Syndromic Obesity

9
Krystal A. Irizarry and Andrea M. Haqq

Irizarry K.A., Haqq A.M. (2018) Syndromic Obesity. In: Freemark M. (eds) Pediatric Obesity. Contemporary Endocrinology. Humana Press, Cham

Overview deletions associated with three genes – SIM1,

BDNF, and TRKB – that are implicated in the
It is well established that genetic mutations and development and plasticity of hypothalamic neu-
chromosomal abnormalities can cause excess rons (Table 9.1).
weight gain and white adipose storage in children
and adults. The term “syndromic obesity” is used
to describe obese patients with cognitive delay, Prader–Willi Syndrome (PWS)
dysmorphic features, organ-specific abnormali-
ties, hyperphagia, and/or other signs of hypotha- Overview: Prader–Willi syndrome (PWS) was
lamic dysfunction [1, 2]. Obesity syndromes are originally described by Andrea Prader, Alexis
often distinguished by specific phenotypes and Labhart, and Heinrich Willi in 1956 [3]. It is the
may be inherited in either an autosomal or an most common syndromic cause of childhood and
X-linked pattern. adult obesity [4, 5].
This chapter focuses on two of the most com- Incidence: PWS occurs in both sexes and all
mon obesity syndromes, Prader–Willi syndrome races with a frequency of approximately 1 in
and Albright’s hereditary osteodystrophy and 10,000 to 1 in 15,000 live births and affects an
highlights other unique disorders including estimated 350,000–400,000 people worldwide
Bardet–Biedl syndrome (BBS), Alstrom syn- [4, 6].
drome, Rapid-onset Obesity with Hypothalamic Clinical Features: A characteristic facial appear-
dysregulation, Hypoventilation, and Autonomic ance is noted in PWS: features include narrow
Dysregulation syndrome (ROHHAD), and bifrontal diameter, almond-shaped palpebral fis-
recently characterized overgrowth syndromes. sures, and down-turned mouth with a thin upper lip.
We also review mutations and chromosomal Small, narrow hands with a straight ulnar border
and tapering fingers and short, broad feet are typical
K.A. Irizarry, MD in Caucasians with the disorder [4]. These features
Department of Pediatrics, University of Rochester are summarized in Fig. 9.1 [7]. One-third of patients
Medical Center, 601 Elmwood Ave, Box 690, with PWS are also fairer (lighter skin, hair, and eye
Rochester, NY 14642, USA
color) than other members of their families.
A.M. Haqq, MD, MHS (*) Additional common features include strabismus,
Department of Pediatrics, University of Alberta,
scoliosis, and/or kyphosis.
1C4 Walter C. Mackenzie Health Sciences Center,
8440 112 St NW, Edmonton, AB T6G 2B7, Canada PWS is distinguishable from other obesity syn-
e-mail: [email protected] dromes by its distinct developmental ­phenotype.

© Springer International Publishing AG 2018 153

M.S. Freemark (ed.), Pediatric Obesity, Contemporary Endocrinology,
https://doi.org/10.1007/978-3-319-68192-4_9
Table 9.1 Overview of causes of syndromic obesity
154

Diagnostic Treatment and future

Syndrome Overview Incidence Clinical features Etiology considerations research
Prader–Willi Originally described 1:10,000– • Characteristic facies, small hands Lack of expression of Appropriate use and
Consider in infant with
syndrome (PWS) in 1956 1:15,000 live and feet, hypopigmentation paternally derived hypotonia and FTT or dosage of rhGH therapy
Common genetic births • Hypotonia and FTT in newborn genes on chromosome obese child with shortPossible central adrenal
obesity syndrome • Short stature, hyperphagia, 15q11-q13 due to: stature and insufficiency
obesity, hypogonadism, delayed • Deletion (~70%) hypogonadism Regulation of ghrelin
motor/cognitive development, • Uniparental disomy All forms of PWS are and design of specific
sleep disturbances, and behavior (~20–30%) ghrelin antagonists
detected by methylation
abnormalities in childhood • Imprinting center analysis Understanding
defect (~5%) abnormalities leading to
the abnormal partitioning
of body fat in PWS
Understanding
autonomic nervous
system function in PWS
Understanding branched
chain amino acid and
fatty acid metabolic
changes in PWS
Albright’s Originally described 1:20,000 • Short stature, round face, obesity, Heterozygous Consider in cases of Treat with oral calcium
hereditary in 1942 (estimated) brachydactyly, subcutaneous inactivating mutations functional supplements and
osteodystrophy calcification, dental and in the GNAS1 gene on hypoparathyroidism (low 1,25-dihydroxyvitamin D
(AHO) sensorineural abnormalities chromosome 20q13.3 Ca, high phosphate, with Monitor blood
• Generalized hormonal resistance Mutations can result increased PTH levels), chemistries and urine
to PTH, TSH, GHRH, and in impaired expression obesity, round face, calcium excretion to
gonadotropins of Gsα mRNA or brachydactyly, and avoid hypercalciuria
• Biochemical functional dysfunctional Gsα mental retardation
hypoparathyroidism (low Ca, proteins Hypomagnesemia and
high phosphate but with Genomic imprinting vitamin D deficiency
increased PTH levels) of GNAS1 explains should be ruled out
• Pseudo-­pseudohypoparathyroidism variable phenotypes
is AHO phenotype with
normocalcemia and no hormonal
resistance
K.A. Irizarry and A.M. Haqq
 Diagnostic Treatment and future
Syndrome Overview Incidence Clinical features Etiology considerations research
9
Bardet–Biedl Originally described 1:13,500– • Progressive rod–cone dystrophy Rare recessive, Diagnosis often delayed Treatment of renal
syndrome (BBS) in 1866 1:125,000 • Obesity in first year of life genetically until vision deteriorates disease includes dialysis
Depends on postaxial polydactyly heterogeneous Major cause of mortality or transplantation
geographic • Primary hypogonadism condition is renal disease Further studies are
region • GU and renal abnormalities 12 genes (BBS1–12) Association with renal needed to understand
implicated cell carcinoma may and identify key
Defect in primary cilia warrant monitoring defective pathways
and intraflagellar
Syndromic Obesity

transport
Alstrom syndrome Rare multi-organ <1:100,000 • Progressive rod–cone dystrophy ALMS1 gene on Clinical features manifest No treatment that will
(ALMS) disorder first ~450 cases leading to juvenile blindness chromosome 2p13 during teen years cure ALMS or delay
described in 1959 described • Sensorineural hearing loss 80 different ALMS1 Often confused with disease progression
• Early-onset childhood obesity mutations reported other diagnoses Management of
• Diabetes, adult short stature Defect in centrosomes Presence of dilated photophobia
• Mortality due to cardiac failure or basal bodies of cilia cardiomyopathy and Close cardiac
secondary to dilated early hearing loss and monitoring
cardiomyopathy or renal failure absence of digit May require insulin and/
abnormalities distinguish or metformin
from BBS
ROHHAD Complex Exceedingly • Early-onset, rapid, extreme • As yet of yet, • Consider in children • No specific treatment
multisystem disorder rare, less obesity between ages 2 and unknown with constellation of • Strict diet and exercise
with hypothalamic than 100 7 years • Spontaneously syndromic findings to help BMI
dysregulation, reported • Previously healthy and normal occurring • Onset of clinical • Sleep study to
hypoventilation, and cases weight child • No familial features is variable, diagnose and initiating
autonomic • Hypothalamic dysfunction inheritance pattern with exception of the treatment for alveolar
dysregulation • Alveolar hypoventilation with rapid weight gain hypoventilation is
high risk of cardiopulmonary between 2 and 7 years essential
arrest if not identified in a previously healthy, • Screening and
• Autonomic dysregulation normal weight child monitoring for
(temperature instability, GI hypothalamic
dysmotility, ophthalmologic dysfunction,
abnormalities) neurocognitive
dysfunction, seizures,
and ganglioneuromas
(continued)
155
Table 9.1 (continued)
156

Diagnostic Treatment and future

Syndrome Overview Incidence Clinical features Etiology considerations research
SIM1 deletion Originally described Five • Similar phenotype to PWS – SIM1 is a member of Consider SIM1 deletion Further studies are
syndrome in 2000 individuals hypotonia, obesity, hyperphagia, the basic helix–loop– syndrome in patients needed to examine the
reported in developmental delay, almond-­ helix period aryl with PWS-like features relationship between
the literature shaped eyes, strabismus, thin hydrocarbon receptor but a normal PWS testing common variants of
upper lip, hypogonadism, short family Most patients with SIM1 SIM1 and body weight
extremities Expressed in the deletion have a 6q16.2 gain
• Cardiac and neurological supraoptic and deletion
abnormalities distinguish SIM1 paraventricular nuclei
from PWS of the hypothalamus
SIM1 gene may
function downstream
of the MC4R to
control energy balance
BDNF and First described in Rare, case • Hyperphagia, morbid obesity BDNF acting through Consider BDNF or TrkB Further research is
tropomyosin-­ 2006 reports • Complex neurobehavioral TrkB receptor deficiency in patients needed to understand the
related kinase B phenotype including impaired regulates the with morbid obesity and role of BDNF, and its
(TrkB) cognition, memory, and development, hyperphagia receptor, TrkB, in the
nociception differentiation, and regulation of energy
survival of neurons balance in humans
BDNF
haploinsufficiency in
mice or humans leads
to morbid obesity and
hyperphagia
K.A. Irizarry and A.M. Haqq
9 Syndromic Obesity 157

Dolichocephaly (in infancy)

Narrow face

Almond shaped eyes

Hypopigmented Esotropia, myopia

skin/hair/eyes compared
to family
Thin upper lip and downturned
Skin lesions from frequent corners of the mouth
skin picking

Viscous saliva
Small hands and feet

Hypogonadism
-Genital hypoplasia (cryptorchidism,
microphallus, absent or hypoplastic
labia minora or clitoris)

Short Stature

Fig. 9.1 Physical findings in Prader–Willi syndrome Genetics, Metabolomics, Hormonal Function, and New
(Used with permission of Elsevier from Irizarry KA, Approaches to Therapy. Adv Pediatr. 2016;63(1):47–77)
Miller M, Freemark M, Haqq AM. Prader Willi Syndrome:

Newborns with PWS have hypotonia, poor suck, may also have hypogonadotropic hypogonadism
decreased arousal, and failure to thrive and often or arrested pubertal development. Establishing
require tube feedings for several weeks to months. care with a pediatric endocrinologist is essential
This period is followed by progressive obesity by for long-term management.
1–6 years of age with insatiable appetite, short Autonomic nervous system dysfunction is
stature, delayed motor and cognitive develop- thought to be responsible for viscous saliva, high
ment, behavioral difficulties, and sleep distur- pain threshold, skin picking, and high threshold
bances. Stages in the progression from failure to for vomiting [10]. Importantly, individuals with
thrive to hyperphagia and obesity are shown in PWS commonly have a high prevalence of cen-
Fig. 9.2 [8]. tral and obstructive sleep apnea; sleep dynamics
The hypothalamic dysregulation of PWS can must be assessed prior to initiating growth hor-
be associated with pituitary hormone deficien- mone treatment [11].
cies. A recent report showed that as many as 60% Lastly, individuals with PWS are likely to
of PWS patients have an insufficient ACTH have mental health, behavioral, and cognitive dis-
response to metyrapone, consistent with central orders. It is important to counsel families as these
adrenal insufficiency [9]. PWS patients can also behavioral disorders may include obsessive com-
develop central hypothyroidism, which should be pulsive disorder, impaired language develop-
periodically assessed. Short stature is a common ment, anxiety, temper tantrums, skin picking,
characteristic, due in part to deficient or insuffi- stealing food, and, in more extreme cases,
cient growth hormone secretion. PWS patients ­psychosis [4, 12]. Some studies suggest that
158 K.A. Irizarry and A.M. Haqq

Nutritional phases in PWS

Birth 9 mo 25 mo 4.5 yr 8 yr Adulthood

Phase 0 Phase 1a Phase 1b Phase 2a Phase 2b Phase 3 Phase 4

- Low birth - Hypotonia - Appropriate - Weight - Weight increase - Hyperphagia - Appetite varies
weight - Failure to feeding increase begins - Increased appetite - Absent satiety
- pFetal thrive - On the
movement - Assisted growth curve
feeding

Fig. 9.2 Timeline of nutritional phases in Prader–Willi 2016;63(1):47–77. Data from Miller JL, Lynn CH,
syndrome (Used with permission of Elsevier from Driscoll DC, Goldstone AP, Gold JA, Kimonis V, et al.
Irizarry KA, Miller M, Freemark M, Haqq AM. Prader Nutritional phases in Prader-Willi syndrome. Am J Med
Willi Syndrome: Genetics, Metabolomics, Hormonal Genet A. 2011;155a(5):1040–9)
Function, and New Approaches to Therapy. Adv Pediatr.

