NEUROCUTANEOUS

SYNDROMES
• abnormalities of both the integument and central nervous
system

• Familial

• Arise from a defect in differentiation of the primitive

ectoderm
• Neurofibromatosis
• Tuberous sclerosis
• Sturge-Weber syndrome
• von Hippel–Lindau disease
• PHACE syndrome
• Ataxia telangiectasia
• Linear nevus syndrome
• Hypomelanosis of Ito
• Incontinentia pigmenti.
Neurofibromatosis
• autosomal dominant

• Tumors to grow on nerves and result in other

abnormalities such as skin changes and bone deformities

• Neurofibromatosis 1 (NF-1)

• Neurofibromatosis 2 (NF-2)
Neurofibromatosis 1 (NF-1)
• (Von Recklinghausen Disease)

• 1/3,000

• NF1 gene on chromosome region 17q11.2 encodes a

protein also known as neurofibromin
Diagnostic criteria: 2 of the following 7
features
• 1. Six or more café-au-lait macules over 5 mm in greatest
diameter in pre pubertal individuals and over 15 mm in
greatest diameter in post pubertal individuals

• uniformly hyperpigmented, sharply demarcated macular

lesions
• present in almost 100% of patients
• present at birth but increase in size, number, and
pigmentation
• Multiple café-au-lait macules commonly produce a
freckled appearance of non–sun-exposed areas such as
the axillae (Crowe sign)
• predilection for the trunk and extremities but sparing the face
• 2. Axillary or inguinal freckling consisting of multiple
hyperpigmented areas 2-3 mm in diameter

• > 80% by 6 yr of age

• appears between 3 and 5 yr of age

• 3. Two or more iris Lisch nodules

• hamartomas located within the iris

• >74% of patients

• 5% of children <3 yr of age

• 42% among children 3-4 yr of age
• virtually 100% of adults ≥21 yr of age.
• 4. Two or more neurofibromas or 1 plexiform neurofibroma

• during adolescence or pregnancy

• small, rubbery lesions with a slight purplish discoloration of

the overlying skin
• flat, sessile,or pedunculated, and can be readily impressed
into the skin below

• Plexiform neurofibromas: evident at birth and result from

diffuse thickening of nerve trunks that are frequently located
in the orbital or temporal region of the face.
• 5. A distinctive osseous lesion such as sphenoid dysplasia
(which may cause pulsating exophthalmos) or cortical
thinning of long bones with or without pseudoarthrosis

• 6. Optic gliomas - low-grade astrocytomas

• 15% of patients
• tumors enlarge and put pressure on the optic nerves and chiasm
resulting in impaired visual acuity and visual fields
• Extension into the hypothalamus can lead to endocrine deficiencies
or failure to thrive
• diffuse thickening, localized enlargement, or a distinct
focal mass originating from the optic nerve or chiasm
• 7. A first-degree relative with NF-1 whose diagnosis was
based on the aforementioned criteria
“unidentified bright objects (UBOs)”
• Abnormal hyperintense T2 weighted signals in the optic
tracts, brainstem, globus pallidus, thalamus, internal
capsule, and cerebellum
complications
• Learning disability (30%)
• Seizures (8%)
• Scoliosis (10%)
• Cerebral aneurysms or stenosis
• transient cerebrovascular ischemic attacks
• Hemiparesis
• cognitive defects
• Precocious puberty
• Malignant peripheral nerve sheath tumor (MPNST)- 3%
• Hypertension
MANAGEMENT
• close multidisciplinary follow-up – yearly
• ophthalmologic examination, neurologic assessment,
blood pressure monitoring, and scoliosis evaluation
• Neuropsychologic and educational testing

• All symptomatic cases: imaging studies of the brain and

optic tracts
• Malignant tumors are managed with appropriate
neurosurgical measures, radiation therapy, and
chemotherapy

• GENETIC COUNSELING
Neurofibromatosis 2 (NF-2)

• 1/25,000
• The NF2 gene (also known as merlin or schwannomin) is
located on chromosome 22q1.11
• Diagnostic criteria: 1 of the following 4 features

(1) bilateral vestibular schwannomas

(2) a parent, sibling, or child with NF-2
• and
• either unilateral vestibular schwannoma
• or any 2 of the following: meningioma, schwannoma,
glioma, neurofibroma, or posterior subcapsular lenticular
opacities
(3) unilateral vestibular schwannoma
• and
• any 2 of the following: meningioma, schwannoma, glioma,
neurofibroma, or posterior subcapsular lenticular opacities

(4) multiple meningiomas (2 or more)

• and
• unilateral vestibular schwannoma or any 2 of the following:
schwannoma, glioma, neurofibroma, or cataract
• Vestibular schwannomas commonly manifest with tinnitus
and/or hearing loss, and may cause problems with
balance

• Audiology and auditory brainstem-evoked response

• definitive diagnosis is based on MRI findings

Management
• Management of tumors associated with NF2 is primarily
surgical

• depends on tumor size, degree of hearing loss, and

involvement of other cranial nerves or compression of the
brainstem

• (VEGF) inhibitor bevacizumab

Tuberous Sclerosis(Bourneville)
• Autosomal dominant
• 1/6,000

• TSC1 gene is located on chromosome 9q34

• TSC2 gene is on chromosome 16p13.

