic features. Cancer. 1982;49(9):1898–903.
7. Higgins HJ, Voutsalath M, Holland JM. Muir-Torre syndrome: a case report. J Clin Aesthet
Dermatol. 2009;2(8):30–2.
31 Muir-Torre Syndrome 219

8. Cohen PR, Kohn SR, Kurzrock R. Association of sebaceous gland tumors and internal
malignancy: the Muir-Torre syndrome. Am J Med. 1991;90(5):606–13.
9. South CD, Hampel H, Comeras I, Westman JA, Frankel WL, De la Chapelle A. The frequency
of Muir-Torre syndrome among Lynch syndrome families. J Natl Cancer Inst. 2008;
100(4):277–81.
10. Eisen DB, Michael DJ. Sebaceous lesions and their associated syndromes: part II. J Am Acad
Dermatol. 2009;61(4):563–80.
11. Mangold E, Rahner N, Friedrichs N, et al. MSH6 mutation in Muir-Torre syndrome: could this
be a rare finding? Br J Dermatol. 2007;156(1):158–62.
12. Lynch HT, Fusaro RM. The Muir-Torre syndrome in kindreds with hereditary nonpolyposis
colorectal cancer (Lynch syndrome): a classic obligation in preventive medicine. J Am Acad
Dermatol. 1999;41(5):797–9.
13. Hare HH, Mahendraker N, Sarwate S, Tangella K. Muir-Torre syndrome: a rare but important
disorder. Cutis. 2008;82(4):252–6.
14. Marazza G, Masouyé I, Taylor S, et al. An illustrative case of Muir-Torre syndrome: contribution
of immunohistochemical analysis in identifying indicator sebaceous lesions. Arch Dermatol.
2006;142(8):1039–42.
15. Bayliss SJ, Berk DR. Muir-Torre syndrome. In: Bolognia JL, Jorizzo JL, Schaffer JV, editors.
Dermatology. 3rd ed. St. Louis, MO: Elsevier; 2012.
16. Eisen DB, Michael DJ. Sebaceous lesions and their associated syndromes: part I. J Am Acad
Dermatol. 2009;61(4):549–62.
17. Dores GM, Curtis RE, Toro JR, Devesa SS, Fraumeni Jr JF. Incidence of cutaneous sebaceous
carcinoma and risk of associated neoplasms: insight into Muir-Torre syndrome. Cancer.
2008;113(12):3372–81.
18. Akhtar S, Oza KK, Khan SA, Wright J. Muir-Torre syndrome: case report of a patient with
concurrent jejunal and ureteral cancer and a review of the literature. J Am Acad Dermatol.
1999;41(5):681–6.
19. Cohen PR. Muir-Torre syndrome in patients with hematologic malignancies. Am J Hematol.
1992;40(1):64–5.
20. Poleksic S. Keratoacanthoma and multiple carcinomas. Br J Dermatol. 1974;91(4):461–3.
21. Pardo FS, Wang CC, Albert D, Stracher MA. Sebaceous carcinoma of the ocular adnexa:
radiotherapeutic management. Int J Radiat Oncol Biol Phys. 1989;17(3):643–7.
22. Hata M, Koike I, Omura M, Maegawa J, Ogino I, Inoue T. Noninvasive and curative radiation
therapy for sebaceous carcinoma of the eyelid. Int J Radiat Oncol Biol Phys. 2012;82(2):
605–11.
23. Spielvogel RL, DeVillez RL, Roberts LC. Oral isotretinoin therapy for familial Muir-Torre
syndrome. J Am Acad Dermatol. 1985;12(3):475–80.
24. Pettey AA, Walsh JS. Muir-Torre syndrome: a case report and review of the literature. Cutis.
2005;75(3):149–55.
25. Cohen PR, Kohn SR, Davis DA, Kurzrock R. Muir-Torre syndrome. Dermatol Clin. 1995;
13(1):79–89.
Chapter 32
Reed’s Syndrome

Kristen Pacific and Jason Emer

32.1 Introduction

Multiple cutaneous and uterine leiomyomatosis (MCUL), also known as Reed’s

syndrome, is an autosomal dominant genetic condition. Affected individuals have
an increased predisposition to develop benign smooth muscle tumors (leiomyomas)
in the skin and uterus. Affected females frequently develop uterine leiomyomas
(fibroids) that are larger and more numerous and emerge earlier than those in the
general population. Subsets of these patients are at risk for renal cell carcinoma
(RCC) and have been determined to have mutations in the fumarate hydratase (FH)
gene. In individuals or families without RCC, the syndrome may be referred to as
multiple cutaneous leiomyomatosis (MCL) or MCUL. The term hereditary leio-
myomatosis and RCC (HLRCC) refers to families with an increased prevalence of
smooth muscle tumors and RCC as a result of the FH genetic defect. Since cutane-
ous leiomyomas are not exceptionally common, their presence—whether single or
in multiplicity—should raise suspicion of underlying uterine leiomyomas and the
possibility of real disease. Increased clinical awareness is important due to the asso-
ciation between coexisting cutaneous and systemic diseases.

32.2 Background

The coexistence of benign smooth muscle growths in the skin and in the uterus is
known as Reed’s syndrome [1]. In 1973, Reed et al reported on two families in
which members of successive generations demonstrated cutaneous leiomyomas,

K. Pacific, B.A. • J. Emer, M.D. (*)

Department of Dermatology, Mount Sinai School of Medicine, New York, NY, USA
e-mail: [email protected]; [email protected]

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DOI 10.1007/978-1-4614-8344-1_32, © Springer Science+Business Media New York 2014
222 K. Pacific and J. Emer

uterine leiomyomas, and/or leiomyosarcomas, establishing an autosomal dominant

pattern of inheritance [2, 3].
Cutaneous leiomyomas are benign tumors composed of smooth muscle fibers
that arise from either the arrector pili muscles surrounding the hair follicles; the
dartos muscle of genital, nipple, or areola skin or the smooth muscle of the vascula-
ture [4, 5]. In Reed’s syndrome, they appear to be of the type originating from
the arrector pili of the hair follicle [6–8]. Affected individuals with Reed’s syndrome
develop leiomyomas that are larger, more numerous, and emerge earlier than those in
the general population. In addition, affected females develop uterine disease. Since
its first reports, Reed’s syndrome has been reported in only about 100 families
across the globe, making it rare in the general population [1]. Although HLRCC has
been observed in patients of many ethnic backgrounds, the incidence is reportedly
higher among those of Eastern European descent [9]. The association of MCUL
with papillary type 2 RCC is known [10, 11]. The disease predisposing gene has
been identified as fumarate hydrase (FH), a gene encoding an enzyme that operates
in the mitochondrial citric acid cycle (Krebs cycle) and is intimately involved in
cellular energy metabolism [12, 13].
Familial studies have localized the predisposition for Reed’s syndrome to
chromosome 1q42.3–43, namely, the MCUL1 locus of the gene encoding FH [5,
14–16]. The discovery occurred shortly after researchers reported that some
individuals with MCL were also at risk of developing an aggressive form of RCC.
After significant genetic research, germline and somatic mutations along with loss
of heterozygosity in FH of tumor tissue was identified. Mutations of the missense,
nonsense, frameshift, insertion, and splice-site types have been discovered in the FH
gene [13]. Mutation analysis of 21 North American families with HLRCC identified
germline mutations of the FH gene in 100 % (21/21) [9]. Of families with HLRCC,
62 % (13/21) had RCC and 76 % (16/21) had cutaneous leiomyomas. Of female FH
mutation carriers, 100 % (22/22) had uterine fibroids. Other reports have identified
FH mutations in approximately 75 % of MCUL cases [17].
FH alterations are believed to correlate with tumor formation in families with
HLRCC; however, the pathological mechanism for this relationship is not entirely
clear. A cell that lacks functional FH has a subsequent metabolic derangement due
to its defective Krebs cycle [18]. It has been suggested that pseudohypoxia due to
defective enzymatic metabolism may drive cellular transformation and tumorigen-
esis [19]. Additionally, recent genetic analysis suggests that FH may act as a tumor
suppressor gene, but the consequence thereof has yet to be determined.

32.3 Clinical Presentation

Clinical characteristics of HLRCC may include cutaneous leiomyomas, uterine

leiomyomas, and/or renal tumors. Cutaneous leiomyomas are rare in the general
population, but are observed in 76–87 % of HLRCC prognoses thus are cutaneous
marker of systemic disease [20].
32 Reed’s Syndrome 223

Fig. 32.1 Multiple red-

brown papules and nodules
in a cluster on the left
shoulder

Fig. 32.2 Multiple

erythematous papules on
the leg of an adult woman.
She frequently complained
that the lesions would
become tender (Photo credit:
Joshua A. Zeichner, M.D.)

Reed’s syndrome manifests during the second to fourth decade of life, with solitary
or multiple cutaneous leiomyomas, which appear as firm skin-colored or pink-brown
papules or nodules ranging from 0.2 to 2 cm in diameter [5, 7, 11] (Figs. 32.1 and
32.2). A pseudo-Darier sign may be present, which is a transient piloerection or
elevation of a lesion induced by rubbing. The clinical presentation of multiple lesions
has been described in various patterns or distributions, such as bilateral and symmetric,
clustered, linear, zosteriform, dermatomal like, or disseminated [4, 21]. Although
commonly distributed over the trunk, the face may also be affected.
It is important to consider a leiomyoma in any indolent nodular or papular growth
associated with pain. In 89–92 % of cases, patients experience localized photosen-
sitivity and pain upon contact, injury or exposure to change in temperature [20]. An
acute increase in size and/or number of lesions and/or an increase in pain should be
suggestive of worsening disease or the rare possibility of malignant degeneration.
224 K. Pacific and J. Emer

Accurate diagnosis is critical due to the potential for concealed malignancy.

As leiomyomas are classically painful, the complete list of painful papulonodules
should all be taken into consideration on initial evaluation [22]. The popular
pneumonic “LEND AN EGG” represents a list of painful tumors of the skin that
includes leiomyoma, eccrine spiradenoma, neuroma, dermatofibroma, angiolipoma,
neurilemmoma, endometrioma, glomus tumor, and granular cell tumor [23].

32.4 Work-Up

The clinical diagnosis of cutaneous leiomyomas may be challenging and ultimately

requires histopathological analysis. It is important to differentiate a case of simple
benign cutaneous leiomyomas from that of HLRCC. A high index of suspicion is
required in order to ensure that patients are properly screened and receives the
appropriate diagnostic exams (Table 32.1). Histological analyses exhibit very
distinctive characteristics and should be utilized for confirmation of diagnosis.
On microscopic examination, smooth muscle fiber bundles are interspersed with
collagen within the dermis [24, 25]. Special stains, including Masson’s trichrome, Van
Gieson, or phosphotungstic acid–hematoxylin (PTAH), can be used to distinguish
smooth muscle from collagen, since both will appear pink-red on hematoxylin–eosin
stain [26]. The markers of smooth muscle differentiation (desmin and actin) will also
be positive [27]. Immunohistochemical staining will be negative for estrogen and pro-
gesterone receptors in cutaneous leiomyomas, but are positive in uterine leiomyomas
[28]. FH gene enzyme activity in cultured skin fibroblasts or lymphoblastoid cells
may demonstrate decreased activity (≤60 %) [29].
Any individual presenting with cutaneous leiomyomas should be given a
complete physical examination with a comprehensive history, including a focus on
the family and surgical histories. All female patients with MCL should be evaluated
for uterine disease. Currently, the NIH recommends evaluating all patients with
leiomyomatosis for the presence of an occult renal malignancy [29, 30]. Referral to
genetics for further work-up may also be prudent.

Table 32.1 Screening recommendations in a patient with multiple cutaneous leiomyomatosis

Complete history with focus on family and surgical histories
Complete physical examination including pelvic examination
Skin biopsy with special stains such as Masson–Trichrome, Van Gieson, Desmin, and Actin
Pelvic ultrasound
Renal ultrasound
Complete blood count
Complete metabolic panel
Urinalysis
Genetic analysis for fumarate hydratase mutation
Referral to gynecology
Referral to nephrology
Referral to genetic counseling if fumarate hydratase mutation suspected and/or confirmed
32 Reed’s Syndrome 225

32.5 Treatment

Treatment of cutaneous leiomyomas is dictated by the number of lesions and the

degree of discomfort or cosmetic nuisance. Camouflage cosmetics (makeup) and
avoidance of painful triggers, such as cold and/or pressure, may be all that is needed.
When only a few lesions are present, surgical excision is the gold standard for
complete removal, but may have a high rate of recurrence and possibly require skin
grafting for larger lesions [4]. Recurrences have been reported to occur from 6
weeks to more than 15 years following excision [31]. Destructive methods, such as
electrodessication or cryotherapy, may be employed for small, individual, or few
lesions, but little benefit over excision has been demonstrated and unwanted scarring
and recurrence may occur as a consequence [32].
Medical management plays a limited role in hastening the formation of new
lesions and facilitating the resolution of current ones, but can be utilized for symp-
tomatic pain relief. Medications known to affect smooth muscle contraction, such as
nitroglycerine, nifedipine, phenoxybenzamine, and doxazosin, can provide effective
pain relief [4]. The theory behind this method of treatment is that muscle contraction
and subsequent nerve stimulation is responsible for the characteristic stabbing,
shocking, and/or striking pain described by a majority of patients found to have
these tumors [33–35]. Medications that target the activity of nerves are of special
interest because of an increased nerve density within and around leiomyomas [36].
Gabapentin or pregabalin and/or topical analgesics, such as lidocaine or capsaicin,
may be successful in patients with temperature-induced tenderness [37].
Recent studies show promising results from novel therapies such as botulinum
toxin injection and carbon dioxide laser ablation for pain control [38–40]. Botulinum
toxin type A is used in various pain syndromes as it is believed to work by inhibiting
the release of neuropeptides, including substance P and glutamate, thus reducing
central pain signals [41, 42]. Carbon dioxide laser ablation provides an alternative
to invasive surgical techniques, facilitates myolysis, and offers pain relief [40, 43].

References

1. Hereditary leiomyomatosis and renal cell cancer. Available at http://ghr.nlm.nih.gov/condition

=hereditaryleiomyomatosisandrenalcellcancer. Accessed 18 Sep 2012
2. Reed WB, Walker R, Horowitz R. Cutaneous leiomyomata with uterine leiomyomata. Acta
Derm Venereol. 1973;53(5):409–16.
3. Kloepfer HW, Krafchuk J, Derbes V, Burks J. Hereditary multiple leiomyoma of the skin. Am
J Hum Genet. 1958;10(1):48–52.
4. Holst VA, Junkins-Hopkins JM, Elenitsas R. Cutaneous smooth muscle neoplasms: clinical
features, histologic findings, and treatment options. J Am Acad Dermatol. 2002;46(4):
477–90.
5. Costella TM, Romiti N, Almeida JR, et al. Do you know this syndrome? An Bras Dermatol.
2011;86(4):815–24.
6. Orellana Diaz O, Hernandez PE. Leiomyoma cutis and leiomyosarcoma: a 10-year study and
a short review. J Dermatol Surg Oncol. 1983;9(4):283–7.
226 K. Pacific and J. Emer

7. Badeloe S, Frank J. Clinical and molecular genetic aspects of hereditary multiple cutaneous
leiomyomatosis. Eur J Dermatol. 2009;19(6):545–51.
8. Malhotra P, Walia H, Singh A, Ramesh V. Leiomyoma cutis: a clinicopathological series of 37
cases. Indian J Dermatol. 2010;55(4):337–41.
9. Wei MH, Toure O, Glenn GM, et al. Novel mutations in FH and expansion of the spectrum of
phenotypes expressed in families with hereditary leiomyomatosis and renal cell cancer. J Med
Genet. 2006;43(1):18–27.
10. Kiuru M, Launonen V. Hereditary leiomyomatosis and renal cell cancer (HLRCC). Curr Mol
Med. 2004;4(8):869–75.
11. García Muret MP, Pujol RM, Alomar A, et al. Familial leiomyomatosis cutis et uteri (Reed’s
syndrome). Arch Dermatol Res. 1988;280:S29–32.
12. Toro JR, Nickerson ML, Wei MH, et al. Mutations in the fumarate hydratase gene cause hered-
itary leiomyomatosis and renal cell cancer in families in North America. Am J Hum Genet.
2003;73(1):95–106.
13. Alam NA, Olpin S, Leigh IM. Fumarate hydratase mutations and predisposition to cutaneous
leiomyomas, uterine leiomyomas and renal cancer. Br J Dermatol. 2005;153(1):11–7.
14. Tomlinson IP, Alam NA, Rowan AJ, et al. Germline mutations in FH predispose to dominantly
inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet.
2002;30(4):406–10.
15. Kiuru M, Launonen V, Hietala M, et al. Familial cutaneous leiomyomatosis is a two-hit
condition associated with renal cell cancer of characteristic histopathology. Am J Pathol. 2001;
159(3):825–9.
16. Alam NA, Bevan S, Churchman M, et al. Localization of a gene (MCUL1) for multiple
cutaneous leiomyomata and uterine fibroids to chromosome 1q42.3–q43. Am J Hum Genet.
2001;68(5):1264–9.
17. Alam NA, Rowan AJ, Wortham NC, et al. Genetic and functional analyses of FH mutations in
multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer,
and fumarate hydratase deficiency. Hum Mol Genet. 2003;12(11):1241–52.
18. Badeloe S, van Geel M, van Steensel MA, et al. Diffuse and segmental variants of cutaneous
leiomyomatosis: novel mutations in the fumarate hydratase gene and review of the literature.
Exp Dermatol. 2006;15(9):735–41.
19. Sudarshan S, Pinto PA, Neckers L, Linehan WM. Mechanisms of disease: hereditary leiomyo-
matosis and renal cell cancer—a distinct form of hereditary kidney cancer. Nat Clin Pract Urol.
2007;4(2):104–10.
20. Mitchum MD, Adams EG, Holcomb KZ. JAAD Grand Rounds quiz. A 46-year-old man with
agminated papules on the buttock. Reed syndrome. J Am Acad Dermatol. 2012;66(2):337–9.
21. Smith CG, Glaser DA, Leonardi C. Zosteriform multiple leiomyomas. J Am Acad Dermatol.
1998;38(2 Pt 1):272–3.
22. Naverson DN, Trask DM, Watson FH, Burket JM. Painful tumors of the skin: “LEND AN
EGG”. J Am Acad Dermatol. 1993;28(2 Pt 2):298–300.
23. Apatenko AK, Turusov VS. The painful tumours of the skin. Neoplasma. 1968;15(2):
187–202.
24. Lehtonen HJ. Hereditary leiomyomatosis and renal cell cancer: update on clinical and molecular
characteristics. Fam Cancer. 2011;10(2):397–411.
25. Kilpatrick SE, Mentzel T, Fletcher CD. Leiomyoma of deep soft tissue. Clinicopathologic
analysis of a series. Am J Surg Pathol. 1994;18(6):576–82.
26. Spencer JM, Amonette RA. Tumors with smooth muscle differentiation. Dermatol Surg.
1996;22(9):761–8.
27. Miettinen M, Lehto VP, Virtanen I. Antibodies to intermediate filament proteins. The differential
diagnosis of cutaneous tumors. Arch Dermatol. 1985;121(6):736–41.
28. McGinley KM, Bryant S, Kattine AA, et al. Cutaneous leiomyomas lack estrogen and proges-
terone receptor immunoreactivity. J Cutan Pathol. 1997;24(4):241–5.
32 Reed’s Syndrome 227

29. Pithukpakorn M, Toro JR. Hereditary leiomyomatosis and renal cell cancer. In: Pagon RA,
Bird TD, Dolan CR, Stephens K, editors. Genereviews. Seattle, Washington: University of
Washington; 1993–2006.
30. Rongioletti F, Fausti V, Ferrando B, et al. A novel missense mutation in fumarate hydratase in
an Italian patient with a diffuse variant of cutaneous leiomyomatosis (Reed’s syndrome).
Dermatology. 2010;221(4):378–80.
31. Fisher WC, Helwig EB. Leiomyomas of the skin. Arch Dermatol. 1963;88:510–20.
32. Montgomery H, Winkelmann RK. Smooth-muscle tumors of the skin. AMA Arch Derm.
1959;79(1):32–40.
33. George S, Pulimood S, Jacob M, Chandi SM. Pain in multiple leiomyomas alleviated by
nifedipine. Pain. 1997;73(1):101–2.
34. Thompson JA. Jr Therapy for painful cutaneous leiomyomas. J Am Acad Dermatol. 1985;
13(5 Pt 2):865–7.
35. Batchelor RJ, Lyon CC, Highet AS. Successful treatment of pain in two patients with cutane-
ous leiomyomata with the oral alpha-1 adrenoceptor antagonist, doxazosin. Br J Dermatol.
2004;150(4):775–6.
36. Thyresson HN, Su WP. Familial cutaneous leiomyomatosis. J Am Acad Dermatol. 1981;
4(4):430–4.
37. Haugen RN, Tharp MD. The use of gabapentin for recurrent painful attacks with multiple
piloleiomyomas. J Drugs Dermatol. 2008;7(4):401–2.
38. Sifaki MK, Krueger-Krasagakis S, Koutsopoulos A, et al. Botulinum toxin type A-treatment
of a patient with multiple cutaneous piloleiomyomas. Dermatology. 2009;218(1):44–7.
39. Onder M, Adien E. A new indication of botulinum toxin: leiomyoma-related pain. J Am Acad
Dermatol. 2009;60(2):325–8.
40. Christenson LJ, Smith K, Arpey CJ. Treatment of multiple cutaneous leiomyomas with CO2
laser ablation. Dermatol Surg. 2000;26(4):319–22.
41. Aoki KR. Review of a proposed mechanism for the antinociceptive action of botulinum toxin
type A. Neurotoxicology. 2005;26(5):785–93.
42. Aoki KR. Pharmacology and immunology of botulinum toxin type A. Clin Dermatol. 2003;
21(6):476–80.
43. Hindley JT, Law PA, Hickey M, et al. Clinical outcomes following percutaneous magnetic
resonance image guided laser ablation of symptomatic uterine fibroids. Hum Reprod. 2002;
17(10):2737–41.
Chapter 33
Tuberous Sclerosis

Omar Pacha and Adelaide Hebert

33.1 Introduction

Tuberous sclerosis or tuberous sclerosis complex (TSC) is a genetic disorder that

classically causes skin changes, intellectual disability, and seizures. This relatively
common condition often involves the face with angiofibromas (adenoma sebaceum)
that in the earliest stages may be misinterpreted as acne lesions. Variable expressiv-
ity complicates the diagnosis and epidemiology of this autosomal dominant disorder.
Current treatment focuses on mechanical removal of the angiofibromas. Recently,
topical or systemic IL-2 inhibitors like rapamycin have also shown promise as a
therapy [1].

33.2 Background

TSC is caused by a mutation in either the TSC1 or TSC2 genes with resultant loss of
cell growth control. While TSC is an autosomal dominant disorder, the majority
of cases are not inherited. Instead, 65–85 % arise from spontaneous mutations [2].
The two genes are distinct in location and function but produce nearly indistinguish-
able clinical presentation. Mutations in TSC2 are found in more than half of the total
number of patients. In about one fifth of patients, no mutation is identified in either
of the TSC1 or TSC2 genes [3]. The range of prevalence estimates vary widely from
1 in 5,800 to 1 in 25,000 in the Caucasian population [4, 5].
The biological roles of hamartin (the protein product of TSC1) and tuberin (the
protein product of TSC2) have been fairly well defined. They form a multimeric

O. Pacha (*) • A. Hebert

Department of Dermatology, University of Texas Health Science Center,
Houston, Houston, TX, USA
e-mail: [email protected]; [email protected]

J.A. Zeichner (ed.), Acneiform Eruptions in Dermatology: A Differential Diagnosis, 229

DOI 10.1007/978-1-4614-8344-1_33, © Springer Science+Business Media New York 2014
230 O. Pacha and A. Hebert

complex that functions in the mTOR pathway. The mTOR pathway plays an
important role in cell growth and proliferation hence its effect on cell growth.
The loss of function of either gene leads to increased activation of this pathway. The
TSC complex interacts with Rheb, a member of the RAS subfamily, and stimulates
conversion of Rheb to its inactive form. Loss of function TSC complex mutation
leads to an increase in active Rheb, which in turn increases downstream mTOR
expression.

33.3 Clinical Presentation

Presentation for TSC in the skin varies widely from a few subtle angiofibromas to
diffuse angiofibromatosis with shagreen patches and ash-leaf macules, with clinical
manifestations depending largely on the genetic expression in a given patient.
Ash-leaf macules and shagreen patches are more likely to be present either at birth
or shortly thereafter. Angiofibromas, however, may appear at any time but most
often appear in late childhood or early adolescence frequently appearing much like
the papules of acne vulgaris. Angiofibromas are several millimeter in diameter,
fleshy pink to red papules. These can occur singly or in clusters of hundreds often
in a malar distribution (Fig. 33.1). Koenen tumors are subungual fibromas that are
pathognomonic for TSC (Fig. 33.2). Ash-leaf macules are hypopigmented macules
that generally have a single broad side that tapers into a narrow tip, while shagreen
patches are hamartomas of connective tissue that are typically raised, irregularly
shaped, and firmer than surrounding tissue.

Fig. 33.1 Thousands of angiofibromas cover the face of a patient with Tuberous Sclerosis (Photo
credit: Joshua A. Zeichner, M.D.)
33 Tuberous Sclerosis 231

Fig. 33.2 Reddish to flesh-colored, smooth, firm subungual papules. Koenen tumors may also appear
in a periungual distribution, emerging along the nail folds (Photo credit: Joshua A. Zeichner, M.D.)

In addition to the multiple skin findings, TSC also has effects on internal organ
systems as well. The presence of skin changes should prompt a more thorough
work-up to examine for possible renal lesions, neurologic findings, and pulmonary
manifestations. Sequelae from internal organ involvement can cause serious morbidity
and mortality [6].

33.4 Work-Up

Diagnosis of TSC is based upon diagnostic criteria and therefore cannot simply be
made upon any one clinical finding such as the presence of angiofibromas. Diagnosis
of TSC requires associated lesions of two or more organ systems or at least two
different lesions in the same organ to confirm diagnosis [7]. In fact, some of the
so-called pathognomonic features such as intellectual disability and epilepsy are so
common in the general population that they are not specific enough to contribute to
diagnosis [8]. For this reason a list of criteria was set forth to establish consensus as
to a reliable and consistent method of diagnosis [9]. Complete diagnosis and the
evaluation of TSC go beyond the scope of this text; however, one or more angiofi-
bromas, without other appropriate findings, do not suffice for diagnosis nor does it
imply a work-up for TSC is warranted. Angiofibromas occur in over 90 % of indi-
viduals with TSC. However, a variant of angiofibromas occur commonly in the
general population and are known as fibrous papules of the nose or simply fibrous
papules. These may occur singly or multiply but only rarely in as high numbers or
as diffusely as is manifest in the angiofibromas of TSC [10].
232 O. Pacha and A. Hebert

33.5 Treatment

The treatment of TSC depends on the patient’s clinical status and radiologic findings.
Diagnosis and treatment should include appropriate referral to a TSC clinic if pos-
sible with adequate follow-up and screening. Cutaneous lesions can be monitored or
treated depending on patient preference and overall status using mechanical removal
or Argon and /or CO2 laser technologies. More inexpensively, radiofrequency
ablation, chemical peel, and dermabrasion may also be effective [11, 12].
With the discovery of the role of the TSC complex in the mTOR pathway,
utilization of mTOR inhibitors was identified as a potential treatment of all tumors
in TSC patients. One mTOR inhibitor is sirolimus, also known as rapamycin, an
immunosuppressant FDA-approved for use in transplant patients. Sirolimus has
shown promise in clinical trials both systemically and topically for the treatment of
angiofibromas [13, 14]. This therapeutic strategy appears to inhibit angiogenesis by
decreasing production of vascular endothelial growth factor [15]. Ongoing clinical
trials are underway to study sirolimus as an effective and safe for mainstream
treatment.

References

1. Hofbauer GFL, Marcollo-Pini A, Corsenca A, et al. The mTOR inhibitor rapamycin signifi-
cantly improves facial angiofibroma lesions in a patient with tuberous sclerosis. Br J Dermatol.
2008;159:473–5.
2. Osborne JP, Fryer A, Webb D. Epidemiology of tuberous sclerosis. Ann N Y Acad Sci. 1991;
615:125–7.
3. Sancak O, Nellist M, Goedbloed M, et al. Mutational analysis of the TSC1 and TSC2 genes in
a diagnostic setting: genotype–phenotype correlations and comparison of diagnostic DNA
techniques in tuberous sclerosis complex. Eur J Hum Genet. 2005;13:731–41.
4. Morrison PJ. Tuberous sclerosis: epidemiology, genetics and progress towards treatment.
Neuroepidemiology. 2009;33:342–3.
5. OSBORNE JP, FRYER A, WEBB D. Epidemiology of tuberous sclerosis. Ann N Y Acad Sci.
1991;615:125–7. doi:10.1111/j.1749-6632.1991.tb37754.x.
6. Weiner DM, Ewalt DH, Roach ES, Hensle TW. The tuberous sclerosis complex: a comprehensive
review. J Am Coll Surg. 1998;187:548–61.
7. Roach ES, Sparagana SP. Diagnosis of tuberous sclerosis complex. J Child Neurol. 2004;
19:643.
8. Józwiak S, Schwartz RA, Janniger CK, Michałowicz R, Chmielik J. Skin lesions in children
with tuberous sclerosis complex: their prevalence, natural course, and diagnostic significance.
Int J Dermatol. 1998;37:911–7. doi:10.1046/j.1365-4362.1998.00495.x.
9. Roach ES, Gomez MR, Northrup H. Tuberous sclerosis complex consensus conference:
revised clinical diagnostic criteria. J Child Neurol. 1998;13:624–8.
10. Sand M, Sand D, Thrandorf C, Paech V, Altmeyer P, Bechara FG. Review Cutaneous lesions
of the nose 2010. Head Face Med. 2010;6:7.
11. Swaroop MR, Nischal KC, Rajesh Gowda CM, Umashankar NU, Basavaraj HB, Sathyanarayana
BD. Radiofrequency ablation of adenoma sebaceum. J Cutan Aesthet Surg. 2008;1:89.
33 Tuberous Sclerosis 233

12. Kaufman AJ, Grekin RC, Geisse JK, Frieden IJ. Treatment of adenoma sebaceum with the
copper vapor laser. J Am Acad Dermatol. 1995;33:770–4.
13. Salido R, Garnacho-Saucedo G, Cuevas-Asencio I, Ruano J, Galán-Gutierrez M, Vélez A,
Moreno-Giménez J. Sustained clinical effectiveness and favorable safety profile of topical
sirolimus for tuberous sclerosis—associated facial angiofibroma. J Eur Acad Dermatol
Venereol. 2011. doi:10.1111/j.1468-3083.2011.04212.x.
14. Kaufman ME, Curtis AR, Fleischer AB. Successful treatment of angiofibromata of tuberous
sclerosis complex with rapamycin. J Dermatol Treat. 2012;23(1):46–8.
15. Guba M, Von Breitenbuch P, Steinbauer M, et al. Rapamycin inhibits primary and metastatic
tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med.
2002;8:128–35.
 Part V
Other Mimickers of Acne Vulgaris
Chapter 34
Acne Scarring

Neal Bhatia, Consuelo Veronica David, Salar Hazany, and Aman Samrao

34.1 Introduction

The inflammatory lesions caused by acne such as papules, pustules, nodules, and
cysts can result in two types of changes to the skin—temporary pigment changes
and true scarring. These lesions are common and can be just as must a source of
psychologically distress to patients as active acne lesions. While pigment changes are
temporary and resolve on their own over months to years, true scars are permanent.
The appearance of true scars may be improved with various modalities including
intralesional cortisone injections and laser therapies. Pigmentary alteration will be
covered in another chapter, and in the following we will review true scars.

34.2 Background

True scars result from permanent changes to the epidermis, dermis, and subcutaneous
tissue. Following the initial injury, tissue undergoes three stages of wound healing:
inflammation, granulation, and tissue remodeling [1]. During tissue remodeling,
keratinocytes and fibroblasts produce enzymes that dictate the proportion of matrix
metalloproteinases (MMPs) to MMP inhibitors. Exuberance of the wound healing
response, as well as a predominance of either MMPs or MMP inhibitors, determines
how a scar will heal [1]. Acne scars are classified as atrophic or hypertrophic, and a
summary of their clinical appearances is summarized (Table 34.1). Although
research supports a genetic predisposition for the development of keloids, such a
predisposition has not been suggested for atrophic scars.

N. Bhatia, M.D. (*) • C.V. David, M.D. • S. Hazany, M.D. • A. Samrao, M.D.
Division of Dermatology, Harbor-UCLA Medical Center, 1000 W. Carson Street,
Box 259, Torrence, CA 90502, USA
e-mail: [email protected]

J.A. Zeichner (ed.), Acneiform Eruptions in Dermatology: A Differential Diagnosis, 237

DOI 10.1007/978-1-4614-8344-1_34, © Springer Science+Business Media New York 2014
238 N. Bhatia et al.

Table 34.1 Morphologies of acne scars

Morphology Description Shape
Atrophic
Ice pick <2 mm orifice; tapers as it extends to dermis
or subcutaneous tissue
Boxcar (shallow) <0.5 mm, shallow flat-bottomed scars with
sharply demarcated vertical walls

Boxcar (deep) >0.5 mm, flat-bottomed scar with sharply

demarcated vertical walls

Rolling 4–5 mm with sloped borders

Sinus tract Contiguous connections in the dermis and/or

subcutaneous tissue. Sometimes
epithelialized
Hypertrophic
Hypertrophic Papules and plaques that are elevated above
the skin surface to a greater degree than
normal, but remain within the boundaries
of the original area of damage
Keloid Smooth papules and plaques that are elevated
above the skin surface to a greater degree
than normal extend beyond the boundaries
of the original area of involvement. Can
by symptomatic
a
Most of the atrophic scars are based on the Jacob’s classification scheme [4]

In general, patients with darker skin types more commonly develop keloids than
patients of other skin types, although the exact prevalence is not known. It is widely
accepted that keloids develop as a result of a genetic predisposition with an environ-
mental influence. It is unclear whether the predisposition to keloids results in single
Mendelian or polygenetic disorder. Both autosomal dominant with incomplete pen-
etrance and autosomal recessive modes have been reported [2, 3]. Chromosomes
2q23 and 7p11 mutations and HLA-DRB1*15, HLA-DQA1*0104, DQ-B1*0501,
and DQB1*0503 all may play a role [2].

34.3 Clinical Appearance

34.3.1 Atrophic Scars

Atrophic scars are depressions caused by loss of substance in epidermis, dermis, or

subcutis. They may appear pigmented due to increased visibility of vasculature and
how they reflect light [1, 4]. The appearance of these scars may be described as
34 Acne Scarring 239

Fig. 34.1 Atrophic acne

scarring in a man in his
twenties. Boxcar scars with
well-defined borders are
evident on the temples, while
smoother, rolling scars are
present on the cheeks (Photo
credits: Joshua A. Zeichner,
M.D.)

flat-bottomed, narrow, wrinkled, ice pick, depressed, crater-like, atrophic, narrow,

wide, or deep (Fig. 34.1). In 2001, Jacobs et al. proposed a classification system that
unifies the terminology to describe atrophic scars [5]. In this scheme, atrophic scars
are classified as ice pick, rolling, or boxcar. These subtypes are categorized based
on depth, width, and architecture of the lesions. Accurate categorization can provide
guidance to clinicians when determining treatment options.
Ice pick scars are narrow (<2 mm), well-defined, epithelialized tracts that extend
to the deep dermis and even subcutaneous tissue. The scar orifice starts out wide and
tapers at the base. They are frequently seen on the cheeks [5].
Rolling scars are wider than ice pick scars (4–5 mm or larger), but shallow. They
have gently sloped surfaces that create a soft, undulating, uneven appearance of the
skin. Rolling scars result from scarring and tethering of the dermis to the subcutane-
ous tissue [5].
Boxcar scars, like rolling scars, can be shallow, round, square. or oval depressions.
However, they are sharply demarcated and have vertical walls. The base of boxcar
scars is flat and is frequently the same size as the opening at the surface. Boxcar scars
can be divided into shallow (<0.5 mm) and deep (>0.5 mm) [5].
A final form of atrophic scarring that is not included in the Jacob classification is
the sinus tract. Sinus tracts are contiguous connections in the dermis and subcutaneous
tissue which may have more than one epidermal orifice; they can result in significant
morbidity.
240 N. Bhatia et al.

Fig. 34.2 Both hypertrophic

and keloidal scars are present
on the jawline of this woman.
Keloidal scars grow beyond the
border of the original
area of skin damage (Photo
credits: Joshua A. Zeichner,
M.D.)

34.3.2 Hypertrophic Scars

Hypertrophic scars and keloids are two types of scars resulting from over-exuberant
wound healing responses with excess collagen deposition and decreased collage-
nase activity [1]. Hypertrophic scars are lesions that elevate above the skin surface,
but remain within the boundaries of the original area of damage [6]. These lesions
may spontaneously involute. Keloids on the other hand are lesions with collagen
deposition beyond the border of the original wound (Fig. 34.2). Histologically,
keloids are characterized by thick, hyalinized collagen bundles [6, 7]. Keloids can
be painful, itchy, and burn. Importantly, keloids due to acne should not be confused
with acne keloidalis nuchae, a primary cicatricial alopecia that has no association
with acne vulgaris [8].

34.4 Work-Up

The diagnosis of acne scarring is based on clinical appearance, and little work-up is
necessary. Patients should be educated on the difference between post-inflammatory
erythema or pigmentation and true acne scarring. It is important to set realistic
expectations on outcomes, treatment options, and the time course for improvement.
Psychosocial issues should also be addressed, as acne scars can have a large impact
on self esteem and be a source of depression [9].
Scars have distinct histologic appearances. The various atrophic scar subtypes
are similar, with an atrophic epidermis and effacement of the rete ridges. Collagen
fibers are arranged parallel to the epidermis, while blood vessels are oriented
34 Acne Scarring 241

perpendicular to the epidermis [5, 6, 10]. The epidermis of hypertrophic scars is

similar to atrophic ones; however, they contain dense collagen bands and fibroblasts
oriented parallel to the epidermis [8]. Abundant fibroblasts and pale mucinous
stroma are present in newer scars while older scars have fewer fibroblasts [8].
Keloidal scars can be distinguished from hypertrophic scars by their unique hyalin-
ized bundles of collagen. Moreover, keloids contain increased mucin and mast cells
with less prominent blood vessels [8].

34.5 Treatment

Traditional treatments for atrophic acne scarring include surgical interventions,

dermabrasion, and chemical peels. With advances in laser technology, the treatment
armamentarium for scars has vastly expanded, providing patients with more options
and improved outcomes. Hypertrophic scars on the other hand are largely treated
with intralesional triamcinolone. While effective, risks include skin atrophy and
hypopigmentation which improves over several months when it occurs. The risk of
these adverse events increases with higher doses of triamcinolone.
Minor surgical procedures include punch excision, subcision, and punch grafting,
which are performed under local anesthesia in the office. In a punch excision, the
scar tissue is removed with a punch biopsy with or without a primary closure.
A subcision is a lifting procedure, which attempts to raise the base of an atrophic
scar upward towards the surface, making the skin smooth [11]. Using a large gauge
needle probed parallel to the surface of the skin, scar tissue beneath the epidermis is
broken apart [12, 13]. The lesion is left to heal so that new collagen is laid down in
a more cosmetically elegant manner. Punch excision is very effective for ice pick
scarring, whereas subcision is more effective for thick fibrotic scars. Punch grafting
is a two-step method in which the scar is removed using a punch biopsy and replaced
with harvested punched skin from an inconspicuous area [14, 15]. Punch excisions
and grafts are especially helpful for deep, ice pick scars, which are not effectively
treated with subcision, lasers, or similar modalities.
Dermal fillers such as collagen, hyaluronic acid, and calcium hydroxyapatite can
be injected to lift depressed scars and achieve a smooth appearance at the skin’s
surface [11]. Optimal candidate lesions are broad, soft, and stretchable. Caution
should be exercised not to inject hyaluronic acid too superficially in the skin, as to
avoid a Tyndall effect. Lesions with underlying fibrosis are often subcised prior
to placement of the filler.
Chemical peels have shown benefit to atrophic acne scars, even in patients with
dark skin. Medium depth peels using 50 % trichloroacetic acid (TCA), Jessner’s
solution followed by 35 % TCA, or 70 % glycolic acid followed by 35 % TCA can
produce a controlled wound to the level of the upper reticular dermis [16]. Deep
chemical peels reach the mid-reticular dermis and can be useful to treat deep acne
scars. Phenol peels have been the agent traditionally used, but must may cause
cardiac arrhythmia so patients require cardiac monitoring during the procedure.
242 N. Bhatia et al.

Laser resurfacing is especially useful in treating atrophic acne scars. Fractional

photothermolysis (FP) was approved by the FDA in 2006 to treat acne scarring. This
technology creates microscopic zones of thermal damage separated by areas of
intact skin, allowing rapid reepithelialization and recovery. The photothermal injury
produced in the dermis leads to collagen remodeling and improvement of the
appearance of scares. Non-ablative fractional lasers leave the epidermis intact. They
require less postoperative care, but often more treatment sessions needed compared
to their ablative counterparts [17, 18].
While infrequently used since the advent of laser resurfacing, dermabrasion is an
effective treatment for patients with atrophic acne scars. Mechanical dermabrasion
using a diamond fraises or wire brushes causes injury to the dermis and induces dermal
remodeling with fibroplasia, matrix formation, and collagen neogenesis [19, 20].

34.6 Conclusion

Acne is a significant source of morbidity when active as well as when it resolves

with permanent scars. While the best treatment for acne scars is prevention with an
early, effective treatment, several treatment modalities exist to improve the appear-
ance of scars if they do develop. An understanding of the classification of acne scars
is important to manage patient expectations and development a treatment regimen.

References

1. Thiboutot D, Gollnick H, Bettoli V, Dreno B, Kang S, Leyden JJ, et al. New insights into the
management of acne: an update from the global alliance to improve outcomes in acne group.
J Am Acad Dermatol. 2009;60:S1–50.
2. Shih B, Bayat A. Genetics of keloid scarring. Arch Dermatol Res. 2010;302:319–39.
3. Halim AS, Emami A, Salahshourifar I, Kannan TP. Keloid scarring: understanding the genetic
basis, advances, and prospects. Arch Plast Surg. 2012;39:184–9.
4. Rivera AE. Acne scarring: a review and current treatment modalities. J Am Acad Dermatol.
2008;59:659–76.
5. Jacob CI, Dover JS, Kaminer MS. Acne scarring: a classification system and review of treat-
ment options. J Am Acad Dermatol. 2001;45:109–17.
6. Rapini R. Practical dermatopathology. Houston: Elsevier-Mosby; 2012.
7. Verhaegen PD, van Zuijlen PP, Pennings NM, van Marle J, Niessen FB, van der Horst CM,
et al. Differences in collagen architecture between keloid, hypertrophic scar, normotrophic
scar, and normal skin: an objective histopathological analysis. Wound Repair Regen. 2009;
17:649–56.
8. James W, Berger T, Elston D. Andrews’ diseases of the skin clinical dermatology. Philadelphia:
Elsevier-Saunders; 2011.
9. Levy LL, Zeichner JA. Management of acne scarring, part II: a comparative review of
non-laser-based, minimally invasive approaches. Am J Clin Dermatol. 2012;13:331–40.
10. Fabbrocini G, Annunziata MC, D’Arco V, De Vita V, Lodi G, Mauriello MC, et al. Acne scars:
pathogenesis, classification and treatment. Dermatol Res Pract. 2010;2010:893080.
34 Acne Scarring 243

11. Fife D. Practical evaluation and management of atrophic acne scars: tips for the general
dermatologist. J Clin Aesthet Dermatol. 2011;4:50–7.
12. Orentreich D, Orentreich N. Acne scar revision update. Dermatol Clin. 1987;5:359–68.
13. Tsao SS, Dover JS, Arndt KA, Kaminer MS. Scar management: keloid, hypertrophic, atrophic,
and acne scars. Semin Cutan Med Surg. 2002;21:46–75.
14. Johnson WC. Treatment of pitted scars: punch transplant technique. J Dermatol Surg Oncol.
1986;12:260–5.
15. Solotoff SA. Treatment for pitted acne scarring–postauricular punch grafts followed by
dermabrasion. J Dermatol Surg Oncol. 1986;12:1079–84.
16. Al-Waiz MM, Al-Sharqi AI. Medium-depth chemical peels in the treatment of acne scars in
dark-skinned individuals. Dermatol Surg. 2002;28:383–7.
17. Kim S, Cho KH. Clinical trial of dual treatment with an ablative fractional laser and a nonabla-
tive laser for the treatment of acne scars in Asian patients. Dermatol Surg. 2009;35:1089–98.
18. Ong MW, Bashir SJ. Fractional laser resurfacing for acne scars: a review. Br J Dermatol.
2012;166:1160–9.
19. Roenigk Jr HH. Dermabrasion for miscellaneous cutaneous lesions (exclusive of scarring from
acne). J Dermatol Surg Oncol. 1977;3:322–8.
20. Yarborough Jr JM. Ablation of facial scars by programmed dermabrasion. J Dermatol Surg
Oncol. 1988;14:292–4.
Chapter 35
Eosinophilic Pustular Folliculitis

Joy Makdisi and Adam Friedman

35.1 Introduction

First described in Japan by Ofuji in 1970 [1], eosinophilic pustular folliculitis (EPF) is
a noninfectious inflammatory skin disease that manifests with coalescing papulopus-
tular plaques. The disease is histologically characterized by eosinophilic infiltration of
hair follicles. There are three known variants of EPF: classic (as originally described
by Ofuji and predominantly affecting Japanese individuals), HIV-associated, and
infantile.

35.2 Background

The majority of reported EPF cases are related to immunosuppression, while the
classic and infantile EPF are far less common [2]. The classic variant of EPF is
found predominantly in Japanese patients, though any race may be affected [3].
Males are more commonly affected than women, in a ratio generally reported as
4.8:1 [2, 4], though a study in Singapore found a ratio of 1.6:1 [5]. The incidence of
classic EPF is concentrated in the third and fourth decades of life, with the average
age of onset at 30 years [6].
The immunosuppression-related variant chiefly affects HIV-infected individuals,
though cases have also been seen in intravenous drug abusers [7, 8]. There is also a
tremendous male predominance; only six cases have been reported in female
patients [9]. Most cases of HIV-related EPF have been seen in Caucasian patients,
and the majority of cases reported are from the United States and Great Britain.