n­ eurobehavioral outcomes in PWS may be linked clinical and biochemical features of PWS; how-
to either maternal uniparental disomy or paternal ever, no single gene has been determined to be
deletion of 15q11-q13, though additional investi- causative. It is likely that more than one gene
gations are required [12]. While these patients may be required to cause the complete complex
have multiple comorbidities, it is the complica- clinical picture of PWS.
tions of obesity that are the main contributors to The SNURF-SNRPN gene is a major candi-
the morbidity and mortality in PWS. date. Its gene locus is very complex, spanning
Etiology: PWS is caused by lack of expression ~465 kb and consisting of >148 exons, which can
of paternally derived genes on chromosome undergo alternative splicing [16]. SNRPN (small
15q11-q13 [13]. The genes in this region of the nuclear ribonucleoprotein polypeptide N) is an
chromosome are imprinted: imprinted genes are imprinted and paternally expressed gene located
modified by methylation or histone acetylation in on chromosome 15q11.2 within the PWS locus.
different ways depending on the gender of the SNRPN mRNA is expressed throughout the brain
parent from whom they were inherited. The and codes for SNURF (SNRPN upstream reading
majority of PWS cases (~70%) are due to dele- frame), a small nuclear ribonucleoprotein com-
tions spanning 4–4.5 Mb of the paternal 15q11-­ plex, whose exact function remains unknown.
q13. The next most common cause of PWS is SNRPN knockout mice have hypotonia and
maternal uniparental disomy (UPD) (20–30%), impaired feeding, which are also seen in infants
which is due to maternal meiotic nondisjunction with PWS [17].
followed by mitotic loss of a single paternal chro- Several additional paternally expressed
mosome 15. PWS caused by deletions or UPD imprinted genes have been identified in 15q11-­
does not recur in siblings. Additionally, two types q13 including NDN (encoding NECDIN protein)
of imprinting defects occur in ~5% of cases. In and MAGEL2 [18–20]. NECDIN protein is
one case there is a submicroscopic deletion of a expressed within the hypothalamus, and the
genetic element called the imprinting center (IC); NECDIN knockout mice exhibit respiratory
in the other case, there is an abnormal imprint but defects, including abnormal central respiratory
no detectable mutation [14, 15]. There is as much drive, a decrease in GnRH neurons, skin scraping
as a 50% risk of recurrence in a sibling in these behaviors (similar to skin picking seen in PWS
latter cases; prenatal diagnosis may be possible. patients), and increased pain tolerance [17, 21].
The exact gene(s) responsible for PWS is not MAGEL2 is highly expressed in the hypothal-
known, though several candidate genes have been amus. Mice lacking MAGEL2 have increased
identified. Analysis of targeted knockouts in body weight with excess adiposity [22]. Mercer
mice has provided important insights into the and colleagues recently showed that Magel2-
roles that candidate genes may contribute to the null mice do not display anorexia following
9 Syndromic Obesity 159

p­ eripheral administration of leptin [23], suggest- [7], as a result of defective proghrelin processing,
ing a state of leptin resistance. Indeed, arcuate and relative hypoinsulinemia due to impaired pro-
nucleus pro-opiomelanocortin (POMC) neurons insulin. Additionally, hypothalamic dysfunction
did not depolarize in response to leptin in Magel2- may explain the multiple neuroendocrine find-
null mice; there was a progressive loss of leptin ings, including adrenal insufficiency due to
sensitivity beginning at 4 weeks of age. However, impaired processing of corticotropin-releasing
Magel 2-null mice retained an anorectic response hormone, low growth hormone due to impaired
to the melanocortin receptor agonist, processing of growth hormone-releasing hor-
MT-II. Therefore, the loss of MAGEL2 in PWS mone, hypothyroidism due to impaired thyrotro-
may explain the blunted or absent POMC hypo- pin-releasing hormone, and hypogonadotropic
thalamic response to leptin, resulting in hyper- hypogonadism due to impaired pro-GnRH pro-
phagia and obesity [23]. A progressive loss of cessing [27]. Still, there is not a clear explanation
leptin sensitivity provides a potential explanation for cardinal hyperphagic obesity. Theories include
for the later-onset hyperphagia developing in impaired pro-­opiomelanocortin (POMC) process-
PWS children in early childhood [24]. ing to α-MSH and impaired processing of prohor-
Gene expression studies have also generated mone precursors of appetite-regulating hormones
interest in a novel translocation t(4;15)(q27;q11.2) such as neuropeptide Y, Agouti-related peptide
that implicates the snoRNA, PWCR1/HBII-85, (AgRP), oxytocin, and brain-derived neurotrophic
as the cause of PWS in at least one individual factor. As pro-AgRP is antagonistic toward
[25]. The function of known snoRNAs is to α-MSH, the increased levels of pro-AgRP may
guide 2′-O-ribose methylation of mainly ribo- contribute to the characteristic hyperphagia [27].
somal RNAs; however, this novel imprinted Diagnostic Considerations: An expert con-
snoRNA has no known target. It is postulated sensus committee published clinical diagnostic
that snoRNAs might be involved in the posttran- criteria for PWS and created a scoring system of
scriptional regulation of a gene responsible for major and minor criteria for infants aged
PWS. 0–36 months and children aged 3 years to adult
SNORD116 is one snoRNA that is expressed [28]. These criteria are summarized in Table 9.2.
within the appetite-controlling center of the A recent study found global developmental
hypothalamus. SNORD116 deletions in mouse delay and neonatal hypotonia in over 97% of
models result in growth retardation [17] in asso- patients; feeding difficulty in infancy, followed
ciation with hyperghrelinemia and hyperphagia, by exaggerated weight gain after 1 year of age,
similar to the biochemical and clinical picture of hyperphagia, and hypogonadism were noted in
PWS; however, unlike PWS patients, these mice 93% of patients [29]. Thus, a diagnosis of PWS
do not become obese [26]. should be considered in infants with hypotonia
A recent innovative study has highlighted the and failure to thrive at birth and in those with
role of prohormone bioactivity in the pathogene- developmental delays, early childhood-onset
sis of PWS. Burnett and colleagues determined obesity, hypogonadism with genital hypoplasia,
that SNORD116-null mice had functional defects short stature, and behavior disorders in early
in the processing of proinsulin, pro-GH-­releasing childhood.
hormone, and proghrelin and hypothesized that Since clinical criteria were initially defined,
this was due to a deficiency of proconvertase molecular genetic testing has now been refined.
enzyme 1 (PC1) activity [27]. They measured the DNA methylation analysis will detect three forms
prohormone levels in SNORD116-null mice and of PWS and is therefore the most efficient test
wild-type mice, as well as PWS patients and con- available [30]. If the methylation pattern is abnor-
trols. Their results showed a functional defect in mal (signifying one parent of origin), then fluo-
PC1, with higher prohormone compared to hor- rescence in situ hybridization (FISH) can be
mone levels. This may explain several features of used to confirm a chromosomal deletion, and
the PWS ­phenotype including hyperghrelinemia microsatellite probes may be used to verify
­
 160

Table 9.2 Clinical manifestations at various ages suggestive of Prader–Willi syndrome

Decreased Developmental Short stature
fetal Failure to delays/cognitive (disproportional Hypogonadism and Behavioral
Age movement thrive Hypotonia impairments Hyperphagia small hands/feet) pubertal delay disordera
Infancy x X X X
Toddlers to early X X X
childhood
Early childhood to X X X X X
adolescence
Adolescence to X X X X X X
adulthood
Additional Supportive Findings
Characteristic physical exam features: narrow bifrontal diameter, almond-shaped eyes, palpebral fissures, down-turned mouth, thin upper lip, narrow hands with straight ulnar
borders, thick viscous saliva, sleep disturbance/sleep apnea
a
Behavioral disorders: temper tantrums, obsessive compulsive behaviors, skin picking, sneaking food
K.A. Irizarry and A.M. Haqq
9 Syndromic Obesity 161

maternal UPD. Note that high-resolution chro- r­ elative hyperghrelinemia of PWS in early child-
mosome analysis alone is insufficient because hood might be a biologic response to neonatal
false positives and false negatives have occurred failure to thrive. This, however, does not readily
with this method without FISH. An abnormal explain the persistent hyperghrelinemia of PWS
methylation pattern in the presence of normal adolescents and adults.
FISH and uniparental disomy studies suggests an As expected with excess fat deposition, leptin
imprinting center mutation. Analysis for muta- levels are high in obese children with PWS. Yet
tions in the imprinting center is now available for even prior to onset of obesity in young children,
clinical diagnosis in selected laboratories. the anorexigenic hormone peptide YY (PYY) is
lower in PWS compared to obese controls [34];
the response to a high-fat meal was blunted in a
Pathogenesis of Weight Gain study of PWS adolescents and children [35]. This
and Treatment of Obesity in PWS yielded an increase in the ratio of ghrelin to PYY,
which might serve as a marker of orexigenic
Dysregulation of Appetite-Controlling Hormones: drive in PWS [35]. Nevertheless, no clear rela-
The specific cause of hyperphagia in PWS tionships have yet been identified between PWS
remains elusive. Several recent clinical studies eating patterns and the levels of appetite-­
have characterized the secretion of appetite-­ regulating hormones in the circulation.
regulating hormones (ghrelin, PYY, leptin) and Treatment of Obesity in PWS: Until our under-
found unique patterns in PWS compared to con- standing of appetite allows for more targeted
trols with generalized exogenous obesity. treatment, nutritional management and preven-
Ghrelin, an orexigenic hormone produced by the tion of the complications of morbid obesity are
oxyntic cells of the stomach, normally rises prior the mainstay of treatment in PWS. Prior data
to meals and falls in response to nutrient inges- from preschool and school-aged children have
tion (particularly carbohydrate and protein; see shown that a calorie-restricted diet of 7 kcal/cm/
also Chap. 3 on GI Hormones and the Control of day (600–800 kcal/day) can result in weight loss;
Food Intake and Energy Metabolism). Ghrelin a diet of 8–11 kcal/cm/day (800–1300 kcal/day)
levels are lower in obese subjects than in lean allows for weight maintenance [7, 36]. However,
individuals but are consistently higher in PWS the optimal macronutrient content of diet has yet
children and adults than in BMI-matched obese to be determined. It is recommended that nutri-
controls [7, 31, 32] and may in some cases exceed tional management begin early in toddlerhood to
levels seen in age- and gender-matched lean best prevent obesity and related comorbidities,
subjects. including type 2 diabetes and hyperlipidemia. A
A critical question concerns the ontogenesis regular feeding schedule, monitoring of caloric
of hyperghrelinemia in PWS and its relationship intake and weight, and behavior modifications
to feeding and weight gain. Circulating ghrelin that may include restricting access to food supply
concentrations are normally high in infancy and are important [7].
decline progressively during the course of child- More recently, bariatric surgery has been con-
hood development. In a cross-sectional study of sidered for treatment of morbid obesity in
33 infants and young children with PWS and 28 PWS. This was first studied in MAGEL2 knock-
healthy controls, Haqq and colleagues [33] found out (KO) mice that had been fed a high-fat diet
that one-third of the PWS subjects had ghrelin for 10 weeks. When KO mice underwent sleeve
levels greater than the upper range of normal con- gastrectomy, they had loss of body fat, lower fast-
trols. Interestingly, the hyperghrelinemia in PWS ing glucose levels, and reduced dietary fat intake
infants was noted prior to the onset of hyperpha- [37]. In a recent clinical study, 24 PWS patients
gia and adiposity; indeed highest levels were between 5 and 18 years with morbid obesity
observed in PWS infants with lowest weight underwent sleeve gastrectomy and had annual
for age z-scores. It has been proposed that the follow-up for 5 years [38]. Prior to surgery these
162 K.A. Irizarry and A.M. Haqq

patients had several obesity comorbidities, Adolescents with PWS may have delayed or
including obstructive sleep apnea, dyslipidemia, arrested pubertal development. Treatment with
hypertension, and type 2 diabetes. After surgery, estrogen or testosterone should be initiated and
patients had marked reductions in BMI and monitored by experienced centers. Sex steroid
remission of approximately 80% of comorbidi- replacement can have many benefits including
ties. Sleeve gastrectomy is thought to alter appe- improved bone mineralization and bone mass
tite and satiety and induce weight loss by accrual, increased muscle mass, and heightened
changing the metabolic and neuroendocrine well-being with achievement of secondary sex
milieu of the gut, with increased postprandial characteristics. Pubertal induction with sex ste-
concentrations of the anorexigenic hormones roids is timed to best track along a normal puber-
GLP1 and PYY and decreases in the levels of the tal time course. Less commonly, PWS children
orexigenic hormone ghrelin [39, 40]. Certainly can develop precocious puberty; however, treat-
questions of the long-term sustainability of bar- ment with gonadotropin-releasing hormone ana-
iatric surgery in PWS have been raised, and fol- logs is usually withheld as pubertal advancement
low-­up studies are needed to determine long-term is self-limited [43]. While no cases of paternity
efficacy as well as safety, including effects on have been found with PWS, there are case reports
skeletal growth and bone mineralization. of pregnancies in PWS females. These pregnan-
Neuroendocrine Dysfunction: Individuals cies have resulted in two children without genetic
with PWS may have hypothalamic dysfunction mutation and two children with Angelman syn-
beginning early in utero with continuation in drome [44, 45].
infancy and childhood. Therefore, close moni- Growth Hormone Treatment: The use of
toring of neuroendocrine function is warranted. growth hormone (GH) is now FDA approved
In particular, identifying and treating central for treatment of short stature in PWS. GH treat-
adrenal insufficiency is critical; it is suspected ment of PWS infants and children has been
to be a cause of death in some patients. While shown in randomized trials to exert favorable
some of these had been treated with growth effects on growth, body mass index, body com-
hormone, the effects of growth hormone ther- position, and motor and cognitive development
apy on adrenal function remain unknown [41]. [46–48]. Growth velocity is increased in child-
Metyrapone testing has estimated that central hood and final height is augmented [49]. GH
adrenal insufficiency may occur in up to 60% of reduces fat mass, increases lean body mass and
PWS cases, though more recent low-dose ACTH bone mineral density, and increases resting
stimulation tests estimated prevalence to be as energy expenditure (REE), with improved fatty
low as 14% [42]. acid oxidation [49–54]. Improvements in physi-
Central hypothyroidism occurs in as many as cal strength, respiratory muscle tone, and
20–30% of PWS patients [11]. It is recommended peripheral chemoreceptor sensitivity to carbon
that children be screened for thyroid dysfunction dioxide have also been reported [49, 50, 54].
at diagnosis and yearly thereafter. In infants, One study has also reported a trend toward
screening should be conducted within the first improvement in overall sleep quality, including
3 months of life as thyroid hormone plays a cen- reduction in the number of hypopnea and apnea
tral role in neurodevelopment. Thyroid function events with administration of GH [54]. Further
tests should also be monitored after beginning studies investigating the optimal timing of ini-
growth hormone treatment, as growth hormone tiation, dosage, and duration of growth hor-
can increase peripheral conversion of free T4 to mone treatment in children and adults with
triiodothyronine [11]. Treatment with levothy- PWS are needed.
roxine should be initiated if hypothyroidism is Controversy persists about whether growth
identified. hormone treatment causes an excess of mortality
9 Syndromic Obesity 163

beyond that expected from PWS alone. There p­ erformed prior to GH therapy, with close moni-
have been approximately 28 cases of sudden toring of sleep quality (Fig. 9.3) [7].
death in PWS children undergoing treatment As with sex steroids, GH treatment should be
with GH [55, 56]. These have been concentrated initiated by experienced centers. The recom-
in young children with a history of respiratory mended GH dosage is 0.5–1 mg/m2/day with
obstruction/infection or severe obesity [57–59] adjustment to maintain insulin-like growth factor-
and have occurred early in the course of GH ­I (IGF-I) levels in the normal range. Lower doses
therapy. The exact cause of the sudden deaths of GH may be effective; therefore, it seems pru-
has not been determined. Possibilities include dent to initially begin with subtherapeutic doses
impaired ventilatory responsiveness to hyper- and to increase gradually to insure that the drug is
capnia and hypoxia, increased lymphoid tissue well tolerated. Children receiving GH therapy
or tonsillar hyperplasia, and adrenal insuffi- should be monitored for thyroid dysfunction, glu-
ciency. Alternatively, there may in fact be no true cose intolerance, and worsening scoliosis.
increased mortality above that expected from the Patients with PWS often develop anxiety and
PWS diagnosis alone. Indeed, other studies sug- obsessive compulsive disorder and neurologic dis-
gest that GH increases ventilator responsiveness orders including narcolepsy; seizures are less com-
to carbon dioxide and improves sleep quality in mon. Additionally, they are prone to scoliosis with
children with PWS [54]. Until studies defini- or without growth hormone treatment. Therefore,
tively address these issues, we recommend that a multispecialty care with specialized consultations
pretreatment airway and sleep evaluation be for management of PWS is recommended.