• The TSC1 gene encodes a protein called hamartin.

• The TSC2 gene encodes the protein tuberin.

• loss of either tuberin or hamartin results in the formation

of numerous benign tumors (hamartomas)
• severe mental retardation and incapacitating seizures to
normal intelligence and a lack of seizures
• skin and brain, heart, kidney, eyes, lungs, and bone

• “classic” triad of clinical features comprising mental

retardation,intractable epilepsy, and adenoma sebaceum
Major features
Minor features
Diagnostic Certainty Criteria
• Definite TSC
• 2 major features or
• 1 major feature + 2 minor features

• Probable TSC
• 1 major feature + 1 minor feature

• Possible TSC
• 1 major feature or
• 2 or more minor features
 CNS
• cortical tuber
• Formed while in utero

• Subependymal nodules
• Candle dripping appearance

• can grow into subependymal giant cell astrocytomas- SEGAs

• Hydrocephalus

• epilepsy, cognitive impairment, and autism spectrum disorders

• infantile spasms and a hypsarrhythmic EEG pattern
• myoclonic epilepsy
SKIN LESIONS
• hypomelanotic macules- on the trunk and extremities
• using Wood ultraviolet lamp
• at least 3 hypomelanotic macules
• Polygonal, ash leaf-shaped, confetti-shaped

• Facial angiofibromas(adenoma sebaceum)

• 4 and 6 yr
• tiny red nodules over the nose and cheeks

• Shagreen patch - connective tissue hamartoma

• roughened,raised lesion with an orange-peel consistency located
primarily in the lumbosacral region
• Koenen’s tumors- sub ungal
Retinal lesions
• 2 types:
• hamartomas (elevated mulberry lesions or plaque like
lesions)
• white depigmented patches
Others
• cardiac rhabdomyomas - resolve spontaneously

• angiomyolipomas of kidney – benign

• Single or multiple renal cysts

• Lymphangioleiomyomatosis (LAM) is the classical

pulmonary lesion
Diagnostic and Follow-Up
Management in Tuberous Sclerosis Complex
Management
• follow-up
• treatment of epilepsy and behavioral disorders and
identification of learning disabilities
• Vigabatrin – infantile spasms
• Rapamycin, an mTOR antagonist - subependymal giant
cell tumors and renal angiomyolipoma

• Everolimus for SEGA

Sturge-Weber Syndrome
• (Encephalofacial Angiomatosis)
• sporadic vascular disorder
• 1 per 50,000

• a facial capillary malformation (port-wine stain)

• abnormal blood vessels of the brain (leptomeningeal

angioma)

• Abnormal blood vessels of the eye leading to glaucoma.

• Patients present with

• Seizures
• Hemiparesis
• Strokelike episodes
• Headaches
• Developmental delay
ETIOLOGY
• somatic mutations

• anomalous development of the embryonic vascular bed in

the early stages of facial and cerebral development

• Low flow angiomatosis of the leptomeninges appears to

result in a chronic hypoxic state leading to cortical atrophy
and calcifications
CLINICAL MANIFESTATIONS
• facial port-wine stain - present at birth
• unilateral
• always involves the upper face and eyelid, in a distribution
consistent with the ophthalmic division of the trigeminal
nerve

• 8-33% in those with a port-wine stain

• Buphthalmos and glaucoma of the ipsilateral eye

• epilepsy in 75-90% - 1st yr of life
• focal tonic-clonic and contralateral to the side of the facial
capillary malformation

• Transient strokelike episodes & Hemiparesis

• thrombosis of cortical veins

• mental retardation or severe learning disabilities (50%)

DIAGNOSIS
• MRI with contrast
• leptomeningeal
enhancement in
the left hemisphere

• atrophy is noted
ipsilateral to the
leptomeningeal
angiomatosis
• Calcifications in
a head CT
• Lateral skull
radiograph

• (the “tram-
track sign”).
types according to the Roach Scale
• 1. Type I: Both facial and leptomeningeal angiomas; may
have glaucoma

• 2. Type II: Facial angioma alone (no CNS involvement);

may have glaucoma

• 3. Type III: Isolated leptomeningeal angiomas; usually no

glaucoma
MANAGEMENT
• Anticonvulsants
• Hemispherectomy – refractory seizures

• Surveillance for complications including glaucoma,

buphthalmos, and behavioral abnormalities

• Pulsed dye laser therapy for - port-wine stain

Von Hippel–Lindau Disease
• 1 : 36,000
• Autosomal dominant
• tumor suppressor gene – VHL

• affects many organs, including

• the cerebellum, spinal cord, retina, kidney, pancreas, and
epididymis

• basic pathologic lesion is a capillary hemangioblastoma

features
• Cerebellar hemangioblastomas
• increased intracranial pressure.