J. Makdisi, B.S. (*) • A. Friedman, M.D.

Department of Medicine, Montefiore – Albert Einstein College of Medicine,
1300 Morris Park Ave Ullmann 107, Bronx, NY 10461, USA
e-mail: [email protected]

J.A. Zeichner (ed.), Acneiform Eruptions in Dermatology: A Differential Diagnosis, 245

DOI 10.1007/978-1-4614-8344-1_35, © Springer Science+Business Media New York 2014
246 J. Makdisi and A. Friedman

Patients tend to present to the doctors’ offices later in the course of their disease,
often once they have established acquired immunodeficiency syndrome [10].
The pathophysiology of EPF is largely unknown. Theories on its etiology take
into account the prominent eosinophilic cellular infiltrate, the folliculocentric char-
acter of the lesions, and the distribution of the eruption. Hypersensitivity reactions
to infection or medication, as well as an autoimmune etiology have been proposed
as possible mechanisms of EPF [2]. For example, EPF can present similarly to a
fungal folliculitis with respect to both its clinical and histological features; it is
hypothesized that the folliculitis may be attributable to immune hyperreactivity to
dermatophytes or other fungi [11]. This theory is supported by the positive thera-
peutic response in patients treated with antifungal agents [2]. Other possible
antigenic sources investigated include mites (Demodex folliculorum and Demodex
brevis) and bacteria (Leptotrichia buccalis) [2]. In addition, medications such as
carbamazepine, minocycline, allopurinol, timepidium bromide [3, 12, 13], and
silicone tissue injections [14] have been reported as possible causes of EPF skin
reactions.
Given the high incidence of eosinophilic pustular reactions in the setting of
coexisting immune dysfunction, it has been suggested that immune dysregulation
may also be a contributing factor to EPF [15]. Furthermore, it has been proposed
that the HIV-associated variant of EPF may also be an autoimmune disorder, with a
component of sebum behaving as the target antigen [10, 16]. Of note, there are also
cases of EPF in HIV-negative immunocompromised states, such as in lymphoma
patients after autologous peripheral blood stem cell and allogeneic bone marrow
transplantation [3, 17]. It is likely that this variant of EPF is a nonspecific manifesta-
tion that presents in the setting of a compromised immune system and may be pro-
voked by various antigens [2]. Given these reported findings, it is critical to evaluate
EPF patients for coexisting systemic disease [2]. Though many hypotheses have
been proposed, more research is required to further elucidate the mechanism and
conclusively determine the pathophysiology of EPF.

35.3 Clinical Presentation

Though HIV-related EPF and classic EPF (a.k.a. Ofuji’s disease) appear similar
histologically, they differ clinically. The classic form arises in healthy patients and
generally presents with chronic, recurring, sterile, folliculocentric papules and pus-
tules [10, 18]. These lesions usually develop into confluent annular plaques with
central clearing [2]. The classic distribution includes seborrheic areas such as the
face (85 %), back, and trunk (59 %), as well as non-hair-bearing areas such as
the palms and soles (20 %) [2, 16, 18]. The lesions typically resolve without scarring,
but may develop postinflammatory hyperpigmentation. Furthermore, pruritus affects
<50 % of patients [10].
In HIV-associated EPF, immunocompromised patients universally present with a
defining feature: chronic, severe, intractable pruritus [10]. Rather than confluent
35 Eosinophilic Pustular Folliculitis 247

Fig. 35.1 Flesh colored and excoriated papules on face (Photo credits: Joshua A. Zeichner, M.D.)

Fig. 35.2 Post-inflammatory pigmentation and excoriations on the chest. The patient complained
of extreme itching, yet no primary lesions are visible. The patient is HIV positive (Photo credits:
Joshua A. Zeichner, M.D.)

clusters, the lesions present as discrete, erythematous, perifollicular papules and

pustules and are usually heavily excoriated (see Figs. 35.1 and 35.2) [6, 10, 19].
There are more rare presentations with confluent erythematous, plaques [20]. The
distribution of HIV-associated EPF is predominantly on the trunk, though a signifi-
cant number of patients also have head and neck lesions [8, 20–22]. Acral involve-
ment is uncommon [10], in contrast to classic EPF [18].
248 J. Makdisi and A. Friedman

35.4 Work-Up

Patients with suspected EPF should have a complete blood count with differential, as
peripheral eosinophilia has been found in up to 35 % of classic EPF patients [1, 6]
and 50 % of HIV-associated EPF patients [8, 10, 21, 22]. In the classic form, a mild
to moderate leukocytosis may be present, whereas a leukopenia may be present in
the HIV-associated variant [18]. Serum IgE levels have also been reported to be
elevated significantly in a large number of HIV-associated EPF patients, as com-
pared to levels in HIV controls [21, 23]. Patients tend to have a CD4 count less than
250–300 cells/ml [21].
The EPF variants share common findings on histopathologic analysis: noninfec-
tious infiltration of eosinophils. Eosinophilic spongiosis and pustulosis are seen on
pathology, particularly in the infundibulum of the hair follicle [18]. The infiltrate
often extends to the adjacent sebaceous gland and duct [18]. In addition, there is a
perivascular and perifollicular infiltrate consisting of lymphocytes [18]. When tak-
ing the biopsy, it is necessary o acquire an entire papule or pustule with a contiguous
follicle for adequate histopathological diagnosis. In addition, because EPF is
folliculocentric, serial sections may be necessary to visualize the inflamed follicle
and confirm the diagnosis [2, 10]. Routine hematoxylin and eosin stain should be
performed, as well as specific stains for fungi and bacteria.
If a microbial infection is suspected in the differential diagnosis, skin swabs
for microscopy and culture and scrapings for mycologic examination should be performed.
It is clinically difficult to distinguish between the different HIV-associated
folliculitides, including EPF and infective folliculitis. However, routine bacterial
and fungal cultures are usually negative in HIV-associated EPF [21, 24]. Furthermore,
histology is diagnostic and can be used to differentiate between infective folliculitis
and EPF [10].

35.5 Treatment

A myriad of treatment options have been described with variable results. Topical
corticosteroids are the first-line treatment for all forms of EPF [6]. The dose is
modified depending on the age of the patient: mild to moderate potency for children
and moderate to high potency for adults [2, 6]. Topical tacrolimus also appears to be
an effective first-line agent [6, 25].
Classic EPF is often treated with nonsteroidal anti-inflammatory drug deriva-
tives, most commonly oral indomethacin [3, 5, 6, 10]. Throughout the many years
of use by Japanese dermatologists, it appears to be the most effective treatment for
the classic form of the disease. One case series of 25 patients found indomethacin
to be effective in 92 % of patients [26].
If topical corticosteroids and oral indomethacin are unsuccessful in treating HIV-
associated EPF, a variety of other treatment options can be utilized. These include
35 Eosinophilic Pustular Folliculitis 249

itraconazole, metronidazole, and 5 % permethrin cream [3, 6, 10]. In addition,

antihistamines, including cetirizine and cyproheptadine, are often utilized in the
treatment of HIV-associated EPF because of the severe pruritus that is characteristic
of the disease [6, 10, 27].
HIV-associated EPF can develop 3–6 months after beginning highly active antiretro-
viral therapy, but interestingly, it also responds quite well to the therapy [6, 28, 29].
It is best to reassure patients that as the immune system is strengthened and the CD4
count rises above 250, the disease shows improvement and often complete resolution [2].
If the topical and oral agents discussed above prove ineffective, phototherapy
with ultraviolet B (UVB) is considered the “gold standard” treatment and can often
be curative [6].
There are several other EPF treatments that demonstrate some efficacy but it is
less certain if the benefit of these treatments outweighs their risk. These include
psoralen plus UVA (PUVA) photochemotherapy, which has been utilized with some
therapeutic success [10, 30]. However, ultraviolet treatments cease to be efficacious
once they are withdrawn [2]. Systemic corticosteroids have also been used with suc-
cess, but caution must be taken to avoid the many well-known potential adverse
effects of prolonged systemic steroid use [2]. Other treatments in this category
include synthetic retinoids, oral cyclosporine, interferon-α, and interferon-γ [6].
In addition, twice daily dapsone has also shown some therapeutic success [31].
Finally, in chronic EPF that is unresponsive to the treatments discussed above, ionizing
radiation has proven to be effective [6].
Whereas HIV-associated EPF tends to resolve with highly active antiretroviral
therapy and the subsequent rising CD4 counts, classic EPF tends to follow a chronic
and relapsing course for many years. Because of this, the prognosis is generally
considered poor [2]. More recently, patients have achieved complete remission with
indomethacin and tacrolimus [2].

35.6 Conclusion

EPF is a noninfectious papulopustular disease characterized by an eosinophilic

infiltrate concentrated perifollicularly. It exists in three distinct variants, and though
it can occur in persons with normal immune status, it is a possible sign of immuno-
suppression. Though the etiology is unclear, several hypotheses suggest that it is
likely multifactorial; hypersensitivity to various antigenic stimuli in combination
with immune dysregulation are both discussed in the literature. A variety of treat-
ment options are available, though a definitive successful treatment strategy is not
obvious. Because the pathophysiology remains unclear, EPF treatment must be
tailored to individual patients according to their subtype. Often patients go through
several courses of treatment and medication changes before achieving successful
results. Due to the chronic relapsing course, most EPF patients need maintenance
treatment [5]. It is hoped that with continued research and increased awareness of
the disease, earlier diagnosis and more effective treatment can be realized.
250 J. Makdisi and A. Friedman

References

1. Ofuji S. Eosinophilic pustular folliculitis. Dermatologica. 1987;174(2):53.

2. Nervi SJ, Schwartz RA, Dmochowski M. Eosinophilic pustular folliculitis: a 40 year retrospect.
J Am Acad Dermatol. 2006;55(2):285–9.
3. Dmochowski M SR. Eosinophilic pustular folliculitis. eMedicine Dermatology [journal serial
online]. 2006. Available at: http://emedicine.com/derm/topic120.htm. Accessed 15 Dec 2012.
4. Takematsu H, Nakamura K, Igarashi M, Tagami H. Eosinophilic pustular folliculitis. Report of
two cases with a review of the Japanese literature. Arch Dermatol. 1985;121(7):917.
5. Tang MBY, Tan E, Chua SH. Eosinophilic pustular folliculitis (Ofuji’s disease) in Singapore:
a review of 23 adult cases. Australas J Dermatol. 2003;44(1):44–7.
6. Ellis E, Scheinfeld N. Eosinophilic pustular folliculitis: a comprehensive review of treatment
options. Am J Clin Dermatol. 2004;5(3):189–97.
7. Ferrandiz CRM, Barranco JC, Clotet B, Lorenzo JC. Eosinophilic pustular folliculitis in
patients with acquired immunodeficiency syndrome. Int J Dermatol. 1992;31(3):193–5.
8. Basarab T, Jones RR. HIV‐associated eosinophilic folliculitis: case report and review of the
literature. Br J Dermatol. 1996;134(3):499–503.
9. Hayes BB, Hille RC, Goldberg LJ. Eosinophilic folliculitis in 2 HIV-positive women. Arch
Dermatol. 2004;140(4):463.
10. Fearfield L, Rowe A, Francis N, Bunker C, Staughton R. Itchy folliculitis and human immu-
nodeficiency virus infection: clinicopathological and immunological features, pathogenesis
and treatment. Br J Dermatol. 1999;141(1):3.
11. Haupt HM, Stern JB, Weber CB. Eosinophilic pustular folliculitis: fungal folliculitis? J Am
Acad Dermatol. 1990;23(5):1012–4.
12. Kimura K, Ezoe K, Yokozeki H, Katayama I, Nishioka K. A case of eosinophilic pustular
folliculitis (Ofuji's disease) induced by patch and challenge tests with indeloxazine hydrochlo-
ride. J Dermatol. 1996;23(7):479.
13. Maejima H, Mukai H, Hikaru E. Eosinophilic pustular folliculitis induced by allopurinol and
timepidium bromide. Acta Derm Venereol. 2002;82(4):316–7.
14. Wong TW, Tsai YM, Lee J, Hsu ST, Sheu HM. Eosinophilic pustular folliculitis (Ofuji’s
disease) in a patient with silicone tissue augmentation. J Dermatol. 2004;31(9):727.
15. Magro CM, Crowson AN. Eosinophilic pustular follicular reaction: a paradigm of immune
dysregulation. Int J Dermatol. 1994;33(3):172–8.
16. Takematsu H, Tagami H. Eosinophilic pustular folliculitis. Studies on possible chemotactic
factors involved in the formation of pustules. Br J Dermatol. 2006;114(2):209–15.
17. Keida T, Hayashi N, Kawashima M. Eosinophilic pustular folliculitis following autologous
peripheral blood stem-cell transplantation. J Dermatol. 2004;31(1):21.
18. Johnston R. Chapter 15: Diseases of cutaneous appendages. In: Weedon D, editor. Weedon’s
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19. Buchness MR, Lim HW, Soter NA. AIDS-related eosinophilic pustular folliculitis. J Am Acad
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20. Soeprono FF, Schinella RA. Eosinophilic pustular folliculitis in patients with acquired immu-
nodeficiency syndrome: report of three cases. J Am Acad Dermatol. 1986;14(6):1020–2.
21. Rosenthal D, LeBoit PE, Klumpp L, Berger TG. Human immunodeficiency virus-associated
eosinophilic folliculitis: a unique dermatosis associated with advanced human immunodefi-
ciency virus infection. Arch Dermatol. 1991;127(2):206.
22. Frentz G, Niordson AM, Thomsen K. Eosinophilic pustular dermatosis: an early skin marker
of infection with human immunodeficiency virus? Br J Dermatol. 1989;121(2):271–4.
23. Maurer T, Berger T. Serum IgE levels in eosinophilic folliculitis—an inflammatory disease of
HIV infection. J Invest Dermatol. 1994;102:619.
24. McCalmont TH, Altemus D, Maurer T, Berger TG. Eosinophilic folliculitis. The histologic
spectrum. Am J Dermatopathol. 1995;17(5):439.
35 Eosinophilic Pustular Folliculitis 251

25. Kabashima K, Sakurai T, Miyachi Y. Treatment of eosinophilic pustular folliculitis (Ofuji’s

disease) with tacrolimus ointment. Br J Dermatol. 2004;151(4):949–50.
26. Ota T, Hata Y, Tanikawa A, Amagai M, Tanaka M, Nishikawa T. Eosinophilic pustular folliculitis
(Ofuji’s disease): indomethacin as a first choice of treatment. Clin Exp Dermatol. 2001;
26(2):179–81.
27. Harris D, Ostlere L, Buckley C, Johnson M, Rustin M. Eosinophilic pustular folliculitis in an
HIV‐positive man: response to cetirizine. Br J Dermatol. 1992;126(4):392–4.
28. Moyle M, Woolley IJ, Thevarajan I, Korman TM. Eosinophilic folliculitis: an example of
‘immune reconstitution folliculitis’? AIDS. 2004;18(17):2350–2.
29. Rajendran PM, Dolev JC, Heaphy Jr MR, Maurer T. Eosinophilic folliculitis: before and after
the introduction of antiretroviral therapy. Arch Dermatol. 2005;141(10):1227.
30. Buchness MR, Lim HW, Hatcher VA, Sanchez M, Soter NA. Eosinophilic pustular folliculitis
in the acquired immunodeficiency syndrome. N Engl J Med. 1988;318(18):1183–6.
31. Steffen C. Eosinophilic pustular folliculitis (Ofuji’s disease) with response to dapsone therapy.
Arch Dermatol. 1985;121:921–3.
Chapter 36
Favre-Racouchot Syndrome

Silvina Pugliese, Andrea Smith, Rachel Epstein, and Abel Torres

36.1 Introduction

Favre-Racouchot syndrome (nodular elastosis with cysts and comedones) is a distinct

variant of solar elastosis most frequently found in elderly Caucasian men. The esti-
mated prevalence is 1.5–6 % in the general population. This syndrome is character-
ized by yellow nodules and plaques accentuated by enlarged, open comedones and
dilated cysts, often accompanied by other cutaneous findings of actinic damage.

36.2 Background

The prevalence of Favre-Racouchot syndrome in the 40–60 year-old population is

estimated at 6 %, while a more recent study of 25–74 year-olds identified a preva-
lence of 1.4 % [1, 2]. A study of agricultural workers found a 2.5 % prevalence [3].
Favre-Racouchot is more common in elderly, Caucasian males. Many of the affected
individuals have a chronic history of excessive ultraviolet (UV) radiation from
occupational and recreational exposures.
A number of theories have been postulated regarding the etiology of Favre-
Racouchot. Extensive UV damage has been strongly associated with the development
of this disorder, with actinic damage believed to cause degeneration of elastin,
and structural loss leading to the abnormal enlargement of comedones [4]. Hedelund
confirmed this association by finding that both UV-A1 and UV-B exposure provoked
comedonal and cystic formation in a patient with Favre-Racouchot, with UV-B radia-
tion leading to more extensive skin changes [5]. This relationship is so well established

S. Pugliese, M.D. (*) • A. Smith, M.D. • R. Epstein, D.O. • A. Torres, M.D.

Department of Dermatology, Loma Linda University, 11370 Anderson Street Suite 2600,
Loma Linda, CA 92354, USA
e-mail: [email protected]

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DOI 10.1007/978-1-4614-8344-1_36, © Springer Science+Business Media New York 2014
254 S. Pugliese et al.

that Lim et al. have recently identified Favre-Racouchot as a consequence of UV

exposure [6]. It should be noted that host predisposition plays a modulating role, as
many individuals with chronic UV exposure do not develop Favre-Racouchot.
Multiple case reports have linked radiation therapy to the development of Favre-
Racouchot, including Breit et al., who reported a case that developed a mere 2 weeks
after cessation of radiation therapy to the nasopharynx and neck [7].
Smoking is associated with a higher incidence of developing Favre-Racouchot
syndrome. This relationship is believed to be dose-dependent, as smokers with
Favre-Racouchot were found to have a significantly greater pack-year smoking
history than smokers without Favre-Racouchot [8]. For years, smoking has been
implicated in photoaging and has been found to particularly affect the development
of comedones [9].
Lastly, systemic and topical steroids have been postulated to play a contributing
role in the development of Favre-Racouchot [5]. UV damage, smoking, radiation
therapy, and corticosteroids stimulate the associated clinical features of Favre-
Racouchot disease via atrophy of the skin, loss of normal elastic fibers, keratinization
of the pilosebaceous follicle, and increased comedone formation [10].

36.3 Clinical Presentation

Favre-Racouchot develops in areas of extensive sun exposure, and is classically

found periorbitally, with predilection for the skin adjacent to the lateral canthi, as
well as the malar eminences. Early changes include yellow plaques accentuated by
enlarged, open, black comedones. These plaques later develop into distinct nodules.
In addition to comedones, later lesions also show cystic dilations filled with retained
keratin. Furrows are often present. Inflammatory lesions are not associated with
Favre-Racouchot [10, 11]. These findings are usually bilateral, although they can be
unilateral (Fig. 36.1).
Given its association with UV exposure, other skin findings linked to actinic
damage often coexist (e.g., actinic keratoses, cutis rhomboidalis nuchae, and skin
cancer). To date, this syndrome is not directly associated with any systemic symp-
toms or internal malignancies. The differential diagnosis for this disorder includes
chloracne, cutis rhomboidalis nuchae, colloid milium, and actinic granuloma [12].

36.4 Work-Up

When evaluating a patient for Favre-Racouchot syndrome, a pertinent history

should be taken with special attention to smoking habits, history of UV light expo-
sure, radiation exposure, topical or systemic corticosteroid use, and routine use of
comedogenic cosmetics.
36 Favre-Racouchot Syndrome 255

Fig. 36.1 Periorbital cystic

nodules and enlarged open
comedones on a background
of chronic actinic damage

A differential diagnosis, as noted above, should be entertained given any pertinent

historical findings. An important differential diagnosis is chloracne from toxin
exposures such as aromatic hydrocarbons. Recognizing this diagnosis may have
clinical, therapeutic, and even financial implications for the patient especially if
there was an occupational exposure.
The time course of development of lesions may help point to the etiology. For
example, Patterson et al. report a woman with rapid development of Favre-Racouchot
comedones after radiation therapy [10]. Generally, affected patients will report a long
gradual development of lesions in sun-exposed areas.

36.5 Treatment

Treatment for Favre-Racouchot has traditionally been difficult as it is often invasive

and the unsightly lesions recur. The condition largely has aesthetic implications.
No increase in skin cancers, ulcerations, or infections has been reported to our knowl-
edge. Therefore, the features that most concern the patient should guide formation of
treatment goals.
Prior therapies should be elucidated from the patient. Any contributing factors, if
found, should be discontinued such as smoking or application of topical steroid
formulations. Consistent and appropriate sun protection and avoidance should be
emphasized.
Two main components need to be addressed when discussing therapeutic options:
the presence of large disfiguring open comedones and the photodamaged surrounding
skin.
256 S. Pugliese et al.

Historically, chemical peels in conjunction with manual abrasion techniques

were treatment standards. However, currently, the mainstay of therapy for Favre-
Racouchot remains the topical retinoids [13]. The topical retinoids are first-line
treatment for several reasons including their ability to address both the comedonal
and photoaging aspects of Favre-Racouchot [7]. This therapy is non-invasive and
can be applied in the comfort of the patient’s home.
The disadvantage of topical retinoid therapy is that it is not very effective in
resolving the larger and deeper comedones. Kaya et al. propose that topical retinoids
are only effective on small comedones <1 mm in size [14]. Another adverse effect is
their potential to cause significant irritation. However, these patients with thickened
skin secondary to photodamage may better tolerate topical retinoid therapy [13].
A precursor to retinoic acid called retinaldehyde has been reported to be effective
with less irritant effect than the topical retinoids [10]. Retinaldehyde is commer-
cially available in a variety of over-the-counter retinol-containing products.
Oral retinoids have also been reported to be effective in the treatment of Favre-
Racouchot. Low dose isotretinoin is the most frequently reported regimen with
dosing ranging from 0.05 to 0.1 mg/kg for 4–6 months [10]. Oral isotretinoin is
generally used in conjunction with topical retinoids. Disadvantages to this approach
include but are not limited to serious side effects such as transaminitis, hyperlipid-
emia, a possible association with inflammatory bowel disease, and severe xerosis.
Comedonal extraction is still an important component of treatment for the large
open comedones characteristic of Favre-Racouchot. Most often a traditional come-
done extractor is used to do this. Kaya et al. also proposed a more efficient method
for extracting these large open comedones on loose, thin skin using a standard
dissecting forceps [14]. Mavilia et al. have also reported using forceps for extraction
with CO2 laser [15]. Comedone extraction is an effective therapeutic tool especially
when combined with other treatment modalities including topical retinoids, derm-
abrasion, and even superficial CO2 laser.
Comedone extraction can easily and quickly be performed in the office setting
and allows for immediate improvement in appearance. Unfortunately, the comedones
frequently recur after extraction, as the epithelial lining of the cyst is still present.
In addition, extraction may result in superficial skin infections and inflammation. To
prevent this, topical antibacterial ointments, such as mupirocin, are recommended
for 5–14 days following extractions [14, 15].
Finally, in more severe cases, surgical interventions can be considered. Simple
excisions can be used to excise large plaques and nodules. If necessary, excisions
can be staged allowing for decreased tension on wounds during healing. Surgical
therapies are particularly challenging for Favre-Racouchot, as the skin is by definition
thin with damaged elastic fibers and altered collagen rendering it very friable. This
makes it difficult to close any defects with ideal cosmesis. Sharkey et al. reported a
case where incisional wound healing was poor and required both a staged excision
and dermabrasion to obtain an acceptable cosmetic result [16].
Overall, the most efficacious treatments are those that combine therapeutic
modalities. Since there is no cure for this condition, successive treatments are often
necessary. Patients with this syndrome need to be treated with individually tailored
36 Favre-Racouchot Syndrome 257

regimens. Avoidance of risk factors such as excessive sun exposure, long term ste-
roid use, and tobacco should be discussed. The importance of proper sun protection
should also be addressed to help limit the potential actinic damage. When consider-
ing therapeutic options, physicians must take into consideration their patient’s skin
type, predominant lesion, likelihood of recurrence, and willingness to undergo
high-risk procedures. Even though this condition is not life threatening, it can result
in significant psychological, emotional, and social distress. Quality of life must
therefore be taken into consideration when treating this relatively benign skin
condition.

References

1. Aguis JRG. Grouped periorbital comedones. Br J Dermatol. 1964;76:158–64.

2. Schäfer T, Merkl J, Klemm E, Wichmann HE, Ring J, KORA Study Group. The epidemiology
of nevi and signs of skin aging in the adult general population: results of the KORA-survey
2000. J Invest Dermatol. 2006;126(7):1490–6.
3. Cellini A, Offidani A. An epidemiological study on cutaneous diseases of agricultural workers
authorized to use pesticides. Dermatology. 1994;189(2):129–32.
4. Sams Jr WM. Sun-induced aging. Dermatol Clin. 1986;4:509–16.
5. Hedelund L, Wulf HC. Favre-Racouchot disease provoked by UV-A1 and UV-B exposure.
Arch Dermatol. 2004;140(1):129–31.
6. Lim HW, James WD, Rigel DS, Maloney ME, Spencer JM, Bhushan R. Adverse effects of
ultraviolet radiation from the use of indoor tanning equipment: time to ban the tan. J Am Acad
Dermatol. 2011;64(5):893–902.
7. Breit S, Flaig MJ, Wolff H, Plewig G. Favre-Racouchot-like disease after radiation therapy.
J Am Acad Dermatol. 2003;49(1):117–9.
8. Keough GC, Laws RA, Elston DM. Favre-Racouchot syndrome: a case for smokers’ comedones.
Arch Dermatol. 1997;133(6):796–7.
9. Green AC, Hughes MC, McBride P, Fourtanier A. Factors associated with premature skin
aging (photoaging) before the age of 55: a population-based study. Dermatology. 2011;
222(1):74–80.
10. Patterson WM, Fox MD, Schwartz RA. Favre-Racouchot disease. Int J Dermatol. 2004;
43(3):167–9.
11. Calderone DC, Fenske NA. The clinical spectrum of solar elastosis. J Am Acad Dermatol.
1995;32:1016–24.
12. Lewis KG, Bercovitch L, Dill SW, Robinson-Bostom L. Acquired disorders of elastic tissue:
part I. Increased elastic tissue and solar elastotic syndromes. J Am Acad Dermatol. 2004;
51(1):1–21.
13. Rallis E, Karanikola E, Verros C. Successful treatment of Favre-Racouchot disease with 0.05%
tazarotene gel. Arch Dermatol. 2007;143:810–2.
14. Kaya TI, Tursen AC, Yazici GI. A simple open comedone extraction technique for Favre-
Racouchot disease. Photodermol Photoimmunol Photomed. 2005;21:275–7.
15. Mavilia L, Campolmi P, Santoro G, Lotti T. Combined treatment of Favre-Racouchot syndrome
with a superpulsed carbon dioxide laser: report of 50 cases. Dermatol Ther. 2010;23:S4–6.
16. Sharkey MJ, Keller RA, Grabski WJ, McCollough ML. Favre-Racouchot syndrome: a combined
therapeutic approach. Arch Dermatol. 1992;128:615–6.
Chapter 37
Hidradenitis Suppurativa

Deanna M. Sikorski and Kenneth J. Tomecki

37.1 Introduction

Hidradenitis suppurativa (HS), also known as acne inversa, is a chronic, debilitating

inflammatory disease characterized by painful subcutaneous nodules and abscesses
of intertriginous areas that contain both apocrine glands and terminal hairs.

37.2 Background

HS typically begins during the second and third decade of life, most often between
the ages of 21 and 23, although cases of prepubertal HS and postmenopausal HS
occasionally occur. The prevalence rate varies between 0.03 and 4 %, but true preva-
lence is probably 1 % in the general population [1, 2]. Women are more likely to be
affected than men and disease distribution varies by gender. The groin and inframa-
mmary regions are more commonly affected in women, while the buttocks, perineum,
and perianal area are more commonly affected in men.
The pathogenesis of HS is unclear and may include genetic, infectious, hormonal,
behavioral, and even host defense factors. Once thought to be a disorder of the apo-
crine gland, HS actually represents follicular plugging as the primary event. As such,
inflammation of the apocrine gland is not essential and apocrinitis is a secondary
phenomenon.
Approximately 40 % of HS patients have familial HS, inherited as an autosomal
dominant trait with 100 % penetrance. The likely defect may be a dysfunctional γ
(gamma)-secretase-Notch pathway with mutations in Presenilin-1 (PSEN1), Presenilin

D.M. Sikorski, M.D. (*) • K.J. Tomecki, M.D.

Department of Dermatology, The Cleveland Clinic Foundation, 9500 Euclid Avenue A61,
Cleveland, OH 44195, USA
e-mail: [email protected]

J.A. Zeichner (ed.), Acneiform Eruptions in Dermatology: A Differential Diagnosis, 259

DOI 10.1007/978-1-4614-8344-1_37, © Springer Science+Business Media New York 2014
260 D.M. Sikorski and K.J. Tomecki

Enhancer-2 (PSENEN), and Nicastrin (NCSTN) genes, which encode proteins integral
to γ (gamma)-secretase enzyme [3]. Gamma-secretase cleaves type 1 transmembrane
proteins such as Notch, and mice without Notch-1 have occluded hair follicles, thought
to be the initiating pathogenic event in HS.
HS is a component of the follicular occlusion tetrad which includes acne conglo-
bata, dissecting cellulitis of the scalp, and pilonidal cysts. Known associations include
acne vulgaris (30–70 %), obesity (51–75 %), smoking (70–89 %), and Crohn’s
disease. HS occasionally occurs with some genetic disorders, specifically keratosis-
ichthyosis-deafness (KID) syndrome, Dowling-Degos Disease, SAPHO syndrome,
PAPA syndrome, pachyonychia congenita, and Fox-Fordyce disease [1, 4].

37.3 Clinical Presentation

The onset of HS is usually insidious, typically affecting overweight or obese patients

who develop tender, indurated papules, pustules, and subcutaneous nodules in the
intertriginous areas (Figs. 37.1 and 37.2). Exact diagnosis may not be apparent
initially, leading to incomplete evaluation and treatment. Disease may remit sponta-
neously within 7–10 days or persist for many months as non-tender nodules with
subsequent recurrences. Disease distribution corresponds with the “milk line” loca-
tion of apocrine-related mammary tissue in mammals, typically affecting the axillae
most frequently (approximately 70 % of the time), followed by inguinal areas, inner
thighs, perianal and perineal areas, mammary and inframammary area, buttocks,
and less often the pubic region, scrotum, vulva, chest, scalp, and retroauricular
region. Perianal and perineal disease is associated with more debilitation compared

Fig. 37.1 Hidradenitis of the axillae and chest

37 Hidradenitis Suppurativa 261

Fig. 37.2 Hidradenitis of the groin

to axillary disease; most patients with perianal and perineal involvement have
recurrent disease and poorer quality of life [5].
During the course of the disease, additional nodules and plaques develop de novo
or from extension of existing nodules, either on affected or adjacent skin or occa-
sionally at distant sites. Fifty percent of patients experience a prodrome consisting
of burning, stinging, pain, and pruritus, with or without hyperhidrosis, occurring
12–48 h before disease onset. The subcutaneous coalescence of neighboring cysts
or the lateral extension of proliferating pilosebaceous material with rupture to the
surface produces deep dermal abscesses and interlinked sinus tracts, which may
lead to the formation of honeycombed fistulous tracts with chronic infection.
Drainage from these tracts is common and may be serous, purulent, bloody, or a
mixture and is often malodorous.
Ultimately, over time, disease becomes quiescent, invariably healing with scarring.
Occasionally, indolent cysts may develop on the face, behind the ears, at the nape of
the neck, on the trunk, and in the genital area. These cysts are more common in men.
Sinus tracts can coalesce to form hypertrophic, fibrous fistulae, and subcutaneous
sinus networks can form characteristic hypertrophic scars or dense, ropelike fibrotic
bands. Fifty percent of patients develop the “tombstone comedone” of permanently
dilated pores within an old “burned out” area of disease.
Most patients with chronic or untreated HS develop complications, e.g., anal,
urethral, and rectal strictures, fistulae, and fecal incontinence from genitofemoral
involvement or contractures and compromised mobility, especially in the axillae
and thighs, from axillary or perianal disease. Other sequelae include spondyloar-
thropathy, pyogenic granuloma, lymphedema, lymphangiectasia [6], scrotal and
vulvar edema, secondary infections including cellulitis and even septicemia,
epidural abscesses, and sacral osteomyelitis. Metabolic sequelae are uncommon,
262 D.M. Sikorski and K.J. Tomecki

but anemia, hypoproteinemia, and amyloidosis occasionally occur. Affected patients

have a 4.6-fold increase in cutaneous SCC reported in HS patients with the mean
time at diagnosis 25 years after the onset of HS. Most of the skin cancer (61 %)
occurs in the perineum or on the buttocks, with men primarily affected (4:1). Skin
cancer is often invasive and nearly half of affected patients die within 2 years of
diagnosis. HS patients reportedly have a 50 % greater risk of malignancy, especially
buccal cancer and primary hepatic cancer, though smoking and alcohol abuse are
confounding variables that may explain this increase.
HS exhibits significant psychological and physiologic morbidity and social
and economic hardships which contribute to a decreased quality of life. In one study,
144 HS patients, using the Dermatology Quality of Life Index (DQLI) questionnaire,
had a mean score of 8.9, worse than mild to moderate psoriasis or alopecia. The high
score was related to pain, malodorous discharge, genital disease or areas of intimacy,
and lack of medical care related to patient hesitancy to disclose signs and symptoms.
Another study of 61 hospitalized HS patients revealed similar results, with pain as
the primary effect on quality of life. HS patients with severe disease are often unem-
ployed, poor, and socially isolated. Employed patients with HS lose an average of
2–7 days of work per year, a number that tends to be greater in women.

37.4 Work-Up

The diagnosis is made clinically and biopsy is rarely necessary. The differential
diagnosis includes infectious and inflammatory diseases such as acne, carbuncles,
furuncles, inflamed cysts, fistulous abscess, granuloma inguinale, lymphogranuloma
venereum, tuberculous abscess, noduloulcerative syphilis, actinomycosis, blastomyco-
sis, nocardiosis, and cat scratch disease. HS can resemble Crohn’s disease; if suggestive,
GI and surgical evaluation may be necessary. Drainage warrants bacterial, fungal, and
mycobacterial culture, which may reveal Staphylococcus aureus or Gram-negative
organisms. Disease severity is variable and is quantified by the older Hurley scale or
newer Sartorius scale.

37.5 Treatment

There is no uniformly successful therapy for HS. Standard treatment depends on the
extent and severity of disease. Purely medical treatment is invariably prolonged
since permanent cure is uncommon. Regardless of severity, all patients deserve
information and education regarding preventative measures including the impor-
tance of good daily hygiene coupled with antimicrobial cleansers and reduction of
heat, friction, and excessive sweating, including use of loose-fitting clothing.
Adjunctive therapy should include smoking cessation, weight reduction, and support
group referral.
37 Hidradenitis Suppurativa 263

Medical therapies include topical and systemic antibiotics, topical and systemic
retinoids, systemic and intralesional corticosteroids, anti-androgens, dapsone,
cyclosporine, and anti-TNF-alpha inhibitors. Mild HS is often treated with intral-
esional corticosteroids and/or short courses of topical or oral antibiotics, with
selection based on sensitivities of cultured organisms, most commonly clindamy-
cin or a tetracycline. Complete remission with antibiotic treatment is rare, but
combination therapy with oral clindamycin and rifampicin [8] or with rifampicin,
moxifloxacin, and metronidazole has produced remissions in patients with mild to
moderate HS. Anti-androgen therapy with ethinylestradiol, cyproterone acetate,
and finasteride has proven to be helpful in many patients. TNF-alpha inhibitors
such as infliximab [9], etanercept [10], and adalimumab [11] have been effective in
some patients with moderate to severe disease, but long-term results have been
poor and the side effect profile of these drugs and their cost have limited their use.
Despite successful use in acne, oral retinoids have not been shown to be effective
in treating HS.
Surgical interventions with botulinum toxin, radiotherapy, carbon dioxide laser,
long-pulsed neodymium: yttrium-aluminum-garnet (YAG) laser [12], and photody-
namic [13] therapy have shown success in some patients. Incision and drainage has
little benefit since recurrence is so common. Surgical excision remains one of the most
successful therapies for recalcitrant HS, despite its appreciable morbidity and compli-
cations such as infection, scarring, graft failure, ischemic necrosis of myocutaneous
flaps, and recurrence. A recent review of 72 surgical HS patients showed a recurrence
rate of 54 % following excision to fascia with primary closure, but 19 % recurrence
with myocutaneous flap and 13 % recurrence with split thickness skin graft [14].

References

1. Alikhan A, Lynch PJ, Eisen DB. Hidradenitis suppurativa: a comprehensive review. J Am

Acad Dermatol. 2009;60:539–61.
2. Revuz JE, Canoui-poitrine F, Wolkenstein P, et al. Prevalence and factors associated with
hidradenitis suppurativa: results from two case–control studies. J Am Acad Dermatol.
2008;59:596–601.
3. Wang B, Yang W, Wen W, et al. Gamma-secretase gene mutations in familial acne inversa.
Science. 2010;330:1065.
4. Danby FW, Margesson LJ. Hidradenitis suppurativa. Dermatol Clin. 2010;28:779–93.
5. Matusiak L, Bieniek A, Szepietowski JC. Hidradenitis suppurativa markedly decreases quality
of life and professional activity. J Am Acad Dermatol. 2010;62:706–8.
6. Moosbrugger EA, Mutasim DF. Hidradenitis suppurativa complicated by severe lymphedema
and lymphangiectasias. J Am Acad Dermatol. 2011;64:1223–4.3.
7. Simonart T. Hidradenitis suppurativa and smoking. J Am Acad Dermatol. 2010;62:149–50.
8. Wall D, Kirby B. Rifampicin and clindamycin for hidradenitis. J Am Acad Dermatol. 2011; 64:790.
9. Grant A, Gonzalez T, Montgomery MO, Cardenas V, Kerdel FA. Infliximab therapy for
patients with moderate to severe hidradenitis suppurativa: a randomized, double-blind,
placebo-controlled crossover trial. J Am Acad Dermatol. 2010;62:205–17.
10. Lee RA, Dommasch E, Treat J, et al. A prospective clinical trial of open-label etanercept for
the treatment of hidradenitis suppurativa. J Am Acad Dermatol. 2009;60:565–73.
264 D.M. Sikorski and K.J. Tomecki

11. Blanco R, Martínez-Taboada VM, Villa I, et al. Long-term successful adalimumab therapy in
severe hidradenitis suppurativa. Arch Dermatol. 2010;145:580–84.
12. Mahmoud BH, Tierney E, Hexsel CL, Pui J, Ozog DM, Hamzavi IH. Prospective controlled
clinical and histopathologic study of hidradenitis suppurativa treated with the long-pulsed
neodymium:yttrium-aluminium-garnet laser. J Am Acad Dermatol. 2010;62:637–45.
13. Syed ZU, Hamzavi IH. Photomedicine and phototherapy considerations for patients with skin
of color. Photodermatol Photoimmunol Photomed. 2011;27:10.
14. Rambhatla PV, Lim HW, Hamzavi I. A systematic review of treatments for hidradenitis
suppurativa. Arch Dermatol. 2012;148:439–46.
Chapter 38
Perioral Dermatitis

Bryan Gammon and Bethanee J. Schlosser

38.1 Introduction

Perioral dermatitis (PD), a common acneiform facial eruption, was first described in
the 1950s. The terms “light-sensitive seborrheid” and “steroid-induced rosacea-like
dermatitis” were previously used to describe this condition [1, 2]. Given the now
recognized periorbital, perinasal, and perioral distribution of lesions, the term peri-
orificial dermatitis may be most appropriate [3].

38.2 Background

The exact etiology and pathogenesis of PD has not been elucidated. However, an
association with the use/misuse of topical corticosteroids has been well established.
Corticosteroid exposure through intranasal, inhaled, and systemic modes of delivery
has also been reported to incite PD [4–8]. Not all cases of PD demonstrate a history
of corticosteroid exposure [9].
Other specific environmental factors have not been identified, and patients do not
exhibit photosensitivity. Suggestions of microbiologic pathogenesis due to Candida
species, Demodex folliculorum, or fusiform bacteria have not been substantiated.
Allergic contact dermatitis to constituents of dentifrices (i.e., fluoride) and cosmet-
ics has been reported as a contributing factor in some cases although rechallenge
with these same products after resolution of PD may not consistently incite recur-
rence of PD.
Although PD has been considered by some to be a variant of acne rosacea, the
distribution of inflammatory lesions and absence of persistent background erythema
and telangiectasia differentiate PD from acne rosacea.
PD affects both adults and children. Adult PD disproportionately affects females
of reproductive age (25–40 years old). Pediatric PD affects both girls only slightly

B. Gammon, M.D. (*) • B.J. Schlosser, M.D., Ph.D.

Department of Dermatology, Northwestern University, Chicago, IL, USA

J.A. Zeichner (ed.), Acneiform Eruptions in Dermatology: A Differential Diagnosis, 265

DOI 10.1007/978-1-4614-8344-1_38, © Springer Science+Business Media New York 2014
266 B. Gammon and B.J. Schlosser

more often than boys with onset typically before 5 years old. Pediatric PD in
children as young as 6 months has been reported [10]. There appears to be no racial
predilection in pediatric or adult PD. PD has been shown to occur in siblings, but
genetic predisposition has not been further elucidated [11].

38.3 Clinical Presentation

PD classically presents with erythematous papules, pustules, and occasionally

vesicles on a background of variable erythema and fine scaling involving the
perioral, periorbital, and perinasal skin (Figs. 38.1 and 38.2a). Inflammatory lesions
may be singular or clustered with symmetric or unilateral distribution. Sparing of
the skin immediately surrounding (within 5 mm) the vermilion border has been

Fig. 38.1 Erythematous papules and pustules on a background of erythema and fine scaling
involving the perioral and perinasal skin. Sparing of the skin immediately surrounding the vermil-
ion border

Fig. 38.2 (a) A patient at baseline before therapy for perioral dermatitis (b) 6 weeks after therapy
with oral doxycycline and topical metronidazole for perioral dermatitis (c) 12 weeks after therapy
with oral doxycycline and topical metronidazole for perioral dermatitis
38 Perioral Dermatitis 267

Table 38.1 Clinical differential diagnosis of perioral dermatitis

Disorder Distinguishing clinical features
Acne rosacea Predilection for central face including the nose;
background persistent erythema and telangiectasia
Acne vulgaris Presence of comedones +/− nodulocystic lesions; possible
truncal involvement
Allergic contact dermatitis Rare pustules; potential exposure elicited through history
Cutaneous candidiasis Concomitant angular cheilitis or intraoral candidiasis;
immunocompromised host; +KOH microscopy,
fungal culture
Demodex folliculorum Associated pruritus; immunocompromised host; +KOH
infestation (dermatitis, microscopy
demodicosis, folliculitis)
Eosinophilic folliculitis Pruritic papules and pustules; possible upper trunk
involvement; immunocompromised (HIV+) host
Gram-negative folliculitis Predominance of pustules in perioral distribution; history
of antibiotic exposure
Impetigo Pustules and erosions with honey-colored crust; +bacterial
culture
Irritant contact dermatitis Rare pustules; presence of fissures; potential exposure
elicited through history
Lupus erythematosus Malar erythema; absences of pustules; photo-exacerbation;
non-facial eruption and systemic symptoms
Sarcoidosis Firm erythematous to brown papules; +diascopy;
multisystem involvement (pulmonary, ocular,
musculoskeletal)
Seborrheic dermatitis Predilection for nasolabial folds; greasy scale; possible
scalp, brow and ear involvement
Tinea faciei, tinea incognito, +KOH microscopy, fungal culture; possible scalp
Majocchi’s granuloma involvement
Definitions: KOH = potassium hydroxide

noted as a clinical hallmark (Fig. 38.1). Associated burning, stinging, or itching is

commonly reported. Granulomatous PD manifests as skin-colored, erythematous,
or yellow-brown papules. Exclusive perioral involvement is less common than
multisite disease, and PD without perioral lesions (i.e., exclusive perinasal and/or
periorbital lesions) is rare [10]. Extrafacial involvement is uncommon, and patients
do not exhibit systemic symptoms.
PD is typically self-limited and resolves over several weeks to months. Recurrence
is uncommon when corticosteroid exposure is avoided. Scarring is atypical.
The clinical differential diagnosis of PD includes both infectious and
noninfectious inflammatory disorders (Table 38.1). A thorough history, clinical
examination, review of systems, and simple diagnostic procedures (potassium
hydroxide (KOH) microscopy) are usually sufficient to differentiate PD from its
mimics. Patients who fail to respond to standard PD treatment or who exhibit an
atypical clinical presentation should be reevaluated with additional diagnostic
testing as needed.
268 B. Gammon and B.J. Schlosser

38.4 Work-Up

The diagnosis of PD is typically rendered based on history and clinical presentation.

Laboratory evaluation, biopsy, and microbiologic cultures are usually not performed.
A thorough history often reveals preceding or current facial skin corticosteroid expo-
sure, by topical or other routes; rebound exacerbation of the eruption upon cessation
of corticosteroid use is characteristic.
Exposure to potential contactants should be investigated in order to differentiate
PD from allergic and irritant contact dermatitis; cutaneous patch testing may be
helpful [12, 13]. KOH microscopy of skin scrapings may be helpful in differentiat-
ing PD from demodicosis, perioral candidiasis, and tinea faciei [14, 15].
PD shows significant histopathologic overlap with acne rosacea. Biopsy of PD
typically reveals mild spongiosis of the epidermis and follicular infundibulum with
perivascular and perifollicular lymphohistiocytic inflammation in the papillary and
superficial reticular dermis [16]. Papillary dermal edema can be seen. Perifollicular
granulomas and multinucleate giant cells are sometimes evident, particularly in cases
of granulomatous PD [17].