Screening History
1.Dietary Intake
2.Sleep History
3.Screen for central adrenal insufficiency

Normal Abnormal
Polysomnography(PSG) Intervention
1.ENT consult for
T&A
2.Pulmonary
Start Growth Hormone consult for
(0.5-1mg/m2/day or 0.1-0.15mg/kg/week CPAP/BiPAP

Monitoring

History and Physical Exam

1.Obtain sleep history at each visit
2.Evaluate for scoliosis every 6 months Repeat PSG post-intervention
Labs
1.IGF-1(Target+1-2-SDS),IGF BP-3
2.Free T4,TSH
3.HbA1c,fasting glucose and insulin
Diagnostic Studies
Repeat PSG every 1-2 years depending on clinical symptoms If normal,reconsider GH
and sleep history treatment

Fig. 9.3 Algorithm for initiation of growth hormone M, Haqq AM. Prader Willi Syndrome: Genetics,
(GH) therapy in Prader–Willi syndrome (Used with per- Metabolomics, Hormonal Function, and New Approaches
mission of Elsevier from Irizarry KA, Miller M, Freemark to Therapy. Adv Pediatr. 2016;63(1):47–77)
164 K.A. Irizarry and A.M. Haqq

 ritical Gaps in Knowledge and New

C weight adiponectin concentrations and
Therapeutic Approaches increased ratios of HMW/total adiponectin
and higher insulin sensitivity in PWS chil-
1. As noted previously [7, 33–35], children and dren compared to BMI-­ matched controls
adults with PWS have high fasting and post- [68, 69]. The lack of visceral fat and the
prandial levels of total ghrelin, an orexigenic relative hyperadiponectinemia may protect
peptide produced in the stomach. In contrast, PWS individuals against metabolic compli-
total ghrelin levels are suppressed in children cations of obesity such as insulin resistance,
and adults with “exogenous” obesity or with type 2 diabetes, and hypertriglyceridemia
obesity caused by mutations in leptin or the [66]. Future studies are needed to under-
melanocortin-4 receptor [32, 60, 61]. Young stand the mechanisms that lead to abnormal
PWS infants, who have not yet developed partitioning of body fat in PWS and its meta-
hyperphagia or obesity, have median fasting bolic consequences.
total ghrelin levels similar to age- and sex-­ 4. Several features of PWS – including abnor-
matched controls. However, a subset (33%) mal temperature regulation, altered sleep
of young PWS is already hyperghrelinemic control (excessive daytime somnolence and a
[33]. The high circulating concentrations of primary abnormality of the circadian rhythm
ghrelin may be critical for the pathogenesis of of rapid eye movement sleep), increased pain
weight gain in PWS because ghrelin stimu- tolerance, and decreased salivation – suggest
lates appetite and weight gain in rodents and dysfunction of the autonomic nervous sys-
human adults. Octreotide treatment in chil- tem (ANS). However, the evidence for ANS
dren with PWS has been shown to decrease dysfunction is inconclusive. One study
fasting ghrelin concentrations, but does not reported diminished parasympathetic ner-
alter body weight [62–64]. Octreotide, how- vous system function based on higher resting
ever, is a nonspecific inhibitor of ghrelin and pulse rates and lesser increases in diastolic
reduces PYY levels [65], making interpreta- blood pressure upon standing [10]. However,
tion of its effects on food intake and weight when controlling for body mass index (BMI),
gain difficult [35]. Strategies that specifically other studies report no differences in ANS
inhibit ghrelin action and/or increase PYY function (control of heart rate and blood
secretion or action might reduce orexigenic pressure) in PWS subjects [70]. Interestingly,
drive in PWS. necdin-null mice have abnormal outgrowth
2. Recent studies demonstrate that agonists for of sympathetic neurons, predominantly from
the melanocortin-4 receptor (setmelanotide) the superior cervical ganglion (the most ros-
can cause striking weight loss in subjects tral of the paravertebral sympathetic gangli-
with mutations in POMC. (See Chap. 2 on ons innervating the pupil, lacrimal and
Central Control of Energy Metabolism and salivary glands, and cerebrum). Therefore,
Hypothalamic Obesity and Chap. 8 on future studies examining the autonomic sys-
Monogenic Obesity.) Current studies are tem in PWS will likely lead to further under-
exploring the efficacy of setmelanotide in standing of the autonomic nervous system’s
adults with PWS. contribution to the control of energy homeo-
3. PWS individuals demonstrate abnormal par- stasis in PWS.
titioning of body fat and lean mass. Whole-­ 5. Finally, some preliminary evidence points to
body magnetic resonance imaging (MRI) alterations in fatty acid and branched chain
has found that PWS adults have greater fat amino acid metabolism in individuals with
mass relative to fat-free mass, but signifi- PWS [69]. Future studies are needed to
cantly less visceral adiposity compared to explore the roles of specific metabolites in the
obese controls [66, 67]. Our group has also pathogenesis of obesity and insulin resistance
demonstrated higher total and high ­molecular in PWS.
9 Syndromic Obesity 165

Albright’s Hereditary result from decreased energy expenditure rather

Osteodystrophy than increased energy intake. Recent animal
studies have shown that disruption of Gsα signal-
Overview: Albright’s hereditary osteodystrophy ing in hypothalamic pathways leads to defective
(AHO) was first described in 1942 in a child with energy expenditure [75]. More recent clinical
short stocky build, round face, short metacarpals studies have confirmed these findings and show
and metatarsals, and numerous areas of soft tis- reduction in absolute resting energy expenditure
sue calcification [71]. AHO can be an isolated and relative resting energy expenditure compared
finding or associated with pseudohypoparathy- to obese controls [76]. Moreover, dietary data
roidism. Pseudohypoparathyroidism is character- revealed these PHP1A clinical subjects con-
ized by end-organ resistance to parathyroid sumed less than the daily allowance of calories,
hormone (PTH) action in the kidneys and bone, suggesting that reduced energy expenditure likely
resulting in the constellation of physical findings accounts for early-onset obesity [76].
of AHO. There may also be more generalized Etiology: Autosomal dominant heterozygous
resistance to hormones that signal through inactivating mutations in the GNAS1 gene on
G-protein-coupled receptors [71]. chromosome 20q13.3 form the basis for Gsα defi-
Incidence: The incidence of AHO is approxi- ciency of patients with AHO [77]. The GNAS1
mately 1:20,000 individuals. gene consists of 13 exons and 3 alternate initial
Clinical Features: There are several forms of exons with different promoters, allowing for for-
pseudohypoparathyroidism. Patients with pseu- mation of four different isoforms via alternative
dohypoparathyroidism type 1a (PHP type 1a) splicing [78]. Interestingly, some mutations result
have a generalized resistance to hormones signal- in impaired expression of Gsα mRNA, while oth-
ing through G-protein-coupled receptors (PTH, ers result in dysfunctional Gsα proteins.
thyroid-stimulating hormone (TSH), growth Several lines of evidence suggest that genomic
hormone-­releasing hormone (GHRH), and gonad- imprinting of GNAS1 explains the variable phe-
otropins) and a constellation of developmental notypes that occur with identical GNAS1 gene
defects that is referred to as AHO. The AHO phe- defects. First, PHP type Ia and pseudo-PHP fre-
notype includes short stature, round face, obesity, quently occur in the same family, but not in the
brachydactyly, and subcutaneous calcification. same generation. Second, nearly all cases of
Some individuals are reported to have dental and maternal transmission of Gsα deficiency lead to
sensorineural abnormalities. Additionally pri- PHP type 1a, whereas paternal transmission of
mary hypothyroidism (due to TSH resistance), the same mutation leads to pseudo-PHP [79, 80];
GH deficiency (secondary to GHRH resistance), this suggests that variable AHO phenotypes orig-
and hypogonadism (due to gonadotropin resis- inate from differential tissue-specific genomic
tance) are common [72]. Hypocalcemia associ- imprinting.
ated with PTH resistance can lead to nervous Diagnostic Considerations: A diagnosis of
excitability, cramps, tetany, hyperreflexia, con- AHO should be considered in an individual with
vulsions, and tetanic crisis. In contrast to PHP functional hypoparathyroidism (hypocalcemia
type 1 A, individuals with pseudo-pseudohypo- and hyperphosphatemia) and increased PTH con-
parathyroidism have the phenotype of AHO but centrations or in those with clinical features of
have normocalcemia and lack hormone resis- AHO such as obesity, round face, brachydactyly,
tance [73]. and cognitive delay. It should be noted that pri-
Both isolated AHO and PHP type 1a can occur mary hypothyroidism in PHP type 1A may be
in the same family and are due to a functional tis- detected at an early age, before the emergence of
sue deficiency of the alpha subunit of the obesity, hypogonadism, or disturbances in cal-
G-protein-coupled receptor (Gsα). Generalized cium metabolism.
obesity develops in 50–65% of AHO patients Importantly, hypomagnesemia and vitamin D
[74]. The etiology of the obesity is thought to deficiency should be excluded, as these states can
166 K.A. Irizarry and A.M. Haqq

mimic the biochemical features of AHO. Synthetic delay (54–81%), behavior abnormalities (33%),
PTH [1–34] peptide is available, and various pro- hearing loss (21%), ataxia/imbalance (40–86%),
tocols exist for diagnosis of AHO based on intra- type 2 diabetes (6–48%), and, occasionally, con-
venous infusion of PTH and measurement of genital heart disease (7%) [87–90]. Many of
resulting urine cAMP, phosphorus, and creatinine these features are not present at birth; rather, they
concentrations. GNAS1 gene analysis is also avail- develop over time by the second decade of life.
able through various commercial laboratories. Polycystic kidney disease and complications of
Treatment and Future Research: Treatment obesity (type 2 diabetes, hypertension, and hyper-
with oral calcium supplements and cholesterolemia) are the leading causes of prema-
1,25-­dihydroxyvitamin D is needed to normalize ture death in BBS [88]. The obesity of BBS
calcium, phosphate, and PTH levels and thereby manifests as rapid progressive weight gain and
prevent hyperparathyroid bone disease. Blood hyperphagia in the first year of life and has been
chemistries and urine calcium excretion should associated with reduced physical activity com-
be monitored at least twice yearly to avoid hyper- pared to obese controls [91]. The typical neu-
calciuria and nephrocalcinosis. Although a num- robehavioral profile of BBS consists of reduced
ber of defects in GNAS1 are responsible for IQ (mean 75.81 ± 14.01), impaired fine motor
AHO, the molecular mechanisms underlying function, decreased olfaction, impaired vision,
hormone resistance and imprinting defects and social skills deficits [92].
remain incompletely understood. Further charac- Etiology: BBS is a genetically heterogeneous
terization of novel GNAS1 defects will likely condition with significant intrafamilial variabil-
advance our knowledge of this disorder, and ity. Previously BBS was determined to have auto-
additional characterization of the obese pheno- somal recessive inheritance; however, more
type of AHO will likely aid in our understanding recent gene analysis of BBS asymptomatic gene
of the molecular mechanisms of body weight mutation carriers suggests possible incomplete
regulation. penetrance [89].
In 2003, Ansley and colleagues were the first
to propose that BBS is caused by a defect at the
Bardet–Biedl Syndrome basal body of ciliated cells [93]. DNA sequenc-
ing and whole exome sequencing technologies
Overview: In 1866 Drs. Laurence and Moon now implicate 19 genes in the etiology of BBS
described four siblings with retinal dystrophy, [88, 89], all of which are involved in ciliary
obesity, and cognitive impairment, as well as development or intraflagellar transport. Primary
small external genitalia and an abnormal gait in cilia play central roles in cell signaling, sensing,
the males [81]. A similar phenotype that included and mediating inputs such as mechanical cues to
polydactyly was then described by Bardet and chemical and paracrine signaling through hedge-
Biedl [82, 83]. hog, Wnt, and platelet-derived growth factor
Incidence: BBS is rare; its prevalence ranges (PDGF) pathways; thus, primary cilia play a key
from 1 in 125,000–160,000 in Europe [84, 85] to role in development to maintain cellular and tis-
1 in 13,500 in the Bedouin of Kuwait [86] and sue homeostasis [94].
1 in 17,500 in Newfoundland, Canada [84]. BBS 1, 2, 4, 5, 6, and 8 localize to the basal
Clinical Features: BBS is characterized by six body and pericentriolar region; BBS 6, 10, and
primary features: progressive rod–cone dystro- 12 are likely chaperones that facilitate protein
phy (90–100% prevalence), obesity (72–92%), folding and account for one-third of cases. BBS 3
postaxial polydactyly (extra digits) (63–81%), (a member of the Ras superfamily of small GTP-­
primary hypogonadism (98%), cognitive impair- binding proteins) and BBS 11 (an E3 ubiquitin
ment (50%), and genitourinary tract malforma- ligase) encode known proteins [95–102]
tions and progressive renal dysfunction (24%). (Table 9.1). Establishing genotype–phenotype
Additional secondary features include speech correlations has been challenging. However,
9 Syndromic Obesity 167