• hemangioblastoma of the spinal cord

• producing abnormalities of proprioception and disturbances of gait
and bladder dysfunction

• MRI
Total surgical removal of the tumor is curative.
• Retinal angiomas (25%)
• small masses of thin-walled capillaries that are fed by
large and tortuous arterioles and venules
• located in the peripheral retina so that vision is unaffected.
• Exudation lead to retinal detachment and visual loss.

• Diagnosis: ophthalmoscopy with fluorescein retinal

angiography
• Retinal angiomas are treated with photocoagulation and
cryocoagulation
• Others:
• Cystic lesions of the kidneys, pancreas, liver, and
epididymis
• And pheochromocytoma

• Renal carcinoma is the most common cause of death

Linear Nevus Syndrome
• Facial nevus - forehead and nose and tends to be midline
• Neurodevelopmental abnormalities

• Cortical dysplasia, glial hamartomas, and low-grade

gliomas
• Hemimegalencephaly and enlargement of the lateral
ventricles
• Epilepsy in 75%
• Mental retardation in 60%
• Focal neurologic signs including hemiparesis and
homonymous hemianopia
PHACE Syndrome
• posterior fossa malformations
• hemangiomas,
• arterial anomalies
• coarctation of the aorta and other cardiac defects
• eye abnormalities

• PHACES syndrome when ventral developmental defects

including sternal clefting and/or a supraumbilical raphe
• Dandy-Walker malformation
• Hypoplasia or agenesis of the cerebellum, cerebellar
vermis, corpus callosum, cerebrum, and septum
pellucidum

• facial hemangioma ipsilateral to the aortic arch

• aplasia or hypoplastic carotid arteries, aneurysmal carotid

dilation, aberrant left subclavian artery
• coarctation of aorta

• glaucoma, cataracts, microphthalmia, optic nerve hypoplasia

• ventral defects (sternal clefts)

Incontinentia Pigmenti
• (BLOCH-SULZBERGER DISEASE)

• NEMO; it encodes a protein that participates in the

nuclear factor kappa B (NF-kB) signaling pathway
• dermatologic, dental, and ocular abnormalities

• X-linked dominant

• Has 4 phases
 1st phase
• evident at birth or in the 1st few weeks

• consists of erythematous linear streaks and plaques of vesicles

• on the limbs and circumferentially on the trunk
• linear configuration is unique

• Epidermal edema and eosinophil-filled intraepidermal vesicles

• Blood eosinophilia as high as 65%

• resolves by 4 mo of age
2nd phase
• blisters on the distal limbs become dry and hyperkeratotic,
forming verrucous plaques
• involute within 6 mo

• Epidermal hyperplasia, hyperkeratosis,and papillomatosis

3rd or pigmentary stage
• develops over weeks to months and may overlap the
earlier phases
• Hyperpigmentation is more on the trunk

• macular whorls, reticulated patches, flecks, and linear

streaks follows blascko lines
• persist throughout childhood

• Vacuolar degeneration of the epidermal basal cells and

melanin in melanophages of the upper dermis as a result
of incontinence of pigment
4th stage
• hairless, anhidrotic, hypopigmented patches or Streaks

• mainly on the flexor aspect of the lower legs and less

often on the arms and trunk
Other lesions
• Scarring Alopecia

• Dental anomalies - late dentition, hypodontia, conical

teeth, and impaction

• CNS - motor and cognitive developmental retardation,

seizures, microcephaly, spasticity, and paralysis

• Ocular anomalies - neovascularization, microphthalmos,

strabismus,optic nerve atrophy, cataracts, and
retrolenticular masses
Ataxia telangiectasia
• autosomal recessive
• Incidence- 1/40,000
• Degenerative diseases of the central nervous system

• beginning at about age 2 yr and progressing to loss of

ambulation by adolescence

• mutations in the ATM gene located at 11q22-q23

• Oculomotor apraxia of horizontal gaze
• difficulty fixating smoothly on an object and therefore overshooting
the target with lateral movement of the head, followed by refixating
the eyes

• Strabismus

• Nystagmus
• Telangiectasia
• on the bulbar conjunctiva, over the bridge of the nose, and on the
ears and exposed surfaces of the extremities
• skin shows a loss of elasticity.

• Abnormalities of immunologic function that lead to

frequent sinopulmonary infections include decreased
serum and secretory IgA as well as diminished IgG2,
IgG4, and IgE levels

• greater chance of developing lymphoreticular tumors as

well as brain tumors
Incontinentia Pigmenti Achromians
(Hypomelanosis of Ito)
• hypopigmented lesions on any part of the head, trunk, or
limbs,either unilaterally or bilaterally in whorls
• Palmes , soles , mucus membranes spared

• central nervous system abnormalities include mental

retardation, language disabilities, seizures, and motor
system dysfunction.
• Scoliosis, thoracic & limb deformity
• Ocular abnormalities include strabismus, epicanthic folds,
myopia, optic nerve hypoplasia, and hypopigmentation of
the fundus
• Skin biopsy
• dyskeratosis, increased dermal mastocytes, and pilosebaceous
abnormalities

• Electron microscopy
• few melanosomes,
• reduction in the number of melanosomes in keratinocytes

• Abnormal signals in white matter - MRI

THANK YOU