38.5 Treatment

There are no FDA-approved therapies for PD. While the therapeutic armamentarium
for the treatment of PD is large, the level of evidence supporting many of the available
agents is poor. Two systematic, evidence-based reviews of the literature suggest that
some of the strongest evidence supports “zero therapy” for PD, i.e., withdrawal of any
offending or exacerbating agents, such as topical or inhaled corticosteroids or cosmet-
ics [18, 19]. Multiple trials have demonstrated that avoidance of topical corticosteroids
and cosmetics results in improvement in 4 weeks and resolution within an average of
2–3 months. It is well recognized that continued use of topical corticosteroids and
cosmetics prolongs PD regardless of treatment employed.
Cutaneous irritation and sensitivity may limit the utility of topical agents for PD
though use of a gentle non-medicated cleanser and moisturizer may reduce this
tendency. Topical metronidazole, as monotherapy or in combination with oral
antibiotics, has demonstrated efficacy for PD (Fig. 38.2a–c). Use of topical metro-
nidazole gel 0.75 % twice daily in children with PD demonstrated significant
improvement after 8 weeks and resolution after 14 weeks [20]. A prospective,
randomized, double-blind study comparing metronidazole cream 1 % twice daily
with oral tetracycline 250 mg twice daily demonstrated significant reduction in pap-
ule number in the metronidazole group and complete resolution in the tetracycline
group after 8 weeks [21].
Topical erythromycin may also provide benefit [22]. Topical erythromycin
emulsion 2 % twice daily was superior to placebo in clearing papules with an
average time to clearance of 7 weeks; topical erythromycin demonstrated similar
efficacy to oral tetracycline [23]. A case series reported that 98 % of 700 patients
cleared on topical erythromycin [24].
38 Perioral Dermatitis 269

Pimecrolimus has been shown to expedite resolution of PD but may offer limited
long-term benefit. Two randomized, placebo-controlled trials of adults with PD
independently demonstrated that pimecrolimus cream 1 % twice daily significantly
reduced erythema, scaling, and papule number after 2 weeks compared with vehicle.
After 4 weeks, however, there was no significant difference between pimecrolimus
and vehicle [25, 26].
Oral tetracycline remains the gold standard for the treatment of PD. Randomized
controlled trials and large case series support the use of oral tetracycline as a first-
line agent [27]. Oral tetracycline (250 mg twice daily) has been shown to be more
effective for PD than topical metronidazole or topical erythromycin [21, 23]. Severe
perioral dermatitis recalcitrant to erythromycin ointment 2 % has been shown to
respond to oral tetracycline [24]. The use of doxycycline or minocycline in PD is
supported by case reports and small series [7, 28, 29].
Additional therapeutic options for PD are supported by small, uncontrolled trials
or case series which fail to assess whether an agent is more efficacious than zero
therapy. Open-label studies of azelaic acid cream 20 % twice daily reported complete
clearance within 5–6 weeks [30, 31]. A split-face study using photodynamic therapy
(PDT) with 5-aminolevulinic acid showed greater lesion reduction with PDT than
topical clindamycin gel 1 % at 1 month (92 % vs. 80 %); photosensitivity and post-
inflammatory hyperpigmentation complicated PDT treatment [32]. A retrospective
review of 25 patients treated with sodium sulfacetamide/sulfur 10/5 % reported
clearance in 14 of 25 (56 %) after an average of 1.2 months of treatment [33]. Limited
case reports detail the efficacy adapalene gel 0.1 % and isotretinoin [34, 35].

38.6 Conclusion

Perioral dermatitis is facial dermatosis of unclear etiology, but is frequently associ-

ated with preceding corticosteroid use. Patients typically present with erythematous
papules around the mouth, nose, and eyes. Treatment should include withdrawal
of offending agents including cosmetics and topical corticosteroids. Depending on
severity, topical metronidazole or an oral tetracycline should be instituted for at
least 8 weeks. Topical erythromycin applied twice daily provides greater benefit
than zero therapy. Pimecrolimus cream may promote rapid clearance of PD papules
but shows limited efficacy over the long term.

References

1. Frumess GM, Lewis HM. Light-sensitive seborrheid. AMA Arch Dermatol. 1957;
75(2):245–8.
2. Mihan R, Ayres Jr S. Perioral dermatitis. Arch Dermatol. 1964;89:803–5.
3. Kihiczak GG, Cruz MA, Schwartz RA. Periorificial dermatitis in children: an update and
description of a child with striking features. Int J Dermatol. 2009;48(3):304–6.
4. Hafeez ZH. Perioral dermatitis: an update. Int J Dermatol. 2003;42(7):514–7.
270 B. Gammon and B.J. Schlosser

5. Dubus JC, Marguet C, Deschildre A, et al. Local side-effects of inhaled corticosteroids in

asthmatic children: influence of drug, dose, age, and device. Allergy. 2001;56(10):944–8.
6. Poulos GA, Brodell RT. Perioral dermatitis associated with an inhaled corticosteroid. Arch
Dermatol. 2007;143(11):1460.
7. Adams SJ, Davison AM, Cunliffe WJ, Giles GR. Perioral dermatitis in renal transplant
recipients maintained on corticosteroids and immunosuppressive therapy. Br J Dermatol.
1982;106(5):589–92.
8. Clementson B, Smidt AC. Periorificial dermatitis due to systemic corticosteroids in children:
report of two cases. Pediatr Dermatol. 2012;29(3):331–2.
9. Wilkinson DS, Kirton V, Wilkinson JD. Perioral dermatitis: a 12-year review. Br J Dermatol.
1979;101(3):245–57.
10. Nguyen V, Eichenfield LF. Periorificial dermatitis in children and adolescents. J Am Acad
Dermatol. 2006;55(5):781–5.
11. Weston WL, Morelli JG. Identical twins with perioral dermatitis. Pediatr Dermatol.
1998;15(2):144.
12. Nedorost ST. Medical pearl—the evaluation of perioral dermatitis: use of an extended patch
test series. J Am Acad Dermatol. 2007;56(5 Suppl):S100–2.
13. Arutjunow V. Perioral dermatitis—an allergic disease? Hautarzt. 1978;29(2):89–91.
14. Bradford LG, Montes LF. Perioral dermatitis and Candida albicans. Arch Dermatol. 1972;
105(6):892–5.
15. Hsu CK, Hsu MM, Lee JY. Demodicosis: a clinicopathological study. J Am Acad Dermatol.
2009;60(3):453–62.
16. Hogan DJ. Perioral dermatitis. Curr Probl Dermatol. 1995;22:98–104.
17. Urbatsch AJ, Frieden I, Williams ML, Elewski BE, Mancini AJ, Paller AS. Extrafacial and
generalized granulomatous periorificial dermatitis. Arch Dermatol. 2002;138(10):1354–8.
18. Hall CS, Reichenberg J. Evidence based review of perioral dermatitis therapy. G Ital Dermatol
Venereol. 2010;145(4):433–44.
19. Weber K, Thurmayr R. Critical appraisal of reports on the treatment of perioral dermatitis.
Dermatology. 2005;210(4):300–7.
20. Miller SR, Shalita AR. Topical metronidazole gel (0.75%) for the treatment of perioral derma-
titis in children. J Am Acad Dermatol. 1994;31(5 Pt 2):847–8.
21. Veien NK, Munkvad JM, Nielsen AO, Niordson AM, Stahl D, Thormann J. Topical metroni-
dazole in the treatment of perioral dermatitis. J Am Acad Dermatol. 1991;24(2 Pt 1):258–60.
22. Bikowski JB. Topical therapy for perioral dermatitis. Cutis. 1983;31(6):678–82.
23. Weber K, Thurmayr R, Meisinger A. A topical erythromycin preparation and oral tetracycline
for the treatment of perioral dermatitis: a placebo-controlled trial. J Dermatol Treat. 1993;
4:57–9.
24. Weber K. How I, treat perioral dermatitis: non-compliance with the treatment guidelines.
Dermatology. 2003;207(2):215.
25. Oppel T, Pavicic T, Kamann S, Brautigam M, Wollenberg A. Pimecrolimus cream (1%)
efficacy in perioral dermatitis—results of a randomized, double-blind, vehicle-controlled
study in 40 patients. J Eur Acad Dermatol Venereol. 2007;21(9):1175–80.
26. Schwarz T, Kreiselmaier I, Bieber T, et al. A randomized, double-blind, vehicle-controlled
study of 1% pimecrolimus cream in adult patients with perioral dermatitis. J Am Acad
Dermatol. 2008;59(1):34–40.
27. Macdonald A, Feiwel M. Perioral dermatitis: aetiology and treatment with tetracycline. Br J
Dermatol. 1972;87(4):315–9.
28. Misago N, Nakafusa J, Narisawa Y. Childhood granulomatous periorificial dermatitis: lupus
miliaris disseminatus faciei in children? J Eur Acad Dermatol Venereol. 2005;19(4):470–3.
29. Rosso JQ. Management of papulopustular rosacea and perioral dermatitis with emphasis on
iatrogenic causation or exacerbation of inflammatory facial dermatoses: use of doxycycline-
modified release 40mg capsule once daily in combination with properly selected skin care as
an effective therapeutic approach. J Clin Aesthet Dermatol. 2011;4(8):20–30.
38 Perioral Dermatitis 271

30. Jansen T. Azelaic acid as a new treatment for perioral dermatitis: results from an open study.
Br J Dermatol. 2004;151(4):933–4.
31. Jansen T, Melnik BC, Schadendorf D. Steroid-induced periorificial dermatitis in children–
clinical features and response to azelaic acid. Pediatr Dermatol. 2010;27(2):137–42.
32. Richey DF, Hopson B. Photodynamic therapy for perioral dermatitis. J Drugs Dermatol.
2006;5(2 Suppl):12–6.
33. Bendl BJ. Perioral dermatitis: etiology and treatment. Cutis. 1976;17(5):903–8.
34. Jansen T. Perioral dermatitis successfully treated with topical adapalene. J Eur Acad Dermatol
Venereol. 2002;16(2):175–7.
35. Smith KW. Perioral dermatitis with histopathologic features of granulomatous rosacea:
successful treatment with isotretinoin. Cutis. 1990;46(5):413–5.
Chapter 39
Photocontact Dermatitis

Nicholas Gulati and Emma Guttman-Yassky

39.1 Introduction

Photocontact dermatitis (PCD) belongs to the category of skin diseases known as

photodermatoses, which are skin disorders caused or aggravated by ultraviolet (UV)
radiation and/or visible light. PCD is divided into two categories: phototoxic and
photoallergic. Phototoxic (photo-irritant) reactions are caused by direct damage to
tissue resulting from light activation of the photosensitizing agent without an immu-
nological basis. On the other hand, photoallergic reactions are cell-mediated
immune responses in which the antigen is the light-activated photosensitizing agent
and these reactions only occur after previous specific sensitization. PCD can be
caused by either cutaneous contact or systemic uptake [1]. Chronic actinic dermati-
tis, a condition which is clinically similar to photodermatitis, can occur both as a
sequelae of photoallergic reactions or de novo [2].

39.2 Background

The exact prevalence of PCD in the general population is not known. However,
estimates of its frequency have ranged from 7 to 15 % for phototoxicity and 4 to 8 %
for photoallergy [3–6].
Common phototoxic agents include coal-tar derivatives, dyes, antiarrhythmics,
diuretics, non-steroidal anti-inflammatory drugs (NSAIDs), phenothiazines,

N. Gulati, B.A. (*)

Laboratory for Investigative Dermatology, The Rockefeller University, 1230 York Ave,
New York, NY 10065, USA
e-mail: [email protected]
E. Guttman-Yassky, M.D., Ph.D.
Department of Dermatology, Mount Sinai NY, New York, NY, USA

J.A. Zeichner (ed.), Acneiform Eruptions in Dermatology: A Differential Diagnosis, 273

DOI 10.1007/978-1-4614-8344-1_39, © Springer Science+Business Media New York 2014
274 N. Gulati and E. Guttman-Yassky

quinolones, tetracyclines, thiazides, sulfonamides, sulfonylureas, and, most commonly,

plant-derived furocoumarins including psoralen. When phototoxicity results from
exposure to a plant, vegetable, or fruit, the resulting dermatitis is called phytopho-
todermatitis. Examples of vegetables/fruits causing phytophotodermatitis include
limes, figs, and parsley [7–9].
Photoallergic agents frequently encountered are sunscreens, fragrances, antibac-
terials, and NSAIDs [10]. UV filters used in sunscreens which commonly act as
sensitizers include isopropyl dibenzoylmethane (now off the market), benzophe-
none-3, benzophenone-10, butyl methoxydibenzoyl-methane, oxybenzone, and
p-aminobenzoic acid (PABA) [11, 12]. The UVB filter octyl methoxycinnamate, on
the other hand, rarely produces photoallergic reactions [13]. Ketoprofen, an NSAID,
although not commonly used topically, has been found to cause 82 % of contact
photoallergies in a large retrospective study [14]. However, the relative potency of
different agents to cause PCD is not well studied. This information is difficult to
ascertain in the general population because most studies consider only the people
who seek medical attention for preexisting skin conditions [15].
PCD is caused by compounds which absorb specific wavelengths of light
(absorption spectrum). This spectrum usually approximates the wavelengths which
lead to the clinical reaction (action spectrum). Most phototoxic sensitizers have
action spectrums in the UV range but some are in the visible light range.
Phototoxic reactions are thought to be mediated through generation of oxygen
free radicals, superoxide anions, hydroxyl radicals, and singlet oxygen, which in
turn causes cytotoxic effects. Different phototoxic agents act at various cell sites
such as the nucleus or cell membrane. There is also variety in the way different
people handle drugs, thus potentially accounting for the range of susceptibilities to
these reactions [16].
Although the exact mechanism of photoallergy is unknown, it is thought to
involve an exogenous low molecular weight compound (hapten) combining with an
endogenous protein only in the presence of UV or visible light in order to create an
antigenic conjugate. This conjugate can then lead to a delayed-type hypersensitivity
response in the skin and therefore the clinical appearance of dermatitis. In support
of this theory, the photoallergen tetrachlorosalicylanilide has been shown to bind
non-covalently to human serum albumin. However, upon irradiation with UV light,
a covalently bound conjugate is formed [17]. Photoconjugates such as this are able
to induce photoallergic responses when injected into guinea pigs [18].
The presumed initial step in the induction of delayed-type hypersensitivity is the
uptake of applied hapten by antigen-presenting cells (APCs) such as Langerhans
cells [19, 20]. Next, these APCs migrate to the local draining lymph nodes where
they stimulate the proliferation of antigen-specific T cells [21, 22].
Uptake by APCs (in the context of photoallergy) is made easier by cell apoptosis,
a process which could also explain the phototoxic capabilities of certain chemicals.
To this end, several agents known to cause photoallergy and/or phototoxicity have
been found to preferentially induce keratinocyte apoptosis upon irradiation with
UVA light as compared to no irradiation [23].
39 Photocontact Dermatitis 275

39.3 Clinical Presentation

Phototoxic reactions are similar in appearance to a sunburn, exhibiting erythema,

edema, stinging, and burning in areas exposed to the sun (Fig. 39.1). Sometimes, ves-
icles, bullae, and onycholysis are observed. Phototoxic agents might also occasionally
cause delayed reactions with manifestations occurring after hours or several days.
Symptoms resolve spontaneously with hyperpigmentation (due to stimulation of
melanin synthesis) and desquamation over a time course of days to weeks; the eruption
is rarely persistent [24].
Acute lesions of photoallergic reactions are limited to sun-exposed skin which
has been in contact with the photoallergen. Patients usually present with pruritus
and eczematous dermatitis with bullae and vesicles being rare. On repeated contact,
lichenification occurs. In some cases, spreading to covered sites is possible as UVA-
mediated reactions can occur under thin clothing [25].
PCD can present with variable severity depending on many factors such as the
amount of the photosensitizer and the location, the nature of the activating radiation,
thickness of the horny layer, degree of melanin pigmentation, and immunological
status. Phototoxic and photoallergic reactions can be difficult to discriminate clinically,
but there are several useful characteristics that can serve to distinguish the two. For
example, phototoxic reactions can occur upon first exposure while photoallergic
reactions require previous sensitization. Also, photoallergic reactions may “flare”

Fig. 39.1 Erythematous, tender plaques on the face that developed after application of a sunscreen
and exposure to UV light outside. The robust photocontact dermatitis became secondarily infected,
with the development of yellow crusted plaques (Photo credit: Joshua A. Zeichner, M.D.)
276 N. Gulati and E. Guttman-Yassky

at distant previously involved sites while phototoxic reactions do not. Furthermore,

the concentration of allergen required for a photoallergic reaction is often lower than
that needed for a phototoxic reaction [26].

39.4 Work-Up

To diagnose PCD, it is necessary to question possible exposure to various photosen-

sitizers such as medications, cosmetics, fragrances, and plant extracts. In order to
distinguish PCD from the commoner allergic contact dermatitis, it is essential
to validate a history of UV or visible light exposure. A valuable diagnostic clue is
preferential involvement of photoexposed sites with relative sparing of shadow sites
within the scalp, under the chin and nose, behind the ears, and around the eyes. Skin
lesions usually develop in the spring or summer seasons due to high levels of sun
exposure.
On histological examination, phototoxic reactions are characterized by sporadic
necrotic keratinocytes with lymphocytic and neutrophilic dermal infiltrates. Despite
causing a sunburn-like dermatitis, phototoxic reactions occur upon exposure to UV
doses normally well-tolerated by the individual as opposed to the overdoses of
UV radiation which lead to sunburn. The histological appearance of photoallergic
reactions resembles an allergic contact dermatitis reaction. This includes parakera-
tosis, irregular acanthosis, and spongiosis as well as a lymphocytic infiltrate with
some eosinophils in the dermis [27].
Key to the investigation of PCD is the photopatch test, a tool conceptually similar
to the standard patch test. In this procedure, the agents to be tested are prepared in a
vehicle such as petrolatum and a small volume is placed within plastic or metal
chambers. After these chambers are prepared, they are applied in duplicate sets to
the patient’s skin. This duplication is important as photoallergens can also cause
contact hypersensitivity. Usually after 48 h, the chambers are removed and the skin
at the site of one set is irradiated with a light source. Then, usually at 24–72 h from
the irradiation, both test sites are visually inspected and any observed reactions are
graded in terms of severity. A positive reaction is defined as erythema, edema, and/
or vesiculation at a test site. If this occurs only at the irradiated site, a diagnosis of
PCD is indicated. Reactions equally positive at both sites are interpreted as an
allergic contact dermatitis while reactions positive at both sites but stronger at the
irradiated one are interpreted as both allergic and photoallergic contact dermatitis
[28]. Having observations over several timepoints (i.e., 48 and 72 h) is useful
because photoallergic reactions exhibit delayed onsets with courses increasing in
severity while phototoxic reactions peak early on and then diminish.
The many steps involved in photopatch testing are not well standardized, and
different health-care centers use slightly different timepoints, etc. Risks of photopatch
testing include inadvertent sensitization to test materials, discomfort at test sites,
“flares” at previously involved sites, and persistent hyperpigmentation at test sites.
39 Photocontact Dermatitis 277

39.5 Treatment

Individuals with acute PCD reactions including erythema and edema may find relief
with ice-cold compresses of Burow’s solution in a 1:10 dilution. For acute photo-
toxic reactions, aspirin or other NSAIDs can be used. Alternatively, for generalized
cases, systemic corticosteroid therapy may provide prompt symptomatic relief.
The mainstay of treatment of PCD is avoidance of the offending agents as well as
appropriate photoprotection. Protective clothing such as long-sleeved shirts and hats
should be worn and sunscreens should be applied (provided they are not the offend-
ing agent) [29]. As needed, changes in lifestyle including avoidance of midday sun
as well as alterations in leisure and occupational activities may be recommended.
Special UV-absorbing plastic can be installed over windows and windscreens to
improve photoprotection. For chronic cases that only respond to systemic corticoste-
roids and which have high morbidity, immunosuppressive agents such as azathioprine
can be used [30].

39.6 Conclusion

Photocontact dermatitis is an inflammatory, facial dermatosis as a result of an

immune-mediated or directly toxic reaction from an exogenous source. Correct diag-
nosis is important for proper management of the acute flare and prevention of future
recurrences.

References

1. Lehmann P. Diagnostic approach to photodermatoses. J Dtsch Dermatol Ges. 2006;4(11):

965–75.
2. Hawk JLM. Chronic actinic dermatitis. Photodermatol Photoimmunol Photomed. 2004;
20(6):312–4.
3. Fotiades J, Soter NA, Lim HW. Results of evaluation of 203 patients for photosensitivity in a
7.3-year period. J Am Acad Dermatol. 1995;33(4):597–602.
4. Selvaag E. Clinical drug photosensitivity. A retrospective analysis of reports to the Norwegian
Adverse Drug Reactions Committee from the years 1970–1994. Photodermatol Photoimmunol
Photomed. 1997;13(1–2):21–3.
5. Crouch RB, Foley PA, Baker CS. Analysis of patients with suspected photosensitivity referred
for investigation to an Australian photodermatology clinic. J Am Acad Dermatol. 2003;
48(5):714–20.
6. Wong SN, Khoo LSW. Analysis of photodermatoses seen in a predominantly Asian population
at a photodermatology clinic in Singapore. Photodermatol Photoimmunol Photomed. 2005;
21(1):40–4.
7. Wagner AM, Wu JJ, Hansen RC, Nigg HN, Beiere RC. Bullous phytophotodermatitis associ-
ated with high natural concentrations of furanocoumarins in limes. Am J Contact Dermatitis.
2002;13(1):10–4.
278 N. Gulati and E. Guttman-Yassky

8. Polat M, Oztas P, Dikilitas MC, Alli N. Phytophotodermatitis due to Ficus carica. Dermatol
Online J. 2008;14(12):9.
9. Lagey K, Duinslaeger L, Vanderkelen A. Burns induced by plants. Burns. 1995;21(7):542–3.
10. Bylaite M, Grigaitiene J, Lapinskaite GS. Photodermatoses: classification, evaluation and
management. Br J Dermatol. 2009;161 Suppl 3:61–8.
11. Schauder S, Ippen H. Contact and photocontact sensitivity to sunscreens. Review of a 15-year
experience and of the literature. Contact Derm. 1997;37(5):221–32.
12. Szczurko C, Dompmartin A, Michel M, Moreau A, Leroy D. Photocontact allergy to oxyben-
zone: ten years of experience. Photodermatol Photoimmunol Photomed. 1994;10(4):144–7.
13. Darvay A, White IR, Rycroft RJ, et al. Photoallergic contact dermatitis is uncommon. Br J
Dermatol. 2001;145(4):597–601.
14. Diaz RL, Gardeazabal J, Manrique P, et al. Greater allergenicity of topical ketoprofen in
contact dermatitis confirmed by use. Contact Derm. 2006;54(5):239–43.
15. Agin PP, Ruble K, Hermansky SJ, McCarthy TJ. Rates of allergic sensitization and irritation
to oxybenzone-containing sunscreen products: a quantitative meta-analysis of 64 exaggerated
use studies. Photodermatol Photoimmunol Photomed. 2008;24(4):211–7.
16. Ferguson J. Photosensitivity due to drugs. Photodermatol Photoimmunol Photomed. 2002;
18(5):262–9.
17. Kochevar IE, Harber LC. Photoreactions of 3,3’,4’,5-tetrachlorosalicylanilide with proteins.
J Invest Dermatol. 1977;68(3):151–6.
18. Pendlington RU, Barratt MD. Molecular basis of photocontact allergy. Int J Cosmet Sci.
1990;12(2):91–103.
19. Atarashi K, Kabashima K, Akiyama K, Tokura Y. Stimulation of Langerhans cells with
ketoprofen plus UVA in murine photocontact dermatitis to ketoprofen. J Dermatol Sci. 2007;
47(2):151–9.
20. Miyachi Y, Takigawa M. Mechanisms of contact photosensitivity in mice: II. Langerhans cells
are required for successful induction of contact photosensitivity to TCSA. J Invest Dermatol.
1982;78(5):363–5.
21. Gerberick GF, Ryan CA, Von Bargen EC, Stuard SB, Ridder GM. Examination of tetrachloro-
salicylanilide (TCSA) photoallergy using in vitro photohapten-modified Langerhans cell-
enriched epidermal cells. J Invest Dermatol. 1991;97(2):210–8.
22. Gerberick GF, Ryan CA, Fletcher ER, Howard AD, Robinson MK. Increased number of
dendritic cells in draining lymph nodes accompanies the generation of contact photosensitivity.
J Invest Dermatol. 1991;96(3):355–61.
23. Kurita M, Shimauchi T, Kobayashi M, et al. Induction of keratinocyte apoptosis by photosen-
sitizing chemicals plus UVA. J Dermatol Sci. 2007;45(2):105–12.
24. Epstein JH. Phototoxicity and photoallergy. Semin Cutan Med Surg. 1999;18(4):274–84.
25. Lankerani L, Baron ED. Photosensitivity to exogenous agents. J Cutan Med Surg. 2004;
8(6):424–31.
26. Stein KR, Scheinfeld NS. Drug-induced photoallergic and phototoxic reactions. Expert Opin
Drug Saf. 2007;6(4):431–43.
27. Hölzle E, Lehmann P, Neumann N. Phototoxic and photoallergic reactions. J Dtsch Dermatol
Ges. 2009;7(7):643–9.
28. Anon X. Photopatch testing—methods and indications. British Photodermatology Group. Br J
Dermatol. 1997;36(3):371–6.
29. Fourtanier A, Moyal D, Seité S. Sunscreens containing the broad-spectrum UVA absorber,
Mexoryl SX, prevent the cutaneous detrimental effects of UV exposure: a review of clinical
study results. Photodermatol Photoimmunol Photomed. 2008;24(4):164–74.
30. Yap LM, Foley P, Crouch R, Baker C. Chronic actinic dermatitis: a retrospective analysis of
44 cases referred to an Australian photobiology clinic. Australas J Dermatol. 2003;
44(4):256–62.
Chapter 40
Post-inflammatory Pigment Alteration

Rajiv I. Nijhawan and Andrew F. Alexis

40.1 Introduction

Post-inflammatory pigment alteration is a common sequela of acne vulgaris in

darker skin types (Fitzpatrick skin phototypes IV–VI). Acne-associated dyschromia
contributes considerably to the psychological and emotional distress experienced by
acne patients and can often be of greater concern to the patient than the acne itself
[1–3]. Post-inflammatory hyperpigmentation is seen much more frequently than
post-inflammatory hypopigmentation; however, it is important to keep in mind that
in addition to acne itself, various acne treatments can cause hyper- or hypopigmen-
tation as a result of irritation.

40.2 Background

Post-inflammatory pigment alteration especially hyperpigmentation is a common

presenting concern, especially in acne patients [4, 5]. In a hospital-based dermatol-
ogy practice in New York City, dyschromia was the second most common present-
ing diagnosis second to acne in black patients [5]. Of note, in another study, 65.3 %
of African-Americans, 52.7 % of Hispanics, and 47.4 % percent of Asians all had
hyperpigmented macules secondary to acne [6]. While the multifactorial pathogen-
esis of acne appears to be the same in all skin types and ethnic populations [1], the
innate qualities of each patient such as skin color and sensitivity to inflammation
markedly individualizes this disease. The differences in skin color are attributed to
the varying degrees of epidermal density and distribution of the melanin, activity of

R.I. Nijhawan, M.D. • A.F. Alexis, M.D., M.P.H. (*)

Department of Dermatology, St. Luke’s-Roosevelt Hospital Center, 1090 Amsterdam Avenue,
Suite 11B, New York, NY 10025, USA
e-mail: [email protected]

J.A. Zeichner (ed.), Acneiform Eruptions in Dermatology: A Differential Diagnosis, 279

DOI 10.1007/978-1-4614-8344-1_40, © Springer Science+Business Media New York 2014
280 R.I. Nijhawan and A.F. Alexis

the enzyme tyrosinase, variations in number, size, and groupings of the melano-
somes, as well as the efficiency of melanosome transfer to keratinocyte [7–10].
A key characteristic in skin of color is the tendency for melanocytes to exhibit
labile responses to inflammation and injury [11, 12], which contributes to the high
prevalence of post-inflammatory hyperpigmentation in darker skin types.
Inflammatory mediators, including prostaglandins and leukotrienes, can stimulate
increased melanin synthesis, which can lead to increased pigment in the epidermis
alone or also in the dermis [13]. When there is dermal involvement, there is disrup-
tion of the basal layer that leads to macrophages engulfing the melanin and the for-
mation of melanophages. In addition, a study by Halder et al. examined biopsies in
thirty black patients with acne vulgaris and found the presence of inflammation
histologically even in clinically noninflammatory lesions such as comedones. In
addition, papules and pustules displayed considerable inflammation histologically
that extended significantly beyond the margins of each lesion [14]. While subclini-
cal inflammation is likely a feature of acne vulgaris in all skin types, it may contrib-
ute to the tendency toward dyschromias in acne patients with skin of color [2].

40.3 Clinical Presentation

Post-inflammatory hyperpigmentation (PIH) from acneiform lesions appears as mac-

ules or patches of darker skin color in contrast to the patient’s natural skin color (see
Fig. 40.1). With dermal deposition of melanin, the duration of the hyperpigmentation

Fig. 40.1 An African-American woman with Fitzpatrick skin type VI and severe post-
inflammatory hyperpigmentation associated with acne vulgaris
40 Post-inflammatory Pigment Alteration 281

is prolonged and can last several months to years. Hypopigmentation can also be seen
in acne patients as a sequela of irritant dermatitis from topical acne therapies. It can
also be seen with the use of skin lightening agents to lighten PIH, typically presenting
with perilesional halos of hypopigmentation.

40.4 Work-Up

Post-inflammatory pigment alteration from acne is generally a clinical diagnosis

based on medical history and examination without need for laboratory tests, biop-
sies, or culture. Wood’s lamp examination may assist the clinician in assessing the
location of pigment involved as is used in melasma. Increased epidermal melanin
usually enhances with Wood’s lamp examination, whereas dermal pigment does
not, though a mixed pattern can be noted [15]. It is important to be mindful of the
potential for minocycline-induced pigmentation to mimic acne-associated PIH;
however, the bluish gray pigment, the tendency to develop within preexisting scars,
and frequent involvement of the mucous membranes and nail beds are distinguish-
ing characteristics.

40.5 Treatment

One of the hallmarks of post-inflammatory hyperpigmentation management is sun

protection with broad-spectrum sunscreens including physical blockers to prevent
both ultraviolet and visible light induced melanogenesis [16] as well as wearing
wide-brimmed hats and adhering to overall sun avoidance. Education regarding
sunscreen use is especially important in patients with darker skin types (i.e., multi-
racial, Hispanic, black) since they are less likely to apply sunscreen when compared
to non-Hispanic whites [17]. Cosmetic camouflage can be a useful adjunct. In
regard to hyperpigmentation specific treatments, topical agents attempt to interfere
with the enzymatic processes of melanin production, especially the rate-limiting
enzyme tyrosinase. A combination of modalities is often needed for optimal man-
agement (see Table 40.1) [18].
Because of the often disfiguring nature of post-inflammatory hyperpigmentation,
patients often attempt to self-treat these hyperpigmented areas with over-the-
counter, herbal, and prescription fading, lightening, and bleaching agents from
beauty supply stores and various pharmacies before even seeing a dermatologist.
Hydroquinone (1,4 dihydroxybenzene), a tyrosinase inhibitor, is one of the most
widely used bleaching agents. Branded and generic formulations are available in
concentrations of 2–4 %, although higher concentrations can be compounded by
specialty pharmacists [19]. The efficacy of hydroquinone, a first-line therapy for
hyperpigmentation for close to 50 years [13], can be enhanced with consistent use
broad-spectrum sun protection [20]. The most common side effects with use of
282 R.I. Nijhawan and A.F. Alexis

Table 40.1 Management options for post-inflammatory hyperpigmentation

Mainstay
• Broad-spectrum sunscreens
• Avoidance of intense sun exposure
• Early aggressive anti-inflammatory treatment of acne vulgaris to prevent development of
dyschromias
• Tincture of time (spontaneous resolution of PIH with adequate control of primary inflamma-
tory disorder)
Adjunctive therapies
• Cosmetic camouflage
• Topical skin lightening agents (hydroquinone, azelaic acid, cosmeceuticals)
• Topical retinoids
• Chemical peels (superficial)
• Microdermabrasion

hydroquinone are the risks of a “halo” of hypopigmentation on perilesional skin,

irritant contact dermatitis (which must be monitored closely as this can potentiate
post-inflammatory pigment alteration), and rarely exogenous ochronosis. The
hypopigmented “halo” can be minimized by instructing patients to apply the bleach-
ing agent using a cotton swab only to the darker areas to minimize the application
on normal skin. When it does occur, hydroquinone application to the affected area(s)
should be discontinued until repigmentation ensues, typically within several weeks.
Additional topical agents have also become mainstays of post-inflammatory
hyperpigmentation management. Multiple studies have evidenced the efficacy of
topical retinoids, not only for the management of acneiform eruptions themselves,
but also for dyschromias [21–23]. Proposed mechanisms of topical retinoids for the
improvement of hyperpigmentation include inhibition of tyrosinase induction in
melanocytes, enhancement of desquamation that speed up sloughing of melanin in
keratinocytes, inhibition of melanosome transfer from melanocytes to keratino-
cytes, allowing greater penetration of other active ingredients, and redistribution or
dispersion of epidermal melanin [24, 25]. Clinicians must also be aware of the
potential of topical retinoids to induce irritation that could also potentially potenti-
ate post-inflammatory pigment alteration [22].
Studies of dual or triple agent combination therapies that may include a topical
retinoid, hydroquinone, and a topical corticosteroid in comparison to single agents
have shown to be more effective with a more rapid response in pigment disorders
[26–31]. In a multicentered, investigator blinded, randomized study of 792 patients
with post-inflammatory hyperpigmentation secondary to acne vulgaris that com-
pared triple combination cream (fluocinolone acetonide 0.01 %, hydroquinone 4 %,
and tretinoin 0.05 %) to each of its dyads, results indicated more patients treated
with triple therapy for 8 weeks achieved clear or almost clear status than any of the
dyad comparators [30]. Other therapeutic considerations for dyschromia include
products containing azelaic acid, kojic acid, and glycolic acid [32–34].
Cosmeceuticals have become increasingly popular for consumers interested in
hyperpigmentation remedies. Certain ingredients in these products have been sub-
ject to or are currently being evaluated in blinded controlled studies including soy,
40 Post-inflammatory Pigment Alteration 283

liquiritin (licorice extract), N-acetylglucosamine, niacinamide, mequinol (4-hydroxyanisole),

vitamin C (ascorbic acid), oligopeptide, rucinol, tranexamic acid, and N-undecyl-10-
enoyl-l-phenylalanine [19, 35–38]. Products that include soy or nicotinamide pre-
vent melanosome transfer [39–41], while hydroquinone, arbutin, licorice, azelaic
acid, and kojic acid inhibit tyrosinase [39]. Newer combination formulations such as
emblica, kojic acid, and glycolic acid (Skinceuticals); lipo-hydoxy acid, glycolic
acid, and kojic acid (La Roche-Posay); and kojic acid, licorice extract, and vitamin
C (Neostrata) may also be useful adjuncts to the treatment of PIH. Potential emerg-
ing products for pigment disorders include grape seed extract, ellagic acid, linoleic
acid, aleosin, green tea extracts, and lignin peroxidase [39, 42, 43]. While topical
therapies are usually the initial approach to the treatment of post-inflammatory
hyperpigmentation, physical therapies, such as chemical peels and microdermabra-
sion, may also be used as adjuncts to improve treatment outcomes.
Superficial chemical peels such as salicylic acid (20–30 %), glycolic acid (20–
70 %), trichloroacetic acid [TCA] (10–25 %), and Jessner’s solution as an adjunc-
tive approach with topical agents may help improve hyperpigmentation by removing
excess epidermal melanin and enhancing penetration of topical bleaching agents
[39]. Various studies have reported that the addition of serial glycolic acid chemical
peels to a topical regimen is beneficial for the treatment of hyperpigmentation from
melasma with a trend toward more rapid and greater improvement [44–46], and this
approach can similarly be applied to post-inflammatory hyperpigmentation. Burns
et al. specifically studied this hyperpigmentation in nineteen patients with darker
skin and found a trend toward more rapid and greater improvement when six serial
glycolic acid peels were added to a topical regimen of 2 % hydroquinone/10 %
glycolic acid gel twice daily as well as tretinoin 0.05 % cream at bedtime in com-
parison to those who only maintained the topical regimen without receiving the
chemical peels [47].
In regard to serial salicylic acid peels, a study of 35 Korean patients receiving
30 % salicylic acid peels biweekly for 12 weeks found this to be a safe and
effective therapy for acne in Asian patients [48]. However, there is limited evi-
dence and some conflicting data regarding the efficacy of salicylic acid peels in
the treatment of post-inflammatory hyperpigmentation [49–51], thus larger sys-
temized studies are needed to better assess the utility of salicylic acid peels in
post-inflammatory hyperpigmentation. When peels are performed on darker
skin types, a conservative approach with slow titration of acid concentration is
recommended to avoid adverse effects such as persistent redness, crusting, and
pigmentary abnormalities. Discontinuation of topical retinoids 1 week prior to
the chemical peel as well as application of sunscreen immediately following the
chemical peel helps to minimize the risk of pigmentary complications following
chemical peels.
While there is an increasing amount of literature on chemical peels for dyschro-
mias, there is limited literature on photodynamic and other light-/laser-based thera-
pies in the management of post-inflammatory hyperpigmentation [1, 19, 52]. Lasers
are unpredictable in the treatment of hyperpigmentation and therefore are usually
reserved for failures of combination topical therapy and chemical peels.
284 R.I. Nijhawan and A.F. Alexis

If considered, skin type should always be taken into account given the high risk of
post-inflammatory hyperpigmentation [32]. While fractional nonablative lasers may
be useful for hyperpigmentation, optimal treatment parameters for dyschromias in
skin of color have not been well established and treatment outcomes are unpredict-
able; however, lower treatment levels and prophylactic use of hydroquinone both
before and after laser treatment are recommended to minimize post-treatment
hyperpigmentation [53–55].
Post-inflammatory hyperpigmentation secondary to acne vulgaris can be an
extremely challenging process to manage, and thus the prevention of such lesions is
paramount with early intervention and meticulous sun protection. Anti-inflammatory
agents (including systemic therapies where appropriate) should be initiated as early
as possible in patients prone to post-inflammatory hyperpigmentation [56].
Combination therapies with the addition of lightening agents have shown to be ben-
eficial, and chemical peels can be considered as second-line approaches. New thera-
peutic agents, however, are needed including alternatives to hydroquinone and
improved strategies for the treatment of resistant dermal pigmentation.

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Chapter 41
Pseudofolliculitis Barbae

Angela Lamb and Gregory N. Yañez

41.1 Introduction

Pseudofolliculitis barbae (PFB), also known as razor bumps or barber’s itch, is a

common inflammatory condition of shaved areas that predominately affects darkly
pigmented men with curly hair [1, 2]. The classic presentation is an African
American man presenting with painful and/or pruritic inflammatory papules and
pustules in distribution of the shaven beard. The mustache area is usually spared [3].
One survey of patients at a New York City clinic found that among women with
PFB, the most common hair removal methods were tweezing followed by shaving,
electrolysis, waxing, depilatory use, and laser treatments [4]. The only definitive
treatment is to stop all attempts at hair removal to allow the epidermis time to
recover from the inflammatory state. In chronic cases or cases where patients con-
tinue to shave the affected areas, firm papules and even keloid scars may be appreci-
ated on exam.

41.2 Background

In darkly pigmented men of African ancestry, PFB has an estimated prevalence of

45–85 % [2, 5]. The prevalence and severity of symptoms is diminished in lighter
patients. Women also develop this disorder in groomed areas where the hair is

A. Lamb, M.D. (*)

Department of Dermatology, Mount Sinai Hospital, 638 Columbus Avenue,
New York, NY 10024, USA
e-mail: [email protected]
G.N. Yañez, B.A.
Icahn School of Medicine at Mount Sinai Class of 2015, New York, NY, USA
e-mail: [email protected]

J.A. Zeichner (ed.), Acneiform Eruptions in Dermatology: A Differential Diagnosis, 289

DOI 10.1007/978-1-4614-8344-1_41, © Springer Science+Business Media New York 2014
290 A. Lamb and G.N. Yañez

tightly curled such as the axilla and groin regions [4, 6]. Some authors have also
noted perimenopausal women can suffer from PFB as higher androgen levels simu-
late hair growth in the beard area [4]. A survey of patients at the Skin of Color
Center in New York found that 83 % of their patients with PFB were between ages
11 and 30 with the average age of 22, and among female patients 98 % were of
African ancestry and 2 % were Hispanic [4].
There are two types of lesions in pseudofolliculitis barbae: intrafollicular and
transfollicular lesions. The initiating event in the pathogenesis of pseudofolliculitis
barbae is generally thought to be shaving; however it should be noted that female
PFB patients report grooming via tweezing, electrolysis, waxing, and use of depila-
tory agents [4]. A better working understanding may be to consider any grooming
technique that causes trauma as a potential inciting event in PFB pathogenesis.
Since most patients develop PSB secondary to shaving, an understanding of how
shaving in particular leads to PFB is helpful. Shaving leaves an oblique cut at the
distal end of the hair strand [7]. The curved morphology of the hair and hair follicle
in patients with curly hair contributes to formation of lesions as the hair grows.
Instead of growing straight out, it curves back into the epidermis or dermis. Helical
and spiral hair types are the most likely to cause these lesions [4]. Intrafollicular
lesions occur when the growing hair penetrates the dermis while still growing within
its follicle of origin. Transfollicular lesions occur when the distal end of the hair
penetrates the skin outside the follicle. Transfollicular lesions typically penetrate
the skin 1.5–2 mm from the originating hair follicle [7].
German researchers have also discovered a genetic risk factor that partially con-
tributes to the PFB phenotype. They found that a single-nucleotide polymorphism
resulting in an abnormal Ala12Thr substitution in the 1A α(alpha)-helical segment
of the accompanying layer-specific keratin K6hf was responsible for a 6.12 odds
ratio increased risk of PFB compared to wild type [8]. In contrast, a curved hair fol-
licle was associated with a 51.27 odds ratio for expression of the PFB phenotype in
the German study population [8]. These researchers note that most other disruptive
keratin mutations are phenotypically silent, and the mutations are only unmasked
phenotypically secondary to mechanical trauma to the tissue [9]. The German
researchers postulate that the stretching of the skin involved with shaving results in
trauma that unmasks PFB, which explain why in many cases, allowing the beard to
grow normally resolves symptoms.
In pseudofolliculitis, inflammation occurs as a result of the body’s inflammatory
response to the ingrown hair. Suppurative parafollicular foci form at the sites where
infiltration occurs [10]. As lesions progress, small, foreign body granulomas and a
mixed inflammatory cell infiltrate become evident [10]. The lesions are sometimes
cleared by a process of transepithelial elimination in which the surface epithelium
grows around the lesion to encase the inflammatory response along with the inciting
ingrown hair [10].
41 Pseudofolliculitis Barbae 291

41.3 Clinical Presentation

The prototypical patient population is darkly pigmented men often of African or

Hispanic ancestry who shave. On presentation, inflamed papules are apparent on the
beard and anterolateral neck (Fig. 41.1). Pustules and abscesses may also be seen.
The mustache area, even when it is shaved daily, is typically spared [3]. The lesions
of acne vulgaris can be distinguished from those of pseudofolliculitis barbae by the
presence of comedones. Firm papules can develop hyperpigmentation, hypertrophic
scars, and, in chronic disease, keloids [3].

41.4 Work-Up

PFB is primarily a clinical diagnosis. In the setting of hirsutism in women with

associated PFB, a hormonal work-up could be considered to rule out an endocrine
disorder. DHEAS and LH/FSH ratio are among the tests to be ordered. If the lesions
have become infected, bacterial culture for selection of appropriate topical or sys-
temic antibiotic therapy may be appropriate. Biopsies are also rarely performed.

Fig. 41.1 Flesh colored

papules and pustules in the
beard of an African American
man (Photo credit: Joshua A.
Zeichner, M.D.)
292 A. Lamb and G.N. Yañez

41.5 Treatment

It is important to understand that in the acute stage of PFB, medical intervention is

warranted as patients can experience significant morbidity from pain and pruritus.
Additionally, patients may struggle to comply with workplace policies that require
employees to be clean shaven. Indeed, military physicians have studied this condi-
tion to resolve conflicts between servicemen with PFB and their commanders over
adherence to military policy that servicemen should be clean shaven [2].
If a patient has a folliculitis along with PFB, a course of systemic antibiotics,
such as minocycline or doxycycline, is warranted. Topical antibiotic therapy with
clindamycin or mupirocin may also be considered. Bacterial cultures of pustules
should be taken prior to commencing antibiotic therapy.
Initial treatment of pustular and papular PFB should be directed towards mini-
mizing inflammation and preventing bacterial superinfection. To that end a course
of topical combined clindamycin benzoyl peroxide is helpful. Additionally, low
potency topical corticosteroids, such as hydrocortisone valerate or desonide, can be
used. Potent topical corticosteroids or intralesional triamcinolone injections should
be reserved for more advanced lesions and should be used cautiously on the face.
Topical retinoids are useful as therapy as well. Kligman and Mills found that treti-
noin 0.05 % solution applied twice a day for 8 weeks improved symptom of papules
in 78.95 % of study patients. The treatment worked best in those with more mild
cases of PFB. They speculated that tretinoin’s efficacy was due to a reduction of
hyperkeratosis caused by repeated trauma to the epidermis [11].
While topical and oral therapies help reduce inflammation, they do not address
the underlying pathophysiology of PFB. The root causes are attempts to groom the
beard whether it be by shaving, plucking, etc. The patient should be counseled that
shaving contributes to the lesions. Some sources contend that most inflammatory
papules resolve after 1 month of not shaving [7]. It can take 2–6 weeks of shaving
cessation for complete resolution of symptoms [4]. The author’s approach is to
advise the patient to discontinue shaving until he sees resolution of papules and
pustules in concert with therapies recommended above.
In patients who need to maintain a clean-shaven appearance for work or personal
preference, education must be provided on proper grooming practices. Patients
should take a shower then apply a warm water compress to the face before shaving.
This hydrates the skin and the hairs so that they can be more easily shaved.
Additionally patients should shave with the grain, avoid pulling the skin taut to
reduce tension and minimize trauma, and clean the blade frequently to avoid trac-
tion from hair buildup [4]. Some authors also recommend applying a cool compress
after shaving [4].
Patients should select grooming tools that minimize trauma to the skin. A man-
ual razor, clipper, or electric razor that does not give an extremely close shave is
best. While somewhat controversial, some authors suggest avoiding razors with
multiple blades, as they give a very close shave [4]. Manual razors with a guard that
prevents a close shave and electric razors have been shown to be good choices for
41 Pseudofolliculitis Barbae 293

PFB patients. In one study, use of one such manual razor specially made for PFB
patients conferred a 25 % or greater reduction in the number of lesions for 72.7 %
of study participants with 86.4 % of patients reporting some improvement [12].
A study of electric rotary razors found that 90 % of the 300 participants switched to
use the razors after the trial period [13].
For women with PFB, topical eflornithine is an option that can help decrease the
rate of hair growth and thickness of individual hairs. This often decreases the fre-
quency of hair removal techniques. Unfortunately, hair growth rate resumes to its
normal rate after cessation. Laser hair removal is another frequently recommended
option. This addresses both the desire to be clean shaven along with addressing the
root cause of PFB.

41.6 Conclusion

Pseudofolliculitis barbae is a chronic condition resulting from an interplay of both

the hair and the skin. Chronic inflammation from ingrown hairs is the primary
cause. Treatment is directed at reducing this inflammation as well as minimizing the
underlying trauma caused by hair removal processes. This condition has a large
psychosocial and emotional impact, so proper education of patients is extremely
important.