studies now suggest that mutations in BBS2, h­ ypothalamic neurons that impair trafficking of
BBS3, and BBS4 are associated with ocular man- leptin receptors and thereby reduce leptin signal
ifestations [103]; patients with mutations in transduction [113]. However, recent data sug-
BBS16/SDCCAG8 have renal disease but no gest that leptin resistance might be a marker of
polydactyly [104]; patients with mutations in obesity in BBS, rather than the causative initiat-
BBS6, BBS10, or BBS12 present with more ing factor [114].
severe renal disease [105]. Recent studies in mice suggest that weight
Although not proven, the renal abnormalities gain in BBS results from an energy imbalance.
seen in BBS are thought to be secondary to disor- When fed the same diets, BBS mice had increased
dered cilia function. This is supported by features abdominal adiposity, decreased locomotion, and
of the oakridge polycystic kidney disease mouse hyperphagia compared to control mice; this sug-
mutant (orpkd) which exhibits dilated proximal gests that obesity in BBS reflects both increased
tubules and cysts and has short and malformed energy intake and decreased energy expenditure
cilia [106]; the mutation in this mouse maps to a [115, 116]. CNS mis-localization of G-protein-­
gene encoding polaris, a protein required for coupled receptors (GPCRs) involved in regula-
assembly of renal cilia. Subsequent studies in tion of energy balance, such as neuropeptide Y2
cystic diseases of the kidney and BBS have illus- receptor, and the brain-derived neurotrophic fac-
trated that cilia in the epithelium of the renal tor (BDNF) receptor, TrkB, may limit energy
tubules play a critical role in kidney tissue expenditure. Finally, BBS proteins play a key
homeostasis [107, 108]. The retinal degeneration role in the differentiation of adipocytes, suggest-
in BBS is also associated with impaired intrafla- ing that a defect in adipogenesis and related
gellar transport (IFT) across the connecting cil- abnormalities in circulating adipokines might
ium, which links the photoreceptor inner and contribute to the pathogenesis of obesity in BBS
outer segments [109, 110]. The BBS proteins [113].
also play a role in transportation of rhodopsin to Diagnostic Considerations: Commercial labs
the base of the connecting cilium (CC); therefore, now conduct multigene sequencing of BBS
retinal degeneration in BBS is thought to result genes. However, the diagnosis of BBS is often
from both defective transport of cargo proteins to delayed until visual deterioration manifests due
the base of the CC and defects in IFT-mediated to rod–cone dystrophy; night blindness typically
transport across the CC [111]. Interestingly, the emerges around 8 years of age, followed by loss
polydactyly of BBS is postaxial, which may of peripheral vision and blindness by 15 years of
result from a combination of defects in hedgehog age [88]. Other characteristic findings that could
and other signaling pathways (Wnt) [111]. warrant gene sequencing include postaxial poly-
Recent investigations have also evaluated the dactyly, early-onset obesity, male hypogonado-
contribution of genes associated with Bardet– tropic hypogonadism, and female genitourinary
Biedl syndrome to the production and mainte- tract malformations (hypoplastic fallopian tubes
nance of pancreatic β-cells. Loss of bbs1 or bbs4 and uterus, vaginal atresia, and hydrometrocol-
results in a significant increase in β-cell mass. pos). Early diagnosis is important as renal dis-
Additionally, bbs-1-deficient β-cells are suscep- ease is progressive and remains a major cause of
tible to apoptosis, but an increase in cell number mortality in BBS. Renal abnormalities are vari-
is maintained via beta cell proliferation. This able but commonly include cystic tubular disease
might explain the later onset of diabetes demon- and anatomic malformations; most patients also
strated in BBS patients; diabetes may occur even- have a urinary concentration defect [117].
tually as a result of an inability to compensate for Additionally, an excess of early-onset renal cell
a high degree of β-cell death [112]. carcinomas in obligate carriers of BBS mutations
The mechanisms leading to obesity in BBS necessitates that BBS patients be carefully moni-
remain elusive. It is theorized that excess tored for development of malignancies [118].
weight gain could result from ciliary defects in The majority of adults have obesity complicated
168 K.A. Irizarry and A.M. Haqq

by hypertension, type 2 diabetes mellitus, and Endocrinologic manifestations include hyper-

dyslipidemia. Some BBS patients have given insulinemia (92%) and acanthosis nigricans
birth to healthy children [88]. (68%), diabetes mellitus (median age of onset of
Treatment and Future Research: Therapeutic 16 years; 82%), hypertriglyceridemia (nearly
strategies in BBS remain supportive pending the 100%), infertility (hypergonadotropic hypogo-
development of novel and targeted treatments. nadism; 77%), increased androgen production
Chronic renal dialysis or transplantation is cur- and hirsutism in females, primary hypothyroid-
rently the only successful mode of managing ism, growth hormone deficiency, and bone–skel-
renal disease in most patients. Further studies etal abnormalities [124, 125]. In younger patients,
examining long-term outcomes after renal trans- mortality is primarily due to cardiac failure sec-
plantation are needed. ondary to dilated cardiomyopathy [123]. In older
As improvements in gene testing have contin- subjects, renal failure is the most common cause
ued, new treatments have been trialed in animal of death [124]. Advanced early-onset, non-­
studies. Gene therapy for treatment of blindness alcoholic fatty liver diseases (NAFLD) with
has been successful in selected mouse experi- fibrosis (disproportionate to age, BMI and diabe-
ments [89]. For example, subretinal injection of tes duration) are also common and lead to high
the BBS gene within an adenovirus construct res- morbidity/mortality in AS [126]. Fibrosis in mul-
cued rhodopsin and preserved eye function in tiple organs has been reported. Finally, a recent
mice [119, 120]. Other studies in BBS knockout MRI study in AS reports a high incidence of total
mice have attenuated weight gain by administra- empty sella (34%) and partial empty sella (19%).
tion of melanotan II, a melanocortin receptor These findings raise the importance of screening
agonist that reduced food intake [113]. for pituitary dysfunction [127]. Note that many
Setmelanotide, a new melanocortin-4 receptor of the characteristic features of AS emerge as the
agonist, may also be beneficial in controlling children grow.
weight gain in the BBS population [121]. Etiology: The ALMS1 gene on chromosome
2p13 was identified by two independent research
groups in 2002. ALMS1 encodes a 4169 amino
Alstrom Syndrome (AS) acid protein that contains a large 47 amino acid
tandem repeat domain [128, 129]. The function
Overview: Alstrom syndrome (AS) is a rare auto- of the ALMS protein remains unknown. However,
somal recessive multi-organ disorder caused by it is expressed ubiquitously and is thought to be
mutations in ALMS1. It was first described in involved in the function of centrosomes or basal
1959 [122]. bodies [130]. In support of this theory, ALMS1
Incidence: AS has an estimated prevalence of knockout mice demonstrate abnormal ciliary
<1:100,000 [123]. Approximately 800 cases have structure and recapitulate many features of the
been described since it was first reported [124]. human syndrome including obesity, hyperinsu-
Clinical Features: AS exhibits much phenotypic linemia, hypogonadism, retinal degeneration,
variability, even within families. Characteristic fea- and renal dysfunction. The phenotype is reversed
tures include progressive rod–cone dystrophy by a prematurely truncated N-terminal fragment
beginning in infancy and leading to juvenile blind- of ALMS1 [130, 131].
ness (90% by age 16 years), sensorineural hearing Until recently, approximately 80 different
loss (89%; mean age of 5 years), early-onset ALMS1 mutations, located primarily in exons 8,
childhood obesity (nearly 100%), and adult short 10, and 16, have been implicated in AS [132].
stature (due to early rapid growth and early fusion However, the wider incorporation of automated
of growth plates) [125]. Most patients have nor- sequencing to genotype patients with AS has now
mal intelligence, although delayed fine and gross uncovered additional disease-causing mutations
motor and language development are described in in ALMS1 [133]. These are located in exons 3, 5,
some [124]. 8, 9, 10, 12, 14, 15, 16, 17, 18, 19, and 21 and in
9 Syndromic Obesity 169

introns 2, 9, and 15. Mutational hotspots for with angiotensin-converting enzyme (ACE)
ALMS1 occur in exons 8, 10, and 16. The major- inhibitors is indicated in those with cardiomyop-
ity of mutations are nonsense or frameshift athy. Weight management and exercise are
abnormalities that are predicted to cause prema- important in managing the metabolic disorders in
ture protein truncation; studies to date suggest no AS. Many patients eventually require insulin sen-
strong genotype–phenotype correlation [132]. sitizers (metformin and/or thiazolidinediones) or
There is phenotypic variation in visual acuity, insulin therapy. Hormonal replacement with thy-
hearing loss, cardiomyopathy, and hepatic mani- roxine and/or testosterone is useful when indi-
festations within families. Thus, there seem to be cated. The benefits and risks of the use of growth
interactions between numerous genetic modifi- hormone therapy in AS are not fully understood
ers, environmental or infectious exposures, and at this time; thus, GH treatment is still considered
other variables leading to variations in age of investigational. Further elucidation of the func-
onset and severity of clinical phenotype in AS tion of ALMS1 will provide insight into the
patients. pathogenesis of AS and other uncommon forms
Diagnostic Considerations: Diagnosis can be of obesity, diabetes, and retinal disease.
challenging in young children, as many of the
characteristic clinical features (type 2 diabetes
mellitus and hepatic, pulmonary, and renal dys- Rapid-Onset Obesity
function) do not manifest until the teenage years. with Hypothalamic Dysregulation,
Alstrom syndrome is often confused with other Hypoventilation, and Autonomic
conditions early in life. For example, photopho- Dysregulation Syndrome (ROHHAD)
bia in infancy might be misclassified as Leber
congenital amaurosis or achromatopsia, and Overview: ROHHAD syndrome is a complex
childhood obesity and type 2 DM often lead to an multisystem disorder associated with rapid onset
incorrect diagnosis of Bardet–Biedl syndrome of hyperphagia and obesity between 2 and 7 years
(BBS). The presence of dilated cardiomyopathy, of age. It was first described nearly 50 years ago,
early hearing loss, and absence of digit abnor- yet the etiology remains unknown [134, 135].
malities are often helpful in distinguishing Incidence: ROHHAD is exceedingly rare;
between BBS and Alstrom syndrome. A diagno- fewer than 100 cases have been reported in the
sis of Alstrom syndrome is proven when two literature [136]. It occurs sporadically, without
ALMS1 mutations (one from each parent) are any suggestive family history.
identified in a patient. However, lack of confir- Clinical Features: ROHHAD syndrome is a
mation of a gene mutation does not exclude the complex disease with hallmark features of hypo-
diagnosis, and repeated clinical monitoring is thalamic, respiratory, and autonomic dysfunction.
recommended. Patients often come to attention in the preschool
Treatment and Future Research: Currently years due to the development of rapid weight gain
there is no treatment that will cure Alstrom syn- of 20–30 lbs over a 3–6-month period [136]. It can
drome or delay or reverse the progression of dis- be confused with other syndromes that cause
ease. Management of photophobia in young early-onset obesity [134]; there is progressive
children with red-tinted glasses is helpful to alle- accumulation of adipose tissue in the face, trunk,
viate distress with bright lights. Total vision loss and breasts. Height velocity declines, mimicking
should be anticipated, and early development of the effects of the hypercortisolism of Cushing’s
Braille or other nonvisual language skills is very syndrome. However, unlike classic Cushing’s syn-
important. There is no specific treatment for sen- drome, there is neither facial plethora nor striae.
sorineural hearing loss; hearing aids or cochlear Individuals with ROHHAD also have delayed or
implants may be helpful. absent pubertal development. Interestingly,
Monitoring of cardiac function with echocar- approximately one-half of patients will develop
diography is essential in all patients. Treatment hypernatremia without true diabetes insipidus.
170 K.A. Irizarry and A.M. Haqq

Major comorbidities [134, 136] include devel- tion. Patients often have delayed or absent
opmental delay and seizures. Autonomic dysreg- puberty and low gonadotropins, suggesting cen-
ulation is manifest as temperature instability, GI tral hypogonadotropic hypogonadism. There
dysmotility (constipation and chronic diarrhea may also be hypernatremia without polyuria,
most commonly), and ophthalmologic dysfunc- polydipsia, or urine hypoosmolality. Leptin lev-
tion, altered pupillary responses to light, strabis- els are comparable to age-matched children with
mus, alacrima, and oculomotor apraxia. Most similar BMI. Urine and plasma catecholamines,
worrisome is central hypoventilation (with or VMA, HVA, and plasma adrenal steroids in
without obstructive sleep apnea), which can lead patients with ganglioneuromas are normal [135].
to cardiopulmonary arrest [134]. When these tumors have been resected, there
One-half of patients will develop ganglioneu- have been no changes in phenotype or biochemi-
romas of the adrenal glands and posterior medi- cal parameters.
astinum, despite normal urine catecholamines, A sleep study is essential to identify obstruc-
VMA, HVA, and plasma adrenal steroid levels tive or central sleep apnea. Affected children
[135]. often have alveolar hypoventilation during sleep
Etiology: The etiology of ROHHAD syn- with hypercarbia and hypoxemia, but do not have
drome is unclear. Patients with Phox 2 mutations the expected increased rate or depth of breathing
have congenital central hypoventilation and [134]. This can lead to sudden death in bed.
hypothalamic dysfunction and may develop neu- Treatments and Future Therapies: With an
ral tumors [134] but do not have hyperphagia or elusive etiology and complex phenotype, treat-
obesity. Barclay and colleagues conducted whole ment and management are challenging. Strict diet
exome sequencing (WES) on seven ROHHAD and exercise programs have been successful in
subjects, the tumors from four patients, and the improving BMI; however, the multisystem clini-
unaffected monozygotic twin of one subject cal features were not improved. As previously
[136]. They discovered 13 de novo gene variants; described, patients develop growth failure with
however, no two patients had the same variants in low serum IGF-1 and submaximal growth hor-
the same gene. Further work is being done to mone response to stimulation testing. However,
evaluate non-exomic risk factors and possible growth hormone treatment has not been shown to
epigenetic mechanisms of disease. improve BMI or other clinical features. Positive-­
Diagnostic Considerations: Ize-Ludlow and pressure ventilation should be considered when
coworkers defined the basic criteria for diagnosis central hypoventilation is diagnosed; oxygen or
of ROHHAD: (1) rapid-onset, extreme weight tracheostomy may be required for some patients.
gain after age 1.5 years in a previously healthy,
normal weight child, (2) hypothalamic dysfunc-
tion, (3) alveolar hypoventilation, and (4) auto- Overgrowth Syndromes
nomic dysregulation [134]. Given that ROHHAD
syndrome is associated with hormonal dysregula- Infants born large for gestational age (birth
tion, diagnosis requires exclusion of other causes. weight greater than 4000 g) frequently come to
The rapid-onset obesity with declining height the attention of primary care providers. The more
velocity should prompt evaluation for hypercorti- common causes for fetal macrosomia are
solism as well as growth hormone deficiency and included in Table 9.3; however, macrosomia can
hypothyroidism. Diurnal rhythm of plasma corti- signal underlying disease or a fetal overgrowth
sol, 24-hour urine-free cortisol levels, and syndrome that may have systemic effects.
response to high-dose dexamethasone are nor- The characteristic features of several over-
mal. Plasma IGF-1 levels may be low in some growth syndromes and their associated
patients, and the growth hormone response to ­comorbidities are outlined in Table 9.4 [137].
stimulation may be submaximal [134]. There is Generally, syndromic causes of overgrowth have
variable hyperprolactinemia and TSH dysregula- several common features, including multiple
9 Syndromic Obesity 171

congenital anomalies, developmental delay with Sotos syndrome, Weaver syndrome, and
cognitive impairment, and predisposition toward Beckwith–Wiedemann syndromes.
neoplasia. Children with overgrowth syndromes Sotos Syndrome: Sotos syndrome has an esti-
have elevated birth weight that persists into post- mated prevalence of 1 in 14,000 live births
natal life; both weight and length are increased [137]. The etiology most commonly is due to
for age. This distinguishes the overgrowth syn-
dromes from most early-onset obesity syndromes
(i.e., PWS, BBBS, AHO, ROHHAD). Children Table 9.3 Non-pathologic causes of fetal macrosomia
with mutations in the melanocortin-4 receptor Maternal diabetes
can have relative tall stature in the presence of Family history of fetal macrosomia
severe early-onset obesity, but in contrast to chil- Maternal obesity
dren with fetal overgrowth syndromes, they have Excessive maternal weight gain during pregnancy
normal weights at birth. Here we will focus on Familial tall stature