References

1. Garcia Rl Jr WJW. PSeudofolliculitis barbae in a woman. Arch Dermatol. 1978;114(12):1856.

2. Alexander WID AM. Pseudofolliculitis barbae in the military. A medical, administrative and
social problem. J Natl Med Assoc. 1974;66(6):459–64, 79. Pubmed Central PMCID:
PMC2609333.
3. Edlich RF, Haines PC, Nichter LS, Silloway KA, Morgan RF. Pseudofolliculitis barbae with
keloids. J Emerg Med. 1986;4(4):283–6.
4. Perry PK, Cook-Bolden FE, Rahman Z, Jones E, Taylor SC. Defining pseudofolliculitis barbae
in 2001: a review of the literature and current trends. J Am Acad Dermatol. 2002;46(2 Suppl
2):S113–9.
5. Brauner GI, Flandermeyer KL. Pseudofolliculitis barbae 2. Treatment. Int J Dermatol.
1977;16(6):520–5.
6. Alexander A. PSeudofolliculitis diathesis. Arch Dermatol. 1974;109(5):729–30.
7. Strauss JSKA. Pseudofolliculitis of the beard. AMA Arch Dermatol. 1956;74:533–42.
8. Winter H, Schissel D, Parry DAD, Smith TA, Liovic M, Birgitte Lane E, et al. An unusual
Ala12Thr polymorphism in the 1A [alpha]-helical segment of the companion layer-specific
keratin K6hf: evidence for a risk factor in the etiology of the common hair disorder pseudofol-
liculitis barbae. J Investig Dermatol. 2004;122(3):652–7.
9. Irvine AD, McLean WHI. Human keratin diseases: the increasing spectrum of disease and
subtlety of the phenotype–genotype correlation. Br J Dermatol. 1999;140(5):815–28.
10. Pinkus H. Chronic scarring pseudofolliculitis of the negro beard. Arch Derm Syphilol.
1943;47(6):782–92.
294 A. Lamb and G.N. Yañez

11. Kligman Am Jr MOH. Pseudofolliculitis of the beard and topically applied tretinoin. Arch
Dermatol. 1973;107(4):551–2.
12. Alexander AM. Evaluation of a foil-guarded shaver in the management of pseudofolliculitis
barbae. Cutis. 1981;27(5):534–7, 40–2. PubMed PMID: 7238107. Epub 1981/05/01. eng.
13. Garcia R, Henderson R. The adjustable rotary electric razor in the control of pseudofolliculitis
barbae. J Assoc Milit Dermatol. 1978;4:28.
Chapter 42
Pustular Psoriasis

Sebastian Bernardo and Mark Lebwohl

42.1 Introduction

Psoriasis is a polygenic, chronic inflammatory skin disease linked to dysregulation

of the immune system that classically presents as sharply demarcated erythematous
plaques with silvery scale [1, 2]. In some patients, the condition can manifest as a
generalized pustular variant that can follow a severe, potentially life-threatening
course that demands urgent dermatological evaluation and treatment [1]. While pus-
tules may be a part of the clinical picture in both pustular psoriasis and acne vul-
garis, comedones are classically absent in the former. Further, pustular psoriasis
commonly spares the face, even in its generalized form. Unlike severe acne, patients
presenting with pustular psoriasis may be toxic appearing on physical exam and be
found to have hematological abnormalities and electrolyte imbalances that repre-
sent a true dermatologic emergency.

42.2 Background

Psoriasis is the most prevalent autoimmune disease in the United States. Affecting
approximately 2.2 % of the American population, psoriasis is associated with sig-
nificant patient morbidity and is estimated to cost $11.25 billion in direct and indi-
rect health care costs annually [3, 4].

S. Bernardo, M.D.
Department of Dermatology, Mt. Sinai School of Medicine,
161 West 86th Street, Apt 1a, New York, NY 10024, USA
M. Lebwohl, M.D. (*)
Department of Dermatology, Mt. Sinai School of Medicine,
5 East 98th Street, 5th Floor, New York, NY 10029, USA
e-mail: [email protected]

J.A. Zeichner (ed.), Acneiform Eruptions in Dermatology: A Differential Diagnosis, 295

DOI 10.1007/978-1-4614-8344-1_42, © Springer Science+Business Media New York 2014
296 S. Bernardo and M. Lebwohl

Although pustular psoriasis is reported to occur in less than 5 % of individuals

with psoriasis, its potential for severe complications and mortality warrants imme-
diate workup and appropriate management [1, 2]. Pustular psoriasis can present in
childhood but is more commonly seen in middle-aged adults [5, 6]. While adult men
and women are affected equally, pustular psoriasis is more common in boys than
girls by a ratio of 3:2 among pediatric patients [1, 6, 7]. When all psoriatic variants
are included, Caucasians are more commonly affected than African Americans
(2.5 % vs. 1.3 %) [8]. As an individual subtype, however, pustular psoriasis has no
racial predilection [9, 10].
The pathophysiology underlying pustular psoriasis has not been clearly delin-
eated. Cutaneous cytokine and immune dysregulation coupled with environmental
triggers are most likely responsible. HLA-B27, HLA-Aw19, and HLA-Bw35 have
all been described as haplotypes that increase the likelihood of a pustular psoriatic
phenotype [2]. Genetic predispositions that contribute to alterations in the cytokine
milieu of the skin may help to explain the complex tissue alterations associated with
pustular psoriasis. Upregulation of proinflammmatory cytokines such as TNF-α,
Il-8, VEGF, and growth-related oncogene (Gro)-alpha in conjunction with reduced
activity of anti-inflammatory molecules such as Il-36Ra increase microvascular per-
meability and allow leukocytes to interact with keratinocytes and endothelial cells
[11–15].
In addition to what is occurring under the skin’s surface, several environmental
triggers have been associated with pustular psoriasis. Withdrawal of systemic corti-
costeroids is the most common precipitating cause and has been consistently docu-
mented in the literature as inducing or aggravating this condition [1, 16–20]. Specific
medications such as lithium, antimalarials, beta-blockers, and irritating topical
therapies have been implicated as well [20]. TNF-α inhibitors, which have emerged
as effective therapeutic options for pustular psoriasis, have also been documented as
inducing this condition for unknown reasons [21–25]. Other precipitating factors
include infections (especially group B strep), pregnancy, hypocalcemia, seasonal
variation, stress, exposure to sunlight, and menstruation [2, 5, 6, 17, 26].

42.3 Clinical Presentation

Psoriasis is a disease with a broad spectrum of clinical presentations that include

pustular psoriasis, a variant characterized by sterile pustules forming on erythema-
tous, inflamed skin that desquamates as the pustules dry (Fig. 42.1) [12, 27]. Pustules
in psoriasis may occur in many settings and may be generalized or localized.
Generalized subtypes of pustular psoriasis include the von Zumbusch, annular,
and exanthematic variants. In von Zumbusch, or acute GPP, disease onset is abrupt,
explosive, and characterized by burning erythema that quickly spreads to affect
large areas of skin [28, 29]. Clusters of pinpoint, sterile pustules develop and
coalesce to form circinate lakes of pus. As these pustules rupture, crusting and scal-
ing soon follow with new crops of pustules appearing after these crusts have been
42 Pustular Psoriasis 297

Fig. 42.1 Pustular psoriasis—sterile pustules on erythematous skin. Borrowed from the Mount
Sinai Dermatology collection

Fig. 42.2 Pustular psoriasis—von Zumbusch variant. Borrowed from the Mount Sinai Dermatology
collection

shed (Fig. 42.2) [27]. The acute phase is associated with fever, fatigue, headache,
chills, malaise, onycholysis, and burning [29]. With large areas of skin involved,
patients are susceptible to infection, fluid loss, hypothermia, and electrolyte abnor-
malities, a combination that represents a medical emergency that demands immediate
workup and appropriate treatment.
298 S. Bernardo and M. Lebwohl

Fig. 42.3 Pustular psoriasis—annular variant. Borrowed from the Mount Sinai Dermatology
collection

The annular subtype of pustular psoriasis is characterized by scattered gyrate or

annular lesions consisting of erythema and scaling with pustulation at advancing
edges. Over a period of hours to days, lesions enlarge by centrifugal expansion
while healing occurs centrally (Fig. 42.3) [2, 9, 27]. It is the most common form of
GPP in children and is associated with fever, malaise, and systemic manifestations
that are milder than cases of von Zumbusch [6, 9].
The exanthematic variant is typically triggered by infection or medications such
as lithium in patients without a history of psoriasis. An acute eruption of small pus-
tules appears and recedes within a couple of days without systemic symptoms [2,
27]. There is an overlap with this form of pustular psoriasis and the pustular drug
eruption known as acute generalized exanthematous pustulosis (AGEP) [2].
When GPP occurs during pregnancy, it is referred to as impetigo herpetiformis.
Usually occurring in the third trimester, lesions usually begin in the flexural and
genitocrural regions and tend to cluster, enlarging centrifugally (Fig. 42.4). It is
associated with severe constitutional symptoms and can be fatal in some cases
[30–32].
Pustules in psoriasis may be localized to the palms and soles, paronychial tis-
sues, or occur at the periphery of plaque-like lesions [31]. In palmoplantar pustulo-
sis, lesions can reach 0.5 cm in diameter and are localized to the hands and feet
(Figs. 42.5 and 42.6). Pustular content can turn brown while involuting beneath
caloused skin of the palms and soles (Fig. 42.7) [27]. Desquamation follows soon
thereafter [2]. The disease is chronic and in one series, only 28 % of patients were
disease free upon reexamination 10 years later [2]. Stress and focal infections have
been described as triggering factors [2].
42 Pustular Psoriasis 299

Fig. 42.4 Impetigo herpetiformis. Borrowed from “The Skin and Systemic Disease: A Color Atlas
and Text” [66]

Fig. 42.5 Palmar pustular psoriasis. Borrowed from the Mount Sinai Dermatology collection

In acrodermatitis of hallopeau, pustulation of the distal portions of the fingers

and toes is followed by scaling and crust formation [2]. Paronychia, skin atrophy,
onychodystrophy, onycholysis, and osteolysis of the distal phalanges may be seen
[33] (Fig. 42.8). Following a chronic-relapsing course, this variant of pustular pso-
riasis is frequently difficult to treat and patients may transition into developing other
subtypes of psoriasis [2].
300 S. Bernardo and M. Lebwohl

Fig. 42.6 Plantar pustular

psoriasis. Borrowed from
“The Skin and Systemic
Disease: A Color Atlas and
Text” [66]

Fig. 42.7 Plantar pustular psoriasis with involuting lesions. Borrowed from the Mount Sinai
Dermatology collection
42 Pustular Psoriasis 301

Fig. 42.8 Acrodermatitis of hallopeau. Borrowed from the Mount Sinai Dermatology collection

42.4 Workup

The diagnosis of pustular psoriasis can usually be made on the basis of its clinical fea-
tures. However, when the diagnosis is in question, pustular psoriasis has unique patho-
logical and laboratory findings that allow it to be distinguished from other psoriatic
variants. A punch biopsy allows for optimal visualization of disease histology, which is
predominantly characterized by neutrophil accumulation [2]. Migrating from sinuous,
dilated capillaries within the dermis, neutrophils collect between residual keratinocyte
plasma membranes accompanied by intercellular edema [31]. This forms a macropus-
tule in the epidermis that begins as a spongiform pustule of Kogoj and develops into a
large munro macroabscess [27]. Histological features of psoriasis vulgaris may also be
present and include parakeratosis, elongation of epidermal rete ridges, and a perivascu-
lar lymphocytic or mixed inflammatory infiltrate within the papillary dermis [27, 34].
Laboratory findings associated with pustular psoriasis include neutrophilia with WBC
counts as high as 30,000, absolute lymphopenia, hypoalbuminemia, hypocalcemia, ane-
mia, decreased creatinine clearance, and elevations in ESR, transaminases, alkaline
phosphatase, and bilirubin [9, 29, 35, 36]. Cultures of pustules are sterile. However,
since the protective functions of the skin are lost in GPP, patients have succumbed to
staphylococcal sepsis and blood cultures may be warranted.

42.5 Treatment

Although many systemic and topical treatments have been described as effec-
tive management options for patients with pustular psoriasis, no evidence-
based consensus has been reached regarding the correct therapeutic hierarchy
302 S. Bernardo and M. Lebwohl

Table 42.1 Systemic therapies

Medication class Medication Dosing
Retinoids Acitretin 25–50 mg PO daily [9, 60]
Isotretinoin 1 mg/kg PO daily [9]
Antimetabolites Methotrexate Single weekly PO dose: 7.5–25 mg (37.5 mg
maximum in severe cases) [2]
Divided weekly PO dose: 2–5 mg three times every
12 h for 3 doses for cumulative total dose of
6–15 mg weekly (30 mg maximum in severe
cases) [2]
Parenteral dosing: 40–50 mg maximum dose IM or
IV weekly [2]
Alkylating agents Cyclosporine 3 mg/kg/day PO in two divided doses (5 mg/kg/day
maximum in severe cases) [2]
Biologics Infliximab One 5 mg/kg IV dose at weeks 0, 2, and 6. Then
every 8 weeks up to week 46 [53]
Adalimumab 40 mg SC every one or two weeks [50, 64]
Etanercept 25–50 mg sq once or twice weekly [49]
Psoralens 8-MOP 0.4–0.6 mg/kg PO given 1–3 h before phototherapy [65]

Table 42.2 Topical therapies

Medication class Medication Dosing
Corticosteroids Fluocinonide Apply cream or ointment 15, 30, 60, 120 g [9]
Desoximetasone twice daily [9] 15, 60, 120 g [9]
Halcinonide 15, 60, 240 g [9]
Clobetasol 15, 30, 45, 60 g [9]
Vitamin D3 Calcipotriol Available as ointment, cream, or lotion formulation.
analogues Apply twice daily (50 μg/g concentration).
Maximum weekly dose 100 g [2]
Calcitriol Apply ointment twice daily (3 μg/g concentration).
Maximum weekly dose 210 g [2]
Bath PUVA 8-MOP (solution) 15–20 min immersion in 0.5–5 mg/L 8-MOP
bathwater immediately followed by
phototherapy [2]

to follow. In all cases, effective treatment begins by removing precipitating

factors that may induce or aggravate the condition, many of which had been
discussed previously [37]. Recommendations for generalized and localized
disease will be discussed. For specific medication dosing, refer to Tables 42.1
and 42.2.
42 Pustular Psoriasis 303

42.5.1 Generalized Disease

In the acute setting, topical therapies are frequently ineffective in patients with gen-
eralized disease, and management with systemic agents in an experienced burn unit
is often necessary to prevent patient morbidity and mortality (Table 42.1). In con-
junction with starting therapy for GPP, supportive measures such as bedrest,
compresses, fluid replacement, correction of electrolyte abnormalities, as well as
antibiotics and serial blood cultures are essential in urgent cases [9, 29]. First-line
therapy includes oral retinoids such as acitretin and isotretinoin [1, 38]. Retinoid
therapy was effective in 84 % of patients in one large retrospective study [39]. Side
effects include hypertriglyceridemia, xerosis, hair loss, hepatotoxicity, and cheilitis
[6, 40, 41].
Methotrexate or cyclosporine are also first-line therapies for GPP [1]. Both have
been consistently documented as valuable treatment options for GPP and were
effective in 76.2 % and 71.2 % of patients, respectively, in a large, multicenter study
of 385 patients with GPP in Japan [1, 9, 16, 32, 39, 42–47]. Before initiating therapy
with either agent, it is necessary to obtain a detailed medical history and frequent
blood tests to prevent potentially severe side effects such as methotrexate-induced
bone marrow toxicity [1]. Advantages of methotrexate are its efficacy, affordability,
and convenient weekly oral dose [40]. It is limited by its teratogenicity and side
effects, which include myelosuppression, hepatotoxicity, and pulmonary toxicity
[48]. Cyclosporine has been used safely during pregnancy and its rapid onset makes
it effective in managing acute GPP [1, 32]. However, the side effects of nephrotoxic-
ity, hypertension, and immunosuppression limit its use [48].
The advent of biological agents has added another medication class to the
dermatologist’s armamentarium in the treatment of GPP. The efficacy of infliximab,
adalimumab, and etanercept has been documented in several reports in the
literature, including cases that were refractory to methotrexate, acitretin, and other
systemic therapies [6, 49–53]. With a faster onset of action than adalimumab or
etanercept, infliximab may be particularly useful in life-threatening cases of GPP
with systemic involvement [1]. As a class, the biologics are generally well tolerated.
They potentially increase the risk of infections and carcinogenesis so baseline test-
ing with a complete metabolic panel, CBC, LFTs, and tuberculosis screening should
be performed with appropriate follow-up [1, 50].

42.5.2 Localized Disease

Localized cases may be managed with superpotent topical steroids or light therapies
but may require systemic treatment with retinoids, methotrexate, cyclosporine, or
biologics in refractory cases [46, 54–58] (Table 42.2). Topical corticosteroids can
be given as monotherapy, used under occlusion for increased penetration, or com-
bined with newer vitamin D analogues such as calcitriol or calcipotriene [1].
Unfortunately, many patients fail to respond to topical therapy and other treatment
304 S. Bernardo and M. Lebwohl

modalities are required. Both oral and bath “soak” PUVA therapies have been con-
sistently shown to be effective management options for patients with palmoplantar
pustulosis [1, 29, 59–61]. In the first 4 weeks of treatment, oral PUVA has been
found to be slightly more effective than bath PUVA but the former has more sys-
temic side effects such as nausea [59]. Combination therapy with PUVA and reti-
noids has been found to be more effective than PUVA alone and is associated with
a reduction in the number of PUVA sessions and UVA dose required for clearing
[60, 62, 63].

42.6 Conclusion

Several effective therapies for pustular psoriasis have emerged since von Zumbusch
described his case over 100 years ago. Going forward, much remains to be learned
and the development of evidence-based guidelines for treatment is imperative.
Continued research will yield a better understanding of the complex interactions
underlying disease pathogenesis and identify new targets for improved therapy.

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Chapter 43
Rosacea

Joseph Bikowski

43.1 Introduction

Rosacea, a chronic, inflammatory skin condition, is estimated to affect ten million

Americans [1]. Characterized by a centrofacial distribution of acneiform papules
and pustules, diffuse erythema, and frequently but not always telangiectases [2],
rosacea is a highly visible disease that has been associated with negative influences
on affected individuals’ quality of life [3, 4]. Although the disease is generally
thought to be of primarily cosmetic consequence, patients have reported stinging
and pain associated with rosacea [5], and functional impairments may result from
severe rhinophyma [6]. A number of treatment options are available—both topical
and systemic—for the management of rosacea in its various presentations. With a
proper diagnosis, a rational therapeutic strategy, and supportive skin care and patient
education, control of rosacea is possible.

43.2 Background

Rosacea is generally considered a disease that affects individuals in middle age;

the incidence is shown to increase with age and peak in those over age 65 [7].
While the majority of individuals with rosacea are women (69 %), men may be
prone to more severe presentations [8]. The vast majority of rosacea patients
(96 %) are Caucasian [8].

J. Bikowski, M.D. (*)

Director, Bikowski Skin Care Center, 500 Chadwick Street, Sewickley, PA, USA
e-mail: [email protected]

J.A. Zeichner (ed.), Acneiform Eruptions in Dermatology: A Differential Diagnosis, 309

DOI 10.1007/978-1-4614-8344-1_43, © Springer Science+Business Media New York 2014
310 J. Bikowski

The pathophysiology of rosacea is not well elucidated, although the clinical features
of the disease are well documented. Based on recent molecular studies, current under-
standing holds that vascular and inflammatory manifestations of the disease are medi-
ated by an altered innate immune response [1, 9]. Recently, the antimicrobial peptide
cathelicidin and its activator kallikrein-5 have been found to contribute to the exacer-
bated immune response in rosacea [10]. Neutrophils have also been shown to induce
inflammation associated with rosacea and are thought to promote the release of reactive
oxygen species [11]. Other inflammatory mediators implicated in the development of
rosacea include histamine, serotonin, bradykinin, or prostaglandins [1].
Chronic UV exposure has been suggested to play a role in the pathophysiology
of rosacea, causing damage to dermal connective tissues, which facilitates and exac-
erbates the effects of vasodilation and vascular pooling [12]. A recent study involv-
ing 1,000 patients, however, failed to demonstrate an association between UV
exposure and papulopustular rosacea [13].
Environmental trigger factors may be associated with exacerbation of rosacea
and may initiate the flushing and blushing response in susceptible individuals. The
degree to which any individual is affected, if at all, by a given trigger is variable.
Commonly cited triggers include thermally hot beverages or foods, alcoholic drinks,
and/or spicy foods [14].

43.3 Clinical Presentation

The classic presentation of rosacea includes a primarily centrofacial distribution of

acneiform papules and pustules on a background of erythema and telangiectases [2].
However, rosacea presents across a continuum from mild signs and symptoms, such
as transient flushing and dryness, to severe manifestations of persistent erythema,
edema, and phymatous formations. Ocular involvement is common but potentially
under-recognized [15, 16].
A National Rosacea Society Expert Committee has identified four primary rosa-
cea subtypes [5]. Subtype 1, erythematotelangiectatic rosacea (ETR) is a common
presentation, characterized by flushing and persistent facial erythema. Telangiectases
are common but not always present (Fig. 43.1). Subtype 2, papulopustular rosacea
(PPR) often coexists with ETR. It is characterized by persistent central facial ery-
thema with transient papules, pustules, or both in a central facial distribution
(Fig. 43.2). Phymatous rosacea constitutes Subtype 3 and may include thickened
skin, nodules, and anatomical enlargement (Fig. 43.3). Although rhinophyma
(enlargement of the nose) is most common, other manifestations include phymas of
the chin, forehead, and ears. Only a minority of patients will progress to phymatous
rosacea. Most, if not all, of these will be men.
Ocular rosacea, symptoms of which include interpalpebral conjunctival hyper-
emia, foreign-body sensation, burning or stinging, dryness, itching, light sensitivity,
blurred vision, telangiectasia of the conjunctiva and lid margin, is Subtype 4
(Fig. 43.4).
Fig. 43.1 Erythematotelangiectatic rosacea (ETR, Subtype 1) is characterized by flushing and
persistent central facial erythema. Telangiectases are common but not always present

Fig. 43.2 Papulopustular

rosacea (PPR, Subtype 2)
is characterized by persistent
central facial erythema
with transient papules and/or
pustules
312 J. Bikowski

Fig. 43.3 Phymatous rosacea (Subtype 3) is characterized by thickened skin, nodules, and ana-
tomical enlargement

Fig. 43.4 Ocular rosacea (Subtype 4) is characterized by interpalpebral conjunctival hyperemia,

foreign-body sensation, burning or stinging, dryness, itching, light sensitivity, blurred vision, tel-
angiectases of the conjunctiva, and lid margin

While the classification system is helpful for recognizing signs and symptoms of
rosacea and understanding disease progression, its clinical relevance may be lim-
ited. In fact, an international consensus committee has emphasized the importance
of implementing therapy based on signs and symptoms of the specific presenting
case rather than its classification [10].
Rosacea may be mistaken for acne vulgaris, though the two are distinguished by
the presence (acne) or absence (rosacea) of comedones. Furthermore, while rosa-
cea’s centrofacial distribution includes the forehead, lesions are not typically
43 Rosacea 313

Table 43.1 Differential diagnosis of rosacea

Condition Distinguishing feature
Acne vulgaris Presence of comedones
Perioral dermatitis Involvement about the mouth (sparing the vermillion border),
nasolabial folds, and chin
Steroid-induced dermatitis History of topical application of corticosteroids to the face
Involvement of skin adjacent to the vermillion border
Demodex dermatitis +/− Papules/pustules
Responds to treatment with topical crotamiton or permethrin

present at the hairline. By contrast, lesions may be concentrated at the hairline in

some acne presentations.
Perioral dermatitis and steroid induced dermatitis, sometimes erroneously termed
steroid rosacea, should also be ruled out. As its name indicates, perioral dermatitis is
focused about the mouth, nasolabial folds, and chin, sparing a clear area between the
eruption and the vermillion border [17]. Steroid-induced dermatitis, which frequently
mimics this distribution of lesions, is most easily recognized via patient questioning,
admitted history of topical application of corticosteroids to the face, and involvement
of the skin adjacent to the vermillion border [18] (Table 43.1).

43.4 Work-Up

There are no diagnostic tests for rosacea. When ocular rosacea is suspected, patients
may be referred for ophthalmic evaluation and treatment. Patients with rosacea
should be educated about ocular involvement and be encouraged to attend to their
ocular health.
Despite historic associations of rosacea with acne vulgaris, the two are of dis-
tinctly different etiologies, and there is no microorganism widely accepted as caus-
ative in rosacea. An association between rosacea and the Demodex folliculorum
mite has been identified, although no evidence has elevated this correlation to cau-
sation [19]. In fact, there is some evidence that a distinct condition termed Demodex
dermatitis may exist that is frequently inaccurately diagnosed as rosacea [20]. This
condition, which is characterized by facial erythema, dryness, scaling, and rough-
ness with or without papules/pustules, responds to treatment with topical crotami-
ton or permethrin; such therapeutic response may confirm the diagnosis of Demodex
dermatitis rather than rosacea.

43.5 Treatment

Among the treatment options for rosacea are both topical and systemic formulations
(Table 43.2). Increasingly, laser and light-based interventions are emerging for the
management of vascular and phymatous irregularities, which are generally not
314 J. Bikowski

Table 43.2 Rosacea therapies

Treatment Known or suspected activities in rosacea
Topical antimicrobial formulations: sodium Antibacterial, anti-inflammatory
sulfacetamide/sulfur, metronidazole
Azelaic acid Antibacterial, keratolytic,
anti-inflammatory
Systemic antibiotics (conventional) Anti-inflammatory
Anti-inflammatory dose doxycycline (40 mg, Anti-inflammatory
controlled release)
Oral isotretinoin Anti-inflammatory, immunomodulatory
Laser and Light devices (pulsed dye laser and IPL) Destroy vessels/vascular structures,
reduce erythema
Surgical correction and ablative laser surgery Mechanical debulking of phymas

amenable to pharmacologic intervention. Topical agents for rosacea include various

formulations of sodium sulfacetamide and sulfur, metronidazole, azelaic acid, and
benzoyl peroxide/clindamycin. Oral agents include antibiotics in conventional and
subantimicrobial doses as well as isotretinoin.
Given the potential influence of triggers in exacerbating rosacea, treatment
should be aimed at identifying and avoiding these as much as possible. Additionally,
because rosacea is associated with dysfunction of the epidermal barrier [21], skin-
care intended to cleanse and moisturize without causing irritation or dryness is con-
sidered essential to successful management. Soap-free moisturizing cleansers and
scientifically formulated moisturizers containing ceramides may help restore epi-
dermal barrier function [22]. Cosmetics, specifically a green-tinted foundation, may
be used to camouflage the redness of rosacea.
Topical antimicrobial formulations, including sodium sulfacetamide and sulfur,
metronidazole, and clindamycin, are thought to provide benefit primarily via anti-
inflammatory effects. More than 60 years ago, topical sodium sulfacetamide 10 %
and sulfur 5 % were the first agents approved for the treatment of acne vulgaris,
seborrheic dermatitis, and rosacea. Sodium sulfacetamide is a sulfonamide with
antibacterial activity, while sulfur is keratolytic.
Topical metronidazole is available in both 0.75 % and 1 % topical formulations
that have been shown to be safe and effective for the treatment of PPR either used
alone or in combination with oral antibiotics [23]. Metronidazole’s mechanism of
action in rosacea is hypothesized to involve anti-inflammatory and antimicrobial
properties [23].
Azelaic acid is a naturally occurring dicarboxylic acid originally used as a 20 %
cream to treat acne vulgaris. Azelaic acid 15 % aqueous gel was approved in 2002
for the treatment of mild to moderate papulopustular rosacea. The efficacy of aze-
laic acid 15 % gel in rosacea may be linked to the inhibition of neutrophil-mediated
reactive oxygen species [24]. Azelaic acid also has antibacterial, keratolytic, and
anti-inflammatory properties. Its efficacy in the management of PPR has been dem-
onstrated in various studies [25].
A meta-analysis of available data on topical rosacea therapies suggests that either
topical metronidazole or azelaic acid is appropriate for the management of rosacea
43 Rosacea 315

subtype 2 [26]. These agents do not offer significant efficacy for diffuse erythema,
telangiectases, or phymatous formations.
A first-in-class topical alpha-agonist received FDA approval for the treatment of
the erythema of rosacea in August 2013. Brimonidine gel 0.33 % is a once-daily
topical agent that was shown in clinical trials to provide a significantly greater
improvement in the facial redness of rosacea than vehicle gel. The drug has vaso-
constrictive properties that are believed to confer the redness reducing effects.
Additional topical vasoconstrictors are in development for use in rosacea.
Conventional antibiotics are still used in the management of rosacea, with their
efficacy presumed to be associated with their anti-inflammatory effects. The avail-
ability of anti-inflammatory dose doxycycline (40 mg, controlled release) has modi-
fied the approach to systemic rosacea therapy [27]. Anti-inflammatory dose
doxycycline is shown to be at least as effective as conventional doxycycline doses
for the treatment of PPR but with a reduction in side effects [26] and no risk of
contributing to the development of bacterial resistance [27]. Like topical interven-
tions, oral antibiotics confer greatest efficacy in managing the signs and symptoms
of PPR rather than the other subtypes.
Use of topical and systemic agents in combination is expected to enhance thera-
peutic responses and maintain results [27, 28]. Topical and systemic agents may
also be used in combination with devices, which are increasingly used for the reduc-
tion of erythema and telangiectases associated with rosacea. Specifically, pulsed
dye laser and intense-pulsed light (IPL) devices that target hemoglobin as the target
chromophore are used to treat erythema and telangiectases [29].
Oral isotretinoin, which has both anti-inflammatory and immunomodulatory
properties, has been used as a treatment for severe rosacea, particularly phymatous
presentations [30, 31]. Surgical correction and ablative laser surgery may also be
used to manage phymas.

43.6 Conclusion

Rosacea is a chronic, inflammatory facial dermatosis frequently confused with acne

vulgaris. While the papulopustular subtype of rosacea presents with pustules, other
clinical features (such as centrofacial erythema and a lack of comedones) distinguish
rosacea from acne. Both topical and oral therapies can help reduce inflammation in
rosacea, but light-based treatments are required to address underlying erythema.

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Chapter 44
Rosacea Fulminans

Cristina Caridi and Joshua A. Zeichner

44.1 Introduction

Rosacea fulminans is a rare dermatosis characterized by the sudden onset of coalescing

nodules and draining sinuses on the face, typically affecting young women. First
reported in 1940 by the name pyoderma faciale, it was thought to be an infiltrative
pyoderma, possibly caused by tuberculosis, despite being unable to identify a cause
[1]. It was not until 1992 that it was suggested that the condition was a form of
rosacea, as all patients also experienced flushing and blushing along with the rapid
and volatile onset. The term rosacea fulminans was then proposed [2]. Despite
research, a bacterial infection has not been shown to play a pathogenic role, further
evidence that the condition is not a pyoderma, but rather a severe variant of rosacea
[3]. Rosacea fulminans has also been referred to as granulomatous rosacea.

44.2 Background

The pathophysiology of rosacea fulminans is unknown. Hyperactivity of the innate

immune system, severe emotional stress, hormonal changes (including those during
pregnancy), and an association with inflammatory bowel disease have all been sug-
gested [2, 4–7]. Helicobacter pylori bacteria have been identified in the gastric
mucosa of patients with both rosacea and rosacea fulminans and is thought to stimu-
late production of vasoactive molecules, including prostaglandins, histamine, and
various cytokines [8, 9]. A more in-depth review of the pathophysiology may be
found in the rosacea chapter of this book.

C. Caridi, B.A. (*) • J.A. Zeichner, M.D.

Department of Dermatology, Mt. Sinai School of Medicine, New York, NY, USA

J.A. Zeichner (ed.), Acneiform Eruptions in Dermatology: A Differential Diagnosis, 317

DOI 10.1007/978-1-4614-8344-1_44, © Springer Science+Business Media New York 2014
318 C. Caridi and J.A. Zeichner

While extremely rare, rosacea fulminans is also assumed to be highly under-

reported. Approximately 80 cases have been published since the 1940s. It occurs
almost exclusively in healthy females in the second to third decades, but ages range
from the teens into the 50s [1, 2]. There is no associated history with acne vulgaris
[3], but many patients may have an underlying diagnosis of rosacea [10, 11].

44.3 Clinical Presentation

Rosacea fulminans is characterized by a sudden and explosive onset of large indu-

rated erythematous plaques, nodules, papules, pustules, and draining sinuses
restricted to the face (Fig. 44.1). Patients generally has previously unblemished skin
[1, 2, 11]. The most severely affected areas of the face include the forehead, nasal
bridge, cheeks, and chin [3]. Comedones are characteristically absent and the trunk
is spared. Large abscesses may be interconnected through sinus tracts that discharge
copious amounts of pus [2].
No true prodrome exists prior to the onset of the disease. However, there are
reports of patients who develop a sudden onset of excessive skin oiliness prior to the
eruption [1, 2]. Patients are otherwise healthy, though some experience fatigue, dis-
comfort, or general malaise. One patient has been reported to develop rosacea ful-
minans in association with erythema nodosum [12]. Another report documented a
case of severe ocular involvement presenting with blurry vision. Ophthalmologic
exam revealed severe blepharitis with advanced keratitis and ocular perforation.
While ocular involvement is common in traditional rosacea, it is not usually present
in rosacea fulminans [11].

Fig. 44.1 An indurated,

erythematous plaque on the
left cheek of a woman in her
30s. Pustules and papules are
evident within the plaque,
and the patient complains of
tenderness in the area (Photo
credit: Joshua A. Zeichner,
M.D.
44 Rosacea Fulminans 319

Because of the particularly ferocious nature of the disease, patients may become
depressed, anxious, and isolated because of the appearance [2, 13]. Scarring is
common and expected and can range from minimal damage to keloids [2, 14].

44.4 Work-up

The diagnosis of rosacea fulminans is largely clinical, although supportive labs and
a skin biopsy can be performed. Some patients have been documented to have a
mild anemia, leukocytosis, increased erythrocyte sedimentation rate (ESR), ele-
vated C-reactive protein (CRP), and positive rheumatoid factor and antinuclear anti-
bodies [1, 2, 4, 14, 15]. Skin biopsy reveals evidence of inflammation, with massive
neutrophil infiltration in early stages and epithelioid cell granulomas in older lesions
[4, 12, 16]. Bacterial pathogens have not been consistently recovered, and most
bacteria identified are commensal skin flora [2, 3]. Isolated cases report identifica-
tion of Staphylococcus aureus and gram-negative bacteria [3, 5].

44.5 Treatment

If untreated, rosacea fulminans generally resolves after approximately 1 year,

although aggressive therapy is usually given to avoid the development of permanent
scars. The most commonly effective treatment for rosacea fulminans is oral isotreti-
noin, usually in combination with oral corticosteroids to reduce the risk of an initial
flare. Isotretinoin is typically dosed at 0.5 mg/kg/day for the first month then
increased to 1 mg/kg/day at month 2, depending on the clinical appearance. Just as
in acne vulgaris, the target cumulative dose is 120–150 mg/kg [2, 4, 11, 17–19].
Oral dapsone, oral and topical antibiotics, benzoyl peroxide, and topical and sys-
temic corticosteroids, among others, have all been reported as well [2, 5, 6, 18, 20].
Oral azithromycin has also been shown to be effective in a pregnant woman [15].
Surgical interventions have been associated with poor outcomes. Incision and
drainage of abscesses and sinus should not be performed as it can lead to excessive
scarring [2]. Early biopsy, however, can help correctly diagnose a patient early in
the course of the disease and ultimately results in a more rapid treatment [16].

44.6 Conclusion

Rosacea fulminans is a rapidly occurring, severe facial dermatosis thought to be an

extreme variant of rosacea. It results in significant scarring, both physically and
emotionally. Early diagnosis with prompt treatment (usually with oral isotretinoin)
is important to minimize long-term sequelae.
320 C. Caridi and J.A. Zeichner

References

1. O’Leary PA, Kierland RR. Pyoderma faciale. Arch Dermatol. 1940;41:451–62.

2. Plewig G, Jansen T, Kligman AM. Pyoderma faciale a review and report of 20 additional cases:
is it rosacea? Arch Dermatol. 1992;128:1611–7.
3. Sudy E, Urbina F. Pyoderma faciale: gram-negative recovery by means of needle aspiration.
Cont Med Educ. 2002;69:261–4.
4. Ferahbas A, Utas S, Mistik S, Uksal U, Peker D. Rosacea fulminans in pregnancy case report
and review of the literature. Am J Clin Dermatol. 2006;7(2):141–4.
5. Massa MC, Su WP. Pyoderma faciale: a clinical study of twenty-nine patients. J Am Acad
Dermatol. 1982;6:84–91.
6. Dessoukey MW. Pyoderma faciale: manifestation of inflammatory bowel disease. Int J
Dermatol. 1996;35:724–6.
7. Manna V, Marks R, Holt P. Involvement of immune mechanisms in the pathogenesis of rosa-
cea. Br J Dermatol. 1982;107:203–8.
8. Rebora A, Drago F, Parodi A. May helicobacter pylori be important for dermatologists?
Dermatology. 1995;191:6–8.
9. Szlachcic A, Sliwowski Z, Karczewska E, Bielana W, Pytko-Poloncyzk J, Konturek SJ.
Helicobacter pylori and its eradication in rosacea. J Physiol Pharmacol. 1999;50:777–86.
10. Ormond P, Rogers S. Case 3: pyoderma faciale (PF) (rosacea fulminans). Clin Exp Dermatol.
2003;28:107–8.
11. de Morais e Silva FA, Bonassi M, Steiner D, Ribeiro da Cunha TV. Rosacea fulminans in
pregnancy with ocular perforation. J Ger Soc Dermatol. 2011;9:542–3.
12. Akhyani M, Daneshpazhooh M, Ghandi N. The association of pyoderma faciale and erythema
nodosum. Clin Exp Dermatol. 2007;32:275–7.
13. Fender AB, Ignatovitch Y, Mercurio MG. Pyoderma faciale. Cutis. 2008;81:488–90.
14. Firooz A, Firoozabadi MR, Dowlati Y. Rosacea fulminans (pyoderma faciale): successful
treatment of a 3-year-old girl with oral isotretinoin. Int J Dermatol. 2001;40:203–5.
15. Fuentalsaz V, Ara M, Corredera C, et al. Rosacea fulminans in pregnancy: successful treatment
with azithromycin. Clin Exp Dermatol. 2011;36(6):674–6.
16. Helm TA, Schechter J. Biopsy may help identify early pyoderma faciale (rosacea fulminans).
Cutis. 2006;77:225–7.
17. Lewis VJ, Holme SA, Wright A, Antsey AV. Rosacea fulminans in pregnancy. Br J Dermatol.
2004;151:917–9.
18. Marks VJ, Briggaman RA. Pyoderma faciale: successful treatment with isotretinoin. J Am
Acad Dermatol. 1987;17:1062–3.
19. Ortonne JP. Oral isotretinoin treatment policy: do we all agree? Dermatology. 1997;195 Suppl
1:34–7.
20. Bormann G, Gaber G, Fischer M, Marsch WC. Dapsone in rosacea fulminans. J Eur Acad
Dermatol Venereol. 2001;15(5):465–7.
Chapter 45
Sarcoidosis

Laura Thornsberry and Joseph English III

45.1 Introduction

Sarcoidosis is a multiorgan noninfectious granulomatous disease which can manifest

in the integumentary system in a variety of ways, one of the most common being
a maculopapular, acneiform facial eruption. Although sarcoidosis is generally cat-
egorized as a pulmonary disease, it involves the skin in approximately 25–30 % of
cases. The etiology of sarcoidosis remains unknown. The polymorphic cutaneous
lesions are grouped into specific and nonspecific lesions. The characteristic histo-
logical finding in sarcoidosis, the noncaseating granuloma, is present in the spe-
cific lesions of cutaneous sarcoidosis, including macules, papules, plaques,
subcutaneous nodules, infiltrative scars, and lupus pernio. The nonspecific lesions
of cutaneous sarcoidosis, such as erythema nodosum (EN), calcifications, ery-
thema multiforme, and clubbing, lack this feature. Sarcoidosis is a diagnosis of
exclusion based on a combination of clinical, histological, and radiographic evi-
dence. Since cutaneous sarcoidosis is frequently present at the onset of systemic
disease, the dermatologist is often the first health-care provider to evaluate the
patient. Biopsy-proven cutaneous sarcoidosis warrants a further workup for sys-
temic disease. Corticosteroids are the mainstay of treatment for symptomatic sar-
coidosis, followed by antimalarial and immunosuppressive medications.

L. Thornsberry, M.D. (*)

Department of Internal Medicine, PGY-1, UPMC Montefiore Hospital, University of
Pittsburgh, N-713, 200 Lothrop Street, Pittsburgh, PA 15213, USA
e-mail: [email protected]
J. English III, M.D.
Department of Dermatology, University of Pittsburgh, Pittsburgh, PA USA
e-mail: [email protected]

J.A. Zeichner (ed.), Acneiform Eruptions in Dermatology: A Differential Diagnosis, 321

DOI 10.1007/978-1-4614-8344-1_45, © Springer Science+Business Media New York 2014
322 L. Thornsberry and J. English III

45.2 Background

There are many theories surrounding the etiology of sarcoidosis, but the cause(s) of
the disease is still unknown. A multicenter trial of over 700 patients, entitled “A
Case Control Etiologic Study of Sarcoidosis (ACCESS),” was unable to identify a
specific antigen in sarcoidosis but did establish an increased risk of the disease with
exposure to mold and musty odors, agricultural chemicals and aerosols, and insec-
ticides [1]. In sarcoidosis, normal tissue function is disrupted by noncaseating gran-
ulomas. The formation of the noncaseating granuloma begins with macrophages
and dendritic cells (antigen-presenting cells) using class II major histocompatibility
(MHC) complexes to present an unknown antigen(s) to CD4+ T cells [2]. Through
interactions with the MHC and costimulatory molecules, the T cell becomes acti-
vated and ignites a TH1 inflammatory response. The T cells release IL-2 and IFN-γ
to recruit additional T cells, as well as stimulate macrophages to produce TNF-α,
leading to the differentiation of macrophages into epithelioid cells and formation of
multinucleated giant cells [2].
In the United States, there are two peaks for sarcoidosis, in people between 25
and 35 years and in women between 45 and 65 years [3]. Sarcoidosis is more com-
mon in African Americans (although all races can be affected), and this group is
more likely to present with advanced disease and have a poorer prognosis [4]. The
highest incidence of disease in the United States in African American women in
their fourth decade of life [3]. Sarcoidosis persists as a progressive disease in
30 % but has a mortality of less than 5 % [5]. The most common causes of death
are progressive pulmonary fibrosis or other pulmonary or cardiac complications
[4]. The first-degree relatives of people with sarcoidosis are at a 5-time increased
risk for developing the disease [6]. Recent research has proposed certain genetic
susceptibilities associated with the disease. An increased risk of sarcoidosis is
associated with HLA-DRB1 and a splice site mutation in the gene butyrophilin-
like 2 (BTNL2) [7].

45.3 Clinical Presentation

Cutaneous sarcoidosis is a clinically polymorphic disease. Many atypical presenta-

tions of cutaneous sarcoidosis have been reported, including but not limited to ich-
thyosiform, ulcerative, erythrodermic, hypopigmented, photo-distributed, verrucous,
morpheaform, and lichenoid sarcoidosis [8]. Maculopapular eruptions are the most
common specific lesion and tend to occur on the head, neck, perioral region, eye-
lids, and nasolabial folds. The papules are usually small (3–5 mm), monomorphic,
and flesh-colored without epidermal change. The papules may also be red, viola-
ceous, or hyperpigmented, and groups of papules may coalesce into annular lesions
or plaques. This presentation of sarcoidosis may present similar to other acneiform
eruptions of the face (Figs. 45.1 and 45.2). The differential diagnosis includes acne,
45 Sarcoidosis 323

Fig. 45.1 Papular sarcoidosis

in the T zone

Fig. 45.2 Papular sarcoidosis

of the malar checks

rosacea, granulomatous periorificial dermatitis, and granulomatous rosacea.

Sarcoidosis differs from acne vulgaris in that there is no comedonal component and
lesions are not pustular in nature. The majority of the time the difference can be
determined clinically but biopsy can easily distinguish these entities. Although
maculopapular sarcoidosis may not seem significant, Mana [9] reported a series in
which four out of 14 patients with maculopapular lesions developed chronic cutane-
ous, pulmonary, or ocular sarcoidosis [9].
324 L. Thornsberry and J. English III

45.4 Workup

The diagnosis of sarcoidosis requires careful integration of clinical, radiographic,

and histological information, as well as the exclusion of other granulomatous dis-
eases. Evaluation begins with a thorough history and physical examination focusing
on the skin, lungs, heart, eyes, lymph nodes, and nervous system. When sarcoidosis
is suspected, the skin is often the most accessible and least invasive option available
for obtaining a biopsy. If the biopsy reveals noncaseating granulomas, the stains and
tissue cultures must be negative for infectious agents, such as Mycobacteria, fungi,
leishmaniasis, and syphilis, and foreign body granulomas must also be excluded [9].
When a diagnosis of cutaneous sarcoidosis is suspected, the patient needs to be
evaluated for systemic sarcoidosis. This will require consultation with several spe-
cialty physicians.
Evaluation for pulmonary sarcoidosis begins with a chest radiograph and pul-
monary function tests. Pulmonary manifestations are present in approximately
90 % of patients with sarcoidosis. The radiograph most commonly reveals bilat-
eral hilar lymphadenopathy, but may also show infiltrates or fibrosis, while the
pulmonary function tests may demonstrate a restrictive pattern with decreased
diffusing capacity [10, 11]. High-resolution computed tomography (CT) of the
chest is not usually indicated, but can be used to further evaluate patients with
atypical chest radiographs [10]. Cardiac sarcoidosis is initially evaluated by elec-
trocardiogram and echocardiogram [10]. Heart failure or symptoms such as palpi-
tations and syncope are only present in 5 % of patients and usually indicate
advanced disease [12]. Cardiac magnetic resonance imaging (MRI) is a specific
but not sensitive test for detecting structural cardiac disease [12]. Ocular sarcoid-
osis most commonly presents as uveitis, but can ultimately result in blindness,
thus a complete ophthalmologic evaluation is recommended [10]. Neurosarcoidosis
is present in up to 15 % of patients with systemic disease [8]. Evaluation may
include radiographs of the skull, electroencephalography, CT scan, and/or MRI of
the central nervous system [8].
In addition laboratory testing includes complete blood counts, liver and kidney
function tests, serum calcium level, creatinine kinase and aldolase, and urinalysis.
The serum angiotensin-converting enzyme (SACE) level is increased in 60 % of
patients with sarcoidosis, but it is neither sensitive nor specific, and can be elevated
in common diseases, such as diabetes and osteoarthritis [4, 9].

45.5 Treatment

There is no FDA-approved treatment for sarcoidosis, and there is limited evidence-

based medicine regarding the treatment of cutaneous sarcoidosis [13]. In terms of cuta-
neous sarcoidosis, corticosteroids (oral and intralesional) are the mainstay of treatment
[14, 15]. Corticosteroids provide anti-inflammatory and immunosuppressive effects,
45 Sarcoidosis 325

theoretically decreasing granuloma formation [16]. The dosing ranges and sched-
ules of corticosteroids are highly variable, and there is not adequate evidence sup-
porting their use for cutaneous sarcoidosis [11]. Historically, oral prednisone has
been reported as effective for cutaneous sarcoidosis, but randomized controlled tri-
als are needed [14, 17, 18]. Given the extensive side effects of systemic corticoste-
roids, they are generally only used for expansive disfiguring cutaneous lesions after
local steroids have failed [3]. Corticosteroids must be tapered slowly over weeks to
months to avoid disease flares.
Hydroxychloroquine is an antimalarial agent which is thought to work by
decreasing antigen presentation by APCs, resulting in decreased T-cell activa-
tion and decreased granuloma formation [19]. The efficacy of antimalarials in
cutaneous sarcoidosis has been reported since the 1960s, but there have not been
any randomized controlled trials for this indication [20, 21]. More recent studies
have reported regression of cutaneous sarcoidosis with hydroxychloroquine
(2–3 mg/kg/day for up to 12 weeks) [22] or chloroquine (500 mg daily for 14
days, then 250 mg for long-term maintenance) [23]. Antimalarial medications
require frequent eye exams (at least yearly) for ototoxicity. Methotrexate, a
dihydrofolate reductase inhibitor, has emerged as a second-line treatment for
cutaneous sarcoidosis, typically prescribed at doses of 10–30 mg/week [16].
Webster [24] reported clearing of refractory cutaneous sarcoidosis in three
patients with 15 mg/week for up to 11 months [24]. Baughman [25] reported
improvement in 16 out of 17 patients treated with methotrexate over a period of
2 years and with average doses of 28 mg/week [25]. Minocycline (200 mg/day)
has been reported in one open prospective study of 12 patients with refractory
cutaneous sarcoidosis, with 8 patients experiencing complete regression and 2
with partial regression after 12 months, but with 3 suffering relapse of disease
after stopping this therapy [26].
Other medications that have been reported for the treatment of sarcoidosis
include pentoxifylline [27], thalidomide [28–32], allopurinol [33, 34], isotretinoin
[35, 36], infliximab [37, 38], adalimumab [39], azathioprine [40], cyclophospha-
mide [40], cyclosporine [41], chlorambucil [42, 43], leflunomide [44, 45], and mel-
atonin [46], but randomized controlled trials are needed to evaluate these treatments.
Non-pharmaceutical options include lasers, dermabrasion, excision, and photother-
apy (PUVA, UVB, and photodynamic therapy).

45.6 Conclusion

Sarcoidosis is a systemic disease affecting multiple organ systems. Cutaneous

lesions may be mistaken for acne but can be distinguished based on the lack of
comedones and the distinct histological appearance. Prompt diagnosis is important,
as the skin may be a presenting sign of widespread disease. Multiple therapies are
effective, and patients often require oral medications for internal disease as well as
topicals for cutaneous lesions.
326 L. Thornsberry and J. English III

References

1. Newman L, ACCESS Research Group. A case control etiologic study of sarcoidosis: environ-
mental and occupational risk factors. Am J Respir Crit Care Med. 2004;170(12):1324–30.
2. Noor A. Immunopathogenesis of sarcoidosis. Clin Dermatol. 2007;25:250–8.
3. English J. Sarcoidosis. J Am Acad Dermatol. 2001;44(5):725–43.
4. Heath C. Sarcoidosis: are there differences in your skin of color patients? J Am Acad Dermatol.
2012;66(1):121.e1–14.
5. Morgenthau A. Recent advances in sarcoidosis. Chest. 2011;139:174–82.
6. Judson M. The diagnosis of sarcoidosis. Clin Chest Med. 2008;29:415–27.
7. Valentonyte R. Sarcoidosis is associated with a truncating splice site mutation in BTNL2. Nat
Genet. 2005;37:357–64.
8. English J. Sarcoidosis. In: Callen J, editor. Dermatologic signs of internal disease. China:
Saunders Elsevier; 2009.
9. Mana J. Cutaneous involvement in sarcoidosis. Arch Dermatol. 2007;133:882–8.
10. Costabel U. Systemic evaluation of a potential cutaneous sarcoidosis patient. Clin Dermatol.
2007;25:303–11.
11. Izikson A, English JC. Cutaneous sarcoidosis. In: Williams H, editor. Evidence-based derma-
tology. 2nd ed. London: Wiley-Blackwell; 2008.
12. Skold C. Determination of cardiac involvement in sarcoidosis by magnetic resonance imaging
and Doppler echocardiography. J Intern Med. 2002;252(5):465–71.
13. Iannuzzi M. Sarcoidosis. JAMA. 2011;305(4):391–9.
14. Russo G. Cutaneous sarcoidosis: diagnosis and treatment. Complement Ther. 1994;20:418–21.
15. Wilson N. Cutaneous sarcoidosis. Postgrad Med J. 1998;74:649–52.
16. Badgwell C. Cutaneous sarcoidosis therapy updated. J Am Acad Dermatol. 2007;56:69–83.
17. Albertini J. Ulcerative sarcoidosis: case report and review of the literature. Arch Dermatol.
1997;133:215–9.
18. Veien N. Cutaneous sarcoidosis: prognosis and treatment. Clin Dermatol. 1986;4:75–87.
19. Fox R. Mechanism of action of antimalarial drugs: inhibition of antigen processing and pre-
sentation. Lupus. 1993;2 Suppl 1:S9–12.
20. Morse S. The treatment of sarcoidosis with chloroquine. Am J Med. 1961;1961:779–84.
21. Siltzbach L. Chloroquine therapy in 43 patients with intrathoracic and cutaneous lesions. Acta
Med Scand. 1964;176 Suppl 425:302–6.
22. Jones E. Hydroxychloroquine is effective therapy for control of cutaneous sarcoidal granulo-
mas. J Am Acad Dermatol. 1990;23:487–9.
23. Zic J. Treatment of cutaneous sarcoidosis with chloroquine. Arch Dermatol. 1991;
127:1034–40.
24. Webster G. Weekly low-dose methotrexate for cutaneous sarcoidosis. J Am Acad Dermatol.
1991;24:451–4.
25. Lower E. Prolonged use of methotrexate for sarcoidosis. Arch Intern Med. 1995;155:846–51.
26. Bachelez H. The use of tetracyclines for the treatment of sarcoidosis. Arch Dermatol.
2001;137:69–73.
27. Zabel P. Pentoxifylline in treatment of sarcoidosis. Am J Respir Crit Care Med. 1997;155:
1665–9.
28. Carlesimo M. Treatment of cutaneous and pulmonary sarcoidosis with thalidomide. J Am
Acad Dermatol. 1995;32:866–9.
29. Rousseau L. Cutaneous sarcoidosis successfully treated with low doses of thalidomide. Arch
Dermatol. 1998;134:1045–6.
30. Lee J. Disfiguring cutaneous manifestation of sarcoidosis treated with thalidomide: a case
report. J Am Acad Dermatol. 1998;39:835–8.
31. Baughman R. Thalidomide for chronic sarcoidosis. Chest. 2002;122:227–32.
32. Nguyen Y. Treatment of cutaneous sarcoidosis with thalidomide. J Am Acad Dermatol.
2004;50:235–41.
45 Sarcoidosis 327

33. Samuel M. Sarcoidosis: initial results on six patients treated with allopurinol. Br J Dermatol.
1984;111 Suppl 26:20.
34. Voelter-Mahlknecht S. Treatment of subcutaneous sarcoidosis with allopurinol. Arch
Dermatol. 1999;135:1560–1.
35. Waldinger T. Treatment of cutaneous sarcoidosis with isotretinoin. Arch Dermatol.
1983;119:1003–5.
36. Georgiou S. Cutaneous sarcoidosis: complete remission after oral isotretinoin therapy. Acta
Derm Venereol. 1998;78:457–9.
37. Baughman R. Infliximab in cutaneous sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis.
2001;18:70–4.
38. Meyerle J. The use of infliximab in cutaneous sarcoidosis. J Drugs Dermatol. 2003;2:413–4.
39. Heffernan M. Adalimumab for treatment of cutaneous sarcoidosis. Arch Dermatol.
2006;142:17–9.
40. Baughman R. Alternatives to corticosteroids in the treatment of sarcoidosis. Sarcoidosis Vasc
Diffuse Lung Dis. 1997;14:121–30.
41. Rebuck A. Cyclosporin in pulmonary sarcoidosis. Lancet. 1987;1:1486.
42. Kataria Y. Chlorambucil in sarcoidosis. Chest. 1980;78:36–43.
43. Isreal H. Chlorambucil treatment of sarcoidosis. Sarcoidosis. 1991;8:35–41.
44. Baughman R. Leflunomide for chronic sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis.
2004;21:43–8.
45. Majithia V. Successful treatment of sarcoidosis with leflunomide. Rheumatology.
2003;42:700–2.
46. Cagnoni M. Melatonin for treatment of chronic refractory sarcoidosis. Lancet. 1995;346:
1229–30.
Chapter 46
Seborrheic Dermatitis

Elizabeth Farhat and Linda Stein Gold

46.1 Introduction

Seborrheic dermatitis is a chronic inflammatory papulosquamous skin condition

that commonly involves the sebum-rich areas of the scalp, ears, face, chest, and
skinfolds. It typically has a chronic, relapsing course that can range in severity from
asymptomatic dandruff of the scalp to extensive skin involvement resulting in exfo-
liative erythroderma. Patients are otherwise healthy, but it has been noted to be a
marker for human immunodeficiency virus (HIV) infection as well as some neuro-
logic diseases. It is thought to be linked to a reaction to Malassezia furfur
(Pityrosporum ovale), but the relationship is complex.

46.2 Background

46.2.1 Epidemiology

Seborrheic dermatitis peaks during time periods of increased sebum production ini-
tially during infancy and later during adolescence and adulthood. It is generally
divided into infantile seborrheic dermatitis and adult seborrheic dermatitis which
generally occurs in those aged 30–60 years [1]. Up to 70 % of infants may develop
seborrheic dermatitis within the first 3 months of life which usually resolves by
1 year of age [2]. The prevalence in healthy adults is between 1 % and 3 %, more
commonly seen in males than females, and typically worsens during the winter

E. Farhat, M.D. • L.S. Gold, M.D. (*)

Department of Dermatology, Henry Ford Health System, 6530 Farmington Road,
West Bloomfield, MI 48322, USA
e-mail: [email protected]

J.A. Zeichner (ed.), Acneiform Eruptions in Dermatology: A Differential Diagnosis, 329

DOI 10.1007/978-1-4614-8344-1_46, © Springer Science+Business Media New York 2014
330 E. Farhat and L.S. Gold

months [3]. Many consider dandruff, pityriasis simplex, to be the mildest form of
seborrheic dermatitis which may affect up to 50 % of the population [4].
Seborrheic dermatitis has been noted to be a marker for HIV infection and may
be the presenting sign [5, 6]. The prevalence of seborrheic dermatitis in early HIV
infection is 36 % and 50–83 % in patients with acquired immunodeficiency syn-
drome (AIDS) [7–9]. Patients with Parkinson’s disease have increased sebum pro-
duction as well as an increased prevalence of seborrheic dermatitis. Treatment with
l-dopa results in with both quantitative sebum reduction and clinical improvement
of seborrhea [10]. This increased prevalence also occurs in patients with neuroleptic-
induced Parkinsonism after the use of neuroleptic drugs such as chlorpromazine
hydrochloride and haloperidol and in those with mood disorders such as schizo-
phrenia, depression, and anxiety [11, 12]. Seborrheic dermatitis is seen in other
genetic disorders including familial amyloidosis with polyneuropathy and Down’s
syndrome [13–15].
The role of ultraviolet (UV) light on seborrheic dermatitis is unclear. Patients
frequently report improvement after exposure to sunlight [16]. Also, seborrheic der-
matitis is noted to flare during the winter months [17]. However, mountain guides
who have increased UV exposure were noted to have increased prevalence of sebor-
rheic dermatitis thought to be secondary to UV-induced immunosuppression [18].
Additionally psoralen plus UVA (PUVA) light treatment can induce seborrheic der-
matitis, whereas narrowband UVB (NBUVB) has been used to successfully treat
severe disease [19, 20].

46.2.2 Pathophysiology

The etiology of seborrheic dermatitis is controversial with no genetic disposition

noted. It appears to be related to active sebaceous glands given the predilection for
body sites with increased sebaceous distribution. There also may be a hormonal
influence as the disease emerges at puberty and is more common in men, which may
be secondary to androgenic stimulation of the pilosebaceous unit increasing sebum
production [3]. However, the amount of sebum excretion in patients with seborrheic
dermatitis is not increased compared to unaffected individuals, and sebaceous
glands themselves are not actively involved in its pathogenesis [21]. It is thought
that sebaceous glands may instead have a more permissive role that allows for
growth of lipophilic Malassezia fungi (formerly Pityrosporum ovale) [22].
The relationship between Malassezia yeast and seborrheic dermatitis has been
debated for years. Malassezia yeasts are lipid-dependent components of normal
skin flora. Initially it was thought that these yeasts were the underlying cause of
seborrheic dermatitis because scalp cultures from patients with dandruff revealed
increased amounts of Pityrosporum. Later investigations, however, revealed no cor-
relation between the amount of P. ovale present and disease severity [23, 24]. Others
believed that an initial impairment of desquamation led to increased nutrient avail-
ability allowing yeast to flourish. The yeasts, themselves, are not pathogenic [25].
46 Seborrheic Dermatitis 331

Nevertheless, antifungal medications have been shown to improve scaling and

itching of the scalp associated with seborrheic dermatitis [26].
The current thought is that seborrheic dermatitis occurs in susceptible individu-
als caused by an inflammatory process mediated by oleic acid which is released
from sebaceous triglycerides in the presence of Malassezia yeast [27]. Analysis of
genomes from M. globosa and M. restricta revealed a functional lipase gene (LIP1)
and several phospholipase genes with expression detected on the human scalp [28, 29].
The lipase and phospholipase activity of the yeast cleaves sebaceous gland triglyc-
erides into free fatty acids which induces flaking and inflammation in patients with
an altered stratum corneum. Other proposed mechanisms include direct release of
proinflammatory cytokines (IL-6, IL-8, IL-1alpha) and a decrease in anti-
inflammatory cytokines (IL-10) from keratinocytes in response to Malassezia spe-
cies [30]. This is possibly due to an irritant non-immunogenic stimulation induced
by the yeast [31].

46.3 Clinical Presentation

Seborrheic dermatitis presents as well-demarcated erythematous patches or plaques

with a greasy, white or yellow scale located on the sebum-rich areas of the body
including the scalp, external auditory meatus, postauricular area, face, central chest,
and intertriginous areas including axillae and groin folds (Figs. 46.1 and 46.2).
Rarely, it can present as a solitary lesion in the male external genital area [23].
It may be associated with blepharoconjunctivitis with scaling and erythema of the
eyelid margin and inflammation of the conjunctiva. Itching is usually minimal and
may be confined to the scalp. In infants it can present as cradle cap of the scalp or
as diaper dermatitis. In patients with HIV the clinical presentation can be more
explosive and dramatic and may be presenting sign in some patients. The differen-
tial diagnosis is extensive (Table 46.1). Scalp psoriasis can be differentiated from
seborrheic dermatitis using dermoscopy which demonstrates red dots and globules,

Fig. 46.1 Erythematous,

scaly patches primarily
affected the medial cheeks
and nasolabial folds. While
the patient complained of
acne, she did not present with
any comedonal lesions. She
also had scale in the
eyebrows and scalp. Her rash
improved with use of topical
ketoconazole cream
332 E. Farhat and L.S. Gold

Fig. 46.2 Typical

erythematous scaly patches in
the beard and nasolabial folds

twisted red loops, and glomerular vessels in psoriasis in contrast to arborizing vessels
and atypical or absent vascular patterns in seborrheic dermatitis [32].

46.4 Work-Up

46.4.1 Laboratory

Seborrheic dermatitis is a clinical diagnosis based on history and physical

examination. For definitive diagnosis biopsy can be performed for histopathologic
examination.

46.4.2 Biopsies

Histopathology demonstrates moderate acanthosis with accentuated rete ridges,

mound-like parakeratotic scale crusts, and occasional foci of suprapapillary spon-
giosis [33]. Chronic lesions become more psoriasiform appearing with irregular
acanthosis, focal parakeratosis but lack the exocytosis of neutrophils or Munro’s
microabscesses seen in psoriasis.

46.4.3 Cultures

Fungal culture or potassium hydroxide preparation can be performed to rule out

tinea capitis or tinea versicolor.
46 Seborrheic Dermatitis 333

Table 46.1 Clinical presentation and differential diagnosis of seborrheic dermatitis

Diagnosis Clinical findings Differentiation
Infantile seborrheic Erythematous patches and plaques
dermatitis on scalp with greasy scaling
and crusting (cradle cap) and
patches in axillae; inguinal
folds may have oozing,
crusting, satellite lesions
Atopic dermatitis Erythematous eczematous patches Later onset after 3rd month,
located on the face, scalp, and more inflammation, more
extensor surfaces of the body pruritus; patients are much
with crusting more uncomfortable, irritable
Irritant diaper dermatitis Erythematous patches confined to Spares skinfolds, less scaling
diaper area
Candidiasis of diaper Beefy red patches with satellite Potassium hydroxide preparation
area pustules or fungal culture
Infantile psoriasis Sharply demarcated erythematous Difficult to distinguish, may be
patches in diaper area more well demarcated
Langerhans’ cell Letterer-Siwe in infants <1 year: Multisystem disease with
histiocytosis skin-colored papules, scaling osteolytic bone lesions,
and crusting of scalp, flexural diabetes insipidus, tender
neck, axilla, perineum lesions, petechiae, purpura,
nail changes
Wiskott-Aldrich Dermatitis involving face, scalp, X-linked recessive disorder, low
syndrome flexural areas platelets, infections
Leiner’s disease Poorly defined seborrheic Fever, anemia, diarrhea,
dermatitis-like erythroderma infection, C3 and C5
deficiency
Pityriasis simplex Fine scaling of the scalp and
(dandruff) hair-bearing areas of the face
with minimal underlying
erythema
Tinea capitis Diffuse scaling of the scalp Direct microscopic exam or
especially Trichophyton fungal culture is diagnostic
tonsurans can occur without
hair loss and can be patchy
Pityriasis amiantacea Thick, asbestos-like scales May be associated with psoriasis
adherent to tufts of scalp hairs in 1/3, atopic dermatitis,
seborrheic dermatitis, or tinea
capitis
Adult seborrheic Erythematous symmetric patches
dermatitis with greasy scales on the
eyebrows, nasolabial creases,
postauricular, scalp, chest
Psoriasis Well-demarcated erythematous Look for involvement of elbows
patches with thick silvery- and knees in psoriasis, nail
white micaceous adherent scale involvement, arthritis;
on scalp, extensor surfaces dermoscopic findings (see
above)
Dermatomyositis May present with erythema and Poikiloderma, hair loss, muscle
scaling of posterior scalp weakness; skin biopsy
(continued)
334 E. Farhat and L.S. Gold

Table 46.1 (continued)

Diagnosis Clinical findings Differentiation
Rosacea May have erythematous patches or May occur with seborrheic
papules on the nose and cheeks dermatitis or blepharitis; less
with subsequent development scaling; associated with
of telangiectasias flushing and specific triggers
Drug-related seborrheic Scaly erythema or papulopustules Reported in patients with
dermatitis-like on glabella, eyebrows, hand-foot syndrome
eruption nasolabial creases, posterior- associated with erlotinib [84]
auricular area, and scalp with or sorafenib [84], also seen
or without swelling, erythema, with recombinant IL-2 [84],
and pain of palms and soles PUVA, [20] isotretinoin [84],
and cimetidine [84]
Systemic lupus Malar rash on face can mimic Systemic symptoms, photosensi-
erythematosus seborrheic dermatitis tivity, positive ANA, biopsy
Tinea versicolor Scaly hyper- or hypopigmented Direct microscopic examination
macules on trunk reveals spores and hyphae
Pityriasis rosea Erythematous scaly macules in Inverse variant may mimic, look
“Christmas tree” distribution for larger herald patch

46.5 Treatment

Seborrheic dermatitis is a chronic intermittent condition often requiring long-term

therapeutic options for maintenance treatment. Topical treatments including anti-
fungals, corticosteroids, keratolytics, and topical immunomodulator medications
are typically used (Table 46.2). Rarely, systemic antifungals or phototherapy can be
employed for severe or refractory cases.

46.5.1 Antifungals

Topical antifungals are the mainstay of seborrheic dermatitis treatment. The

mechanism of azole antifungals involves inhibition of ergosterol (a fungal cell
wall component) via the cytochrome P450 system in addition to anti-inflammatory
properties through blockage of 5-lipoxygenase production [10]. Ketoconazole
2 % has been shown to be effective in randomized controlled studies with
improvement in erythema, scaling, and pruritus using the cream, gel, foam, and
shampoo formulations [34–37]. A recent meta-analysis also showed strong evi-
dence for the effectiveness of ketoconazole when compared to vehicle [38].
Bifonazole has also demonstrated efficacy in randomized controlled trials using
both the 1 % shampoo and 1 % cream preparations [39, 40]. This may be aug-
mented if used in conjunction with urea 40 % ointment which acts as a keratolytic
and enhances penetration [41].
46 Seborrheic Dermatitis 335

Table 46.2 Topical treatments for seborrheic dermatitis

Medication Formulation Use Other info/adverse reactions
Ketoconazole Cream 2 % Twice daily Pregnancy Category C
Gel 2 % Once daily Burning and irritation (<3 %)
Foam 2 % Twice daily
Shampoo 1 %/2 % 1–2× weekly
Bifonazole Cream 1 % Once daily Not available in the United States
Shampoo 1 % 3× per week
Ciclopirox Gel 0.77 % Twice daily Pregnancy Category B
Shampoo 1 % Twice weekly Burning and pruritus
Hydrocortisone Cream 1 %/2.5 % Twice daily Pregnancy Category C
Fluocinolone Solution 0.01 % 1–2× daily Pregnancy Category C
Scalp oil 0.01 % Nightly Oil is in peanut oil vehicle but
Shampoo 0.01 % Daily thought to be safe in peanut
allergy
Metronidazole Gel 0.75 %/1 % 1–2× daily Pregnancy Category B
Burning, stinging, pruritus
Tacrolimus Ointment 0.1 % Twice daily Pregnancy Category C
Pimecrolimus Cream 1 % Twice daily Black-box warning: lymphoma and
skin cancer
Lithium Ointment 8 % Twice daily Not available in the United States

Ciclopirox is a hydroxypyridone derivative with antifungal, antibacterial,

and anti-inflammatory properties. Its mechanism of action involves inhibition of
uptake of essential compounds which alters cellular permeability [42].
Ciclopirox 1 % shampoo and 1 % cream have demonstrated improvement for
scalp and facial seborrheic dermatitis in randomized, double-blind trials [43, 44].
The frequency of treatment using ciclopirox 1 % shampoo is one to two times
weekly with maintenance every 1–2 weeks [45]. Ciclopirox 1 % cream had
similar efficacy as ketoconazole 2 % foaming gel, and ciclopirox 1.5 % sham-
poo was as effective as ketoconazole 2 % shampoo in randomized trials [46, 47].
There are also multiple over-the-counter antifungal preparations. A random-
ized, placebo-controlled, double-blinded trial comparing ketoconazole and sele-
nium sulfide demonstrated similar efficacy of selenium sulfide 2.5 % shampoo for
irritation and itching associated with moderate to severe seborrheic dermatitis, but
ketoconazole 2 % shampoo was better tolerated [48]. Adverse effects include xan-
thotrichia or yellow hair discoloration [49]. Zinc pyrithione 1 % shampoo did
demonstrate benefit but was inferior to ketoconazole 2 % shampoo in an open-
label comparison trial [50]. A combination ciclopirox 1.5 %/zinc pyrithione 1 %
shampoo was more effective than ketoconazole 2 % foaming gel in a clinical trial
investigating erythema, pruritus, global efficacy, and quality of life [51]. Tea tree
oil 5 % shampoo showed benefit when compared to placebo for mild to moderate
dandruff [52].
336 E. Farhat and L.S. Gold

46.5.2 Antibiotics

Topical metronidazole 1 % gel was shown to be superior to placebo, but metronida-

zole 0.75 % gel was no different than placebo in several double-blind randomized
trials [53–56]. In contrast, an additional study found metronidazole 0.75 % gel to be
as effective as ketoconazole 2 % cream [57].

46.5.3 Corticosteroids

Short-term topical corticosteroid treatment can be employed for severe inflamma-

tion or pruritus. Side effects including atrophy, telangiectasias, dyspigmentation,
and steroid-induced rosacea limit their use. Twice-daily application of hydrocorti-
sone 1 % cream showed similar improvement to ketoconazole 2 % cream in double-
blind comparative studies [58, 59]. A single-blind study of ketoconazole 2 %
foaming gel or betamethasone dipropionate 0.05 % lotion demonstrated superiority
of ketoconazole for symptoms, tolerability, and global evaluation by both patient
and physician for areas on the scalp, eyelashes, nasolabial folds, and chest with
significant reduction in P. ovale [60]. The combination of ketoconazole 2 % sham-
poo twice weekly with clobetasol proprionate 0.05 % shampoo twice weekly pro-
vided greater efficacy than ketoconazole alone for severe scalp disease [61].
Fluocinolone acetonide 0.01 % solution, shampoo, and oil have been helpful for
patients with scalp involvement [62, 63].

46.5.4 Immunomodulators

Tacrolimus and pimecrolimus are nonsteroidal anti-inflammatory agents that inhibit cal-
cineurin and decrease subsequent cytokine production and can be used off label as ste-
roid-sparing agents. Tacrolimus 0.1 % ointment showed improvement in seborrheic
dermatitis in open-label pilot studies with side effects of burning and irritation [64, 65].
Tacrolimus was also as effective as topical betamethasone 17-valerate lotion [66].
Pimecrolimus cream 1 % was superior to vehicle and as effective as betamethasone
17-valerate 0.1 % cream in randomized clinical trials [67, 68]. The black-box warning
for rare cases of lymphoma seen in animal models has limited use of these agents.

46.5.5 Lithium Salts

The activity of lithium salts on seborrheic dermatitis is thought to be anti-

inflammatory, possibly secondary to reduction of expression of Toll-like receptor 2
by keratinocytes [69]. Randomized, placebo-controlled, multicenter trials using
lithium succinate 8 % or lithium gluconate 8 % ointment twice daily showed
46 Seborrheic Dermatitis 337

improvement in all symptoms of seborrheic dermatitis [70, 71]. Furthermore, a trial

of lithium gluconate 8 % ointment was more effective than ketoconazole 2 % emul-
sion twice weekly [72]. Lithium succinate 8 % ointment was also effective in treat-
ing HIV-positive patients [73].

46.5.6 Other Topical Treatments

Coal tar 4 % shampoo was shown to be superior to placebo in a small randomized

controlled trial [74]. Other shampoos include lipohydroxy acid (LHA) 0.1 % and
1.3 % salicylic acid which showed improvement in global efficacy and cosmetic
acceptability [75].
Topical emollients have also been employed for treatment of seborrheic derma-
titis including Promiseb™ topical cream which maintains moisture in the affected
areas. Similarly, MAS064D (Sebclair) includes a compound of emollients, anti-
inflammatory and antimycotic agents with improvement in erythema, scaling, and
pruritus when compared to vehicle in a small randomized, double-blind trial [76].
A novel agent contains Regul™, a topical modulator of toll-like receptor 2, which is
involved in IL-8 expression after contact with Malassezia yeast, may prevent relapses of
seborrheic dermatitis [77]. Cecropin A(1–8)-magainin2(1–12) hybrid peptide analog
P5, an antimicrobial peptide, was also shown to inhibit the expression of IL-8 and toll-
like receptor 2 in M. furfur-infected keratinocytes and furthermore downregulated
NF-kB activation [78]. This may be a potential therapeutic agent in the future.

46.5.7 Oral Antifungals

Itraconazole showed efficacy in open non-comparative trials at 200 mg daily for

1 week followed by 200 mg every 2 weeks or 200 mg for 2 consecutive days monthly
[79–81]. A randomized trial using weekly fluconazole 300 mg did not show
improvement compared to placebo [82]. Terbinafine 250 mg daily showed signifi-
cant improvement when compared to placebo in a subpopulation of patients with
unexposed areas including scalp, sternum, and interscapular areas but no benefit in
those with exposed areas such as face involved [83]. The use of systemic antifungals
is limited by the adverse side effect profile.

46.5.8 Phototherapy

In a small open prospective trial, narrowband ultraviolet B phototherapy given three

times weekly starting at 70 % of the minimal erythema dose, increasing by 20 % per
treatment for 8 weeks, led to marked improvement or complete clearance in patients
with severe seborrheic dermatitis [84].
338 E. Farhat and L.S. Gold

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61. Ortonne JP, Nikkels AF, Reich K, Ponce Olivera RM, Lee JH, Kerrouche N, et al. Efficacious
and safe management of moderate to severe scalp seborrhoeic dermatitis using clobetasol pro-
pionate shampoo 0·05% combined with ketoconazole shampoo 2%: a randomized, controlled
study. Br J Dermatol. 2011;165:171–6.
62. Falk MS. Fluocinolone acetonide in propylene glycol. Arch Dermatol. 1963;88:928–9.
63. Kircik L. The evolving role of therapeutic shampoos for targeting symptoms of inflammatory
scalp disorders. J Drugs Dermatol. 2010;9:41–8.
64. Meshkinpour A, Sun J, Weinstein G. An open pilot study using tacrolimus ointment in the
treatment of seborrheic dermatitis. J Am Acad Dermatol. 2003;49:145–7.
65. Braza TJ, DiCarlo JB, Soon SL, McCall CO. Tacrolimus 0.1% ointment for seborrhoeic der-
matitis: an open-label pilot study. Br J Dermatol. 2003;148:1242–4.
66. Shin H, Kwon OS, Won CH, Kim BJ, Lee YW, Choe YB, et al. Clinical efficacies of topical
agents for the treatment of seborrheic dermatitis of the scalp: a comparative study. J Dermatol.
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46 Seborrheic Dermatitis 341

67. Warshaw EM, Wohlhuter RJ, Liu A, Zeller SA, Wenner RA, Bowers S, et al. Results of a
randomized, double-blind, vehicle-controlled efficacy trial of pimecrolimus cream 1% for the
treatment of moderate to severe facial seborrheic dermatitis. J Am Acad Dermatol.
2007;57:257–64.
68. Rigopoulos D, Ioannides D, Kalogeromitros D, Gregoriou S, Katsambas A. Pimecrolimus
cream 1% vs. betamethasone 17-valerate 0.1% cream in the treatment of seborrhoeic dermati-
tis. A randomized open-label clinical trial. Br J Dermatol. 2004;151:1071–5.
69. Ballanger F, Tenaud I, Volteau C, Khammari A, Dréno B. Anti-inflammatory effects of lithium
gluconate on keratinocytes: a possible explanation for efficiency in seborrhoeic dermatitis.
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70. Efalith Multicenter Trial Group. A double-blind, placebo-controlled, multicenter trial of lith-
ium succinate ointment in the treatment of seborrheic dermatitis. J Am Acad Dermatol.
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71. Dreno B, Moyse D. Lithium gluconate in the treatment of seborrhoeic dermatitis: a multi-
center, randomised, double-blind study versus placebo. Eur J Dermatol. 2002;12:549–52.
72. Dreno B, Chosidow O, Revuz J, Moyse D, Study Investigator Group. Lithium gluconate 8% vs
ketoconazole 2% in the treatment of seborrhoeic dermatitis: a multicentre, randomized study.
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73. Langtry JA, Rowland Payne CM, Staughton RC, Stewart JC, Horrobin DF. Topical lithium
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74. Davies DB, Boorman GC, Shuttleworth D. Comparative efficacy of shampoos containing coal
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75. Seite S, Rougier A, Talarico S. Randomized study comparing the efficacy and tolerance of a
lipohydroxy acid shampoo to a ciclopiroxolamine shampoo in the treatment of scalp sebor-
rheic dermatitis. J Cosmet Dermatol. 2009;8:249–53.
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77. Ionescu MA, Baroni A, Brambilla L, Cannavò SP, Cristaudo A, Vedove CD, et al. Double
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78. Ryu S, Choi SY, Acharya S, Chun YJ, Gurley C, Park Y, et al. Antimicrobial and anti-
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79. Shemer A, Kaplan B, Nathansohn N, Grunwald MH, Amichai B, Trau H. Treatment of moder-
ate to severe facial seborrheic dermatitis with itraconazole: an open non-comparative study. Isr
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80. Kose O, Erbil H, Gur AR. Oral itraconazole for the treatment of seborrhoeic dermatitis: an
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81. Baysal V, Yildirim M, Ozcanli C, Ceyhan AM. Itraconazole in the treatment of seborrheic
dermatitis: a new treatment modality. Int J Dermatol. 2004;43:63–6.
82. Cömert A, Bekiroglu N, Gürbüz O, Ergun T. Efficacy of oral fluconazole in the treatment of
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83. Vena GA, Micali G, Santoianni P, Cassano N, Peruzzi E. Oral terbinafine in the treatment of
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84. Pirkhammer D, Seeber A, Hönigsmann H, Tanew A. Narrow-band ultraviolet B (ATL-01)
phototherapy is an effective and safe treatment option for patients with severe seborrhoeic
dermatitis. Br J Dermatol. 2000;143:964–8.
Chapter 47
Steatocystoma Multiplex

Alejandra Vivas and Jonette Keri

47.1 Introduction

Steatocystoma multiplex (SM) is one of the infrequent forms of keratin disorders

characterized by multiple benign sebaceous gland papules and/or nodules, usually
located in hair-covered areas where pilosebaceous glands are well developed;
however this condition may occur anywhere on the body. Though it is mostly
thought to be a hereditary autosomal dominant disease associated to missense
mutations of the keratin 17 (K17) gene, many sporadic cases have been reported.
This suggests the disease may have a multifactorial etiology. Steatocystoma
simplex is the sporadic solitary tumor counterpart to SM and has no hereditary
tendency. Diagnosis is mainly clinical, but histopathology is characteristic and
aids to confirmation of diagnosis when uncertain. Some of the frequent locations
of SM include neck, chest, upper back, proximal extremities, and face, which are
also common areas for acne to present. Due to the many similarities of these two
conditions, SM should be included in the differential diagnosis when evaluating
an acneiform eruption.

A. Vivas, M.D. (*)

Department of Dermatology, University of Miami, 1321 NW 14th Street,
Room 505, Miami, FL 33136, USA
e-mail: [email protected]
J. Keri, M.D., Ph.D.
Department of Dermatology and Cutaneous Surgery, Veterans Hospital,
University of Miami, Miami, FL, USA

J.A. Zeichner (ed.), Acneiform Eruptions in Dermatology: A Differential Diagnosis, 343

DOI 10.1007/978-1-4614-8344-1_47, © Springer Science+Business Media New York 2014
344 A. Vivas and J. Keri

47.2 Background

The exact etiopathogenesis has not been completely elucidated, but keratin 17 (K17)
has been proposed as a central element in the formation of hereditary steatocystomas.
This protein of keratin-containing intermediate filaments is found in several epithelial
structures such as the ungual bed, hair follicles, and sebaceous glands. The area where
the mutations of the gene K17 occur in SM is identical to mutations found in patients
with pachyonychia congenita type 2 (PC-2) [1]. A variety of mutations have been
described in patients with either steatocystoma multiplex or PC-2, and all of them are
localized to the helix initiation 1A domain of the K17 gene [2]. Therefore these two
conditions are thought to be connected and can present simultaneously with the addi-
tional typical features of PC-2, i.e., hypertrophic nail dystrophy and focal hyperkera-
tosis of the palms, soles, knees, and elbows [3]. Hybrid lesions with histological
features of both conditions have been described [4]. SM has also been reported to be
related to acrokeratosis verruciformis, hypertrophic lichen planus [5], and eruptive
vellus hair cysts (EVHCs) [6]. Some authors suggest that SM and EVHCs belong to
one spectrum of the same disease that should be referred as to “multiple piloseba-
ceous cysts” which would be a more appropriate diagnosis than the terms of EVHCs
and steatocystoma multiplex [7]. On the other hand, some state that they are two sepa-
rate entities based on the expression of different keratins. Lesions of SM express kera-
tins 10 and 17, in contrast to EVHCs which express only keratin 17 [8].
Recently two missense mutations (R94H and N92S) of the K17 gene were iden-
tified in two Chinese pedigrees. N92S is a novel mutation for SM, whereas R94H is
a recurrent mutation. Interestingly R94H was also previously found in a sporadic
case of PC-2 [2].
Other hypotheses have been formulated to explain this rare condition including
hamartomatous malformation of the pilosebaceous duct junction [9, 10] sebaceous
retention cysts, a variant of a dermoid cyst or a nevoid formation of abortive hair
follicles where sebaceous glands attach [11]. Also the occurrence of trauma, infec-
tion, or immunological conditions might be implicated [12].
SM usually begins in adolescence or early adult life and seems to be equally
distributed among both genders although it has been proposed that it is more fre-
quently found in males [13]. Although rarely, this condition has been described in
newborns [14] as well as in elderly [15]. The association of SM to the development
of sebaceous glands and common presentation during puberty suggest a hormonal
trigger for lesion growth.

47.3 Clinical Presentation

SM present in a monomorphous fashion as numerous asymptomatic round-to-oval,

skin-colored to yellowish papules or nodules with smooth surface. The sites of pre-
dilection are the trunk (especially the presternal area), neck, axilla, inguinal region,
47 Steatocystoma Multiplex 345

Fig. 47.1 Non-tender,

flesh-colored, subcutaneous
nodules in the axilla (Photo
credit: Joshua A. Zeichner,
M.D.)

Fig. 47.2 Non-tender,

flesh-colored, subcutaneous
nodules on the forehead
(Photo credit: Joshua A.
Zeichner, M.D.)

scalp, and proximal extremities (Fig. 47.1). Less common locations include face,
scrotum [16], acral distribution in which involvement of distal extremities is more
prominent [17], and breasts [18] among others (Fig. 47.2). In more severe cases the
lesions can be generalized, polymorphous, and present with joint symptoms and
deteriorated general status, as described in one of the variants referred as to SM
generalisata [19].
Lesions are variable in size, tend to grow slowly, and have a sebum content that
can appear as a clear oily liquid or as a yellowish creamy material [11]. Although
usually asymptomatic, complication with secondary inflammatory changes can
occur. One of the distinctive characteristics that may differentiate this condition
from others, specifically from acne, is the absence of surface punctum.
346 A. Vivas and J. Keri

Several localized forms of SM have been described such as eruptive SM of the

scalp [20], facial papular variant [21, 22], and sebocystomatosis, which comprises
multiple lesions of SM confined to the forehead and frontal scalp accompanied by
congenital alopecia [23]. Steatocystoma suppurativa is a scarring inflammatory
version of this disorder [24].

47.4 Workup

The diagnosis of SM is primarily clinical. However for some cases a biopsy may be
needed. The typical histopathological finding of these lesions is seen in the mid-
dermis with the presence of an encapsulated dermal cyst with infolded walls
composed of stratified, squamous epithelium without a granular layer. In addition
there are flattened sebaceous gland lobules arising from the wall and cellular hyaline
eosinophilic cuticles on the luminal side of the cyst wall similar to that of the
sebaceous duct [25]. Occasionally keratin, vellus hairs, hair follicles, and smooth
muscle components are noted in the lumen [23, 26] adding further evidence to the
hypothesis that SM is a hamartomatous condition [27].
Electron microscopy shows cyst wall cells undergoing trichilemmal keratiniza-
tion similar to that of the isthmus portion of the outer hair sheath [24].
Immunohistochemical analysis has demonstrated that the inner epithelial layer of
the cysts is positive for the specific marker calretinin which could be useful in iden-
tifying these lesions when equivocal [28].
The combined mammographic and sonographic findings can aid in confirming
the diagnosis of the subtype of SM involving the breast [18].
The clinical differential diagnosis of SM includes different forms of acne, erup-
tive vellus hair cysts, epidermoid or dermoid cysts, hidradenitis suppurativa, milia,
pseudofolliculitis barbae, neurofibromatosis, and lipomas [11].

47.5 Treatment

Treatment options are limited and only few present satisfactory results; therefore
this condition carries therapeutic challenge. As the lesions are characteristically
asymptomatic, treatment is usually not necessary. However as previously mentioned
some lesions can grow larger, present with inflammation, and develop symptoms
such as discomfort or pain and even can rupture with concomitant drainage [29].
In addition this condition can be cosmetically undesirable representing a psychologi-
cal burden for the patient, especially when lesions are located in visible areas.
In these cases surgical excision or incision and drainage are the standard treatments.
However conventional excision techniques have shown to be impractical when
treating multiple lesions; therefore new surgical procedures with the use of different
instruments have emerged [30, 31] to increase effectiveness of treatment and patient
47 Steatocystoma Multiplex 347

satisfaction and minimize scarring and recurrence. Alternatives to surgery include

needle aspiration which decreases the size of the lesions, but the result may last only
for a relatively short period of time [32]. Oral retinoids have been used for their anti-
inflammatory properties which may be effective in suppurative lesions and also can
reduce the frequency of new lesions, but the outcomes have been variable and not
particularly encouraging [11]. Limited success and poor cosmetic outcome has been
reported with the use of liquid nitrogen cryotherapy [33]. Other option treatments
include intralesional steroids and lasers [23]. Successful use of carbon dioxide laser
(CO2 laser) [34] and Er:Yag laser has been recently reported with excellent cosmetic
results. The laser wave creates a punctum for subsequent drainage of the content of
the cyst using appropriate devices [35]. Combination treatments are encouraged as
long as satisfactory results are achieved.

References

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patient with early onset steatocystoma multiplex and Hutchinson-like tooth deformity.
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2. Wang JF, Lu WS, Sun LD, et al. Novel missense mutation of keratin in Chinese family with
steatocystoma multiplex. Eur Acad Dermatol Venereol. 2009;23:723–4.
3. Kanda M, Natsuga K, Nishie W, et al. Morphological and genetic analysis of steatocystoma
multiplex in an Asian family with pachyonychia congenita type 2 harbouring a KRT17 mis-
sense mutation. Br J Dermatol. 2009;160:465–8.
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hybrid cysts. Dermatology. 1996;192:64–6.
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response. Cutis. 1988;42:437–9.
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multiplex, eruptive vellus hair cysts, and epidermoid and trichilemmal cysts. Am J
Dermatopathol. 1997;19:250–3.
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toma of the pilosebaceous apparatus. Am J Dermatopathol. 1996;18:548–50.
10. Plewig G, Wolff HH, Braun-Falco O. Steatocystoma multiplex: anatomic reevaluation, elec-
tron microscopy, and autoradiography. Arch Dermatol Res. 1982;272:363–80.
11. Lima AM, Rocha SP, Batista CM, Reis CM, Leal II, Azevedo LE. Case for diagnosis.
Steatocystoma multiplex. An Bras Dermatol. 2011;86:165–6.
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clinical and histological manifestation. Am J Dermatopathol. 1997;19:89–92.
13. Magid ML, Wentzell JM, Roenick Jr HH. Multiple cystic lesions: steatocystoma multiplex.
Arch Dermatol. 1990;126:101. 104.
14. Park YM, Cho SH, Kang H. Congenital linear steatocystoma multiplex of the nose. Pediatr
Dermatol. 2000;17:136–8.
15. Rongioletti F, Cattarini G, Romanelli P. Late onset vulvar steatocystoma multiplex. Clin Exp
Dermatol. 2002;27:445–7.
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16. Stollery N. Photo quiz. Case 2. Steatocystoma multiplex. Practitioner. 2007;251(1701):31. 34.
17. Rollins T, Levin RM, Heymann WR. Acral steatocystoma multiplex. J Am AcadDermatol.
2000;43:396–9.
18. Mester J, Darwish M, Deshmukh SM. Steatocystoma multiplex of the breast: mammographic
and sonographic findings. AJR Am J Roentgenol. 1998;170:115–6.
19. Fekete GL, Fekete JE. Steatocystoma multiplex generalisata partially suppurativa-case report.
Acta Dermatovenerol Croat. 2010;18:114–9.
20. Kumakiri M, Yajima C. Eruptive steatocystoma multiplex on the scalp. J Dermatol.
1991;18:537–9.
21. Nishimura M, Kohda H, Urabe A. Steatocystoma multiplex. A facial papular variant. Arch
Dermatol. 1986;122:205–7.
22. Requena L, Martin L, Renedo G, et al. A facial variant of steatocystoma multiplex. Cutis.
1993;51:449–52.
23. Kim SJ, Park HJ, Oh ST, Lee JY, Cho BK. A case of steatocystoma multiplex limited to the
scalp. Ann Dermatol. 2009;21:106–9.
24. Davey MA. Steatocystoma multiplex treatment & management. In: Elston DM; editor.
Medscape reference. http://emedicine.medscape.com/article/1059725-treatment. Accessed 11
Dec 2011.
25. Yamada A, Saga K, Jimbow K. Acquired multiple pilosebaceous cysts on the face having the
histopathological features of steatocystoma multiplex and eruptive vellus hair cysts. Int J
Dermatol. 2005;44:861–3.
26. Thomas VD, Swanson NA, Lee KK. Benign epithelial tumors, hamartomas, and hyperplasias.
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27. Cho S, Chang SE, Choi JH, Sung KJ, Moon KC, Koh JK. Clinical and histologic features of
64 cases of steatocystoma multiplex. J Dermatol. 2002;29:152–6.
28. Riedel C, Brinkmeier T, Kutzne H, Plewig G, Frosch PJ. Late onset of a facial variant of ste-
atocystoma multiplex—calretinin as a specific marker of the follicular companion cell layer.
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29. Cuperus E, Leguit RJ, Sigurdsson V. Steatocystoma multiplex, a rare distribution of a rare
disease. Eur J Dermatol. 2010;20:402–3.
30. Choudhary S, Koley S, Salodkar A. A modified surgical technique for steatocystoma multi-
plex. J Cutan Aesthet Surg. 2010;3:25–8.
31. Lee SJ, Choe YS, Park BC, Lee WJ, Kim do W. The vein hook successfully used for eradica-
tion of steatocystoma multiplex. Dermatol Surg. 2007;33:82–4.
32. Düzova AN, Sentürk GB. Suggestion for the treatment of steatocystoma multiplex located
exclusively on the face. Int J Dermatol. 2004;43:60–2.
33. Apaydin R, Bilen N, Bayramgürler D, Başdaş F, Harova G, Dökmeci S. Steatocystoma multi-
plex suppurativum: oral isotretinoin treatment combined with cryotherapy. Australas J
Dermatol. 2000;41:98–100.
34. Madan V, August PJ. Perforation and extirpation of steatocystoma multiplex. Int J Dermatol.
2009;48:329–30.
35. Mumcuoğlu CT, Gurel MS, Kiremitci U, Erdemir AV, Karakoca Y, Huten O. Er: yag laser
therapy for steatocystoma multiplex. Indian J Dermatol. 2010;55:300–1.
Chapter 48
Xanthomas

Libby Rhee and Mark Kaufmann

48.1 Introduction

Cutaneous xanthomas result from the localized accumulation of lipid within the
dermis or connective tissue. They can present anywhere on the body with a variety
of morphologies ranging from discrete macules and papules to nodules and diffuse
plaques, typically with a yellow-to-orange color due to the lipid deposition. In
darker skin types, however, the lesions may appear more red-to-brown in color.
Xanthomas are most commonly associated with hyperlipemic states, which may
be due to primary genetic causes or secondary to other metabolic derangements.
Less frequently, normolipemic xanthomas have been reported in association with
monoclonal gammopathies or without any associated underlying disease.
The major subtypes of xanthomas associated with disorders of lipid metabolism
include tuberous, tendinous, eruptive, planar, and palmar. Xanthelasmas, a type of
planar xanthoma, may or may not be associated with a hyperlipidemia. Prompt rec-
ognition and early diagnosis of the lesions can significantly aid in the management
and prognosis of any potential underlying disease as cutaneous lesions may some-
times precede any systemic signs of symptoms. Moreover, the morphology and dis-
tribution of the xanthomas can suggest a particular lipoproteinemia or another
systemic disease.