Table 9.4 Overgrowth syndromes

Syndrome Etiology Characteristics Multisystemic effects
Sotos syndrome NSD1 mutation Facial appearance – Cognitive impairment
– Autosomal dominant – Broad, prominent forehead – Behavioral disorders
– De novo – Receding frontoparietal (autism spectrum, phobias)
hairline – Cardiac anomalies (ASD,
– Downslanted palpebral VSD, PDA)
fissures – Renal anomalies
– Bitemporal narrowing with (vesicoureteral reflux)
long facies – Scoliosis
– Long chin – Seizures
Developmental delays – CNS abnormalities
– Neonatal hypotonia (ventricular dilatation,
– Delayed gross motor skills hypoplasia or agenesis of
(walking after 15 months) corpus callosum or septum
– Delayed language pellucidum, cerebral
Overgrowth atrophy, small cerebellar
– Large for gestational age vermis)
– Length and head – Neoplasms (ALL,
circumference increased for neuroblastoma)
age
– Advanced bone age
Weaver syndrome EZH2 mutation Facial appearance – Congenital heart defects
– Unclear pathogenic – Macrocephaly (VSD, PDA)
mechanism – Broad forehead – CNS anomalies (cerebral
– Flattened occiput atrophy, pachygyria, cysts
– Large, low-set ears of septum pellucidum)
– Ocular hypertelorism – Neoplasms (ALL,
– Micrognathia lymphoma, neuroblastoma)
– Redundant nuchal skinfolds
Developmental delays
– Gross motor delays
– Intellectual disability varies
among individuals
Overgrowth
– Increased length and head
circumference for age
– Continued postnatal
accelerated growth
– Excessive adult height
(continued)
172 K.A. Irizarry and A.M. Haqq

Table 9.4 (continued)

Syndrome Etiology Characteristics Multisystemic effects
Beckwith–Wiedemann Epigonic and genomic Facial appearance – Abdominal wall defects
syndrome alteration in imprinting – Macroglossia (omphalocele, umbilical
region of chromosome – Anterior ear lobe creases hernia, diastasis recti)
11p15 – Posterior helical pits – Neonatal hyperinsulinemic
– Facial nevus flammeus hypoglycemia
Development – Prematurity
– Normal cognitive – Renal anomalies
development – Cardiomegaly
– At risk for adverse – High risk of embryonal
development from tumors (most commonly
complications of prematurity Wilms’ tumor;
or hypoglycemia hepatoblastoma,
Overgrowth neuroblastoma,
– Large for gestational age adrenocortical carcinoma)
– Pre- and postnatal
length > 97th percentile
– Organomegaly of the liver,
spleen, pancreas, adrenal
glands
– Hemihyperplasia with
asymmetric growth

a heterozygous mutation of the NSD1 gene, s­ yndrome associated with EZH2 mutations [139].
which encodes a histone methyltransferase that Facial features included ocular hypertelorism,
catalyzes the methylation of lysine 36 on his- almond-shaped palpebral fissures, broad fore-
tone 3 (H3K36). The vast majority of identified head, large ears, and retrognathia. In this study,
patients will have de novo mutations [138]. The only 38% of infants were large for gestational
syndrome is characterized by three general fea- age, though infants with EZH2 had increased
tures: characteristic facies (Table 9.4), develop- birth length [139]. Children with Weaver syn-
mental delays, and overgrowth. Infants with drome have accelerated skeletal growth relative
Sotos syndrome are large for gestational age to epiphyseal maturation and, therefore, have
with increased birth length and head circumfer- increased adult height [137]. Those with EZH2
ence and have excessive postnatal growth in mutations also had hypotonia, soft and doughy
early childhood [137, 138]. Tall stature and skin, and poor coordination. Similar to Sotos
macrocephaly persist throughout childhood but syndrome, associated neoplasms have included
normalizes by adulthood. Commonly, the epiph- lymphoma, acute lymphoblastic leukemia, neu-
yses are advanced for age, yet there are no signs roblastoma, and sacrococcygeal teratoma [137].
of precocious puberty. Sotos syndrome may be Beckwith–Wiedemann Syndrome: Beckwith–
associated with scoliosis, seizures, and renal Wiedemann syndrome (BWS) is the most com-
and cardiac anomalies. NSD1 mutations have mon genetic overgrowth syndrome, occurring in
also been identified in neoplasms including neu- approximately 1 in 10,500 births. It is character-
roblastoma, acute lymphoblastic leukemia, and ized by distinct and recognizable features: fetal
sacrococcygeal teratoma [138]. macrosomia, asymmetric overgrowth with hemi-
Weaver Syndrome: Weaver syndrome has hyperplasia, omphalocele or other abdominal
many similar features to Sotos syndrome, making wall defects, macroglossia, hyperinsulinemic
the distinction challenging. Genetic studies have hypoglycemia, renal malformations, organomeg-
identified a heterozygous mutation in EZH2, aly, and a high risk of neoplasms [140]. Patients
a histone methyltransferase for lysine 27 on have distinct facial features including prominent
­histone 3 (H3K27). Tatton-Brown and cowork- forehead, micrognathia, down-turned corners of
ers delineated the clinical features of Weaver the mouth, and triangular facies. The etiology of
9 Syndromic Obesity 173

BWS involves dysregulated imprinting of critical 6q16.1-q21 deletion encompassing the SIM1
regions of chromosome 11p15.5 that encode gene [145]. Features included hyperphagia, obe-
insulin-like growth factor 2, cyclin-dependent sity with 60% lower resting energy expenditure,
kinase inhibitor 1C, and H19. BWS can be caused progressive linear growth failure with growth hor-
by loss of methylation, paternal uniparental mone deficiency, normal puberty, a “reset” osmo-
disomy, gain of methylation, mutation of critical stat with higher than normal serum osmolality and
gene regions, or paternal duplication [140]. normal urine osmolality, central hypothyroidism,
Children with BWS are at high risk of child- and partial central adrenal insufficiency.
hood embryonal tumors: Wilms’ tumor, hepato- Several groups have now confirmed rare vari-
blastoma, neuroblastoma, ganglioneuroma, ants in SIM1 associated with severe early-onset
adrenocortical carcinoma, and others have been obesity [146, 147]. One study demonstrated 13
different heterozygous SIM1 variants in 28 unre-
reported in the literature [137]. The risk of malig-
nancy in BWS reaches 10% in the first decade of lated severely obese patients (among 2100 severe
life [141]. Therefore, early identification of the early-onset obese patients and 1680 controls).
syndrome is essential for tumor surveillance. Nine of the thirteen variants demonstrated
Recommendations for tumor screening have reduced activity and co-segregated with obesity
included ultrasounds every 3 months from in families with variable penetrance. The affected
infancy to age 8 years and routine measurement subjects had hyperphagia, normal basal meta-
of alpha-fetoprotein (AFP) starting as early as bolic rate, and signs of autonomic dysfunction
6 weeks [142]. With advanced molecular diag- [146]. More recently, SIM1 was sequenced [148]
nostics, recent clinical studies have proposed sur-in 283 children presenting with developmental
veillance protocols according to the molecular delay and overweight; novel functional mutations
phenotype of BWS for improved and targeted (c.886A > G/p.R296G and c.925A > G/p.S309G)
early diagnosis [143]. were found in two boys with varying degrees of
cognitive delay and weight abnormalities.
Etiology: SIM1 is the mammalian homolog of
SIM1 Deletion Syndrome the Drosophila transcription factor, single-­
minded, a member of the basic helix–loop–helix
Overview: Human SIM1 (single-minded) dele- period aryl hydrocarbon receptor family of pro-
tion syndrome was first described by Holder and teins. Homozygous deletion of Drosophila
colleagues in a young girl with early-onset obe- single-­minded results in failure of formation of
sity, hyperphagia, and increased linear growth midline central nervous system structures (148).
[144]. The majority of patients with SIM1 deletion syn-
Incidence: Five individuals with SIM1 dele- drome have a 6q16.2 deletion. The initial patient
tion syndrome have been reported in the described by Holder and colleagues had a bal-
literature. anced translocation between chromosomes
Clinical Features: Subjects with SIM1 dele- 1p22.1 and 6q16.2 that disrupted the SIM1 gene
tions exhibit features in common with Prader– [149]. A mouse model of heterozygous SIM1
Willi syndrome including hypotonia, obesity, deletion also exhibits early-onset obesity with
hyperphagia, developmental delay, almond-­ hyperphagia, increased linear growth, hyperinsu-
shaped eyes, strabismus, thin upper lip, hypogo- linemia, hyperleptinemia, normal energy expendi-
nadism, and short extremities. However, patients ture, and a decreased number of neurons in the
with SIM1 deletions may have additional findings paraventricular nucleus (PVN) [150]. Subsequent
including cardiac (bicuspid aortic valve, aortic investigations now show that the Sim1 gene is
stenosis, right branch block) and neurological expressed in the supraoptic nuclei (SON) and para-
abnormalities (polygyria, leukomalacia, Arnold– ventricular nuclei (PVN) of the hypothalamus,
Chiari malformation, seizures, and hearing loss). both important areas involved in the regulation of
Endocrine manifestations of the condition were body weight [151]. More recent studies show that
described in a child with a proximal interstitial SIM1 is required for terminal d­ ifferentiation of
174 K.A. Irizarry and A.M. Haqq

the neurons in the PVN and SON nuclei and sug- of BDNF. Another report described an obese,
gest that SIM1 might function downstream of the hyperphagic tall child with impairment in mem-
melanocortin-4 receptor to control energy bal- ory, cognition, and nociception with a heterozy-
ance [152]: SIM 1 was found to partially rescue gous missense mutation in the neurotrophin
the hyperphagia and obesity of agouti yellow receptor TrkB, the receptor of BDNF [158].
mice (in which melanocortin signaling is defec- Interestingly, among persons with Wilms’ tumor,
tive). This suggests that the melanocortin-­ 4aniridia, genitourinary anomalies, and mental
receptor signals through SIM 1 or its downstream retardation (WAGR) syndrome, BDNF haploin-
targets to control food intake [152]. Finally, a sufficiency is associated with lower serum BDNF
mouse model of postnatal SIM 1 deficiency con- concentrations and childhood-onset obesity
firms that SIM 1’s role in energy balance is not [159]. Finally, several studies link the common
limited to just its role in formation of the PVN, single-nucleotide polymorphism (Val66Met) in
but rather implicates changes in the leptin–mela- the human Bdnf gene to a higher body mass index
nocortin–oxytocin pathways in its regulation of [160–162].
body weight [153]. Incidence: Mutations in BDNF and TrkB are
Diagnostic Considerations: Deletion of the rare genetic causes of human obesity.
6q16.2 region and SIM1 gene deletion should be Clinical Features: BDNF or TrkB haploinsuf-
sought in patients who exhibit Prader–Willi ficiency leads to hyperphagia, morbid obesity, and
syndrome-­like features but a normal cytogenetic a complex neurobehavioral phenotype including
study of the 15q11-q12 region. impaired cognition, memory, and nociception.
Treatment and Future Research: Several Etiology: Acting through its receptor,
genome-wide scans in various populations have tropomyosin-­ related kinase B (TrkB), BDNF
shown strong linkage of loci on chromosome 6q regulates the development, differentiation, and
with obesity and type 2 diabetes-related traits survival of neurons [163]; it is expressed during
[154, 155]. One association study with common developmental stages of neuronal differentiation
single-nucleotide polymorphisms (SNPs) in the and connectivity of synapses [163]. Therefore,
SIM1 gene was performed in two population-­ BDNF plays roles in the formation of neuronal
based cohorts. Mutations in SIM1 were not com- circuits in the brain, including those regulating
monly found in individuals with early-onset energy homeostasis. BDNF and TrkB are
obesity. However, an association was found expressed in areas involved in energy balance,
between BMI in males and in females and homo- including the ventromedial nucleus (VMN), dor-
zygosity for the P352T/A371V haplotype [156]. somedial hypothalamus (DMH), lateral hypo-
Further studies are needed to clarify the relation-thalamus (LH), arcuate nucleus (Arc), and
ship between common variants of SIM1 and paraventricular nucleus (PVN) [164, 165].
body weight gain. BDNF is implicated in energy homeostasis;
hypothalamic expression of BDNF in the ventro-
medial hypothalamus is reduced by fasting, and
BDNF and Tropomyosin-Related BDNF administration causes weight loss in wild-­
Kinase B type mice via reduction in food intake [164].
BDNF administration has also been shown to
Overview: An 8-year-old girl with severe early-­ induce weight loss, prevent overeating, and
onset obesity, hyperactivity, impaired cognition, improve glucose homeostasis in leptin- and leptin
memory, and nociception due to haploinsuffi- receptor-deficient mice, diet-induced obese rats,
ciency of brain-derived neurotrophic factor and animals with reduced melanocortin signaling
(BDNF) was described in 2006 [157]. The child [164, 166–168]. BDNF haploinsufficiency in
had a de novo chromosomal inversion 46, XX, mice leads to hyperphagia, obesity, and hypergly-
inv. [11] (p13p15.3), a region encompassing the cemia and has been implicated in memory and
BDNF gene, and reduced serum concentrations various behavioral abnormalities [169, 170].
9 Syndromic Obesity 175