L. Rhee, D.O. (*)

Department of Dermatology, St. Barnabas Hospital, 4422 Third Avenue,
Bronx, NY 10457, USA
e-mail: [email protected]
M. Kaufmann, M.D.
Department of Dermatology, Icahn School of Medicine at Mt. Sinai,
New York, NY, USA

J.A. Zeichner (ed.), Acneiform Eruptions in Dermatology: A Differential Diagnosis, 349

DOI 10.1007/978-1-4614-8344-1_48, © Springer Science+Business Media New York 2014
350 L. Rhee and M. Kaufmann

48.2 Background

Xanthomatosis is a pan-ethnic phenomenon that affects men and women equally.

They are more common in persons over the age of 50 but have been reported in all
age groups from infancy to the elderly. Despite the high prevalence of hyperlipid-
emia in the general population, which is reported to affect slightly more than half of
all Americans, cutaneous xanthomas only affect a relative minority of individuals
[1]. The precise incidence of xanthomatous skin lesions remains unknown, and it is
difficult to predict who will develop them. It is presumable that patients may not
seek dermatologic care for their skin lesions, which may resolve spontaneously or
with treatment of the underlying lipid abnormality or another associated disease.
The lesions, while pathognomonic or suggestive of specific dyslipidemias, largely
remain a cosmetic concern and can be quite disfiguring depending on their size and
location. Morbidity and mortality are related to elevated serum lipids and the ensu-
ing atherosclerotic disease or pancreatitis.
The precise mechanism of xanthoma formation is yet to be fully elucidated.
A basic understanding of normal lipid metabolism helps to understand the possible
pathogenesis of xanthomas and underlying disorders of lipid metabolism.
In general, it is believed that circulating plasma lipoproteins are able to cross
dermal capillary blood vessels where they are subsequently phagocytosed by mac-
rophages, forming lipid-laden foam cells. The steps regulating this chain of events
still remain unclear [2, 3].
Since lipids are naturally hydrophobic, they are transported in complex struc-
tures known as lipoproteins, which contain a hydrophilic shell composed of phos-
pholipids, free cholesterol, and specific proteins called apolipoproteins or
apoproteins. The triglycerides and cholesterol esters remain within the core for stor-
age or usage of lipids.
Lipoproteins vary in their inner lipid content and are classified by their density.
Triglycerides comprise the major lipid core of chylomicrons and very low-density
lipoproteins (VLDLs). Cholesterol esters are the main component of low-density
lipoproteins (LDLs) and high-density lipoproteins (HDLs) and remnants of chylo-
microns and VLDLs. Apoproteins present on the surface confer specificity and allow
for binding of the respective apoproteins to a particular receptor or target tissue.
There are two major pathways of lipoprotein synthesis: the exogenous pathway
and the endogenous pathway. The exogenous pathway begins with dietary fat,
namely, triglycerides, which are enzymatically degraded by pancreatic lipase and
bile acids into fatty acids and monoglycerides. Following intestinal absorption, the
triglycerides are reformed and packaged into chylomicrons with its specific apopro-
teins and outer shell components. Eventually, the chylomicrons enter systemic cir-
culation and release free fatty acids into peripheral tissues. The hydrolysis of the
triglyceride core is mediated through the action of lipoprotein lipase (LPL), a pro-
teolytic enzyme bound to capillary endothelium. This process continues until only
a chylomicron “remnant” exists. The new chylomicron “remnant” is now predomi-
nately composed of cholesterol ester acquired from circulating HDL molecules and
is subsequently taken up by the liver for hepatic storage [2, 3].
48 Xanthomas 351

The endogenous pathway of lipoprotein synthesis begins in the liver with the
formation of VLDL molecules. The central core of the VLDL, like the chylomicron,
is composed of triglycerides, which are derived from hepatic stores as well as circu-
lating free fatty acids. As with chylomicrons, VLDLs are also cleaved by LPL until
most of the triglycerides are removed and only a similar “remnant” remains. The
VLDL remnant is called an intermediate density lipoprotein (IDL) and is ready to
be taken up by the liver and degraded. The IDLs that escape hepatic uptake are
stripped of their remaining triglyceride core and enter systemic circulation as LDLs.
LDLs deliver cholesterol esters to peripheral tissues where they can be converted
into free cholesterol. Cholesterol is an essential component of many body tissues,
including the selectively permeable cell membrane bilayer and myelin nerve
sheaths. It also serves important roles in adrenal and gonadal steroidogenesis as
well as the production of bile acids. Any excess cholesterol is re-esterified for
hepatic storage [2, 3].
HDL also plays a very important and “protective” role in cholesterol metabo-
lism. Its most important function is to “scavenge” free cholesterol from peripheral
tissues so it can be esterified and transferred to other lipoproteins such as LDLs or
remnants of chylomicrons and VLDLs for reverse transport or transport back to the
liver. The esterification of free cholesterol is mediated by the enzyme lecithin cho-
lesterol acyl transferase (LCAT).
Cholesterol homeostasis involves a complex interweaving of mechanisms.
As such, disorders in lipid metabolism can occur in numerous ways. Inherited
disorders resulting from genetic mutations (primary hyperlipoproteinemia) can
yield absent or defective enzymes, receptors, or receptor ligands, with resultant
overproduction or decreased clearance of lipoproteins. Several mutations are known
to exist and are associated with a unique lipid profile. Additionally, secondary
hyperlipoproteinemias due to an underlying disease that may disrupt lipid metabo-
lism including diabetes mellitus, hypothyroidism, and nephrotic syndrome are not
uncommon. Medications, such as oral retinoids, oral contraceptive pills, antiretrovi-
ral drugs to name a few can also lead to a hyperlipemic state [2, 3].

48.3 Clinical Presentation

Cutaneous xanthomas associated with hyperlipidemia are typically divided into five
main groups depending on morphology and/or location: tuberous, tendinous, erup-
tive, planar, and palmar. Xanthelasma palpebrarum is the most common type of
xanthoma presenting around the eyes. It is considered a subtype of planar xan-
thoma, although it is not necessarily associated with aberrant lipid metabolism
(Fig. 48.1). Xanthoma disseminatum and verruciform xanthoma are not usually
associated with any lipid abnormalities.
Tuberous xanthomas present as firm, painless, pink-to-yellow papules or nod-
ules most commonly on extensor surfaces, especially the elbows and knees, as
well as on pressure-prone areas such as the buttocks (Fig. 48.2). Tuberous xantho-
mas are particularly associated with hypercholesterolemic states such as familial
352 L. Rhee and M. Kaufmann

Fig. 48.1 Xanthelasma:

yellow papules that
commonly present around the
upper and lower eyelids
(Photo credit: Joshua A.
Zeichner, M.D.)

Fig. 48.2 Tuberous

xanthomas: flesh-colored to
erythematous papules that
usually present around
extensor surfaces of the
elbows and knees. This
patient had a family history
of high cholesterol and
developed lesions on the
wrists (Photo credit: Joshua
A. Zeichner, M.D.)

hypercholesterolemia (Type II) and dysbetalipoproteinemia (Type III). They may

also be associated with secondary hyperlipidemias, including nephrotic syndrome
and hypothyroidism. With treatment of the underlying disease, the lesions will
usually resolve slowly over time.
Tendinous xanthomas are slowly progressing, firm, subcutaneous, nodular
deposits of lipid that are associated with tendon sheaths. The Achilles tendon and
extensor tendons of the hands and feet are most often affected. The overlying skin
does not show any changes. Tendinous xanthomas are generally associated with
significant serum lipid elevation, namely, elevated LDL. Familial hypercholesterol-
emia (Type IIa), dysbetalipoproteinemia (Type III), and hepatic cholestasis are all
associated with this type of xanthoma [4].
48 Xanthomas 353

Eruptive xanthomas appear suddenly as crops of red-to-yellow papules 1–4 mm

in diameter on an erythematous base, sometimes imparting an inflammatory appear-
ance to the lesions. They have a predilection for extensor surfaces of the extremities,
buttocks, and hands. Patients often report pain and pruritus with the lesions, and
koebnerization has been reported as a feature. Eruptive xanthomas are associated
with primary (Types I, IV, V; elevated chylomicrons, VLDL, chylomicrons/VLDL,
respectively) or secondary hypertriglyceridemia (diabetes mellitus). Triglyceride
levels often exceed 3,000–4,000 mg/dl and can lead to acute pancreatitis or life-
threatening atherosclerosis if not managed effectively. Unlike tuberous xanthomas,
these lesions often resolve promptly upon treatment of the hypertriglyceridemia [5].
Planar xanthomas occur as yellow-to-orange macules, papules, patches, or
plaques. They can occur anywhere, and often can give a clue to the underlying diag-
nosis depending on their location. For example, palmar crease lesions (xanthoma
striatum palmare) are pathognomonic for dysbetalipoproteinemia (Type III), espe-
cially when tuberous xanthomas are also present. Antecubital fossae or finger web
space lesions are nearly pathognomonic for homozygous familial hypercholesterol-
emia (Type II). Generalized lesions may cover the face, neck, and chest.
Xanthelasma, xanthelasma palpebrarum, is the most common type of xanthoma.
Only about half are associated with an underlying lipid disorder, but a workup is
generally still warranted, especially if the patient is younger and has a strong family
history of dyslipidemia [3, 6].
Planar xanthomas may also be associated with cholestasis as a complication of
biliary disease as well as in normolipemic patients. In the latter clinical scenario, a
monoclonal gammopathy (IgG type), secondary to multiple myeloma, a lymphop-
roliferative disorder such as B-cell lymphoma or chronic myelomonocytic leukemia
(CML), or Castleman’s disease should be ruled out [3].

48.4 Workup

Xanthomas may be idiopathic or indicate more serious systemic disease. Key to the
workup is diagnosing and treating any underlying hyperlipidemia in order to mini-
mize the progression atherosclerotic disease. Any potential secondary causes of dis-
ease need to be excluded as well.
Primary, or inherited forms, of hyperlipidemia are generally a diagnosis of exclu-
sion. Laboratory studies used to either primary or secondary hyperlipidemia should
start with a serum lipid panel, including fasting plasma levels of triglycerides, cho-
lesterol, and HDL cholesterol. LDL and VLDL concentrations can be calculated
using the above information. Chylomicrons can be separated via ultracentrifugation
and electrophoresis, then quantified using immunologic methods.
Certain xanthomas are highly suggestive of specific familial hyperlipoprotein-
emias and can guide the workup and diagnosis: xanthoma striatum palmare are seen
in familial dysbetalipoproteinemia and intertriginous xanthomas in homozygous
familial hypercholesterolemia. Rarely, plane xanthomas may be associated with an
354 L. Rhee and M. Kaufmann

underlying monoclonal gammopathy, and urine or serum protein electrophoresis

can be used as an initial test in this clinical setting. Xanthelasma palpebrarum,
which is only loosely associated with underlying hypercholesterolemia, is charac-
teristically found on the upper and lower eyelids. Imaging studies can aid in deter-
mining the extent of xanthomatous lesions as well as atherosclerotic disease [2–4].
The characteristic histologic finding in xanthomas is the foamy macrophage. The
lipid droplets that fill the macrophage are often dissolved and removed during nor-
mal tissue processing, leaving behind artifactual clefting. Polarized microscopy can
be used to detect cholesterol esters, which are doubly refractile, within the dermis.
All xanthomas contain lipid within the dermal infiltrate, but they may vary in terms
of the content, inflammatory infiltrate, amount and location of the infiltrate within
the dermis, and the presence of extracellular lipid.

48.5 Treatment

Xanthomas are not always associated with hyperlipidemia, but when they are, a
multidisciplinary approach to lowering the lipid levels is essential. First-line thera-
pies include dietary modifications and lipid-lowering agents such as HMG-CoA
reductase inhibitors (“statins”), bile acid-binding resins, fibric acid derivatives, and/
or nicotinic acid. Cutaneous xanthomas generally resolve with correction of the
underlying lipid disorder. Slower growing xanthomas such as tendinous or tuberous
xanthomas may persist for years or never fully resolve in contrast to eruptive xan-
thomas, for example, which often disappear quickly with aggressive lipid-lowering
therapy [1–3].
The cutaneous lesions, particularly xanthelasmas, can be treated by surgical
excision or through locally destructive methods if they are a cosmetic or functional
concern. Laser therapy (CO2; pulsed-dye or erbium:YAG lasers; argon; Q-switched
Nd:YAG; KTP), di- or trichloroacetic acid, electrodesiccation, cryotherapy, intra-
lesional bleomycin, and intralesional corticosteroid injections have all been
reported to be helpful [6]. Unfortunately, the xanthomas often recur despite initial
success, and scarring, pigmentary changes, and koebnerization are potential
adverse effects.

48.6 Conclusion

Several different forms of xanthomas exist. Patients often confuse xanthelasma on

the face with acne vulgaris. The clinical appearance of xanthelasma differs from
acne, and it is treated in different ways. The appearance of xanthomas on the skin
may be a marker for systemic disease, including hyperlipidemia or monoclonal
gammopathy, so a full workup should be performed.
48 Xanthomas 355

References

1. Ford ES, Li C, Pearson WS, Zhao G, Mokdad AH. Trends in hypercholesterolemia, treatment
and control among United States adults. Int J Cardiol. 2010 ;140(2):226–35.
2. Parker F. Xanthomas and hyperlipidemias. J Am Acad Dermatol. 1985;13(1):1–30.
3. Bolognia J, Jorizzo J, Rapini R. Dermatology. 2nd ed. New York: Elselvier Limited; 2008. Print.
4. Tsouli SG, Kiortsis DN, Argyropoulou MI, Mikhailidis DP, Elisaf MS. Pathogenesis, detection
and treatment of Achilles tendon xanthomas. Eur J Clin Invest. 2005;35(4):236–44.
5. Streit E, Helmbold P. 65-year-old man with yellow-orange papules on both forearms. Eruptive
xanthomas. Hautarzt. 2009;60(10):834–7.
6. Rohrich RJ, Janis JE, Pownell PH. Xanthelasma palpebrarum: a review and current manage-
ment principles. Plast Reconstr Surg. 2002;110(5):1310–4.
 Part VI
Pediatric Dermatoses Mimicking Acne
Chapter 49
Periorificial Granulomatous Dermatitis

Jacquelyn Levin, James Del Rosso, and Richard Miller

49.1 Introduction

Periorificial granulomatous dermatitis (PGD) was first reported in 1970 in the

French literature by Gianotti et al. [1]. Gianotti et al. [1] described five Italian chil-
dren ranging in age from 2.5 to 7 years with a distinctive eruption of monomor-
phous papules around the mouth with a granulomatous pattern noted histologically.
In 1974, Marten et al. [2] reported 22 Black children with a similar eruption limited
to the face. In 1989, Frieden et al. [3] termed this disease granulomatous perioral
dermatitis in children. In 1990, Williams et al. [4] reported 5 very similar patients
and coined the term facial Afro-Caribbean childhood eruption (FACE) to reflect that
all their cases occurred in Afro-Caribbean children. In 1996, Knautz et al. [5]
suggested the term childhood granulomatous periorificial dermatitis for this erup-
tion to point out the frequent perinasal or periocular involvement and to avoid the
term FACE which limits the diagnosis to Afro-Caribbeans.
Today, there is still no consensus about the nomenclature of the disease. This
characteristic eruption has been reported in the literature as Gianotti-type perioral
dermatitis [6], facial Afro-Caribbean childhood eruption (FACE) [4, 6–9], sarcoid-
like granulomatous dermatitis [10], childhood granulomatous perioral dermatitis
[3], and childhood granulomatous periorificial dermatitis [4, 5, 11]. In our opinion
periorificial granulomatous dermatitis (PGD) best describes the clinical and

J. Levin, D.O. (*)

Department of Dermatology, Largo Medical Center, 201 14th St SW, Largo, FL 33774, USA
e-mail: [email protected]
J. Del Rosso, D.O.
Touro University College of Osteopathic Medicine,
Henderson, NV, USA
R. Miller, D.O.
Nova Southeastern University College of Osteopathic Medicine,
Tampa, FL, USA

J.A. Zeichner (ed.), Acneiform Eruptions in Dermatology: A Differential Diagnosis, 359

DOI 10.1007/978-1-4614-8344-1_49, © Springer Science+Business Media New York 2014
360 J. Levin et al.

histopathologic characteristics of this skin disease because PGD may not be limited
to a perioral distribution and is histopathologically characterized by the presence of
a granulomatous inflammatory reaction [12].

49.2 Background

The etiology of PGD is unknown, although several theories exist. Many believe that
PGD is the less common granulomatous variant of perioral/periorificial dermatitis
(PD) and that PD and PGD share the same etiologic factors [5, 13–17].
The main etiologic factors in PD are thought to be a decreased stratum corneum
(SC) permeability barrier function [14] from intrinsic factors or deficiencies yet to
be identified or from extrinsic causes such as topical products [15, 16]. The topical
products implicated in PD include contact irritants or allergens in cosmetics and
topical corticosteroids (TCs) [4, 11, 14, 17–20]. While there are no reports in the
literature demonstrating SC permeability barrier dysfunction in PGD, there are con-
flicting reports regarding the pathogenic relationship of PGD to topical products.
Some authors report a pathogenic relationship between PGD and TC use, or to topi-
cal allergens and irritants such as formaldehyde and antiseptic solutions [3, 6,
13, 21], while others specifically state that no etiologic relationship is present
between TC and other products in PGD [22].
Whether the inciting factors are intrinsic or extrinsic, the initiating event for PD as
well as PGD is believed to be the same; damage to the hair follicle which results in
damage to the follicular wall, release of its contents into the surrounding dermis, and
subsequent inflammation [14, 22]. The antigenic component of the ruptured follicle
is unknown; however, it is thought in PGD to provoke a granulomatous response
[22]. There are limited data available to support this theory of pathogenesis.
PGD is a rare skin disease that occurs mostly in children with skin of color
[21, 23]. PGD has been seen healthy children ranging in age from 6 months to 18
years [17, 24, 25]. Afro-Caribbean, African American, and Asian children dominate
the reports, but Caucasian patients are also susceptible [21, 23]. There have been
reports of PGD being more common in boys versus girls [26, 27]; however, the
majority of reports state that both sexes are affected equally [21].

49.3 Clinical Presentation

The primary lesions in PGD are discrete 1–3 mm asymptomatic monomorphous

dome-shaped papules that can range in color from pink red to flesh colored to yel-
low brown (Fig. 49.1) [12, 13, 15, 22]. In some instances there is background ery-
thema and overlying scale present; however, these features are not consistently
present in published cases. The face is always involved in PGD, and lesions are
typically concentrated around the mouth, nose, and/or eyes. PGD characteristically
49 Periorificial Granulomatous Dermatitis 361

Fig. 49.1 Discreet,

monomorphic, dome-shaped
papules on the cheek of a
teenage girl

involves the vermillion border of the lip which helps distinguishes this eruption
from other diseases such as PD [23]. While the majority of cases reported in the
literature are confined to the face, eight reported cases of PGD also had generalized
skin lesions [21]. The patients with extrafacial involvement had lesions on the neck,
upper trunk, extensor wrists, and vaginal area [28, 29]. Importantly, extensive skin
involvement in PGD does not appear to change the duration of the eruption, the
response to treatment, or have any association with any specific underlying internal
diseases [15].
Scarring is variable in PGD. The initial cases described by Gianotti et al. [1] and
several subsequent authors [6, 28, 30] reported the occurrence of small pitted scars
after resolution of the papules. However, the majority of cases since then have
reported no scarring or other sequelae after the resolution of PGD [4, 13, 23].
In the majority of cases where skin biopsies were performed, a dermal granulo-
matous infiltrate was seen concentrated around the upper half of the hair follicles
[12, 13, 15]. In some biopsy specimens, the granulomatous infiltrate was more dif-
fuse, and in some rare cases no granulomas were detected on histologic examination
[2, 4]. Focal epidermal spongiosis is occasionally described; however, there is never
caseation necrosis, and the results of special stains and cultures for acid-fast bacilli
and fungi are always negative [15].
This granulomatous histologic appearance of PGD is not diagnostic. The dif-
ferential diagnosis of small papules with granulomatous histologic features in chil-
dren includes sarcoidosis, fungal or mycobacterial infection, familial juvenile
systemic granulomatosis (Blau syndrome), and granulomatous rosacea in addi-
tion to PGD [15]. In typical cases of PGD, these entities can be differentiated
362 J. Levin et al.

clinically; however, in cases with extrafacial involvement, a more thorough workup

may be needed to establish the diagnosis and exclude other entities in the differen-
tial diagnosis.

49.4 Workup

There is some disagreement concerning the recommended workup when the diag-
nosis of PGD is suspected. Because PGD occurs in healthy children and spontane-
ously resolves within a few months to years without scarring or sequelae, it is often
difficult to justify a biopsy or a thorough systemic evaluation [4]. However, it can be
difficult at times to differentiate PGD from other more serious conditions with
extracutaneous manifestations and potential long-term detrimental sequelae [23].
For this reason, when clinical presentation is not sufficient to diagnose PGD [4, 31],
histopathologic evaluation is recommended, with additional workup directed by the
clinician based on the needs of the individual case. Examples of tests that may be
included in the workup are chest radiograph, ophthalmologic examination, tubercu-
lin skin test, serum calcium, serum angiotensin-converting enzyme level, and the
use of special stains and tissue cultures for fungal or mycobacterial organisms on
histologic sections (Table 49.1) [15, 22, 31, 32].
In the literature, PGD has been likened to many dermatologic disorders with both
cutaneous involvement and cutaneous plus systemic involvement. The main differ-
ential diagnoses of PGD include acne vulgaris, periorificial dermatitis (PD), granu-
lomatous rosacea, sarcoidosis, lupus miliaris disseminatus faciei (LMDF), and
seborrheic dermatitis. Many of the facial dermatoses listed the differential of PGD
are discussed in detail elsewhere in the book as they are also difficult at times to
differentiate from acne vulgaris and other facial dermatoses. Table 49.2 summarizes
the defining characteristics of PGD while Table 49.3 lists the characteristics that
help differentiate the skin diseases listed above from PGD [4, 12, 18].

Table 49.1 Summary of possible workup for selected cases of periorificial granulomatous
dermatitisa,b
• Skin biopsy
Confirm consistency with diagnosis and evaluate for other potential diagnoses such as
sarcoidosis, infectious etiologies, others (see text)
Specimen must contain adequate depth to fully evaluate follicular structures
Special stains and cultures to detect fungal or mycobacterial organism if present
• Chest radiograph
• Ophthalmologic examination
• Tuberculin skin test
• Serum calcium
• Serum angiotensin-converting enzyme level
a
Workup to be determined based on judgement of clinician in cases where clinical diagnosis alone
is questionable
b
References [15, 22, 31, 32]
49 Periorificial Granulomatous Dermatitis 363

Table 49.2 Summary of • Epidemiology

defining characteristics of Rare
periorificial granulomatous
Common in darker skin types
dermatitis
• Onset
6 months to 18 years
• Clinical presentation
Healthy children
Recent history of steroid use
1–3 mm asymptomatic, monomorphous,
multiple dome-shaped papules
Color variable: pink, red, yellow
brown, flesh colored
Individual and/or with confluence
Lesions around the mouth, nose, and/
or eyes
Can involve vermillion border
Can involve extrafacial skin
Face always involved
No systemic symptoms or internal
organ involvement
Spontaneous resolution in months to
years
Usually no scarring
• Histology
Mixed granulomatous infiltrate
around hair follicles
References [4, 11–13, 15, 17, 21–24]

Less commonly reported skin diseases which should be included in the differential
diagnosis of PGD include allergic/irritant contact dermatitis, impetigo, acrodermati-
tis enteropathica, tinea faciei, lip-lickers dermatitis, atopic dermatitis, benign cephalic
histiocytosis, granulosis rubra nasi, glucagonoma syndrome, Blau syndrome, Haber
syndrome, and facial demodicosis.

49.5 Treatment

Patients and parents should be reassured that PGD is a benign, self-limited condi-
tion. Since the disease is benign and self-limited, treatment may be unnecessary.
However, the average reported time for spontaneous resolution is between 1 and 3
years [1, 6, 10, 30, 33–36], and the resolution may be hastened with the use of
appropriate therapy [15]. The time to resolution with treatment varies greatly in the
literature ranging from 1 week to 6 months [17, 20, 37].
There are no available randomized controlled trials providing guidance for the
best treatment in PGD because of the rare nature of this skin disease. Some reviews
dictate the first step in management to be discontinuation of all TCs or any other
364 J. Levin et al.

Table 49.3 Differentiation of periorificial granulomatous dermatitis from other simulant dermatoses
• Acne vulgaris
Comedones, pustules, nodule, and cysts present
High incidence in puberty
• Perioral dermatitis
Most common in young women in third to fourth decade
Pustules present
Spares the vermillion border
No extrafacial eruptions
• Granulomatous rosacea
Most common in young women in third to fourth decade
Centrofacial distribution
Background erythema, flushing, telangiectasias, pustules may be present
No spontaneous resolution
• Sarcoidosis
Rarely presents in children
Multiorgan involvement
Systemic symptoms present
Granulomas on histology do not have surrounding infiltrate and are not centered around a follicle
• Seborrheic dermatitis
Ears, nasolabial folds, eyebrows, and scalp commonly involved
Scale or hyperkeratosis often present
• Lupus miliaris disseminatus faciei
Scarring is present
Most common in Japanese adults
Caseation necrosis on histology
References [4, 12, 18]

possible inciting chemicals or products [12, 13, 24, 34]. Because there may be an
associated rebound or exacerbation of the skin disease after stopping TC use, many
physicians recommend the use of a mild topical corticosteroids daily for a few
weeks to effectively wean patients off more potent TCs; however, there is no scien-
tific evidence that this approach is beneficial [25, 37, 38]. The authors suggest dis-
continuation of TCs without a weaning approach [39].
In the literature there are several case reports demonstrating the effectiveness of
treatment with topical metronidazole, sulfacetamide-sulfur, topical erythromycin, oral
tetracyclines, or oral erythromycin for PGD [4, 15, 21]. Nguyen and Eichenfeld [17]
recommend a 1–2-month trial of topical metronidazole with the addition of oral eryth-
romycin. Urbatsch states that the administration of oral macrolides or tetracyclines,
alone or in combination with topical erythromycin, metronidazole, or sulfur-based
lotions, hastens resolution in most patients [15, 21]. Although oral tetracyclines can be
effective in treating PGD, they should not be used in PGD patients less than 8 years
old as tetracyclines have been known to cause dental enamel discoloration [24, 39].
The availability of subantimicrobial dosing of doxycycline offers an option that may
be effective without exposing the patient to antibiotic selection pressure [39].
49 Periorificial Granulomatous Dermatitis 365

49.6 Conclusion

PGD is a chronic and potentially disfiguring dermatosis, often affecting the face.
It may commonly be mistaken for acne vulgaris, but clinically appears as monomor-
phic papules rather than the comedones, papules, and pustules observed in patients
with acne vulgaris. Treatment can be challenging and requires often long-term com-
bination therapy with both topical and oral medications.

References

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Observations sur 5 cas. Bull Soc Fr Dermatol Syphiligr. 1970;77:341.
2. Marten RH, Presbury DG, Adamson JE, Cardell BS. An unusual papular and acneiform facial
eruption in the negro child. Br J Dermatol. 1974;91:435–8.
3. Frieden IJ, Prose NS, Fletcher V, Turner ML. Granulomatous perioral dermatitis in children.
Arch Dermatol. 1989;125:369–73.
4. Williams HC, Ashworth J, Pembroke AC, Breathnach SM. FACE-facial Afro-Caribbean child-
hood eruption. Clin Exp Dermatol. 1990;15:163–6.
5. Knautz MA, Lesher Jr JL. Childhood granulomatous periorificial dermatitis. Pediatr Dermatol.
1996;13:131–4.
6. Georgouras K, Kocsard E. Micropapular sarcoidal facial eruption in a child: Gianotti-type
perioral dermatitis. Acta Derm Venereol. 1978;58:433–6.
7. Williams HC. Childhood granulomatous periorificial dermatitis. Pediatr Dermatol.
1996;13(6):515.
8. Laude TA, Salvemini JN. Perioral dermatitis in children. Semin Cutan Med Surg. 1999;18(3):
206–9.
9. Smitt JH, Das PK, Van Ginkel JW. Granulomatous perioral dermatitis (facial Afro-Caribbean
childhood eruption [FACE]). Br J Dermatol. 1991;125:399.
10. Falk E. Sarcoid-like granulomatous periocular dermatitis treated with tetracycline. Acta Derm
Venereol. 1985;65:270–2.
11. Tarm K, Creel NB, Krivda SJ, Turiansky GW. Granulomatous periorificial dermatitis. Cutis.
2004;73(6):399–402.
12. Zalaudek I, Di Stefani A, Ferrara G, Argenziano G. Childhood granulomatous periorificial
dermatitis: a controversial disease. J Dtsch Dermatol Ges. 2005;3(4):252–5.
13. Kim YJ, Shin JW, Lee JS, Park YL, Whang KU, Lee SY. Childhood granulomatous periorifi-
cial dermatitis. Ann Dermatol. 2011;23(3):386–8.
14. Dirschka T, Tronnier H, Folster-Holst R. Epithelial barrier function and atopic diathesis in
rosacea and perioral dermatitis. Br J Dermatol. 2004;150:1136–41.
15. Urbatsch AJ, Frieden I, Williams ML, Elewski BE, Mancini AJ, Paller AS. Extrafacial and
generalized granulomatous periorificial dermatitis. Arch Dermatol. 2002;138(10):1354–8.
16. Dirschka T, Weber K, Tronnier H. Topical cosmetics and perioral dermatitis. J Dtsch Dermatol
Ges. 2004;2:194–9.
17. Nguyen V, Eichenfield LF. Periorificial dermatitis in children and adolescents. J Am Acad
Dermatol. 2006;55:781–5.
18. Ahmed I. Clinicopathologic challenge. Childhood granulomatous peri-orificial dermatitis with
extra-facial lesions. Int J Dermatol. 2007;46(2):143–5.
19. Cochran RE, Thomson J. Perioral dermatitis: a reappraisal. Clin Exp Dermatol. 1979;4(1):
75–80.
20. Wilkinson DS, Kirton V, Wilkinson JD. Perioral dermatitis: a 12-year review. Br J Dermatol.
1979;101:245–57.
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21. James W, Berger T, Elston D. Andrews’ diseases of the skin: clinical dermatology. 11th ed.
USA: Elsevier Health; 2011.
22. Makkar R, Ramesh V. On the diagnosis of facial granulomatous dermatoses of obscure origin.
Int J Dermatol. 2005;44(7):606–9.
23. Choi YL, Lee KJ, Cho HJ, Kim WS, Lee JH, Yang JM, et al. Case of childhood granulomatous
periorificial dermatitis in a Korean boy treated by oral erythromycin. J Dermatol.
2006;33(11):806–8.
24. Kuflik JH, Janniger CK, Piela Z. Perioral dermatitis: an acneiform eruption. Cutis. 2001;67:
21–2.
25. Coskey RJ. Perioral dermatitis. Cutis. 1984;34:8.
26. Kim MS, Kim BS, Koh WS, Cho JJ, Chun DK. A case of childhood granulomatous perioral
dermatitis. Korean J Dermatol. 2000;38:526–9.
27. Lee WJ, Yang JH, Lee MW, Choi JH, Moon KC, Koh JK. A case of childhood granulomatous
periorificial dermatitis. Korean J Dermatol. 2008;46:1570–2.
28. Andry P, Bodemer C, Teillac-Hamel D, Fraitag S, DeProst Y. Granulomatous perioral derma-
titis in childhood: eight cases [abstract]. Pediatr Dermatol. 1995;12:76.
29. Hansen KK, McTigue K, Esterly NB. Multiple facial, neck, and upper trunk papules in a black
child: childhood granulomatous perioral dermatitis with involvement of the neck and upper
trunk. Arch Dermatol. 1992;128:1396–7.
30. Husz S, Korom I. Periocular dermatitis: a micropapular sarcoid-like granulomatous dermatitis
in a woman. Dermatologica. 1981;162:424–8.
31. Frieden IJ, Prose NS, Fletcher V, Turner ML. Granulomatous perioral dermatitis or sarcoid?
Arch Dermatol. 1990;126(9):1237–8.
32. Gupta AK, Goldfarb MT, Rasmussen JE. Papular midfacial eruption in a child. Cutaneous
Sarcoidosis. Arch Dermatol. 1989;125(12):1704–5. 1707–8.
33. Gianotti F. Cutaneous benign histiocytosis of childhood. Mod Probl Paediatr. 1975;17:
193–203.
34. El-Saad E-RM. Perioral dermatitis with epithelioid cell granulomas in a woman: a possible
new etiology. Acta Derm Venereol. 1979;60:359–60.
35. Hansen KK, McTigue K, Esterly NB. Multiple facial, neck, and upper trunk papules in a black
child: childhood granulomatous perioral dermatitis with involvement of the neck and upper
trunk. Arch Dermatol. 1992;128:1396–7.
36. Antony FC, Buckley DA, Russell-Jones R. Childhood granulomatous periorificial dermatitis
in an Asian girl—a variant of sarcoid? Clin Exp Dermatol. 2002;27(4):275–6.
37. Manders SM, Lucky AW. Perioral dermatitis in childhood. J Am Acad Dermatol.
1992;27:688–92.
38. Wilkinson DS, Kirton V, Wilkinson JD. Perioral dermatitis: a 12-year review. Br J Dermatol.
1979;101:245–57.
39. Del Rosso JQ. Management of papulopustular rosacea and perioral dermatitis with emphasis
on iatrogenic causation or exacerbation of inflammatory facial dermatoses: use of doxycycline
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an effective therapeutic approach. J Clin Aesthet Dermatol. 2011;4:20–30.
Chapter 50
Keratosis Pilaris Atrophicans

Omar Pacha and Adelaide Hebert

50.1 Introduction

Keratosis pilaris atrophicans faciei (KPAF), also commonly known as ulerythema

ophryogenes, is a rare disorder characterized by erythematous small keratotic
papules that resolve with atrophy and resultant focal alopecia. This uncommon
condition always involves the face, especially the eyebrows. Similarities exist,
both genetically and clinically, to other scarring alopecias with follicular hyper-
keratosis including atrophoderma vermiculatum and keratosis follicularis spinu-
losa decalvans. Some have characterized these clinical entities under a single term
known as keratosis pilaris atrophicans [1]. Currently treatment options produce
generally unimpressive clinical outcomes.

50.2 Background

Keratosis pilaris atrophicans faciei is an autosomal dominantly inherited disorder

with incomplete penetrance. Originally described by Englishman Erasmus Wilson
in 1878, the clinical findings were named folliculitis rubra [2]. In 1889, German
Paul Taenzer coined the term ulerythema ophryogenes, meaning scarring of the
eyebrows [3]. Efforts to determine the precise genetic cause are ongoing, but partial
monosomy of chromosome 18 is the most frequently cited causation [4–6]. The
association of chromosome 18 aneuploidy and KPAF indicates the absence of a
gene, possibly for laminin α1, in the 18p area that regulates follicular keratinization
and formation of sebaceous gland structures [6].

O. Pacha, M.D. (*) • A. Hebert, M.D.

Department of Dermatology, University of Texas Health Science Center,
6655 Travis Street, Suite 600, Houston, TX 77030, USA
e-mail: [email protected]

J.A. Zeichner (ed.), Acneiform Eruptions in Dermatology: A Differential Diagnosis, 367

DOI 10.1007/978-1-4614-8344-1_50, © Springer Science+Business Media New York 2014
368 O. Pacha and A. Hebert

Fig. 50.1 Follicular papules

on the cheek of an adolescent
boy

Onset of the disease is noted a few months after birth, with the usual phenotype
being Fitzpatrick skin type II, blond-haired boys, with the inherited findings occurring
as an autosomal dominant disease with variable penetrance [7]. Pathogenesis is felt to
occur as the result of a plug that forms in the follicular ostium that causes keratotic
follicular papules and hair shaft deformation. Histologically, evidence of hyperkerato-
sis and hypergranulosis of the isthmus and infundibulum of the follicle lead to sur-
rounding inflammation in the dermis. Subsequently, mononuclear cells appear around
the superior follicle with surrounding mucin and destructive changes to connective
tissue. After the disintegration of the follicle, reactive changes surrounding a naked hair
shaft result in further inflammation and finally scarring in the final chronic phase [1].

50.3 Clinical Presentation

KPAF begins shortly after birth and is generally clinically evident before 5 years of
age with erythema and small horny follicular papules emerging laterally from the
eyebrows, often extending to the cheeks and forehead (Fig. 50.1). This condition is
often associated with atopic dermatitis, asthma, and seasonal allergies. On exam many
patients also often have keratosis pilaris on extremity extensor surfaces [8]. Eventually
the affected areas become atrophic with residual scarring alopecia. The cycle contin-
ues through adolescence but generally halts with the beginning of puberty.

50.4 Workup

Diagnosis is based on clinical findings and may be made soon after birth. Since
KPAF is believed to be inherited and is considered a marker of certain genetic
syndromes such as Noonan syndrome [9–11], Rubinstein-Taybi syndrome [12],
50 Keratosis Pilaris Atrophicans 369

Cornelia de Lange syndrome [13], and cardiofaciocutaneous syndrome [14, 15],

workup and appropriate treatment for coexisting disease may be initiated.
Histology depends on disease stage. All follicular keratoses form keratotic plugs
at the follicular orifice of the infundibulum which makes pathologic diagnosis dif-
ficult without relevant clinical history. Therefore, the initial stage of disease is
impossible to distinguish between the various forms based on histology alone. The
superficial dermis contains a predominantly lymphocytic infiltrate surrounding the
follicle with a few neutrophilic granulocytes that progresses to perifollicular fibrosis
with fewer lymphocytes over the course of disease. Further, the atrophic stage is
characterized by dermal sclerosis, atrophy of hair follicles, and formation of horn
cysts. Less commonly, dilated lymph vessels and blood vessels can also be seen. In
the final atrophic phase, the disease has the appearance of a cicatricial alopecia.

50.5 Treatment

There is no apparent universally effective treatment for KPAF. Initial attempts at

treatment were tried with antibiotics including sulfa-based medications, macrolides,
tetracyclines, and penicillin; all have been shown to be ineffective. Oral isotretinoin
has been described as effective by some authors at doses of 1–1.5 mg/kg [16] but
marginal to ineffective by others [1, 17]. Topical keratolytics and topical corticoste-
roids may reduce keratin plugging, obtain mild improvement in the erythema, and
slow progression of the alopecia [1, 18]. Immunomodulators such as cyclosporine
and methotrexate have been reported in other cicatricial alopecias [19–21] but not
KPAF and may represent a viable option. Surgical hair transplantation is a viable
option for many patients and appears to produce durable hair growth, at least in the
eyebrows, that is not susceptible to the lost native facial hair [22, 23].

50.6 Conclusion

KPAF is a progressive scarring condition affecting the face and the eyebrows. While
treatment is challenging, aggressive therapy early after diagnosis may halt progression
of the disease and minimize the onset of permanent scarring and alopecia later in life.

References

1. Baden HP, Byers HR. Clinical findings, cutaneous pathology, and response to therapy in 21
patients with keratosis pilaris atrophicans. Arch Dermatol. 1994;130:469–75.
2. Wilson, Erasmus (1878) Lectures on Dermatology. London. p 217
3. Paul Taenzer (1889) “Ueber das Ulerythema ophryogenes,” Monats. f. prakt. Derwnat.
Hamburg. pp 197–208.viii
4. Nazarenko SA, Ostroverkhova NV, Vasiljeva EO, et al. Keratosis pilaris and ulerythema
ophryogenes associated with an 18 p deletion caused by a Y/18 translocation. Am J Med
Genet. 1999;85:179–82.
370 O. Pacha and A. Hebert

5. Fiorentini C, Bardazzi F, Bianchi T, Patrizi A. Keratosis pilaris in a girl with monosomy 18p.
J Eur Acad Dermatol Venereol. 1999;12 suppl 2:S221.
6. Stratakis, Zouboulis, Gollnick HPM, Orfanos. Keratosis pilaris/ulerythema ophryogenes and
18p deletion: is it possible that theLAMA1 gene is involved? J Med Genet. 2001;38:127.
7. Oranje AP. Others. Keratosis pilaris atrophicans: one heterogeneous disease or a symptom in
different clinical entities? Arch Dermatol. 1994;130:500.
8. Davenport DD. Ulerythema ophryogenes. Arch Dermatol. 1964;89:134–40.
9. Pierini DO, Pierini AM. Keratosis pilaris atrophicans faciei (Ulerythema ophryogenes): a cuta-
neous marker in the Noonan syndrome. Br J Dermatol. 1979;100:409–16.
10. Snell JA, Mallory SB. Ulerythema ophryogenes in Noonan syndrome. Pediatr Dermatol.
1990;7:77–8.
11. Turner AM. Noonan syndrome. J Paediatr Child Health. 2011. doi:10.1111/j.1440-1754.
2010.01970.x.
12. Centeno PG, Roson E, Peteiro C, Pereiro M, Toribio J. Rubinstein-Taybi syndrome and
Ulerythema ophryogenes in a 9-year-old boy. Pediatr Dermatol. 1999;16:134–6.
13. Florez A, Fernandez-Redondo V, Toribio J. Ulerythema ophryogenes in Cornelia de Lange
syndrome. Pediatr Dermatol. 2002;19:42–5.
14. Manci EA, Martinez JE, Horenstein MG, Gardner TM, Ahmed A, Mancao MC, et al.
Cardiofaciocutaneous syndrome (CFC) with congenital peripheral neuropathy and nonorganic
malnutrition: An autopsy study. Am J Med Genet A. 2005;137A:1–8. doi:10.1002/ajmg.a.30834.
15. Borradori L, Blanchet-Bardon C. Skin manifestations of cardio-facio-cutaneous syndrome.
J Am Acad Dermatol. 1993;28:815–9.
16. Layton AM, Cunliffe WJ. A case of ulerythema ophryogenes responding to isotretinoin. Br J
Dermatol. 1993;129:645–6.
17. Burnett JW, Schwartz MF, Berberian BJ. Ulerythema ophryogenes with multiple congenital
anomalies. J Am Acad Dermatol. 1988;18:437–40.
18. Callaway SR, Lesher JL. Keratosis pilaris atrophicans: case series and review. Pediatr
Dermatol. 2004;21:14–7.
19. Ross EK, Tan E, Shapiro J. Update on primary cicatricial alopecias. J Am Acad Dermatol.
2005;53(1):1–37. doi:10.1016/j.jaad.2004.06.015. ISSN 0190–9622.
20. Di Lernia V, Bisighini G. Discoid lupus erythematosus during treatment with cyclosporine.
Acta Derm Venereol. 1996;76:87–8.
21. Mirmirani P, Willey A, Price VH. Short course of oral cyclosporine in lichen planopilaris.
J Am Acad Dermatol. 2003;49:667–71.
22. Goldman GD. Eyebrow Transplantation. Dermatol Surg. 2001;27:352–4. doi:10.1046/j.1524-4725.
2001.00209.x.
23. Barankin B, Taher M, Wasel N. Successful hair transplant of eyebrow alopecia areata. J Cutan
Med Surg. 2005;9:162–4.
Chapter 51
Neonatal and Infantile Acne

Hilary Baldwin

51.1 Introduction

Acne vulgaris is a disease that typically affects teenagers but may continue into
adulthood in some cases. However, acneiform eruptions can occur in the pediatric
population from birth onward. Neonatal acne refers to lesions that develop in the
neonatal period, from birth through 4 weeks old. Some consider neonatal acne to be
synonymous with neonatal cephalic pustulosis. Infantile acne refers to the acneiform
eruption that typically presents in children between 1 month and 1 year old [1].
Making the correct diagnosis can be a challenge, and in some cases the diagnosis of
infantile acne is given whenever comedones are clinically present even if the patient
is a neonate.

51.2 Background

It is estimated that up to 20 % of newborns develop an acneiform eruption. Neonatal

acne occurs much more frequently in boys than girls. Two main theories exist
regarding the condition’s pathophysiology. First, maternal androgens are thought to
stimulate sebaceous glands in neonates [2, 3]. Second, it is postulated that an
increase in neonatal dehydroepiandrosterone (DHEA) stimulates the adrenal glands.
There is a questionable association between neonatal acne and the development of
acne later in adolescence [3].
Neonatal cephalic pustulosis (NCP) is another name given to acneiform erup-
tions seen in neonates. Some experts consider this a separate entity from true
neonatal acne and attribute it to the presence of Malassezia yeast on the skin [4].

H. Baldwin, M.D. (*)

Department of Dermatology, SUNY Downstate School of Medicine, Brooklyn, NY, USA

J.A. Zeichner (ed.), Acneiform Eruptions in Dermatology: A Differential Diagnosis, 371

DOI 10.1007/978-1-4614-8344-1_51, © Springer Science+Business Media New York 2014
372 H. Baldwin

In one study, pustules of the necks of 8 of 13 neonates with acne revealed M. furfur
[5]. However, not all patients with the eruption have positive cultures, suggesting
hypersensitivity to yeast as the causative factor rather than level of colonization
itself [6–8].
Little epidemiological data is available on infantile acne, as it so uncommon.
Expert opinions suggest that it occurs more commonly in boys than girls. Infantile
acne usually presents between 3 and 6 months of age, but it may develop as early as
immediately after birth or as late as 1 year old. While pustular lesions may be pres-
ent in both NCP and infantile acne, the presence of comedonal lesions distinguishes
infantile acne from the pustular lesions of neonatal acne/ NCP [6].

51.3 Clinical Presentation

Neonatal acne typically presents with pustules and erythematous papules on the
cheeks, chin, and forehead (see Fig. 51.1). Lesions less commonly affect the neck,
chest, or scalp. Comedones may occasionally be present as well. Most cases are
mild in severity and self-limited, resolving spontaneously within 3 months [2]. NCP
patients may present predominantly with pustules and inflammatory papules, but
characteristically lack comedones.
Infantile acne may begin in the neonatal period with the presence of comedones
that persist as the child ages. Unlike in neonatal acne, patients with infantile acne
tend to develop inflammatory lesions, including papules, pustules, and in some
cases nodules or cysts [9]. While infantile acne typically resolves by the age of 1
year, it may rarely persist for several years [10]. Inflammatory disease can result in
scarring if not appropriately treated. It also may be associated with the development
of severe acne later in life during adolescence [6].