Diagnostic Considerations: BDNF or TrkB Conclusions

deficiency should be considered in individuals Currently, syndromic obesity is managed by
with early-onset morbid obesity and caloric restriction. The efficacy and durability of
hyperphagia. this approach have been severely limited in most
Treatment and Future Research: There is cases. The genetics involved in these syndromes
some evidence that BDNF-expressing neurons are complex, and defects in multiple genes within
might lie downstream of melanocortin-4 (MC4) a pathway can lead to similar clinical phenotypes.
neuronal pathways, since BDNF mRNA levels In order to develop future effective and i­ nnovative
are reduced in the ventromedial hypothalamus of obesity treatm.ents, it will be imperative to fur-
MC4R knockout mice and levels are restored by ther unravel the molecular defects leading to the
administration of an MC4R agonist, MT-II various syndromic obesity disorders.
[164]. A functional interaction between leptin
and BDNF is also demonstrated by studies show- Acknowledgments This work was supported by the
ing that leptin increases BDNF content in the Canadian Institutes of Health Research [grant numbers
115707 and 119504] and the Stollery Children’s Hospital
VMN and DVC; conversely, there is reduced Foundation through the Women and Children’s Health
hypothalamic BDNF expression in leptin Research Institute to AMH.
receptor-­deficient (db/db) mice [171]. Indeed,
BDNF signaling through its TrkB receptor
appears to be essential for the anorexigenic Editor’s Question
effects of leptin [172].
Further research should elucidate the molecu- What criteria should the clinician use to
lar role of BDNF and its receptor, TrkB, in the distinguish children with early-onset obe-
regulation of energy balance in humans. Data by sity from those who they suspect may be
Pelleymounter and colleagues provide evidence overfed by parents or caretakers?
that BDNF might induce appetite suppression
and weight loss via increases in hypothalamic Authors’ Response
5-HIAA/5-HT [173]. It is possible that BDNF
influences energy balance via effects on develop- We suggest the following criteria to dis-
ment of the hypothalamus or through modulation tinguish pathologic early-onset obesity
of synaptic plasticity in hypothalamic feeding from exogenous obesity:
circuits. For example, BDNF might influence
rewiring of feeding circuits in response to nutri- i. Early-onset obesity occurring prior to
tional cues to increase anorexigenic tone. Others age 5 years.
have shown that induction of hypothalamic ii. Rapid rate of weight gain that is not
BDNF expression leads to selective “browning” attenuated by nutritional or exercise
of white fat through a sympathoneural mecha- intervention.
nism [174]. Furthermore, BDNF is thought to iii. Hyperphagia with absent satiety signals
play a role in the cognitive benefits (enhanced manifest as abnormal food-­ seeking
spatial learning and memory) of running and behavior (hiding or stealing food, eating
intermittent fasting [175]. Finally, the GLP-1 nonfood substances, eating in excess
analogs, exenatide and liraglutide, might reduce despite abdominal pain and/or vomiting).
appetite and exert beneficial neurocognitive iv. Associated neuroendocrine abnormalities
effects, in part, through increasing BDNF pro- (i.e., pituitary hormone abnormalities).
duction [176]. Understanding BDNF and TrkB’s v. Associated features suggesting syn-
mechanistic role in the regulation of body weight dromic or monogenic obesity disorders,
and metabolism will likely lead to novel down- as described in our chapter and in Chap. 9
stream therapeutic approaches for the treatment by Marie Pigeyre and David Meyre.
of human obesity.
176 K.A. Irizarry and A.M. Haqq

References olar RNA species and as an antisense RNA for

UBE3A. Hum Mol Genet. 2001;10(23):2687–700.
17. Bervini S, Herzog H. Mouse models of Prader–
1. Bel CG, Walley AJ, Froguel P. The genetics of
Willi syndrome: a systematic review. Front
human obesity. Nat Rev Genet. 2005;6(3):221–34.
Neuroendocrinol. 2013;34(2):107–19.
2. Farooqi IS, O'Rahilly S. Monogenic obesity in
18. Niinobe M, Koyama K, Yoshikawa K. Cellular and
humans. Annu Rev Med. 2005;56:443–58.
subcellular localization of necdin in fetal and adult
3. Prader A, Labhart A, Ein Syndrom HW, Adipositas
mouse brain. Dev Neurosci. 2000;22(4):310–9.
v. Kleinwuchs, Kryptorchismus und Oligophrenie
19. Muscatelli F, Abrous DN, Massacrier A, Boccaccio
nach myotoniertigem Zustand im Neugeborenalter.
I, Le Moal M, Cau P, et al. Disruption of the mouse
Schweiz Med Wochenschr. 1956;86:1260–1.
Necdin gene results in hypothalamic and behavioral
4. Cassidy SB, Dykens E, Williams CA. Prader-Willi
alterations reminiscent of the human Prader-Willi
and Angelman syndromes: sister imprinted disor-
syndrome. Hum Mol Genet. 2000;9(20):3101–10.
ders. Am J Med Genet. 2000;97(2):136–46.
20. Lee S, Kozlov S, Hernandez L, Chamberlain SJ,
5. Chung WK. An overview of Monogenic and
Brannan CI, Stewart CL, et al. Expression and
Syndromic obesities in humans. Pediatr Blood
imprinting of MAGEL2 suggest a role in Prader-willi
Cancer. 2012;58(1):122–8.
syndrome and the homologous murine imprinting
6. Butler MG. Prader-Willi syndrome: obesity
phenotype. Hum Mol Genet. 2000;9(12):1813–9.
due to genomic imprinting. Curr Genomics.
21. Miller NLG, Wevrick R, Mellon PL. Necdin, a
2011;12(3):204–15.
Prader–Willi syndrome candidate gene, regulates
7. Irizarry KA, Miller M, Freemark M, Haqq
gonadotropin-releasing hormone neurons during
AM. Prader Willi syndrome; genetics, metabolo-
development. Hum Mol Genet. 2009;18(2):248–60.
mics, hormonal function, and new approaches to
22. Bischof JM, Stewart CL, Wevrick R. Inactivation
therapy. Adv Pediatr Infect Dis. 2016;63(1):47–77.
of the mouse Magel2 gene results in growth abnor-
8. Miller JL, Lynn CH, Driscoll DC, Goldstone AP,
malities similar to Prader-Willi syndrome. Hum Mol
Gold JA, Kimonis V, et al. Nutritional phases
Genet. 2007;16(22):2713–9.
in Prader-Willi syndrome. Am J Med Genet A.
23. Mercer RE, Michaelson SD, Chee MJ, Atallah TA,
2011;155a(5):1040–9.
Wevrick R, Colmers WF. Magel2 Is required for
9. de Lind van Wijngaarden RF, Otten BJ, Festen DA,
leptin-mediated depolarization of POMC neurons
Joosten KF, de Jong FH, Sweep FC, et al. High prev-
in the hypothalamic arcuate nucleus in mice. PLoS
alence of central adrenal insufficiency in patients
Genet. 2013;9(1):e1003207.
with Prader-Willi syndrome. J Clin Endocrinol
24. Pravdivyi I, Ballanyi K, Colmers WF, Wevrick
Metab. 2008;93(5):1649–54.
R. Progressive postnatal decline in leptin sensitivity
10. DiMario FJ Jr, Dunham B, Burleson JA, Moskovitz
of arcuate hypothalamic neurons in the Magel2-null
J, Cassidy SB. An evaluation of autonomic nervous
mouse model of Prader-Willi syndrome. Hum Mol
system function in patients with Prader-Willi syn-
Genet. 2015;24(15):4276–83.
drome. Pediatrics. 1994;93(1):76–81.
25. Gallagher RC, Pils B, Albalwi M, Francke
11. Emerick J, Vogt K. Endocrine manifestations and
U. Evidence for the role of PWCR1/HBII-85 C/D
management of Prader-Willi syndrome. Int J Pediatr
box small nucleolar RNAs in Prader-Willi syn-
Endocrinol. 2013;2013(1):14.
drome. Am J Hum Genet. 2002;71(3):669–78.
12. Yang L, Zhan GD, Ding JJ, Wang HJ, Ma D, Huang
26. Ding F, Li HH, Zhang S, Solomon NM, Camper SA,
GY, et al. Psychiatric illness and intellectual dis-
Cohen P, et al. SnoRNA Snord116 deletion causes
ability in the Prader-Willi syndrome with differ-
growth deficiency and Hyperphagia in mice. PLoS
ent molecular defects–a meta analysis. PLoS One.
One. 2008;3(3):e1709.
2013;8(8):e72640.
27. Burnett LC, LeDuc CA, Sulsona CR, Paull D,
13. Nicholls RD, Knepper JL. Genome organiza-
Rausch R, Eddiry S, et al. Deficiency in prohor-
tion, function, and imprinting in Prader-Willi and
mone convertase PC1 impairs prohormone pro-
Angelman syndromes. Annu Rev Genomics Hum
cessing in Prader-Willi syndrome. J Clin Invest.
Genet. 2001;2:153–75.
2017;127(1):293–305.
14. Nicholls RD, Saitoh S, Horsthemke B. Imprinting
28. Holm VA, Cassidy SB, Butler MG, Hanchett JM,
in Prader-Willi and Angelman syndromes. Trends
Greenswag LR, Whitman BY, et al. Prader-Willi
Genet. 1998;14(5):194–200.
syndrome: consensus diagnostic criteria. Pediatrics.
15. Ohta T, Gray TA, Rogan PK, Buiting K, Gabriel
1993;91(2):398–402.
JM, Saitoh S, et al. Imprinting-mutation mecha-
29. Gunay-Aygun M, Schwartz S, Heeger S, O'Riordan
nisms in Prader-Willi syndrome. Am J Hum Genet.
MA, Cassidy SB. The changing purpose of Prader-­
1999;64(2):397–413.
Willi syndrome clinical diagnostic criteria and pro-
16. Runte M, Huttenhofer A, Gross S, Kiefmann M,
posed revised criteria. Pediatrics. 2001;108(5):E92.
Horsthemke B, Buiting K. The IC-SNURF-SNRPN
30. Angulo MA, Butler MG, Cataletto ME. Prader-­
transcript serves as a host for multiple small nucle-
Willi syndrome: a review of clinical, genetic,
9 Syndromic Obesity 177