Fig. 51.1 Neonatal acne in a

1-month-old baby girl.
Erythematous papules and
pustules developed on the
cheeks and chin (Photo
credit: Joshua A. Zeichner,
M.D.)
51 Neonatal and Infantile Acne 373

51.4 Workup

When evaluating a newborn with an acneiform eruption, all causes of a pustular

eruption should be considered. Common conditions in the differential diagnosis
seen in this population are erythema toxicum neonatorum, transient neonatal pustu-
lar melanosis, and miliaria. Less commonly, a bacterial, viral, or fungal infection
may be present. Other dermatoses to be considered include keratosis pilaris, milia,
molluscum contagiosum, sebaceous hyperplasia, or warts. Maternal medications
such as lithium or corticosteroids might be causative. In most cases, laboratory eval-
uation is not necessary. Exceptions are cases in which the neonate demonstrates
significant developmental abnormalities [6, 11].
In cases of suspected infantile acne, especially in those with inflammatory
lesions, disorders associated with excess corticosteroids or androgens must be
evaluated. These include congenital adrenal hyperplasia, a virilizing tumor, or
another underlying endocrinopathy. High blood pressure, hand or foot growth, and
development of secondary sex characteristics are all signs of an underlying disor-
der. In children with no signs of abnormalities other than acne, no further workup
is needed [6, 11].

51.5 Treatment

Neonatal acne/NCP is a benign and self-limited condition that resolves within

weeks without therapy. However, parents are often concerned and request treat-
ment. In these cases, topical azole antifungals may be prescribed [12]. Some experts
suggest ketoconazole 2 % cream twice daily for 1 week. If lesions persist past 1
month, the patient may in fact have early-onset infantile acne requiring treatment
with topical retinoids, benzoyl peroxide, or topical antibiotics [6, 11].
First-line therapy for infantile acne is the use of topical medications. Combination
therapy may be used as needed with topical retinoids and benzoyl peroxide, with or
without topical antibiotics [6, 11]. In some moderate to severe cases, systemic medi-
cations may need to be added. Caution should be taken to avoid tetracycline class
oral antibiotics in children under 8 years old, as they are associated with bone and
tooth abnormalities [13]. Intralesional steroids may be administered and expert
opinions report use oral isotretinoin in select severe patients [6, 11].

51.6 Conclusion

While most common in adolescence, acne can occur as early as the neonatal period.
The lesions observed in newborns is most commonly associated with Malassezia
yeast on the skin surface. However, true comedonal disease does occur. Therapy
should be initiated based on clinical appearance and the parents’ preferences.
374 H. Baldwin

References

1. Friedlander SF, Eichenfield LF, Fowler Jr JF, et al. Acne epidemiology and pathophysiology.
Semin Cutan Med Surg. 2010;29:2–4.
2. Cantatore-Francis JL, Glick SA. Childhood acne: evaluation and management. Dermatol Ther.
2006;19:202–9.
3. Antoniou C, Dessinoti C, Stratigos A, Katsambas AD. Clinical and therapeutic approaches to
childhood acne: an update. Pediatr Dermatol. 2009;26:373–80.
4. Bergman J, Eichenfield LF. Neonatal acne and cephalic pustulosis: is Malassezia the whole
story? Arch Dermatol. 2002;138:255–7.
5. Rapelanoro R, Mortureux P, Couprie B, Malleville J, Taieb A. Neonatal Malassezia furfur
pustulosis. Arch Dermatol. 1996;132:190–3.
6. Eichenfield LF, Baldwin HE, Friedlander SF, Mancini AJ, Yan AC. Pediatric acne manage-
ment: optimizing outcomes. Semin Cutaneous Med Surg. 2011;30 Suppl 1:3S.
7. Bernier V, Weill FX, Hirigoyen V, et al. Skin colonization by Malassezia special in neonates:
a prospective study and relationship with neonatal cephalic pustulosis. Arch Dermatol.
2002;138:215–8.
8. Ayhan M, Sancak B, Karaduman A, Arikan S, Sarhin S. Colonization of neonate skin by
Malassezia species: relationship with neonatal cephalic pustulosis. J Am Acad Dermatol.
2007;57:1012–10128.
9. Tom WL, Friedlander SF. Acne through the ages: case-based observations through childhood
and adolescence. Clin Pediatr (Phila). 2008;47:639–51.
10. Chew EW, Bingham A, Burrows D. Incidence of acne vulgaris in patients with infantile acne.
Clin Exp Dermatol. 1990;15:376–7.
11. Krakowski AC, Eichenfield LF. Pediatric acne: clinical presentations, evaluation, and manage-
ment. J Drugs of Dermatol. 2007;6(6):589–93.
12. Sancak B, Ayhan M, Karaduman A, Arikan S. In vitro activity of ketoconazole, itraconazole
and terbinafine against Malassezia strains isolated from neonates. Microbiyol Bul. 2005;39:
301–8.
13. Gollnick H, Cunliffe W, Berson D, et al. Management of acne: a report from a Global Alliance
to Improve Outcomes in Acne. J Am Acad Dermatol. 2003;49(1 Suppl):S1–37.
Chapter 52
Papular Granuloma Annulare

Rebecca Smith

52.1 Introduction

Granuloma annulare (GA) is a common benign dermatosis usually presenting as

annular plaques composed of intradermal papules. Skin findings were first described
by Fox in 1895 [1], and the designation “granuloma annulare” was introduced by
Radcliff-Crocker in 1902 [2]. The eruption is generally asymptomatic and can spon-
taneously resolve. While the localized type is clinically most common, variants
include disseminated, subcutaneous, and perforating lesions. Although clinically a
ringed lesion is generally seen in the localized form of GA, the less common papu-
lar presentation of granuloma annular is not ringed and therefore could potentially
mimic an acneiform eruption.

52.2 Background

The cause of GA is unknown although it has been reported to follow trauma [3],
viral infections [4], tuberculin skin tests, malignancies [5], solar radiation, and
insect bites [6]. It is hypothesized that a cell-mediated delayed-type hypersensitivity
reaction to an unknown antigen is the inciting event. It has been postulated that the
characteristic rings may form in response to a centralized insult that sets off an
inflammatory chain reaction [7].
Granuloma annulare can occur at any age, but is most commonly diagnosed in
children and young adults. Females are affected twice as commonly as males [8].

R. Smith, M.D. (*)

Fort Mill Dermatology, LLC, 1700 First Baxter Crossing, Suite 101,
Fort Mill, SC 29708, USA

J.A. Zeichner (ed.), Acneiform Eruptions in Dermatology: A Differential Diagnosis, 375

DOI 10.1007/978-1-4614-8344-1_52, © Springer Science+Business Media New York 2014
376 R. Smith

The disseminated form is more common in adults [9]. The condition is usually seen
in otherwise healthy patients but has occasionally been associated with diabetes or
thyroid disease [10]. While the disease is usually sporadic, inherited cases have
been described with an increased incidence of HLA-Bw35 in Israel [11], HLA-B8
in Denmark [12], and HLA-A29, B14, and B15 in Belfast [13]. The association with
these particular phenotypes, however, may simply be population specific.

52.3 Clinical Presentation

GA presents with skin findings only. The most common form of GA is the localized
type which presents as ringed, firm, and flesh-colored to slightly erythematous pap-
ules without scale or epidermal change (insert Fig. 52.1); the ringed papules can
affect any skin surface, but is most commonly found on the extremities. The face and
scalp are only rarely affected. The distribution of GA is approximately 60 % isolated
to hands and arms, 20 % to legs and feet, and 7 % on both the upper and lower
extremities. Fewer than 5 % of patients present with lesions on the trunk [14]. The
rings vary in size and slowly expand reaching up to several centimeters in diameter
with central clearing. Many patients have only a single ring, but multiple lesions are
common. Over half of the patients with localized disease experience spontaneous
resolution within 2 years. A papular umbilicated form of GA without perforation has
been described in school age children on the dorsal hands and fingers [15].
Only rarely would papular GA be confused clinically with acne due to the dif-
ference in location and the lack of epidermal change. A localized papular eruption
of GA on the chest or back could mimic an acneiform eruption, but the lack of
comedones or pustules and the more monomorphous nature of GA would argue
against acne. Papular GA would more often be in the differential diagnosis of
arthropod assault reaction, secondary syphilis, xanthomas, or non-X-histiocytosis.

Fig. 52.1 Flesh-colored,

occasionally pruritic papules
without scale on the inner
wrist (Photo credit: Joshua A.
Zeichner, M.D.)
52 Papular Granuloma Annulare 377

With papular GA, the diagnosis is often difficult due to the lack of the more typical
annular plaques.
The differential diagnosis for classic GA includes annular lichen planus and
tinea corporis. Often children have been unsuccessfully treated for tinea before
presenting to a dermatologist for definitive diagnosis. A potassium hydroxide prep-
aration, the lack of scale, and/or a confirmatory biopsy can differentiate these
entities.
Generalized or disseminated GA consists of hundreds to thousands of individual,
small papules that may form small annular plaques, are usually symmetrical, and
can coalesce into reticulated, circinate, or linear patterns [10]. Unlike other forms of
GA, the trunk is usually involved with a propensity for the neck, forearms, legs, and
extensor elbows. This form may exhibit a slightly more violaceous color. It is
unusual to see involvement of the face, palms, soles, or mucous membranes [9].
Subcutaneous GA is a variant generally seen in young children with large,
asymptomatic, skin colored, rapidly enlarging deep dermal or subcutaneous nod-
ules [16]. They may be solitary or multiple and have a predilection for pretibial skin,
palms, soles, buttocks, fingers, toes, and periorbital areas. The skin overlying the
lesions can ulcerate and often these nodules spontaneously regress. Deep GA can
clinically resemble rheumatoid nodules, deep granulomatous infections, and subcu-
taneous sarcoid.
Perforating GA is a more rare form consisting of asymptomatic, superficial
small-grouped papules with central umbilicated ulcerations and scale crust. These
occur most frequently on the dorsal hands and fingers [17]. Differential diagnosis of
perforating GA includes perforating collagenosis, Kyrle disease, and elastosis per-
forans serpiginosa.

52.4 Workup

Patients with GA are generally healthy and laboratory tests are usually normal and
not recommended. The disseminated form may be seen more commonly in immu-
nocompromised patients such as those with human immunodeficiency virus and
lymphomas. Such patients may also have GA in atypical locations.
Often, the diagnosis can be made clinically, but a confirmatory punch biopsy can
be helpful especially with the less common variants. Histologically, GA is a granu-
lomatous dermatitis exhibiting focal degeneration of collagen and elastin fibers,
mucin deposition, and a perivascular and interstitial lymphohistiocytic infiltrate in
the upper and mid-dermis [18]. It is the increased mucin that is the hallmark of GA
[19]. If not readily apparent on routine stains, using colloidal iron or Alcian blue to
highlight mucin can be helpful. Palisaded granuloma with central connective tissue
degeneration surrounded by histiocytes and lymphocytes is a common pattern seen
microscopically. Often, the pattern is more infiltrative or interstitial with scattered
histiocytes infiltrating between collagen fibers. In perforating GA there is transepi-
dermal elimination of the degenerating collagen bundles.
378 R. Smith

52.5 Treatment

GA is rarely symptomatic, and due to the benign and often self-limited nature,
clinical observation and reassurance are often the treatment of choice. While lesions
can have a chronic relapsing course, they usually persist for only 1–4 years, and
73 % of all lesions disappear within 2 years. Cosmetic disfigurement can prompt the
need for intervention and many modalities have been utilized. First-line therapies
include topical steroids with or without occlusion or intralesional injections of tri-
amcinolone. Complete involution of the entire lesion has been reported to follow
biopsy. Other treatment modalities include cryosurgery [20], topical calcineurin
inhibitors, PUVA [21], and CO2 laser [22].
In general, systemic agents are reserved for more severe generalized cases. GA
has been treated with short-term oral corticosteroids, chlorpropamide, pentoxifyl-
line [23], nicotinamide, niacinamide [24], isotretinoin [25], etretinate [26], salicy-
lates, potassium iodide, vitamin E, fumaric acid esters, antimalarials [27], dapsone
[28], cyclosporine [29], and infliximab. Spontaneous resolution of the disease
makes evaluation of the efficacy of such treatments more difficult. No large, ran-
domized placebo-controlled double-blind studies have been performed.

52.6 Conclusion

The papular form of GA may mimic acne vulgaris in some cases. The lack of
comedones and pustules and the monomorphic papular appearance of this rash clin-
ically distinguish it from acne. While self-limited in most cases, lesions can persist
for months to years, so therapies are targeted towards symptomatic relief and the
unsightly appearance.

References

1. Colcott Fox T. Ringed eruption of the fingers. Br J Dermatol. 1895;7:91.

2. Radcliffe-Crocker H. Granuloma annulare. Br J Dermatol. 1902;14:1–9.
3. Mills A, Chetty R. Auricular granuloma annulare. A consequence of trauma? Am J
Dermatopathol. 1992;14:431–3.
4. Spencer SA, Fenske NA, Espinoza CG, Hamill JR, Cohen LE, Espinoza LR. Granuloma
annulare-like eruption due to chronic Epstein-Barr virus infection. Arch Dermatol.
1988;124:250–5.
5. Barksdale SK, Perniciaro C, Halling KC, et al. Granuloma annulare in patients with malignant
lymphoma: clinicopathologic study of 13 new cases. J Am Acad Dermatol. 1994;31:42–8.
6. Moyer DG. Papular granuloma annulare. Arch Dermatol. 1964;89:41–5.
7. Dahl MV. Is actinic granuloma really granuloma annulare? Arch Dermatol. 1986;122:39–40.
8. Wells RS, Smith MA. The natural history of granuloma annulare. Br J Dermatol. 1963;
75:199–205.
9. Muhlbauer JE. Granuloma annulare. J Am Acad Dermatol. 1980;3:217–30.
52 Papular Granuloma Annulare 379

10. Dabski K, Winkelmann RK. Generalized granuloma annulare: clinical and laboratory findings
in 100 patients. J Am Acad Dermatol. 1989;20:39–47.
11. Friedman-Birnbaum R, Gideoni O, Bergman R, Pollack S. A study of HLA antigen association
in localized and generalized granuloma annulare. Br J Dermatol. 1986;115:329–33.
12. Andersen BL, Verdich J. Granuloma annulare and diabetes mellitus. Clin Exp Dermatol.
1979;4:31–7.
13. Middleton D, Allen GE. HLA antigen frequency in granuloma annulare. Br J Dermatol.
1984;110:57–9.
14. Cronquist SD, Stashower ME, Benson PM. Deep dermal granuloma annulare presenting as an
eyelid tumor in a child, with review of pediatric eyelid lesions. Pediatr Dermatol.
1999;16:377–80.
15. Lucky AW, Prose NS, Bove K, White WL, Jorizzo JL. Papular umbilicated granuloma annu-
lare. Arch Dermatol. 1992;128:1375–8.
16. Felner EI, Steinberg JB, Weinberg AG. Subcutaneous granuloma annulare: a review of 47
cases. Pediatrics. 1997;100:965–7.
17. Shimizu H, Harada T, Baba E, Kuramochi M. Perforating granuloma annulare. Int J Dermatol.
1985;24:581–3.
18. Elder D, Elenitsas R, Jaworsky C, Johnson B. Lever’s Histopathology of the skin. 8th ed.
Philadelphia, PA: Lippincott-Raven Publishers; 1997.
19. Dabski K, Winkelmann RK. Generalized granuloma annulare: histopathology and immunopa-
thology. Systematic review of 100 cases and comparison with localized granuloma annulare.
J Am Acad Dermatol. 1989;20:28–39.
20. Blume-Peytavi U, Zouboulis CC, Jacobi H, Scholz A, Bisson S, Orfanos CE. Successful
outcome of cryosurgery in patients with granuloma annulare. Br J Dermatol. 1994;130:
494–7.
21. Hindson TC, Spiro JG, Cochrane H. PUVA therapy of diffuse granuloma annulare. Clin Exp
Dermatol. 1988;13:26–7.
22. Rouilleault PH. CO2 laser and granuloma annulare. J Dermatol Surg Oncol. 1988;14:120.
23. Rubel DM, Wood G, Rosen R, Jopp-McKay A. Generalised granuloma annulare successfully
treated with pentoxifylline. Australas J Dermatol. 1993;34:103–8.
24. Ma A, Medenica M. Response of generalized granuloma annulare to high-dose niacinamide.
Arch Dermatol. 1983;119:836–9.
25. Ratnavel RC, Norris PG. Perforating granuloma annulare: response to treatment with isotreti-
noin. J Am Acad Dermatol. 1995;32:126–7.
26. Botella-Estrada R, Guillen C, Sanmartin O, Aliaga A. Disseminated granuloma annulare: reso-
lution with etretinate therapy. J Am Acad Dermatol. 1992;26:777–8.
27. Simon Jr M, von den Driesch P. Antimalarials for control of disseminated granuloma annulare
in children. J Am Acad Dermatol. 1994;31:1064–5.
28. Steiner A, Pehamberger H, Wolff K. Sulfone treatment of granuloma annulare. J Am Acad
Dermatol. 1985;13:1004–8.
29. Fiallo P. Cyclosporin for the treatment of granuloma annulare. Br J Dermatol. 1998;138:
369–70.
Chapter 53
Precocious Puberty and Acne

Maria Miyar and Moise L. Levy

53.1  Introduction

Precocious puberty is defined as the onset of breast or pubic hair development

before age 8 in girls and the onset of testicular development of more than 3 ml
before age 9 in boys. The age limit is based on the data from a 1969 study done by
Marshall and Tanner [1]. There is evidence to show that normal puberty in the USA
and Europe is occurring earlier in children [2, 3]. A 2012 study suggested that
puberty in boys might be occurring 6 months to 2 years earlier than documented in
the previous Marshall and Tanner study [4]. In 1999 the Pediatric Endocrine Society
proposed lowering the age limit for precocious puberty to be less than 7 years old in
white girls and less than 6 years old in African-American girls [5]. Some argue that
if the age limit of normal puberty is lowered, children between the ages of 6 and 8
with precocious puberty will be missed, resulting in a loss of height potential [6].
This chapter will describe precocious puberty as it relates to acne and address when
an evaluation and treatment for precocious puberty should be undertaken when a
young child presents with acne.

M. Miyar, M.D.
Department of Dermatology, UT Southwestern, Austin, TX, USA
M.L. Levy, M.D. (*)
Department of Pediatric Dermatology, Dell Children’s Medical Center,
4900 Mueller Blvd., Austin, TX 78723, USA
e-mail: [email protected]

J.A. Zeichner (ed.), Acneiform Eruptions in Dermatology: A Differential Diagnosis, 381

DOI 10.1007/978-1-4614-8344-1_53, © Springer Science+Business Media New York 2014
382 M. Miyar and M.L. Levy

53.2  Background

Precocious puberty is centrally mediated in approximately 90 % of cases through

activation of the hypothalamic-pituitary-gonadal (HPG) axis [7]. It occurs more
often in girls and it is usually attributed to a sporadic cause. In males, however, it is
attributed to a central nervous system abnormality in 75 % of cases. Peripheral or
precocious pseudopuberty, a much less common form of precocious puberty, occurs
when hormones that initiate puberty are produced from a gonadotropin-independent
source or a peripheral source. There is no activation of the HPG axis in peripheral
precocious puberty but some secondary sex characteristics appear. Examples of
peripheral precocious puberty in females include ovarian tumors, autonomously
functioning ovarian cysts, feminizing adrenal tumors, McCune-Albright syndrome,
and exogenous sources of estrogens. Examples in males include congenital adrenal
hyperplasia (CAH), adrenal tumors, Leydig cell tumors, chorionic gonadotropin-­
producing tumors, and familial male precocious puberty. Sometimes peripheral pre-
cocious puberty can activate the HPG axis, and this is known as a mixed type of
precocious puberty and occurs in McCune-Albright syndrome, CAH, and familial
male-limited precocious puberty. A person with precocious puberty normally exhib-
its the sequences of normal puberty with sexual development beginning at an earlier
age than normal [8].
Acne may be the presenting sign of the onset of puberty in children associated
with the onset of adrenarche. In girls this may precede breast or pubic hair develop-
ment [9]. The increase of androgenetic steroids such as dehydroepiandrosterone
sulfate (DHEA-S) stimulates sebum production [10, 11] and plays a role in contrib-
uting to the retention hyperkeratosis central to the pathogenesis of acne [12]. The
prevalence and severity of acne often increases as pubertal maturation occurs [13].
There is normally little androgen production in children between the ages of 1–7
years old [14]. So children presenting to the office with acne at younger ages should
be evaluated for hyperandrogenism [15]. Potential causes include premature adre-
narche, mild forms of congenital adrenal hyperplasia, gonadal or adrenal tumors,
Cushing’s syndrome, and true precocious puberty as described above [12].
Premature adrenarche is an incomplete form of precocious puberty, with evidence
of early development of pubic and or axillary hair without breast development in
girls or testicular development in boys [8].

53.3  Clinical Presentation

The presence of acne in a child between 1 and 7 years old is unusual and raises a
concern for precocious puberty or hyperandrogenemia [16, 17]. Severe or recalci-
trant acne are especially suspicious [17, 18]. These patients usually present with
comedones on the central face, including the mid-forehead, nose, and chin
(Fig.  53.1). Comedones in the concha of the ear are also suspicious (Fig. 53.2).
53  Precocious Puberty and Acne 383

Fig. 53.1  Comedones on the

nose of a 6-year-old girl. In
addition, she had scattered
inflammatory papules on the
cheeks (Photo credit: Joshua
A. Zeichner, M.D.)

Fig. 53.2  Open comedones

on the conchal bowl of the
ear (Photo credit: Joshua A.
Zeichner, M.D.)

Inflammatory lesions may be present as well [9]. The child should be examined for
signs of advanced pubertal development, such as axillary or pubic hair development
and breast development in girls or testicular development in boys. Other signs of
precocious puberty include advanced osseous maturation and a high height and
weight for age [8]. The increased rate of bone maturation can result in premature
epiphyseal closure translating to a shorter adult stature. Approximately 30 % of
girls and an even higher percentage of boys with precocious puberty grow to less
than the 5th percentile of height as adults [2, 8]. While cognitive development is
normal, these children may have emotional and behavioral issues [8].
384 M. Miyar and M.L. Levy

53.4  Workup

Initial evaluation for precocious puberty should include a review of the growth
chart, examination of bone age, and laboratory evaluations. Bone age measurement
can help determine if there is advanced bone age and is considered by some to be
the best screening evaluation for precocious puberty [16–19]. Children with preco-
cious puberty often have a bone age 2–3 standard deviations above their chronologi-
cal age [8]. Moreover, children with high androgen levels have accelerated growth
across standardized growth percentiles [19]. Children with suspected precocious
puberty or hyperandrogenism require a hormonal evaluation, which can be per-
formed by the dermatologist, pediatrician, or more commonly, referral to a pediatric
endocrinologist [20, 21]. Initial screening tests include serum free and total testos-
terone, DHEA-S, estradiol, and ratio of luteinizing hormone (LH) to follicle-­
stimulating hormone (FSH) [19]. Moderate elevation of DHEA-S is suggestive of
an adrenal pathology (e.g., CAH), while extremely high levels of DHEA-S and/or
testosterone are more suggestive of an adrenal tumor [22].
Concentrations of sex hormones may be used to help stage puberty. In both early
normal puberty and the early phase of sexual precocity, serum estradiol is low or
undetectable in girls. Serum testosterone levels are detectable or slightly elevated at
the time of diagnosis in boys. LH levels are also elevated in children with central
sexual precocity. The gonadotropin-releasing hormone (GnRH) stimulation test is
also helpful in diagnosing precocious puberty. The test shows whether there is a
predominance of LH over FSH [23]. Females with poor LH response in the GnRH
stimulation test may also have a leuprolide stimulation test to evaluate for estradiol
levels [8]. Other laboratory tests to be evaluated in working up hyperandrogenism
include prolactin, cortisol, 17α-hydroxyprogesterone, androstenedione, and an
adrenocorticotropic hormone (ACTH) stimulation test [16–18, 22]. Imaging tech-
nology is also helpful as pelvic ultrasonography can detect ovarian and uterine
enlargement in girls. Magnetic resonance imaging (MRI) of the brain is indicated if
true central precocious puberty is suspected [2].

53.5  Treatment

Acne treatment in a child with precocious puberty depends on severity of the acne.
In general, mild cases of comedonal acne can be treated with topical retinoids like
tretinoin or adapalene. Combination therapy is usually most successful using com-
edolytic agent like a retinoid along with topical benzoyl peroxide or salicylic acid
[17]. Mild inflammatory lesions can be treated with topical benzoyl peroxide and/or
topical antibiotics like clindamycin or erythromycin [19]. Fixed-dose combination
products containing more than one active ingredient in one product are good options
for children, as only one product needs to be used. For more severe or recalcitrant
disease, oral antibiotics or oral retinoids may be needed. However, tetracyclines
53  Precocious Puberty and Acne 385

should not be used in children younger than 8 years old due to the potential damage
to the developing bones and teeth [24]. If antibiotics are to be used in children less
than 8 years old, erythromycin and trimethoprim/sulfamethoxazole are treatment
options [18].
If a patient is suspected of precocious puberty, early involvement of a pediatric
endocrinologist is advised. While acne may be managed by dermatologists, cur-
rent hormonal therapies that may be prescribed by endocrinologists include GnRH
agonists and growth hormone (GH). Treatment with GnRH agonists such as leup-
rolide helps prevent early fusion of the epiphyseal plates to avoid unnecessary
short stature [25].

References

1. Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Arch Dis Child.
1969;44(235):291–303.
2. Sørensen K, Mouritsen A, Aksglaede L, Hagen CP, Mogensen SS, Juul A. Recent secular
trends in pubertal timing: implications for evaluation and diagnosis of precocious puberty.
Horm Res Paediatr. 2012;77(3):137–45.
3. Biro FM, Galvez MP, Greenspan LC, Succop PA, Vangeepuram N, Pinney SM, et al. Pubertal
assessment method and baseline characteristics in a mixed longitudinal study of girls.
Pediatrics. 2010;126(3):e583–90.
4. Herman-Giddens ME, Steffes J, Harris D, Slora E, Hussey M, Dowshen SA, et al. Secondary
sexual characteristics in boys: data from the Pediatric Research in Office Settings Network.
Pediatrics. 2012;130(5):e1058–68.
5. Kaplowitz PB, Oberfield SE. Reexamination of the age limit for defining when puberty is
precocious in girls in the United States: implications for evaluation and treatment. Drug and
Therapeutics and Executive Committees of the Lawson Wilkins Pediatric Endocrine Society.
Pediatrics. 1999;104(4 Pt 1):936–41.
6. Midyett LK, Moore WV, Jacobson JD. Are pubertal changes in girls before age 8 benign?
Pediatrics. 2003;111(1):47–51.
7. Cisternino M, Arrigo T, Pasquino AM, Tinelli C, Antoniazzi F, Beduschi L, et al. Etiology and
age incidence of precocious puberty in girls: a multicentric study. J Pediatr Endocrinol Metab.
2000;13 Suppl 1:695–701.
8. Kliegman RM. Nelson textbook of pediatrics. 19th ed. Philadelphia, PA: Elsevier/Saunders;
2011.
9. Lucky AW, Biro FM, Huster GA, Leach AD, Morrison JA, Ratterman J. Acne vulgaris in
premenarchal girls. An early sign of puberty associated with rising levels of dehydroepian-
drosterone. Arch Dermatol. 1994;130(3):308–14.
10. Pochi PE, Strauss JS, Downing DT. Skin surface lipid composition, acne, pubertal develop-
ment, and urinary excretion of testosterone and 17-ketosteroids in children. J Invest Dermatol.
1977;69(5):485–9.
11. Lucky AW, Biro FM, Simbartl LA, Morrison JA, Sorg NW. Predictors of severity of acne
vulgaris in young adolescent girls: results of a five-year longitudinal study. J Pediatr.
1997;130(1):30–9.
12. Mancini AJ, Baldwin HE, Eichenfield LF, Friedlander SF, Yan AC. Acne life cycle: the spec-
trum of pediatric disease. Semin Cutan Med Surg. 2011;30(3 Suppl):S2–5.
13. Lucky AW, Biro FM, Huster GA, Morrison JA, Elder N. Acne vulgaris in early adolescent
boys. Correlations with pubertal maturation and age. Arch Dermatol. 1991;127(2):210–6.
386 M. Miyar and M.L. Levy

14. Reiter EO, Fuldauer VG, Root AW. Secretion of the adrenal androgen, ­dehydroepiandrosterone
sulfate, during normal infancy, childhood, and adolescence, in sick infants, and in children
with endocrinologic abnormalities. J Pediatr. 1977;90(5):766–70.
15. Goldberg JL, Dabade TS, Davis SA, Feldman SR, Krowchuk DP, Fleischer AB. Changing age
of acne vulgaris visits: another sign of earlier puberty? Pediatr Dermatol. 2011;28(6):645–8.
16. Paller AS, Mancini AJ. Hurwitz clinical pediatric dermatology. 4th ed. Edinburgh, NY:
Elsevier Saunders; 2011.
17. Cantatore-Francis JL, Glick SA. Childhood acne: evaluation and management. Dermatol Ther.
2006;19(4):202–9.
18. Antoniou C, Dessinioti C, Stratigos AJ, Katsambas AD. Clinical and therapeutic approach to
childhood acne: an update. Pediatr Dermatol. 2009;26(4):373–80.
19. Lucky AW. A review of infantile and pediatric acne. Dermatology (Basel). 1998;

196(1):95–7.
20. De Raeve L, De Schepper J, Smitz J. Prepubertal acne: a cutaneous marker of androgen
excess? J Am Acad Dermatol. 1995;32(2 Pt 1):181–4.
21. Eichenfield LF, Fowler Jr JF, Friedlander SF, Levy ML, Webster GF. Diagnosis and evaluation
of acne. Semin Cutan Med Surg. 2010;29(2 Suppl 1):5–8.
22. Lucky AW. Hormonal correlates of acne and hirsutism. Am J Med. 1995;98(1A):89S–94S.
23. Iughetti L, Predieri B, Ferrari M, Gallo C, Livio L, Milioli S, et al. Diagnosis of central preco-
cious puberty: endocrine assessment. J Pediatr Endocrinol Metab. 2000;13 Suppl 1:709–15.
24. Ray WA, Federspiel CF, Schaffner W. Prescribing of tetracycline to children less than 8 years
old. A two-year epidemiologic study among ambulatory Tennessee medicaid recipients.
JAMA. 1977;237(19):2069–74.
25. Appelbaum H, Malhotra S. A comprehensive approach to the spectrum of abnormal pubertal
development. Adolesc Med State Art Rev. 2012;23(1):1–14.
 Part VII
Drug-Induced Acneiform Eruptions
Chapter 54
Drug-Induced Acneiform Eruptions

Ha K. Do, Navid Ezra, and Stephen E. Wolverton

54.1 Introduction

Acne vulgaris is a polymorphic inflammatory skin disease, clinically characterized

by mixture of comedones, superficial and deep inflamed papules, pustules, and nod-
ules. It is a chronic inflammation of the pilosebaceous unit. Acneiform drug erup-
tions are a monomorphic inflammatory skin disease lacking comedones with lesions
typically in the same stage. This type of drug eruption has an abrupt onset and is
often associated with various medications (Table 54.1). The pathogenesis of acne-
iform drug eruptions is poorly understood; documented evidence when available
will be presented under the specific drug categories in this chapter.

54.2 Drugs Associated with Acneiform Eruption

54.2.1 Hormones

54.2.1.1 Corticosteroids

Systemic corticosteroids causing acneiform eruption were first reported in 1950s [1].
Exposure to high levels of systemic (oral [2] or intravenous [3]), topical [4, 5], and
inhaled [6–8] corticosteroids can induce or exacerbate acne. Perioral (periorificial)

H.K. Do, M.D. • N. Ezra, M.D. • S.E. Wolverton, M.D. ()

Department of Dermatology, Indiana University School of Medicine,
New York, NY, USA
e-mail: [email protected]; [email protected]; [email protected]

J.A. Zeichner (ed.), Acneiform Eruptions in Dermatology: A Differential Diagnosis, 389

DOI 10.1007/978-1-4614-8344-1_54, © Springer Science+Business Media New York 2014
390 H.K. Do et al.

Table 54.1 Drugs involved with acneiform eruption

Hormones
Oral, inhaled, and topical corticosteroids
Anabolic steroids and androgens
Danazol
Hormonal contraceptives (levonorgestrel)
Neuropsychotropic agents
Tricyclic antidepressants
Amineptine
Maprotiline
Imipramine
Lithium
Antiepileptics
Hydantoin (phenytoin)
Lamotrigine
Valproate
Antipsychotics
Aripiprazole
Targeted therapies
Epidermal growth factor receptor inhibitors (EGFR inhibitors)
Erlotinib
Gefitinib
Imatinib
Epidermal growth factor receptor monoclonal antibodies
Cetuximab
Panitumumab
TNF-α inhibitors
Infliximab
Lenalidomide
G-CSF
Vemurafenib
Retinoids
Etretinate
Cardiac medication
Propranolol
Quinidine
Immunosuppressive agents
Sirolimus
Tacrolimus
Cyclosporine
Azathioprine
Antituberculosis drugs
Isoniazid
Rifampicin
Thiacetazone
Other medications
Gold
(continued)
54 Drug-Induced Acneiform Eruptions 391

Table 54.1 (continued)

Dactinomycin
Dapsone
Halogens
Bromides
Dioxin
Iodides
Vitamins
Vitamin B6 and B12
White petrolatum
Cow udder ointment
Tetraethylthiuram disulfide
Dantrolene
PUVA

dermatitis is an example of a corticosteroid-induced eruption around the mouth [9]

that is often associated with high-potency (class I and II) corticosteroid usage. These
lesions might lack the erythema due to the anti-inflammatory effect of the topical
corticosteroid [10]. However, when the topical agent is discontinued, an exuberant
flare can occur. The acneiform eruptions have a variable onset after a new drug intro-
duction, usually 2–4 weeks, but can take up to several months [11, 12]. Most lesions
clinically present as small, similar-appearing skin colored to pink and red dome-
shaped inflamed papules and pustules, lacking comedones, distributed on seborrheic
areas on face and trunk, and potentially involve the shoulders. A full discussion of
perioral dermatitis is found in a separate chapter of this book.
Some studies have shown topical corticosteroids lead to increased free fatty acids
in skin surface lipids with resultant increased numbers of bacteria within the pilose-
baceous unit [13, 14]. The breakdown of free fatty acid by P. acnes, consequently,
leads to the development of inflammatory papules. Toll-like receptor (TLR), par-
ticularly TLR-2 subtype, has been linked to the pathogenesis of acne vulgaris.
Activated TLR-2, which is stimulated by P. acnes, contributes to the inflammation
seen acne vulgaris. It has been shown that cultured human keratinocytes will
increase TLR-2 gene expression [15] when corticosteroids are added, which is fur-
ther stimulated by P. acnes, tumor necrosis factor-α (TNF-α), and interleukin 1-α.
These findings suggest that corticosteroids have the potential to exacerbate acne
vulgaris and to cause drug-induced acneiform eruptions.

54.2.1.2 Androgens and Anabolic Steroids

In adolescent acne, androgens are known to increase sebum production by acting on

sebocytes to proliferate and differentiate. Likewise, anabolic steroids or other syn-
thetic hormones with androgenic activity will have similar effects on sebaceous
glands [16, 17]. In a Norwegian prospective study, pubertal boys who were treated
392 H.K. Do et al.

with injectable testosterone for premature closure of epiphyseal growth zones had
an increased acne incidence [18]. There is also an increase in acne incidence in
young athletes who take anabolic-androgenic steroid to increase muscle mass
(“body builder acne” or “doping acne”) [19–21].

54.2.1.3 Danazol

Danazol is a derivative of 2,3-isoxazole-17b-ethinyltestosterone. It has an antigo-

nadotropic property by decreasing the production of follicle-stimulating hormone
(FSH) and luteinizing hormone (LH). Consequently, danazol is often used to treat
endometriosis, sexual precocity, and hereditary angioedema. An acute eruption of
nodulocystic acne was reported in a female patient who was on danazol for treat-
ment of endometriosis [22].

54.2.1.4 Hormonal Contraceptives

Hormonal contraceptives containing progestogens with androgenic activity or

low-dose estrogens can cause or exacerbate acne. New onset of acne after placement
of levonorgestrel-releasing intrauterine device can also occur [23, 24]. These patients
developed inflammatory papules along the jaws 1–3 months after device insertion.

54.2.2 Neuropsychotropic Agents

54.2.2.1 Tricyclic Antidepressants

Amineptine is a non-halogenated tricyclic antidepressant that was widely used in

France before its withdrawal from the market in 1999 [25–27]. This drug may
induce florid acneiform eruption consisting of monomorphic noninflammatory pap-
ules and micro- and macrocysts. These lesions were located mainly on the face,
auricles, neck, chest, back, and genitalia. It is rare, but other tricyclic antidepres-
sants, such as maprotiline [28] and imipramine, can occasionally have been known
to trigger acneiform eruption.

54.2.2.2 Lithium

The first few cases linking lithium to causing acneiform eruption appeared in the
early 1970s [29–31]. Lithium triggers neutrophilic cutaneous conditions such as
neutrophilic folliculitis, acneiform, and psoriasiform eruptions [32–34]. Acne
induced by lithium occurs more frequently in males and patients with an allergic
(atopic) history. Inflammatory papules and pustules are distributed on face, axillae,
54 Drug-Induced Acneiform Eruptions 393

groin, arms, and buttocks. There is no direct correlation between lithium dose and
acne appearance or severity. However, high level of lithium can be detected in the
affected areas.

54.2.2.3 Antiepileptics

Various antiepileptic agents have been linked to drug-induced acneiform eruption

[35]. Hydantoin [36] (i.e., phenytoin) and phenobarbital are the two most common
culprits followed by lamotrigine [37] and valproate [38]. In 1980, a case of severe
facial neonatal acne in an infant who had “fetal hydantoin syndrome” was reported
[39]. Phenytoin can cross the placenta and is known to cause several skin manifesta-
tion ranging from acneiform eruption to hypertrichosis on extensor surface of
extremities and gingival hyperplasia [40]. The acne improves when the treatment
was stopped.

54.2.2.4 Antipsychotic Agents

Aripiprazole is an atypical quinolinone antipsychotic agent with antidepressant

properties. It is a partial agonist at the dopamine2 and 5-HT1A receptors but an antag-
onist at the 5-HT2A receptors. Common adverse effects include insomnia, internal
restlessness (akathisia), nausea, and vomiting. Acneiform eruptions have been
reported to occur 10 days after initiating the medication and improve within 10 days
after discontinuing it [41].

54.2.3 Targeted Therapies

Acneiform eruptions are becoming a hallmark side effect for several therapies that
target a specific key molecule involved in the pathophysiology of the disease. This
therapeutic group of targeted therapies includes epidermal growth factor receptor
(EGFR) inhibitors (gefitinib [42], erlotinib [43, 44], and imatinib [45]), EGFR
monoclonal antibodies (i.e., cetuximab [46, 47] and panitumumab [48]), TNF
receptor inhibitors [49] (i.e., infliximab and lenalidomide), and BRAF-V600E
inhibitors.

54.2.3.1 EGFR Inhibitors

EGFRs belong to the tyrosine kinase family and are thought to play a crucial role in
the development and progression of cancer. Several solid tumors of the head and
neck, breast, lungs, ovary, prostate, and colon overexpress EGFRs. Consequently,
EGFR inhibitors are used to treat these cancers.
394 H.K. Do et al.

Acneiform eruptions have quickly become the hallmark cutaneous adverse

effects in patients receiving targeted EGFR inhibitor chemotherapy [50, 51].
Acneiform eruptions occur in 66 % of patients receiving gefitinib, in 75 % of
patients receiving erlotinib, and in 86 % of patients receiving cetuximab during
clinical trials. Patients with past history of adolescent acne or folliculitis are more
prone to have acneiform development. Lesions can occur after the first cycle of
treatment but more often occur between the third and fourth week. Worsening of
acneiform lesions can be observed immediately after each cycle of treatment. The
typical EGFR-induced acneiform eruption consists of inflamed papules and pus-
tules distributed in seborrheic areas on the scalp, face, retroauricular skin, upper
trunk, and shoulders. Comedones are lacking. Pruritus can accompany the rash.
Crusted or hemorrhagic lesions, along with Sweet syndrome-like lesions, have
been reported in more severe forms [52]. A few studies have reported that acneiform
lesion development is a prognostic factor for a good response to the treatment with
longer survival time compared to no acneiform development [53, 54]. A severe
cutaneous adverse effect, however, can require cessation of EGFR inhibitor therapy.
Incidence and severity of acneiform eruption appear to be dose dependent.
Tetracyclines (such as doxycycline or minocycline) can be used to control severe
lesions but do not decrease the incidence of acneiform eruption.
Histologically, EGFR inhibitor-induced acneiform lesions display neutrophilic
folliculitis and perifolliculitis. P. acnes has not been found in the affected hair fol-
licles. The exact pathogenesis of EFGR inhibitor-induced acne still needs further
elucidation. EGFRs are expressed in epidermal keratinocytes, sebocytes, and the
hair follicle outer root sheath. In addition, EGFRs are involved in normal cell
growth and differentiation. p27 is a cell cycle inhibitor that normally prevents
progression from G1 to S phase in the cell cycle. EGFR inhibitors appear to unregulate
the inhibitory effect of p27 and allow hyper-proliferation of the stratum corneum
in follicular infundibulum and abnormal desquamation and, consequently, lead to
the follicular plugging [55]. It is also possible for monoclonal antibodies to activate
the inflammatory cascades by activating neutrophils and complements through the
binding of their Fc domains.

54.2.3.2 TNF Inhibitors

Tumor necrosis factor (TNF) inhibitors are used to treat a wide range of autoim-
mune diseases such as inflammatory bowel disease, rheumatoid arthritis, psoriasis
and psoriatic arthritis, and ankylosing spondylitis. Of the TNF inhibitors, infliximab
is the most reported agent associated with an acneiform eruption [56]. Likewise,
lenalidomide, a second generation of thalidomide, has major TNF inhibitory activ-
ity. Lenalidomide-induced acute acneiform eruption in a multiple myeloma patient
has been reported [57]. The acneiform eruption was cleared with oral doxycycline
100 mg daily after 3 months without stopping lenalidomide therapy.
54 Drug-Induced Acneiform Eruptions 395

54.2.3.3 G-CSF

Granulocyte colony-stimulating factor (G-CSF) is a potent stimulator for bone

marrow to produce neutrophils. There is a case report of worsening of preexisting
acne vulgaris in an adolescent male while receiving chemotherapy and G-CSF for
treatment of mixed germ cell testicular tumor [58].

54.2.3.4 Vemurafenib

Vemurafenib, a BRAF (V600E) inhibitor, was FDA approved in January 2012 for
the treatment of advanced metastatic melanoma. Among the most common cutane-
ous adverse effects associated with vemurafenib are verrucous papillomas and
hand-foot syndrome, along with keratoacanthomas and squamous cell carcinomas.
More recently, a case report of acneiform eruption associated with vemurafenib has
been published [59].

54.2.4 Retinoids

In the late 1980s, several case reports appeared in the medical literature linking
acneiform eruption with oral etretinate [60, 61]. These patients developed acute
onset of severe cystic acne within the first few weeks after the initiation of oral
etretinate for psoriasis treatment. The acneiform eruption gradually improved when
etretinate was discontinued and with using topical erythromycin or oral tetracy-
clines. Etretinate is no longer available in the United States.

54.2.5 Cardiac Medications

An acneiform eruption has been reported in a young adult who started propranolol
for migraine prophylaxis [62]. The lesions completely resolved after propranolol
was discontinued. These lesions recurred within 3 weeks when the patient was
started on nadolol for migraine prophylaxis. Facial acne resolved soon after nadolol
was discontinued. In general, cutaneous adverse effects from beta-blockers class are
rare. The exact pathogenesis linking acneiform eruptions with beta-blockers is still
unclear.
In 1981, the case of a 57-year-old man who develop papulopustules on the chest
and back soon after initiating quinidine for treatment of premature ventricular con-
tractions was reported [63]. The acneiform eruption responded well to topical eryth-
romycin lotion and topical benzoyl peroxide.
396 H.K. Do et al.

54.2.6 Immunosuppressive Agents

54.2.6.1 Sirolimus

Sirolimus, an immunosuppressive drug often used after organ transplantation, has

been associated with acneiform eruptions in several instances [64–67]. The most
commonly observed cutaneous adverse effects of sirolimus include alterations of
the pilosebaceous apparatus, chronic edema, angioedema, and mucous membrane
disorders [68, 69]. Lesions primarily involve the sebaceous regions; however,
lesions often extend to the forearms, inner surface of the arms, cervical area, and
scalp [70, 71]. Sirolimus is thought to have a direct toxic effect on follicles, chemi-
cally modify sebum, and alter EGF and testosterone synthesis [70]. Sirolimus inhib-
its EGF action by inhibiting the mTOR pathway [69]. Testosterone upregulates
EGFR synthesis, and sirolimus downregulates testosterone synthesis. Sirolimus
might induce acneiform lesions predominantly in men because of the downregula-
tion of the EGFR by testosterone suppression [70].

54.2.6.2 Tacrolimus

Tacrolimus is a macrolide derivative which blocks the calcineurin-dependent signal

transduction pathway resulting in T-cell-specific immunosuppressive activity.
Topical tacrolimus is primarily used for treatment of atopic dermatitis but has also
been used to treat other inflammatory and immunologic skin disorders, including
vitiligo. A case of focal acne was reported during topical tacrolimus therapy for
vitiligo [72]. Rosacea-like dermatitis has also been reported during treatment of
facial inflammatory dermatoses with tacrolimus ointment [73]. A similar rosacei-
form eruption has been reported with use of pimecrolimus [74].

54.2.6.3 Cyclosporine

Cyclosporine (CsA) is a potent immunosuppressive agent used after organ trans-

plantation and in the treatment of psoriasis and atopic dermatitis. There have been
reports of cyclosporine-associated acneiform eruptions presenting as severe nodulo-
cystic acne and acne keloidalis nuchae [75, 76]. Highly lipophilic, one of the pos-
sible routes of elimination of CsA may be via the sebaceous gland, which is the
major cutaneous site for the elimination of lipids through sebum. Potentially, CsA
may modify the structure, function, and/or integrity of the pilosebaceous follicle,
thereby inducing an acneiform eruption [77].

54.2.6.4 Azathioprine

Azathioprine is a thiopurine analogue that suppresses the immune system by a wide

variety of mechanisms. It is changed in the liver to a related drug, 6-mercaptopurine,
and then into 6-thioguanine metabolite nucleotides which inhibit cell growth.
54 Drug-Induced Acneiform Eruptions 397

Transplant recipients are at increased risk of developing acneiform eruptions from

azathioprine [78]. One case of azathioprine-induced acneiform drug eruption during
treatment of multiple sclerosis has been reported [79].