and endocrine findings. J Endocrinol Investig. 44. Akefeldt A, Tornhage CJ, Gillberg C. A woman with
2015;38(12):1249–63. Prader-Willi syndrome gives birth to a healthy baby
31. Erdie-Lalena CR, Holm VA, Kelly PC, Frayo girl. Dev Med Child Neurol. 1999;41(11):789–90.
RS, Cummings DE. Ghrelin levels in young 45. Schulze A, Mogensen H, Hamborg-Petersen
children with Prader-Willi syndrome. J Pediatr. B, Graem N, Ostergaard JR, Brondum-Nielsen
2006;149(2):199–204. K. Fertility in Prader-Willi syndrome: a case report
32. Cummings DE, Clement K, Purnell JQ, Vaisse with Angelman syndrome in the offspring. Acta
C, Foster KE, Frayo RS, et al. Elevated plasma Paediatr. 2001;90(4):455–9.
ghrelin levels in Prader Willi syndrome. Nat Med. 46. Festen DA, Wevers M, Lindgren AC, Bohm B, Otten
2002;8(7):643–4. BJ, Wit JM, et al. Mental and motor development
33. Haqq AM, Grambow SC, Muehlbauer M, Newgard before and during growth hormone treatment in
CB, Svetkey LP, Carrel AL, et al. Ghrelin concen- infants and toddlers with Prader-Willi syndrome.
trations in Prader-Willi syndrome (PWS) infants Clin Endocrinol. 2008;68(6):919–25.
and children: changes during development. Clin 47. Festen DAM, De Lind van Wijngaarden R, Van
Endocrinol. 2008;69(6):911–20. Eekelen M, Otten BJ, Wit JM, Duivenvoorden HJ,
34. Goldstone AP, Holland AJ, Butler JV, Whittington et al. Randomized controlled GH trial: effects on
JE. Appetite hormones and the transition to hyper- anthropometry, body composition and body propor-
phagia in children with Prader-Willi syndrome. Int J tions in a large group of children with Prader–Willi
Obes. 2012;36(12):1564–70. syndrome. Clin Endocrinol. 2008;69(3):443–51.
35. Gumus Balikcioglu P, Balikcioglu M, Muehlbauer 48. Myers SE, Whitman BY, Carrel AL, Moerchen V,
MJ, Purnell JQ, Broadhurst D, Freemark M, et al. Bekx MT, Allen DB. Two years of growth hormone
Macronutrient regulation of ghrelin and peptide YY therapy in young children with Prader-Willi syn-
in pediatric obesity and Prader-Willi syndrome. J drome: physical and neurodevelopmental benefits.
Clin Endocrinol Metab. 2015;100(10):3822–31. Am J Med Genet A. 2007;143a(5):443–8.
36. Holm VA, Pipes PL. Food and children with 49. Carrel AL, Myers SE, Whitman BY, Allen
Prader-Willi syndrome. Am J Dis Child. DB. Benefits of long-term GH therapy in Prader-­
1976;130(10):1063–7. Willi syndrome: a 4-year study. J Clin Endocrinol
37. Arble DM, Pressler JW, Sorrell J, Wevrick R, Metab. 2002;87(4):1581–5.
Sandoval DA. Sleeve gastrectomy leads to weight 50. Carrel AL, Myers SE, Whitman BY, Allen
loss in the Magel2 knockout mouse. Surg Obes Relat DB. Growth hormone improves body composition,
Dis. 2016;12(10):1795–802. fat utilization, physical strength and agility, and
38. Alqahtani AR, Elahmedi MO, Al Qahtani AR, Lee growth in Prader-Willi syndrome: a controlled study.
J, Butler MG. Laparoscopic sleeve gastrectomy in J Pediatr. 1999;134(2):215–21.
children and adolescents with Prader-Willi syn- 51. Eiholzer U, l'Allemand D. Growth hormone nor-
drome: a matched-control study. Surg Obes Relat malises height, prediction of final height and hand
Dis. 2016;12(1):100–10. length in children with Prader-Willi syndrome after
39. Karamanakos SN, Vagenas K, Kalfarentzos F, 4 years of therapy. Horm Res. 2000;53(4):185–92.
Alexandrides TK. Weight loss, appetite suppression, 52. Myers SE, Carrel AL, Whitman BY, Allen
and changes in fasting and postprandial ghrelin and DB. Sustained benefit after 2 years of growth hor-
peptide-YY levels after roux-en-Y gastric bypass mone on body composition, fat utilization, physical
and sleeve gastrectomy: a prospective, double blind strength and agility, and growth in Prader-Willi syn-
study. Ann Surg. 2008;247(3):401–7. drome. J Pediatr. 2000;137(1):42–9.
40. Ochner CN, Gibson C, Shanik M, Goel V, Geliebter 53. Carrel AL, Myers SE, Whitman BY, Allen
A. Changes in neurohormonal gut peptides follow- DB. Sustained benefits of growth hormone on
ing bariatric surgery. Int J Obes. 2011;35(2):153–66. body composition, fat utilization, physical strength
41. Stevenson DA, Anaya TM, Clayton-Smith J, Hall and agility, and growth in Prader-Willi syndrome
BD, Van Allen MI, Zori RT, et al. Unexpected are dose-dependent. J Pediatr Endocrinol Metab.
death and critical illness in Prader–Willi syndrome: 2001;14(8):1097–105.
report of ten individuals. Am J Med Genet A. 54. Haqq AM, Stadler DD, Jackson RH, Rosenfeld RG,
2004;124A(2):158–64. Purnell JQ, LaFranchi SH. Effects of growth hormone
42. Corrias A, Grugni G, Crino A, Di Candia S, on pulmonary function, sleep quality, behavior, cog-
Chiabotto P, Cogliardi A, et al. Assessment of cen- nition, growth velocity, body composition, and rest-
tral adrenal insufficiency in children and adoles- ing energy expenditure in Prader-Willi syndrome. J
cents with Prader-Willi syndrome. Clin Endocrinol. Clin Endocrinol Metab. 2003;88(5):2206–12.
2012;76(6):843–50. 55. Bakker B, Maneatis T, Lippe B. Sudden death in
43. Goldstone AP, Holland AJ, Hauffa BP, Hokken-­ Prader-Willi syndrome: brief review of five addi-
Koelega AC, Tauber M. Recommendations for the tional cases. Concerning the article by U. Eiholzer
diagnosis and management of Prader-Willi syndrome. et al.: deaths in children with Prader-Willi syn-
J Clin Endocrinol Metab. 2008;93(11):4183–97. drome. A contribution to the debate about the
178 K.A. Irizarry and A.M. Haqq

safety of growth hormone treatment in children composition phenotypes in youth with Prader-Willi
with PWS (Horm res 2005;63:33-39). Horm Res. syndrome. Metabolism. 2017;69:67–75.
2007;67(4):203–4. 68. Haqq AM, Muehlbauer M, Svetkey LP, Newgard
56. Tauber M, Diene G, Molinas C, Hebert M. Review of 64 CB, Purnell JQ, Grambow SC, et al. Altered dis-
cases of death in children with Prader-­Willi syndrome tribution of adiponectin isoforms in children with
(PWS). Am J Med Genet A. 2008;146a(7):881–7. Prader-Willi syndrome (PWS): association with
57. Schrander-Stumpel CT, Curfs LM, Sastrowijoto P, insulin sensitivity and circulating satiety peptide
Cassidy SB, Schrander JJ, Fryns JP. Prader-Willi syn- hormones. Clin Endocrinol. 2007;67(6):944–51.
drome: causes of death in an international series of 69. Irizarry KA, Bain J, Butler MG, Ilkayeva O,
27 cases. Am J Med Genet A. 2004;124a(4):333–8. Muehlbauer M, Haqq AM, et al. Metabolic profiling
58. Vogels A, Van Den Ende J, Keymolen K, Mortier in Prader–Willi syndrome and nonsyndromic obe-
G, Devriendt K, Legius E, et al. Minimum preva- sity: sex differences and the role of growth hormone.
lence, birth incidence and cause of death for Prader-­ Clin Endocrinol. 2015;83(6):797–805.
Willi syndrome in Flanders. Eur J Hum Genet. 70. Wade CK, De Meersman RE, Angulo M, Lieberman
2004;12(3):238–40. JS, Downey JA. Prader-Willi syndrome fails to alter
59. Van Vliet G, Deal CL, Crock PA, Robitaille Y, cardiac autonomic modulation. Clin Auton Res.
Oligny LL. Sudden death in growth hormone-treated 2000;10(4):203–6.
children with Prader-Willi syndrome. J Pediatr. 71. Albright F, Burnett CH, Smith PH, Parson
2004;144(1):129–31. W. Pseudohypoparathyroidism: an example of Sebright-
60. DelParigi A, Tschop M, Heiman ML, Salbe AD, Bantam syndrome. Endocrinology. 1942;30:922–32.
Vozarova B, Sell SM, et al. High circulating ghre- 72. Levine MA, Germain-Lee E, Jan de Beur S. Genetic
lin: a potential cause for hyperphagia and obesity basis for resistance to parathyroid hormone. Horm
in prader-willi syndrome. J Clin Endocrinol Metab. Res. 2003;60(Suppl 3):87–95.
2002;87(12):5461–4. 73. Albright F, Forbes AP, Henneman PH. Pseudo-­
61. Haqq AM, Farooqi S, O'Rahilly S, Stadler DD, pseudohypoparathyroidism. Trans Assoc Am Phys.
Rosenfeld RG, Pratt KL, et al. Serum ghrelin levels 1952;65:337–50.
are inversely correlated with body mass index, age, 74. Ong KK, Amin R, Dunger DB. Pseudohy­
and insulin concentrations in normal children and poparathyroidism–another monogenic obesity syn-
are markedly increased in Prader-Willi syndrome. J drome. Clin Endocrinol. 2000;52(3):389–91.
Clin Endocrinol Metab. 2003;88:174–8. 75. Chen M, Wang J, Dickerson KE, Kelleher J, Xie T,
62. Haqq AM, Stadler DD, Rosenfeld RG, Pratt KL, Gupta D, et al. Central nervous system imprinting of
Weigle DS, Frayo RS, et al. Circulating ghrelin lev- the G protein Gsα and its role in metabolic regula-
els are suppressed by meals and octreotide therapy tion. Cell Metab. 2009;9(6):548–55.
in children with Prader-Willi syndrome. J Clin 76. Roizen JD, Danzig J, Groleau V, McCormack S,
Endocrinol Metab. 2003;88(8):3573–6. Casella A, Harrington J, et al. Resting energy expendi-
63. Tan TM, Vanderpump M, Khoo B, Patterson M, ture is decreased in Pseudohypoparathyroidism type
Ghatei MA, Goldstone AP. Somatostatin infu- 1A. J Clin Endocrinol Metab. 2016;101(3):880–8.
sion lowers plasma ghrelin without reducing appe- 77. Miric A, Vechio JD, Levine MA. Heterogeneous
tite in adults with Prader-Willi syndrome. J Clin mutations in the gene encoding the alpha-subunit
Endocrinol Metab. 2004;89(8):4162–5. of the stimulatory G protein of adenylyl cyclase
64. De Waele K, Ishkanian SL, Bogarin R, Miranda CA, in Albright hereditary osteodystrophy. J Clin
Ghatei MA, Bloom SR, et al. Long-acting octreotide Endocrinol Metab. 1993;76(6):1560–8.
treatment causes a sustained decrease in ghrelin con- 78. Weinstein LS, Liu J, Sakamoto A, Xie T, Chen
centrations but does not affect weight, behaviour and M. Minireview: GNAS: normal and abnormal func-
appetite in subjects with Prader-Willi syndrome. Eur tions. Endocrinology. 2004;145(12):5459–64.
J Endocrinol. 2008;159(4):381–8. 79. NakamotoJM,SandstromAT,BrickmanAS,Christenson
65. Balikcioglu PG, Balikcioglu M, Muehlbauer MJ, RA, Van Dop C. Pseudohypoparathyroidism type Ia
Purnell JQ, Broadhurst D, Freemark M, et al. from maternal but not paternal transmission of a Gsalpha
Macronutrient regulation of ghrelin and peptide YY gene mutation. Am J Med Genet. 1998;77(4):261–7.
in pediatric obesity and Prader-Willi syndrome. J 80. Davies SJ, Hughes HE. Imprinting in Albright's
Clin Endocrinol Metabol. 2015;100(10):3822–31. hereditary osteodystrophy. J Med Genet.
66. Goldstone AP, Thomas EL, Brynes AE, Bell JD, 1993;30(2):101–3.
Frost G, Saeed N, et al. Visceral adipose tissue and 81. Laurence JZ, Moon RC. Four cases of “retinitis pig-
metabolic complications of obesity are reduced in mentosa” occurring in the same family, and accom-
Prader-Willi syndrome female adults: evidence for panied by general imperfections of development.
novel influences on body fat distribution. J Clin 1866. Obes Res. 1995;3(4):400–3.
Endocrinol Metab. 2001;86(9):4330–8. 82. Bardet G. Sur un syndrome d'obesite congenitale avec
67. Orsso CE, Mackenzie M, Alberga AS, Sharma AM, polydactylie et retinite pigmentaire (contribution a
Richer L, Rubin DA, et al. The use of magnetic l'etude des formes cliniques de l'obesite hypophy-
resonance imaging to characterize abnormal body saire). These de Paris (Le Grand). 1920;470:107.
9 Syndromic Obesity 179

83. A B. Ein Geschwister mit adiposogenitaler 98. Blacque OE, Reardon MJ, Li C, McCarthy J,
Dystrophie. Dtsh Med Wochenschr. 1922;48:1630. Mahjoub MR, Ansley SJ, et al. Loss of C. elegans
84. Beales PL, Warner AM, Hitman GA, Thakker R, BBS-7 and BBS-8 protein function results in cilia
Flinter FA. Bardet-Biedl syndrome: a molecular defects and compromised intraflagellar transport.
and phenotypic study of 18 families. J Med Genet. Genes Dev. 2004;18(13):1630–42.
1997;34(2):92–8. 99. Nishimura DY, Swiderski RE, Searby CC, Berg
85. Klein D, Ammann F. The syndrome of Laurence-­ EM, Ferguson AL, Hennekam R, et al. Comparative
Moon-­ Bardet-Biedl and allied diseases in genomics and gene expression analysis identifies
Switzerland. Clinical, genetic and epidemiological BBS9, a new Bardet-Biedl syndrome gene. Am J
studies. J Neurol Sci. 1969;9(3):479–513. Hum Genet. 2005;77(6):1021–33.
86. Farag TI, Teebi AS. High incidence of Bardet 100. Stoetzel C, Muller J, Laurier V, Davis EE, Zaghloul
Biedl syndrome among the Bedouin. Clin Genet. NA, Vicaire S, et al. Identification of a novel
1989;36(6):463–4. BBS gene (BBS12) highlights the major role of a
87. Green JS, Parfrey PS, Harnett JD, Farid NR, vertebrate-­specific branch of chaperonin-related pro-
Cramer BC, Johnson G, et al. The cardinal mani- teins in Bardet-Biedl syndrome. Am J Hum Genet.
festations of Bardet-Biedl syndrome, a form of 2007;80(1):1–11.
Laurence-Moon-Biedl syndrome. N Engl J Med. 101. Chiang AP, Beck JS, Yen HJ, Tayeh MK, Scheetz
1989;321(15):1002–9. TE, Swiderski RE, et al. Homozygosity map-
88. Beales PL, Elcioglu N, Woolf AS, Parker D, Flinter ping with SNP arrays identifies TRIM32, an E3
FA. New criteria for improved diagnosis of Bardet-­ ubiquitin ligase, as a Bardet-Biedl syndrome
Biedl syndrome: results of a population survey. J gene (BBS11). Proc Natl Acad Sci U S A.
Med Genet. 1999;36(6):437–46. 2006;103(16):6287–92.
89. Suspitsin EN, Imyanitov EN. Bardet-Biedl 102. Stoetzel C, Laurier V, Davis EE, Muller J, Rix S,
Syndrome. Mol Syndromol. 2016;7(2):62–71. Badano JL, et al. BBS10 Encodes a vertebrate-­
90. M'Hamdi O, Ouertani I, Chaabouni-Bouhamed H. specific chaperonin-like protein and is a major BBS
Update on the genetics of bardet-biedl syndrome. locus. Nat Genet. 2006;38(5):521–4.
Mol Syndromol. 2014;5(2):51–6. 103. Heon E, Westall C, Carmi R, Elbedour K, Panton C,
91. Grace C, Beales P, Summerbell C, Jebb SA, Wright Mackeen L, et al. Ocular phenotypes of three genetic
A, Parker D, et al. Energy metabolism in Bardet-­ variants of Bardet-Biedl syndrome. Am J Med Genet
Biedl syndrome. Int J Obes Relat Metab Disord. A. 2005;132A(3):283–7.
2003;27(11):1319–24. 104. Schaefer E, Zaloszyc A, Lauer J, Durand M,
92. Brinckman DD, Keppler-Noreuil KM, Blumhorst C, Stutzmann F, Perdomo-Trujillo Y, et al. Mutations
Biesecker LG, Sapp JC, Johnston JJ, et al. Cognitive, in SDCCAG8/NPHP10 cause Bardet-Biedl syn-
sensory, and psychosocial characteristics in patients drome and are associated with penetrant renal
with Bardet-Biedl syndrome. Am J Med Genet A. disease and absent Polydactyly. Mol Syndromol.
2013;161A(12):2964–71. 2011;1(6):273–81.
93. Ansley SJ, Badano JL, Blacque OE, Hill J, Hoskins 105. Imhoff O, Marion V, Stoetzel C, Durand M, Holder
BE, Leitch CC, et al. Basal body dysfunction is a M, Sigaudy S, et al. Bardet-Biedl syndrome:
likely cause of pleiotropic Bardet-Biedl syndrome. a study of the renal and cardiovascular pheno-
Nature. 2003;425(6958):628–33. types in a French cohort. Clin J Am Soc Nephrol.
94. Novas R, Cardenas-Rodriguez M, Irigoin F, Badano 2011;6(1):22–9.
JL. Bardet-Biedl syndrome: is it only cilia dysfunc- 106. Yoder BK, Tousson A, Millican L, Wu JH, Bugg
tion? FEBS Lett. 2015;589(22):3479–91. CE Jr, Schafer JA, et al. Polaris, a protein dis-
95. Kulaga HM, Leitch CC, Eichers ER, Badano JL, rupted in orpk mutant mice, is required for assem-
Lesemann A, Hoskins BE, et al. Loss of BBS pro- bly of renal cilium. Am J Physiol Renal Physiol.
teins causes anosmia in humans and defects in olfac- 2002;282(3):F541–52.
tory cilia structure and function in the mouse. Nat 107. Hildebrandt F, Otto E. Cilia and centrosomes: a uni-
Genet. 2004;36(9):994–8. fying pathogenic concept for cystic kidney disease?
96. Nishimura DY, Fath M, Mullins RF, Searby C, Nat Rev Genet. 2005;6(12):928–40.
Andrews M, Davis R, et al. Bbs2-null mice have 108. Watnick T, Germino G. From cilia to cyst. Nat
neurosensory deficits, a defect in social domi- Genet. 2003;34(4):355–6.
nance, and retinopathy associated with mislocal- 109. Pazour GJ, Baker SA, Deane JA, Cole DG, Dickert
ization of rhodopsin. Proc Natl Acad Sci U S A. BL, Rosenbaum JL, et al. The intraflagellar trans-
2004;101(47):16588–93. port protein, IFT88, is essential for vertebrate pho-
97. Kim JC, YY O, Badano JL, Esmail MA, Leitch toreceptor assembly and maintenance. J Cell Biol.
CC, Fiedrich E, et al. MKKS/BBS6, a divergent 2002;157(1):103–13.
chaperonin-like protein linked to the obesity disor- 110. Mockel A, Perdomo Y, Stutzmann F, Letsch J,
der Bardet-Biedl syndrome, is a novel centrosomal Marion V, Dollfus H. Retinal dystrophy in Bardet-­
component required for cytokinesis. J Cell Sci. Biedl syndrome and related syndromic ciliopathies.
2005;118(Pt 5):1007–20. Prog Retin Eye Res. 2011;30(4):258–74.
180 K.A. Irizarry and A.M. Haqq