54.2.7 Other Medications

54.2.7.1 Gold

Gold has been reported to be associated with acne. In one case report, a patient with
rheumatoid arthritis first developed an eruption consistent with lichen planus and
subsequently developed acneiform lesions on the face and trunk after gold sodium
thiomalate treatment [80]. Gold is retained in the body for a prolonged duration and
is especially bound in the kidneys, liver, and skin [80].

54.2.7.2 Dactinomycin

Dactinomycin, used in the treatment of solid tumors, has been associated with occa-
sional development of an acneiform eruption. A case was reported of a prepubertal
girl who received dactinomycin in combination with other chemotherapeutic agents
(vincristine and cyclophosphamide), none of which have been implicated in the
development of acne lesions [81]. A rise and fall of serum androstenedione, dehy-
droepiandrosterone, and testosterone levels over a period of time, defined by two
courses of therapy inclusive of dactinomycin, was documented. Gradual improve-
ment of the acneiform eruption was also noted as hormone levels diminished, which
supported a relationship between drug exposure, the presence of the eruption, and
the tested hormone levels [82].

54.2.7.3 Isoniazid

Isoniazid (INH) is a first-line medication in prevention and treatment of tuberculo-

sis. INH-associated acneiform eruptions were reported to occur in 16 % of 2,600
patients receiving a combination of INH and aminosalicylic acid, with 11 % of these
acne patients reported to be slow metabolic inactivators of INH [83]. In another
report, seven patients developed acneiform eruptions associated with INH therapy,
with five of these patients presenting with extensive eruptions and slow INH meta-
bolic inactivation status [83]. A German study suggested acneiform skin lesions
caused by INH are within the concept of acne vulgaris [84]. Factors which should
be taken into account when considering a diagnosis of INH-associated acne are
occurrence in persons older than those typically affected by acne vulgaris, absence
of recent or remote history of acne vulgaris, and a sudden emergence of acneiform
lesions with widespread involvement [83].
398 H.K. Do et al.

54.2.7.4 Rifampin

Rifampin (also named rifampicin) is a bactericidal antibiotic drug of the rifamycin

group. Papular acneiform lesions of the face, neck, and shoulders developed in 8 of
24 males with genitourinary tuberculosis treated with rifampin [85]. Discontinuation
of the medication led to resolution of the acneiform lesions within 3 weeks [85].

54.2.7.5 Dapsone

Dapsone inhibits bacterial synthesis of dihydrofolic acid via competition with para-
aminobenzoate for the active site of dihydropteroate synthetase [86]. A young
female with preexisting mild facial acne vulgaris was treated with oral dapsone fol-
lowing poor response to oral tetracyclines [87]. She soon developed acne fulminans
and hemolysis which resolved with prompt administration of high doses of vitamin
C, oral prednisone, and intravenous methylene blue [87].

54.2.7.6 Halogens

Acneiform eruptions may originate from skin exposure to various industrial chemi-
cals, such as fumes generated in the manufacture of chlorine and its byproducts.
These chlorinated hydrocarbons may cause chloracne, consisting of cysts, pustules,
folliculitis, and comedones. The most potent acneiform-inducing agents are the
polyhalogenated hydrocarbons, notably dioxin (2,3,7,8 tetrachlorodibenzodioxin)
[88]. Notoriously difficult to treat, chloracne can persist for extended time periods
without known additional exposure to chloracnegens [89]. The most acne-prone
locations to “chloracnegens” are the malar crescent (inferior and lateral to the eye)
and the postauricular region. The genitalia, both penis and scrotum, are also vulner-
able anatomic regions. If sufficient exposure has occurred, lesions may involve the
shoulders, chest, back, and, eventually, the buttocks and abdomen. The axillary
regions have been commonly involved only in those patients who have ingested or
inhaled the chloracnegens as the sole or major route of exposure. Cutting and lubri-
cating oils, crude coal tar applied to the skin for medicinal purposes, heavy tar distil-
lates, coal tar pitch, and asbestos are known to cause acneiform eruptions. Acne
venenata is another term applied to this process [90].
Inflammatory acneiform flares have been reported in association with ingestion
of iodides and bromides [91]. Common sources of halogens include some thyroid
medications, expectorants containing potassium iodide, radiographic contrast
media, iodized salt, vitamin and mineral preparations, and some sedatives of histori-
cal interest only. Stimulation of neutrophil function has been suggested, although
the pathogenesis of this reaction is unknown. Initial lesions are often follicular pus-
tules, and later, comedonal lesions can emerge, possibly related to a hyperkeratotic
reaction to chronic inflammation [92].
54 Drug-Induced Acneiform Eruptions 399

54.2.7.7 Vitamins B6 and B12

Megadoses of vitamins B6 and B12 have been reported to induce a facial acneiform
eruption [93]. The histology shows parakeratosis overlying a focally spongiotic epi-
dermis with a mononuclear, perivascular inflammatory infiltrate in the papillary der-
mis. There was dramatic improvement in the acneiform lesions upon discontinue of
the nutritional supplement [93].
Exacerbation or onset of inflammatory acne lesions correlated with vitamins B2
(riboflavin), B6 (pyridoxine), and B12 (cyanocobalamin) intake has been reported
in the European literature [93]. This manifests as an exacerbation of preexisting
acne vulgaris with onset of multiple papules and papulopustules or as an explosive
facial pustular eruption. The pathogenesis is unknown, although it has been postu-
lated that the origin of B6/B12-induced acne may be similar to that of INH-induced
acne [93, 94].

54.2.7.8 White Petrolatum

Most uses for petroleum jelly exploit its lubricating, coating, and moisturizing
potentials. White petrolatum-associated unilateral acne developed in a young
woman attempting to relieve the effects of unilateral facial paralysis (Bell’s palsy)
by massaging the substance onto her face nightly [95]. While generally thought to
be noncomedogenic and safe to use in acne-prone skin, its occlusive properties
could induce a pustular reaction in selected individuals [95].

54.2.7.9 Cow Udder Ointment

Application of cow udder ointment used for treatment of atopic eczema and psoria-
sis was associated with development of widespread and atypical acneiform erup-
tions in two patients [96]. Cow udder ointment contains boric acid and starch in a
wax and oil base.

54.2.7.10 Tetraethylthiuram Disulfide

Tetraethylthiuram disulfide (disulfiram) is commonly used to treat chronic alcohol-

ism by producing an acute sensitivity to alcohol ingestion by blocking acetaldehyde
dehydrogenase conversion of acetaldehyde leading to a higher concentration of the
aldehyde in the blood producing symptoms of a severe hangover. A repeated nodu-
locystic acneiform eruption involving the face, anterior chest, and back, associated
with concurrent ingestion of tetraethylthiuram disulfide, has been reported [97].
With each recurrent episode of acneiform lesions, withdrawal of the drug repeatedly
resulted in resolution of the eruption [97].
400 H.K. Do et al.

54.2.7.11 Dantrolene

Dantrolene is a muscle relaxant that acts by abolishing excitation-contraction cou-

pling in muscle cells. Two middle-aged females undergoing treatment with dan-
trolene for spasticity were reported to have a predominantly comedonal acneiform
eruption [98]. Histologic examination demonstrated keratin-filled cysts in commu-
nication with the surface of the epidermis. In addition to facial involvement, acne-
iform lesions also favored sites of friction and chronic trauma, a distribution specific
to dantrolene acneiform eruptions [98, 99].

54.2.7.12 Psoralen Plus UVA (PUVA)

Oral and topical methoxsalen (8-methoxypsoralen) used along with subsequent

long-wave ultraviolet A (UVA) light exposure (PUVA) is commonly used to treat
psoriasis. Several cases of acne believed to be induced by PUVA treatment have
been reported [100–102]. The distributions reported include the chest and back,
periorally, and localized on the forehead. Acne-like eruptions on the face, induced
by light, were first described using the term “light-sensitive seborrheid” [101, 102].
The designation acne aestivalis (Mallorca acne) is used for papular eruption occur-
ring after intense sun exposure in an anatomic distribution characteristic of acne
vulgaris [101, 102]. Overall, acne vulgaris usually improves during the summer
months with exposure to sunshine, although it may be aggravated in some patients.
This exacerbation is thought to be secondary to eccrine sweating.

54.3 Conclusion

Acne vulgaris and acneiform drug eruptions can easily be overlooked in daily clini-
cal practice. There are no specific diagnostic criteria to define drug-induced acne.
However, several key clinical characteristics (Table 54.2) may help clinicians to

Table 54.2 Acne versus acneiform drug eruption

Acne Acneiform drug eruption
Age of onset Adolescent or early adulthood years Unusual age of onset (>30 years)
Lesion Polymorphic lesions (mixture Monomorphic lesions, lacking
morphology of comedones, papules, comedones and cysts
pustules, and inflamed
subcutaneous nodules)
Lesion Face, upper chest, and upper back Unusual location that extends
distribution where there are high density beyond seborrheic area such as
of sebaceous glands arms, lower back, and genitalia
Temporal No temporal relationship with Lesions started shortly after new
relationship medication drug introduction
Improvement after drug withdrawal
Recurrence after drug introduction
54 Drug-Induced Acneiform Eruptions 401

recognize and diagnose acneiform drug eruptions. Two useful clinical keys to help
diagnose acneiform drug eruptions are the temporal relationship (acne-like eruption
after introduction of a new medication) and the monomorphic lesions (all lesions
are in the same stage and lacking comedones).

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Index

A etiology, 117
Abnormal keratinization, 8, 9 etiopathogenesis, 118
Acne conglobata immune complexes, 118
atrophic and hypertrophic scars, 108 immunofluorescence testing, 121
chromosomal defects, 107–108 laboratory findings, 119
cryotherapy, nodules, 109 Propionibacterium acnes, 118
environmental factors, 107 rheumatoid factor and ANA tests, 121
fulminans, 107 SAPHO syndrome, 117
inflammatory acne, 107 siblings, 118
isotretinoin, 109 treatment, 121–122
musculoskeletal syndrome, 108 Acneiform eruptions
renal amyloidosis, 108 drug-induced (see Drugs)
work-up, 109 PAPA syndrome (see Pyogenic sterile
Acne excoriée arthritis, pyoderma gangrenosum
characterization, 111 and acne (PAPA) syndrome)
clinical presentation, 113 Acne mechanica
facial acne excoriation, 111, 112 clinical presentation, 126
OCD patients, 114 description, 125
patients, 111–112 diagnosis, 126
psychiatric problems, 111 NIOSH workshop, 125
psychogenic excoriation, 112 rubbing, 125, 126
psychopathology, 113 sealed acne-bearing skin, 126
scar formation, 112 surface skin architecture, 125–126
subjective and physiological treatment, 127
symptoms, 114 Acne scarring
treatment, 114–115 atrophic scars, 238–239
Acne fulminans chemical peels, 241
acne vulgaris, 117 dermal fillers, 241
adolescent boys, 118 fibroblasts, 241
androgenic steroids, 118 FP, 242
antistaphylococcal and antistreptococcal hypertrophic scars, 240
antibody, 121 inflammatory lesions, 237
bacterial cultures, 121 keloids scars, 240
bone, 121 laser resurfacing, 242
Caucasian males, 118 MMP inhibitors, 237
clinical presentation, 118–120 morphologies, 237, 238
description, 117 and pigmentation, 240

J.A. Zeichner (ed.), Acneiform Eruptions in Dermatology: A Differential Diagnosis, 405

DOI 10.1007/978-1-4614-8344-1, © Springer Science+Business Media New York 2014
406 Index

Acne vs. acneiform drug eruption, 400 B

Acrocephalosyndactyly (ACS), 179, 180 Bacterial folliculitis
AD. See Autosomal dominant (AD) classification, 43
Adenomatous polyposis coli (APC) clinical appearance
desmoid tumors, 202 bacterial sycosis, 45
diagnosis, FAP, 203 Bockhart impetigo, 44
mutations, 201 distribution, 45
tumor suppressor gene, 201 erythematous papules, 44
Adrenocorticotropin (ACTH) levels furuncles, 45
adrenal carcinoma, 134 incarceration and chronic
adrenal glands, 130 staphylococcus colonization, 45
Cushing’s syndrome, 131, 133–134 MRSA, 44
dependent and independent conditions, papules and pustules, 45
129–130 incidence, 43
pituitary gland, 130 manipulation, 44
ALA. See Aminolevulinic acid (ALA) occlusion/moisture, 43
Amineptine, 392 S. aureus, 44
Aminolevulinic acid (ALA), 35, 36 treatment, 46–47
Androgens, 5 work-up, 45–46
Antibiotics Bartholow, P., 51
clindamycin and erythromycin, 21 Basal cell carcinomas (BCCs)
coagulase-negative staphylococci, 21 and BCNS, 207
pharyngeal colonization with streptococcus neoplasms, 192
pyogenes, 21 oral celecoxib, 211
resistance with monotherapy, 21–22 and PDT, 211
resistant strains, P. acnes, 21 skin examination, 210
side effects, 22 trichoepithelioma, 192
APC. See Adenomatous polyposis vismodegib, 211
coli (APC) Basal cell nevus syndrome (BCNS)
Apert syndrome autosomal dominant, 207
ACS1, 179, 180 cardiac fibromas, 208
craniosynostosis, 180 clinical manifestations, 208
cutaneous manifestations, 180 diagnosis, 210
FGFR2, 179 facial dysmorphism, 208
sebaceous gland activity, 179 intracranial calcification, 209
skeletal abnormalities, 179 and SCCs, 211
skin cultures, 180 Baughman, R., 325
treatment, 180–181 BCCs. See Basal cell carcinomas (BCCs)
Arfan-ul Bari, 157 BCNS. See Basal cell nevus syndrome
Aripiprazole, 393 (BCNS)
Arthritis. See Pyogenic sterile arthritis, Berlin, C., 155
pyoderma gangrenosum and acne Birt-Hogg-Dubé syndrome (BHD)
(PAPA) syndrome clinical presentations
Atrophic scars dermatologic manifestations, 184–185
depressions, 238 pulmonary manifestations, 186
ice pick scars, 239 renal manifestations, 185–186
rolling and boxcar scars, 238–239 diagnosis, 186
sinus tracts, 239 fibrofolliculomas, 183, 186
Autoinflammation, 138, 139 FLCN (see Folliculin (FLCN))
Autosomal dominant (AD), 191 gene locus, 183
Azelaic acid, 22 internal tumors, 183
Azithromycin, 28 laboratory and radiologic tests, 186
Index 407

mTOR pathway, 184 Colville, J.M., 117

pathogenesis, 184 Comedonal post-adolescent (CPAA), 162, 163
treatment Corticosteroids
dermatologic manifestations, 187 description, 389, 391
pulmonary manifestations, 187 toll-like receptor (TLR), 391
renal manifestations, 187 Cortisol
TSC, 184 Cushing’s syndrome, 130
Breit, S., 254 high-dose dexamethasone, 133–134
Brooke-Spiegler syndrome (BSS) overproduction, 131
and AD, 191 plasma and urine, 134
and BCC, 192 production and secretion, 130
biopsies, 193 Cowden syndrome (CS)
and CYLD mutations, 191, 192 acral keratoses, 196, 197
facial papules, etiology, 193 autosomal dominant, 195, 196
and FC, 191 cancers, 198
malignant transformation, 192, 193 cutaneous lesions, 199
and MFT, 191 definition, 195
neoplasms, 192, 193 diagnosis, 198
trichoepitheliomas, 192, 193 disorders, 195
turban tumor, 192 ductal adenocarcinoma, 197
Buffalo hump, 131, 132 mucocutaneous lesions, 196
Burns, R.E., 117 and NCCN guidelines, 198
oral papillomas, 196, 197
prophylactic mastectomy, 199
C and PTEN, 195, 196
Cardiac medications, 395 trichilemmomas, 196
CD2-binding protein 1 (CD2BP1) Cow udder ointment, 399
hyperphosphorylation, 139 CPAA. See Comedonal post-adolescent
IL-1β activation, 139 (CPAA)
mutations, 139 CRMO. See Chronic recurrent multifocal
PAPA syndrome, 145 osteomyelitis (CRMO)
and PSTPIP1, 139 CS. See Cowden syndrome (CS)
CD2BP1. See CD2-binding protein 1 (CD2BP1) Cunliffe, W.J., 17
Chin strap acne, 126 Cushing’s syndrome
Chronic recurrent multifocal osteomyelitis ACTH levels, 129–130, 133–134
(CRMO), 170, 172 adrenal carcinoma, 131, 134
Ciprofloxacin, 46 clinical presentation, 131–133
Clinical presentation, acne cortisol overproduction, 131
adrenarche, 15 description, 129
androgens, 14 diagnosis, 133
conglobate lesions, 13 ectopic tumors, 130
cysts, 13, 15 effects, 130
DHEAS, 15 etiology, 133
grading acne severity, 16–17 exogenous and endogenous
microcomedones, 13 hypercortisolism, 129
nodulocystic acne, 13 iatrogenic, 131
noninflammatory and centrofacial, 14, 16 pituitary-hypothalamic-adrenal
open/closed comedones, 13, 14 axis, 130
papules and pustules, 13, 15 plasma and urine cortisol levels, 134
Propionibacterium acnes, 13 “polyglandular syndrome,” 129
puberty comedonal acne, 15 signs and symptoms, 129
spectrum, acne lesions, 13, 14 treatment, 134
truncal acne characterization, 15, 16 women, 130–131
408 Index

Cutaneous leiomyomas Eichenfield, L.F., 364

clinical characteristics, HLRCC, 222 Eosinophilic pustular folliculitis (EPF)
diagnosis, 224 autoimmune etiology, 246
immunohistochemical staining, 224 blood count, 248
smooth muscle fibers, 222 excoriations, 247
Cyclosporine (CsA), 396 hair follicles, 245
Cylindromatosis (CYLD) and HIV (see Human immunodeficiency
dysfunction, 192 virus (HIV))
germline mutations, 191 immunosuppression, 245
tumor suppressor, 191, 192 inflammatory skin disease, 245
lesions, 246
and Malassezia folliculitis, 60
D oral indomethacin, 248
Dactinomycin, 397 papules, 247
Dantrolene, 400 papulopustular disease, 249
Dapsone, 22, 398 pathophysiology, 246
Davis, E.C., 158 post-inflammatory pigmentation, 247
Dehydroepiandrosterone sulfate (DHEAS), 15 PUVA photochemotherapy, 248
Dermatillomania, 111 routine hematoxylin and eosin stain, 248
Dermatologic manifestations topical corticosteroids, 248
differential diagnosis, 185 and UVB, 249
fibrofolliculomas, 184, 185 EPF. See Eosinophilic pustular folliculitis
skin lesions, 184 (EPF)
trichodiscomas, 184, 185 Epidermal growth factor receptor (EGFR)
DHEAS. See Dehydroepiandrosterone sulfate inhibitors
(DHEAS) erlotinib, 394
Diffuse idiopathic skeletal hyperostosis gefitinib, 394
(DISH), 30 Malassezia folliculitis, 60
Dreno, B., 17 p27, 394
Drugs tyrosine kinase family, 393
cardiac medications, 395 Epidermodysplasia verruciformis (EDV), 73
cow udder ointment, 399 Eruptive vellus hair cysts (EVHCs), 344
dactinomycin, 397 Erythematotelangiectatic rosacea (ETR),
dantrolene, 400 310, 311
dapsone, 398 Erythromycin, 28
gold, 397
halogens, 398
hormones, 389, 391–392
immunosuppressive, 396–397 F
INH, 397 Facial Afro-Caribbean childhood eruption
neuropsychotropic, 392–393 (FACE), 359
PUVA, 400 Fahmy, A., 215
retinoids, 395 Familial adenomatous polyposis (FAP)
rifampin, 398 adenomatous polyps, 203
targeted therapies, 393–395 APC, 201
tetraethylthiuram disulfide, 399 diagnosis, 203, 204
type, 390–391 intestinal manifestations, 202
vitamins B6 and B12, 399 Familial cylindromatosis (FC), 191
white petrolatum, 399 FAP. See Familial adenomatous polyposis
(FAP)
Favre-Racouchot syndrome
E aesthetic implications, 255
EDV. See Epidermodysplasia verruciformis chronic actinic damage, 254, 255
(EDV) comedonal extraction, 256
EGFR inhibitors. See Epidermal growth factor differential diagnosis, 255
receptor (EGFR) inhibitors etiology, 253
Index 409

lesions, 254 cutaneous findings, 202

radiation therapy, 254 desmoid tumors, 204
retinaldehyde, 256 epidermoid cysts, 204
solar elastosis, 253 extracutaneous findings, 202–203
steroids, 254 and FAP, 201
sun protection, 257 gastrointestinal manifestations, 203
surgical interventions, 256 genetic counseling, 204
therapeutic options, 255, 257 intestinal polyps, 204
topical retinoids, 256 manifestations, 202
UV radiation, 253 multiple colorectal adenomas, 203
FC. See Familial cylindromatosis (FC) panoramic dental radiographs, 204
Febrile acne, 117 Genetic syndrome, 138, 146
FH. See Fumarate hydratase (FH) Gianotti, F., 359, 361
Fibroblast growth factor receptor 2 Gold, 397
(FGFR2), 179 Gonadotropin-releasing hormone (GnRH)
Fiddler’s chin, 126 stimulation test, 384
Fitzpatrick skin type VI, 280 Gorlin syndrome
Flat warts BCCs (see Basal cell carcinomas (BCCs))
acneiform lesion, 74 BCNS (see Basal cell nevus syndrome
and acne treatment, 71, 72 (BCNS))
Allium sativum, 75 cardiac fibromas, 208
cantharidin, 74 clinical manifestations, 211
double-stranded DNA virus, 71 diagnosis, 210
EDV, 73 Drosophila melanogaster, 207–208
HIV, 73 facial dysmorphism, 208
HPV (see Human papillomavirus (HPV)) lymphomesenteric cysts, 209
hyperkeratosis and acanthosis, 74 medulloblastoma, 208
hyperpigmented lesions, 72 palmoplantar pitting, 209, 210
immunotherapy, 75 SCCs, 211
keratolytics, 74 SHH ligand, 207
laser therapies, 75 skeletal and ocular abnormalities, 208
nongenital warts, 72 tumors and odontogenic cysts, 211
papillomavirus, 72 Grading acne severity, 16–17
PCR, 71 Gram-negative folliculitis
Folliculin (FLCN) description, 49
and BHD, 183 epidemiology, 50
downregulations, 184 monomorphic follicular papules, 50–51
germline mutation, 183, 186, 187 pathophysiology
tumor suppressor gene, 186 alpha-1-antitrypsin deficiency, 50
Fox, T., 375 characterization, 49–50
Fractional photothermolysis (FP), 242 depressed cell-mediated immunity, 50
Friction, 125, 127 immune defense mechanisms, 50
Frieden, I.J., 359 loofah sponges and exfoliative beauty
Fulton, J.E. Jr., 49 products, 50
Fumarate hydratase (FH) sebaceous follicles, 50
and HLRCC, 222 tetracyclines impair protein synthesis, 50
and MCUL1 locus, 222 staphylococcal pyoderma, 51
mutations, 221 treatment, 52
tumor tissue, 222 type I and II lesions, 51
work-up, 51–52
Granulocyte colony-stimulating factor
G (G-CSF), 395
GA. See Granuloma annulare (GA) Granuloma annulare (GA)
Gardner syndrome (GS) cause, 375
and APC mutations, 201, 203 condition, 375–376
410 Index

Granuloma annulare (GA) (cont.) differential diagnosis, 262

description, 375 follicular occlusion tetrad, 260
differential diagnosis, 377 gamma-secretase, 259–260
eruption, 375 groin, 260, 261
papular, 376–377 medical therapies, 263
perforating, 377 morbidity, 262
as ringed, firm and flesh-colored, 376 nodules and plaques, 261
subcutaneous, 377 perineal disease, 260
treatment, 378 photodynamic therapy, 263
workup, 377 prepubertal and postmenopausal, 259
GS. See Gardner syndrome (GS) skin cancer, 262
surgical excision, 263
and TNF-alpha inhibitors, 263
H tombstone comedone, 261
Halder, R.M., 155, 158, 280 and YAG laser, 263
Halogens, 398 HIV. See Human immunodeficiency virus
Hasumi, H., 184 (HIV)
Hedelund, L., 253 HLRCC. See Hereditary leiomyomatosis and
Hereditary leiomyomatosis and renal cell renal cell cancer (HLRCC)
cancer (HLRCC), 221, 222, 224 HNPCC. See Hereditary nonpolyposis
Hereditary nonpolyposis colorectal cancer colorectal cancer (HNPCC)
(HNPCC), 215–216 Home devices, 37–38
Herpes simplex virus (HSV) Hormonal contraceptives, 392
antiviral treatment, 85 Hormonal therapies
cytopathologic detection, 89 anabolic-androgenic steroid, 391–392
imitator, VZV, 99–100 contraceptives, 30–31, 392
keratoconjunctivitis, 86–88 corticosteroids, 32, 389, 391
molding, 89 danazol, 392
oropharyngeal and orolabial description, 30
cutaneous involvement, 86, 87 spironolactone, 31
labialis, 86, 87 Hot-tub folliculitis
overall incidence, 86 clinical presentation, 56
and PCR, 89 description, 55
primary infections, 86 epidemiology, 56
retrograde axonal transportation, 85 pathophysiology, 55–56
transmission, 85 treatment, 57
treatment work-up, 56
cutaneous infections, 91 HPV. See Human papillomavirus (HPV)
keratoconjunctivitis, 90 HS. See Hidradenitis suppurativa (HS)
mucocutaneous, 90–91 HSV. See Herpes simplex virus (HSV)
neonatal, 91 Human immunodeficiency virus (HIV)
nucleoside analogues, 90 autoimmune disorder, 246
oropharyngeal and orolabial, 90 flat warts, 73
Herpes zoster folliculitides, 248
contralateral edema, 98 leukopenia, 248
disseminated, 99, 101 peripheral eosinophilia, 248
lymphadenopathy, 97 Human papillomavirus (HPV)
macules and papules, 97 double-stranded DNA virus, 71
PHN, 99 and EDV, 73
serologic evidence, 98 myrmecia, 71
trigeminal nerve, 99, 100 and PCR, 71
Hidradenitis suppurativa (HS) Hypercortisolism
acne inversa, 259 ACTH-secreting pituitary adenoma, 132
axillae and chest, 260 Cushing’s disease, 130
Index 411

endogenous, 129, 131 eczema herpeticum, 88

etiology, 129 immune suppression, 87
exogenous, 129, 131 neonatal, 88
treatment, 134 organ transplant, 87
Hyperpigmentation, PIH. See Post-inflammatory primary infections, 86
hyperpigmentation (PIH) Keratosis pilaris atrophicans faciei (KPAF)
Hypothalamic-pituitary-gonadal (HPG) clinical findings, 367
axis, 382 description, 367
diagnosis, 368–369
follicular papules, 368
I histology, 369
Immunohistochemical (IHC), 217 pathogenesis, 368
Immunosuppressive drugs treatment, 369
azathioprine, 396–397 Kligman, A.M., 117, 125, 163, 292
CsA, 396 Kligmanm, A., 126
sirolimus, 396 Knautz, M.A., 359
tacrolimus, 396 KPAF. See Keratosis pilaris atrophicans faciei
Infantile acne (KPAF)
clinical presentation, 372
description, 371
epidemiological data, 372 L
workup, 373 Leventhal, M.L., 149
Inflammatory bowel disease (IBD), 30 Light/photodynamic therapy (PDT)
Innate immune system advantages, 35
inflammation, 4–5 blue light and ALA, 36
skin, 4 definition, 35
TLRs, 4 exogenous photosensitizer, 36
Intense pulsed light (IPL), 36 IPL, 36
Interleukin-1 (IL-1), 229 KTP, 36
IPL. See Intense pulsed light (IPL) mid-infrared light, 37
Isoniazid (INH), 397 PDL, 36
Isotretinoin photothermolysis, 38
anti-inflammatory and antibacterial porphyrin photoexcitation, 35
effects, 29 red light, 36
bone mineralization, 30 sebaceous gland, 39
cheilitis and mucocutaneous dryness, 29 visible light spectrum, 36
DISH and IBD, 30 Lim, H.W., 254
dosing, 29 Liposomes, 23
dyslipidemia, 29 Lucky, A.W., 15
iPLEDGE program, 30
teratogenic and contraindicated during
pregnancy, 30 M
topical agents/oral antibiotics, 29 Macrolides, 28
Maibach, H.I., 51
Malassezia folliculitis
J acne vulgaris, 59
Jacobs, C.I., 239 cetuximab, 60
clinical presentation, 61
corticosteroid therapy, 60
K EGFR inhibitors, 60
Kaya, T.I., 256 eosin stain, 62
Kelly, A.P., 117 EPF, 60
Keratoconjunctivitis hematoxylin, 62
corneal lesions, 87 isotretinoin, 63
412 Index

Malassezia folliculitis (cont.) colonoscopy, 218

lipophilic dimorphic yeast, 59 colorectal carcinoma, 217
microscopic examination, 59, 61 cutaneous manifestations, 216
PAS stain, 62, 63 diagnosis, 216
photodynamic therapy, 63 and HNPCC, 215–216
potassium hydroxide examination, 60 and IHC analysis, 217
spectrum antibiotics, 61 lymphadenopathy, 218
Mammalian target of rapamycin (mTOR) and MSI, 216
and BHD, 184 oral isotretinoin, 217
cell growth, 230 radiotherapy, 217
rapamycin, 232 sebaceous neoplasms, 216, 217
and TSC, 232 visceral malignancies, 215, 218
Mana, J., 323 Multiple cutaneous and uterine
Marshall, W.A., 381 leiomyomatosis (MCUL), 221, 222
Marten, R.H., 359 Multiple familial trichoepithelioma
Matrix metalloproteinases (MMPs), 7, 237 (MFT), 191
Mavilia, L., 256
MCUL. See Multiple cutaneous and uterine
leiomyomatosis (MCUL) N
Melanocortins, 6, 9 National Comprehensive Cancer Network
Methicillin-resistant Staphylococcus aureus (NCCN), 198
(MRSA) NCP. See Neonatal cephalic pustulosis (NCP)
description, 44 Necrotic, 119
empiric therapy, 46 Neonatal acne
eradication, colonization, 46, 47 description, 371
mupirocin ointment, 46 first-line therapy, 373
skin and soft tissue infections, 46 infantile acne, 372
MFT. See Multiple familial trichoepithelioma 1-month-old baby girl, 372
(MFT) pathophysiology, 371
Micronization, 23 topical azole antifungals, 373
Microsatellite instability (MSI), 216 workup, 373
Mills, O.H. Jr., 126, 292 Neonatal cephalic pustulosis (NCP)
MMPs. See Matrix metalloproteinases clinical presentation, 372
(MMPs) description, 371–372
Molluscum contagiosum and infantile acne, 372
acne, 80, 81 treatment, 373
cantharidin, 82 Neubert, U., 50
clinical pearls, 82 Neuropsychotropic drugs
cutaneous and mucosal viral infection, 79 antiepileptics, 393
erythema, 80 antipsychotic agents, 393
host interactions, 80 lithium, 392–393
immune modulating therapies, 81 tricyclic antidepressants, 392
maternal antibodies, 79 Neurotic excoriation, 111
spontaneous resolution, 80, 81 Nguyen, V., 364
transmission, 80 Nickerson, M.L., 183
work-up, 81 Nonsteroidal anti-inflammatory drugs
Moon facies, 131 (NSAIDs), 174
MRSA. See Methicillin-resistant
Staphylococcus aureus(MRSA)
MSI. See Microsatellite instability (MSI) O
mTOR. See Mammalian target of rapamycin Obsessive-compulsive disorder (OCD),
(mTOR) 114–115
Muir, E.G., 215 OCPs. See Oral contraceptive pills (OCPs)
Muir-Torre syndrome (MTS) Oral antibiotics
autosomal dominant disorder, 215 description, 27
Index 413

macrolides, 28 oral tetracycline, 269

tetracyclines, 28–29 PDT treatment, 269
topical benzoyl peroxide, 27 perinasal skin, 266
trimethoprim-sulfamethoxazole, 29 pimecrolimus, 269
Oral contraceptive pills (OCPs), 30–31 steroid rosacea, 265
Oral corticosteroids, 32 topical erythromycin, 268, 269
Osteoporosis, 131, 132 Periorificial granulomatous dermatitis (PGD)
Over-the-counter (OTC) handheld laser characteristics, 362, 363
devices, 37, 38 description, 359
differential diagnosis, 363
etiology, 360
P and FACE, 359
Palmoplantar pustulosis (PPP), 171 vs. other simulant dermatoses, 362, 364
Papular GA, 376–378 and PD, 360
Papulopustular rosacea (PPR), 310, 311 primary lesions, 360, 361
Pathological skin picking, 111 scarring, 361
Pathophysiology treatments, 363–364
adolescent acne, 162 workup, 362
androgens, 162 Peroxisome proliferator-activated proteins
chronic stress, 162 (PPARs), 6
description, 3 PFB. See Pseudofolliculitis barbae (PFB)
development PGD. See Periorificial granulomatous
abnormal keratinization, 8 dermatitis (PGD)
androgens, 5 PHN. See Post-herpetic neuralgia (PHN)
P. acnes, 7–8 Phosphatase and tensin homolog gene (PTEN)
sebum, 6–7 disorders, 195
etiological factors, 162, 163 germline mutation, 195
innate immune system, 4–5 sporadic tumors, 196
5-LOX inhibitors, 9 tumor suppressor, 196
nicotine, 162 Photocontact dermatitis (PCD)
sebaceous gland, 162 acute lesions, 275
Patterson, W.M., 255 antigen-presenting cells (APCs), 274
PCD. See Photocontact dermatitis (PCD) categories, 273
PCOS. See Polycystic ovary syndrome chronic actinic dermatitis, 273
(PCOS) erythematous, 275
PCR. See Polymerase chain reaction (PCR) factors, 275–276
PD. See Perioral dermatitis (PD) histological examination, 276
PDL. See Pulsed dye laser (PDL) photopatch test, 276
PDT. See Photodynamic therapy (PDT) phototoxic agents, 273–274
Perioral dermatitis (PD) prevalence, 273
acne rosacea, 265, 268 treatment, 277
biopsy, 268 UV filters, 274
clinical differential diagnosis, 267 Photodynamic therapy (PDT), 211, 269
clinical presentation, 360–361 Photopatch test, 276
corticosteroids and cosmetics, 268 Photopneumatic therapy, 37
Demodex folliculorum, 265 Phymatous rosacea, 310, 312
diagnosis, 362 PIH. See Post-inflammatory
doxycycline and metronidazole, 266, 268 hyperpigmentation (PIH)
erythema, 266, 267 Pituitary adenoma, 130, 132
etiologic factors, 360 Plewig, G., 117, 156
exposure, corticosteroid, 265 Polycystic ovary syndrome (PCOS)
inciting factors, 360 acne, 149, 150
inflammatory lesions, 266 androgens overproduction, 150
light-sensitive seborrheid, 265 endocrine disorders, 149
414 Index

Polycystic ovary syndrome (PCOS) (cont.) management options, 281, 282

hirsutism, 150, 151 superficial chemical peels, 283
hormonal birth control, 152 Post-inflammatory pigment alteration
hyperandrogenism, 152, 164 hypopigmented “halo,” 281–282
hypothalamus, 150 and PIH, 280–281
menstrual irregularity and infertility, 149 prevalence, 279–280
metabolic diseases, 151 skin color, characteristics, 280
metformin, 153 Wood’s lamp examination, 281
and SHBG, 150 Potassium titanyl phosphate (KTP), 36
spironolactone, 153 PPARs. See Peroxisome proliferator-activated
typical appearance, acne, 150, 151 proteins (PPARs)
work-up, 152 PPP. See Palmoplantar pustulosis (PPP)
Polyglandular syndrome, 129 Precocious puberty
Polymerase chain reaction (PCR), 45, 71, 89, age limit, 381
100, 101 androgen production in children, 382
Pomade acne comedones, 382, 383
comedones, 155, 157 definition, 381
etiopathogenesis, 156 GnRH stimulation test, 384
follicles, 155 HPG axis, 382
inflammatory changes, 157, 158 inflammatory lesions, 383
monomorphic acneiform eruption, 157 screening tests, 384
onset, 155–156 treatment, 384–385
pigmentary alterations, 157 Propionibacterium acnes
scalp and hair, 157 anaerobic bacterium, 170
sebaceous glands, 158 ATRA, 8
skin manifestations, 156 biofilm, 8
treatment, 158 bone biopsies, 170, 174
vulgaris, 155, 157 description, 7
Post-adolescent female acne monocytes to macrophages, 8
acne vulgaris, 167 pathogenesis, innate immune system, 7–8
CPAA, 162, 163 toll-like receptor 2 pathway, 170
disorders, 161 Pseudofolliculitis barbae (PFB)
endocrine abnormalities, 163, 164, 167 description, 289
glucocorticoids, 165 eflornithine, 292–293
hormonal modifying treatments, 165 hair removal methods, 289
late-onset acne, 163 hormonal work-up, 291
oral contraceptives, 166, 167 intrafollicular and transfollicular lesions, 290
pathophysiology, 162–163 medical intervention, 291–292
PCOS, 164 mustache area, 291
persistent acne, 161, 163 papules and pustules, 290, 291
physiological and clinical acne, 161 prevalence and severity, 289–290
pustules and papules, 163, 164 risk factor, 290
spironolactone, 166 shaving, 290
Post-herpetic neuralgia (PHN), 99 treatments, 292
Post-inflammatory hyperpigmentation (PIH) Pseudomonas aeruginosa
anti-inflammatory agents, 284 characterization, 55
cosmeceuticals, 282–283 diagnosis, 56
duration, 280–281 follicular skin infection, 55
Fitzpatrick skin type VI, 280 gram-negative bacterial organism, 55
hydroquinone Psoralen plus ultraviolet A (PUVA), 248, 400
description, 281 Psoriasis
dual/triple agent combination description, 295
therapies, 282 prevalence, 295
hypopigmented “halo,” 281–282 pustular (see Pustular psoriasis)
Index 415

Psychodermatology, 111, 112 multiple cutaneous leiomyomatosis, 224

Psychogenic excoriation, 111, 112 mutations, 222
PTEN. See Phosphatase and tensin homolog papules and nodules, 223
gene (PTEN) pseudohypoxia, 222
Pulsed dye laser (PDL), 36 smooth muscle fiber bundles, 224
Pustular psoriasis Reed, W.B, 221
acrodermatitis of hallopeau, 299, 301 Retinoids, 395
annular variant, 298 Rifampin, 398
clinical presentations, 296 Rosacea
diagnosis, 301 azelaic acid, 314
exanthematic variant, 298 centrofacial distribution, 312–313
generalized disease and treatments, 303 chronic UV exposure, 310
impetigo herpetiformis, 298, 299 classic presentation, 310
involuting beneath caloused skin, 298, 300 description, 309
localized disease and treatments, 303–304 differential diagnosis, 313
palmar pustular psoriasis, 298–300 ETR, 310, 311
pathophysiology, 296 fulminans
prevalence, 296 description, 317
severe acne, 295 diagnosis, 319
sterile pustules, erythematous skin, 296, 297 ferocious nature, 319
systemic and topical treatments, 301–302 indurated and erythematous plaque, 318
von Zumbusch variant, 296–297 ocular involvement, 318
Pyogenic sterile arthritis, pyoderma pathophysiology, 317–318
gangrenosum and acne (PAPA) treatments, 319
syndrome incidences, 309
autoinflammatory disorders, 138 laser and light-based interventions,
bilateral lower extremities, 140, 144 313–314
CD2-binding protein 1 (CD2BP1) gene, 139 ocular, 310, 312
childhood, 140 oral isotretinoin, 315
cutaneous manifestations, 140, 144 pathophysiology, 310
differential diagnoses, 145, 146 phymatous, 310, 312
IL-1 regulatory pathway, 139 PPR, 310, 311
joint manifestations, 140 signs and symptoms, 312
laboratory findings, 145 topical
patients, clinical features, 140–143 antimicrobial formulations, 314
scarring, papulopustular and nodulocystic metronidazole, 314
acne, 140, 144 and systemic agents, 315
synovial biopsies, 145 treatment options, 309, 313, 314
treatment, 146–147 work-up, 313
unique constellation, 144
X-ray of hands, 145
S
SAPHO syndrome. See Synovitis, acne,
R pustulosis, hyperostosis, and osteitis
Radcliffe-Crocker, H., 375 (SAPHO) syndrome
Reed’s syndrome Sarcoidosis
botulinum toxin type A, 225 clinical presentation, 322
cutaneous leiomyomas, 221–224 corticosteroids, 324–325
diagnosis, 224 CT and MRI, 324
FH, 221, 222 description, 321
HLRCC, 221, 222, 224 diagnosis, 324
lesions, 223 etiology, 322
MCUL, 221, 222 hydroxychloroquine, 325
medical management, 225 medications, 325
416 Index

Sarcoidosis (cont.) electron microscopy, 346

methotrexate, 325 etiopathogenesis, 344
noncaseating granuloma, 321 and EVHCs, 344
normal tissue function, 322 lesions, 345
papular, T zone and malar checks, 322, 323 mutations, 344
radiograph, 324 non-tender, flesh-colored and subcutaneous
SCCs. See Squamous cell carcinomas (SCCs) nodules
Sebocytes, 6, 7 in axilla, 345
Seborrheic dermatitis on forehead, 345
biopsies, 332 treatments, 346–347
clinical presentation and differential Stein, I., 149
diagnosis, 331, 333–334 Sweeney, K., 60
cultures, 332 Synovitis, acne, pustulosis, hyperostosis, and
description, 329 osteitis (SAPHO) syndrome
epidemiology, 329–330 acne fulminans, 117
erythematous and scaly patches bone biopsies, 170
in beard and nasolabial folds, 332 chronic rheumatologic disorder, 169
medial cheeks and nasolabial folds, 331 corticosteroids, 174
laboratory, 332 and CRMO, 170, 172
pathophysiology, 330–331 cutaneous presentations, 171
topical treatments genetic predisposition, 169
antibiotics, 336 inflammation, 169
antifungals, 334–335 lipin 2 (LPIN2), 170
coal tar 4 % shampoo, 337 musculoskeletal findings, 171
corticosteroids, 336 and NSAIDs, 174
description, 334, 335 P. acnes, 170, 171, 174
emollients, 337 and PPP, 171
immunomodulators, 336 psoriatic manifestations, 173
lithium salts, 336–337 skin lesions, 171
oral antifungals, 337 treatment, skin manifestations, 173
phototherapy, 337 work-up, 172
Sebum Systemic therapies
androgens and retinoids, 6 description, 27
components, 6 hormonal, 30–32
corticotropin-releasing hormone, 6 isotretinoin, 29–30
CRH receptors, 6 oral antibiotics, 27–29
functional androgen receptors, 6
lipids, 6
lubricating skin and hair, 6 T
melanocortins, 6 Taenzer, P., 367
P. acnes, 6–7 Tagaki, S., 184
PPARs, 6 Tan, J., 17
sebocytes, 6 Tanner, J.M., 381
Severe acne, 117–118 Targeted therapies
Sex hormone-binding globulin (SHBG), 30, 150 EGFR inhibitors, 393–394
Sharkey, M.J., 256 G-CSF, 395
SHH. See Sonic Hedgehog (SHH) TNF inhibitors, 394
SM. See Steatocystoma multiplex (SM) vemurafenib, 395
Sonic Hedgehog (SHH), 207 Taylor, S.C., 157
Spironolactone, 31 Tazarotene and adapalene
Squamous cell carcinomas (SCCs), 211 combination products, 21
Steatocystoma multiplex (SM) maintenance therapy, 21
description, 343 noninflammatory lesions, 20
diagnosis, 346 RAR-β and RAR-γ receptor, 20
Index 417

retinoids, 20 Tumor necrosis factor (TNF) inhibitors

ultraviolet light and BP, 20 alpha (TNF-α), 263
Tetracyclines, 28–29 targeted therapies, 394
Tetraethylthiuram disulfide, 399
Tinea barbae
dermatophyte infections, 68 U
fungal culture, 69 Ulcerative, 117, 118, 121
onychomycosis, 69 Ultraviolet (UV)
oral antifungal therapy, 67 -B (UVB), 249
potassium hydroxide test, 68–69 Favre-Racouchot syndrome, 253
scaly papules, 68, 69 filters, 274
sycosis, 68
treatment, 69
Trichophyton species V
T. mentagrophytes, 67 Van Steensel, M.A., 184
T. rubrum, 68 Varicella zoster virus (VZV)
T. verrucosum, 67 antiviral therapy, 102
zoophilic etiologies, 67, 68 clinical presentation
TLRs. See Toll-like receptors (TLRs) herpes zoster, 97–99
TNF inhibitors. See Tumor necrosis factor primary varicella, 97
(TNF) inhibitors dissemination, 102
Toll-like receptors (TLRs), 4 DNA alpha-herpesvirus, 96
Topical antimicrobials and HSV, 99–100
antibiotics, 21–22 mortality, 96
azelaic acid, 22 neuropathic pain, 96
dapsone, 22 oral acyclovir, 101
Topical retinoids and PCR, 100, 101
RARs and RXRs, 19 and PHN, 102
tazarotene and adapalene, 20–21 reactivation, 95, 96
tretinoin, 20 vaccination, 96
Topical therapies zostavax, 101
antimicrobials, 21–22 Vemurafenib, 395
description, 19 Vitamins B6 and B12, 399
guidelines, 23 VZV. See Varicella zoster virus (VZV)
liposomes, 23
micronization, 23
patient-centered approach, 23 W
retinoids, 19–21 Warts, hypogammaglobulinemia, infections
Torre, D., 215 and myelokathexis (WHIM), 399
Tretinoin, 20 Weary, P.E., 59, 195
Trichophyton species, 67, 68 Weller, T.H., 97
Trimethoprim-sulfamethoxazole, 29 Wheaton, S.W., 179
Tuberous sclerosis complex (TSC) White petrolatum, 399
angiofibromas, 229–231 Williams, H.C., 359
autosomal dominant disorder, 229 Wilson, E., 367
cutaneous lesions, 232 Wood’s lamp examination, 281
diagnosis, 231
fibrous papules, 231
hamartin and tuberin, 229 X
and IL-2 inhibitors, 229 Xanthelasmas
internal organ systems, 231 description, 349, 353
koenen tumors, 230, 231 imaging, 354
and mTOR pathway, 229–230, 232 palpebrarum, 351
sirolimus, 232 treatment, 354
418 Index

Xanthomas subtypes, 349

description, 349 tendinous, 352
eruptive, 353 tuberous, 351–352
first-line therapies, 354 workup and diagnosis, 353–354
foamy macrophage, 354 yellow papules, 351, 352
groups, 351
laser therapy, 354
lipoproteins Y
apolipoproteins/apoproteins, 350 Yttrium-aluminum-garnet (YAG)
cholesterol homeostasis, 351 laser, 75, 187, 263, 354
endogenous pathway, 351
exogenous pathway, 350
high-density (HDLs), 350, 351 Z
low-density (LDLs), 350, 351 Zinc pyrithione, 335
mechanism, formation, 350 Zoophilic dermatophyte infections, 67, 68
planar and palmar, 353 Zostavax®, 101
prevalence, 350 Zoster virus. See Varicella zoster virus (VZV)