111. Zaghloul NA, Katsanis N. Mechanistic insights into 124. Marshall JD, Beck S, Maffei P, Naggert JK. Alstrom
Bardet-Biedl syndrome, a model ciliopathy. J Clin syndrome. Eur J Hum Genet. 2007;15(12):1193–202.
Invest. 2009;119(3):428–37. 125. Marshall JD, Ludman MD, Shea SE, Salisbury SR,
112. Lodh S, Hostelley TL, Leitch CC, O'Hare EA, Willi SM, LaRoche RG, et al. Genealogy, natural
Zaghloul NA. Differential effects on beta-cell history, and phenotype of Alstrom syndrome in a
mass by disruption of Bardet-Biedl syndrome large Acadian kindred and three additional families.
or Alstrom syndrome genes. Hum Mol Genet. Am J Med Genet. 1997;73(2):150–61.
2016;25(1):57–68. 126. Gathercole LL, Hazlehurst JM, Armstrong MJ,
113. Seo S, Guo DF, Bugge K, Morgan DA, Rahmouni Crowley R, Boocock S, O'Reilly MW, et al.
K, Sheffield VC. Requirement of Bardet-Biedl syn- Advanced non-alcoholic fatty liver disease and adi-
drome proteins for leptin receptor signaling. Hum pose tissue fibrosis in patients with Alstrom syn-
Mol Genet. 2009;18(7):1323–31. drome. Liver Int. 2016;36(11):1704–12.
114. Berbari NF, Pasek RC, Malarkey EB, Yazdi SM, 127. Citton V, Maffei P, Marshall JD, Baglione A, Collin
McNair AD, Lewis WR, et al. Leptin resistance GB, Milan G, et al. Pituitary morphovolumet-
is a secondary consequence of the obesity in cili- ric changes in Alstrom syndrome. J Neuroradiol.
opathy mutant mice. Proc Natl Acad Sci U S A. 2016;43(3):195–9.
2013;110(19):7796–801. 128. Hearn T, Renforth GL, Spalluto C, Hanley NA,
115. Fath MA, Mullins RF, Searby C, Nishimura DY, Wei Piper K, Brickwood S, et al. Mutation of ALMS1,
J, Rahmouni K, et al. Mkks-null mice have a pheno- a large gene with a tandem repeat encoding 47
type resembling Bardet-Biedl syndrome. Hum Mol amino acids, causes Alstrom syndrome. Nat Genet.
Genet. 2005;14(9):1109–18. 2002;31(1):79–83.
116. Guo D-F, Rahmouni K. Molecular basis of the obe- 129. Collin GB, Marshall JD, Ikeda A, So WV, Russell-­
sity associated with Bardet–Biedl syndrome. Trends Eggitt I, Maffei P, et al. Mutations in ALMS1
Endocrinol Metab. 2011;22(7):286–93. cause obesity, type 2 diabetes and neurosensory
117. Putoux A, Attie-Bitach T, Martinovic J, Gubler degeneration in Alstrom syndrome. Nat Genet.
MC. Phenotypic variability of Bardet-Biedl syn- 2002;31(1):74–8.
drome: focusing on the kidney. Pediatr Nephrol. 130. Hearn T, Spalluto C, Phillips VJ, Renforth GL,
2012;27(1):7–15. Copin N, Hanley NA, et al. Subcellular localization
118. Beales PL, Reid HA, Griffiths MH, Maher ER, Flinter of ALMS1 supports involvement of centrosome and
FA, Woolf AS. Renal cancer and malformations in basal body dysfunction in the pathogenesis of obe-
relatives of patients with Bardet-Biedl syndrome. sity, insulin resistance, and type 2 diabetes. Diabetes.
Nephrol Dial Transplant. 2000;15(12):1977–85. 2005;54(5):1581–7.
119. Simons DL, Boye SL, Hauswirth WW, Wu 131. Collin GB, Cyr E, Bronson R, Marshall JD, Gifford
SM. Gene therapy prevents photoreceptor death EJ, Hicks W, et al. Alms1-disrupted mice recapitu-
and preserves retinal function in a Bardet-Biedl late human Alstrom syndrome. Hum Mol Genet.
syndrome mouse model. Proc Natl Acad Sci U S A. 2005;14(16):2323–33.
2011;108(15):6276–81. 132. Marshall JD, Hinman EG, Collin GB, Beck S,
120. Seo S, Mullins RF, Dumitrescu AV, Bhattarai S, Cerqueira R, Maffei P, et al. Spectrum of ALMS1
Gratie D, Wang K, et al. Subretinal gene therapy variants and evaluation of genotype-phenotype
of mice with Bardet-Biedl syndrome type 1. Invest correlations in Alstrom syndrome. Hum Mutat.
Ophthalmol Vis Sci. 2013;54(9):6118–32. 2007;28(11):1114–23.
121. Kuhnen P, Clement K, Wiegand S, Blankenstein 133. Marshall JD, Muller J, Collin GB, Milan G,
O, Gottesdiener K, Martini LL, et al. Kingsmore SF, Dinwiddie D, et al. Alstrom syn-
Proopiomelanocortin deficiency treated with a drome: mutation Spectrum of ALMS1. Hum Mutat.
Melanocortin-4 receptor agonist. N Engl J Med. 2015;36(7):660–8.
2016;375(3):240–6. 134. Ize-Ludlow D, Gray JA, Sperling MA, Berry-Kravis
122. Alstrom CH, Hallgren B, Nilsson LB, Asander EM, Milunsky JM, Farooqi IS, et al. Rapid-onset
H. Retinal degeneration combined with obesity, dia- obesity with hypothalamic dysfunction, hypoven-
betes mellitus and neurogenous deafness: a specific tilation, and autonomic dysregulation presenting in
syndrome (not hitherto described) distinct from the childhood. Pediatrics. 2007;120(1):e179–88.
Laurence-Moon-Bardet-Biedl syndrome: a clinical, 135. Bougneres P, Pantalone L, Linglart A, Rothenbuhler
endocrinological and genetic examination based on A, Le Stunff C. Endocrine manifestations of the
a large pedigree. Acta Psychiatr Neurol Scand Suppl. rapid-onset obesity with hypoventilation, hypotha-
1959;129:1–35. lamic, autonomic dysregulation, and neural tumor
123. Minton JA, Owen KR, Ricketts CJ, Crabtree N, syndrome in childhood. J Clin Endocrinol Metab.
Shaikh G, Ehtisham S, et al. Syndromic obesity and 2008;93(10):3971–80.
diabetes: changes in body composition with age and 136. Barclay SF, Rand CM, Borch LA, Nguyen L, Gray
mutation analysis of ALMS1 in 12 United Kingdom PA, Gibson WT, et al. Rapid-onset obesity with
kindreds with Alstrom syndrome. J Clin Endocrinol hypothalamic dysfunction, hypoventilation, and
Metab. 2006;91(8):3110–6. autonomic Dysregulation (ROHHAD): exome
9 Syndromic Obesity 181

sequencing of trios, monozygotic twins and tumours. 151. Michaud JL, Rosenquist T, May NR, Fan
Orphanet J Rare Dis. 2015;10:103. CM. Development of neuroendocrine lineages
137. Edmondson AC, Kalish JM. Overgrowth syndromes. requires the bHLH-PAS transcription factor SIM1.
J Pediatr Genet. 2015;4(3):136–43. Genes Dev. 1998;12(20):3264–75.
138. Tatton-Brown K, Cole TRP, Rahman N. Sotos 152. Kublaoui BM, Holder JL Jr, Tolson KP, Gemelli
Syndrome. In: Pagon RA, Adam MP, Ardinger HH, T, Zinn AR. SIM1 Overexpression partially res-
Wallace SE, Amemiya A, Bean LJH, et al., edi- cues agouti yellow and diet-induced obesity
tors. GeneReviews®. Seattle (WA): University of by normalizing food intake. Endocrinology.
Washington, Seattle.; All rights reserved; 1993. 2006;147(10):4542–9.
139. Tatton-Brown K, Murray A, Hanks S, Douglas J, 153. Tolson KP, Gemelli T, Gautron L, Elmquist JK, Zinn
Armstrong R, Banka S, et al. Weaver syndrome and AR, Kublaoui BM. Postnatal Sim1 deficiency causes
EZH2 mutations: clarifying the clinical phenotype. hyperphagic obesity and reduced Mc4r and oxytocin
Am J Med Genet A. 2013;161a(12):2972–80. expression. J Neurosci. 2010;30(10):3803–12.
140. Ounap K. Silver-Russell syndrome and Beckwith-­ 154. Meyre D, Lecoeur C, Delplanque J, Francke S, Vatin
Wiedemann syndrome: opposite phenotypes with V, Durand E, et al. A genome-wide scan for child-
heterogeneous molecular etiology. Mol Syndromol. hood obesity-associated traits in French families
2016;7(3):110–21. shows significant linkage on chromosome 6q22.31-
141. Mussa A, Di Candia S, Russo S, Catania S, De ­q23.2. Diabetes. 2004;53(3):803–11.
Pellegrin M, Di Luzio L, et al. Recommendations 155. Duggirala R, Blangero J, Almasy L, Arya R, Dyer
of the scientific Committee of the Italian Beckwith– TD, Williams KL, et al. A major locus for fast-
Wiedemann Syndrome Association on the diagnosis, ing insulin concentrations and insulin resistance
management and follow-up of the syndrome. Eur J on chromosome 6q with strong pleiotropic effects
Med Genet. 2016;59(1):52–64. on obesity-related phenotypes in nondiabetic
142. Kalish JM, Deardorff MA. Tumor screening in Mexican Americans. Am J Hum Genet. 2001;68(5):
Beckwith-Wiedemann syndrome-to screen or not to 1149–64.
screen? Am J Med Genet A. 2016;170(9):2261–4. 156. Hung CC, Luan J, Sims M, Keogh JM, Hall C,
143. Maas SM, Vansenne F, Kadouch DJ, Ibrahim A, Wareham NJ, et al. Studies of the SIM1 gene in rela-
Bliek J, Hopman S, et al. Phenotype, cancer risk, tion to human obesity and obesity-related traits. Int J
and surveillance in Beckwith-Wiedemann syndrome Obes. 2007;31(3):429–34.
depending on molecular genetic subgroups. Am J 157. Gray J, Yeo GS, Cox JJ, Morton J, Adlam AL,
Med Genet A. 2016;170(9):2248–60. Keogh JM, et al. Hyperphagia, severe obesity,
144. Bonora E. Relationship between regional fat distri- impaired cognitive function, and hyperactivity asso-
bution and insulin resistance. Int J Obes Relat Metab ciated with functional loss of one copy of the brain-­
Disord. 2000;24(Suppl 2):S32–5. derived neurotrophic factor (BDNF) gene. Diabetes.
145. Izumi K, Housam R, Kapadia C, Stallings VA, 2006;55(12):3366–71.
Medne L, Shaikh TH, et al. Endocrine phenotype 158. Yeo GS, Connie Hung CC, Rochford J, Keogh J,
of 6q16.1-q21 deletion involving SIM1 and Prader-­ Gray J, Sivaramakrishnan S, et al. A de novo muta-
Willi syndrome-like features. Am J Med Genet A. tion affecting human TrkB associated with severe
2013;161A(12):3137–43. obesity and developmental delay. Nat Neurosci.
146. Ramachandrappa S, Raimondo A, Cali AM, Keogh 2004;7(11):1187–9.
JM, Henning E, Saeed S, et al. Rare variants in 159. Han JC, Liu QR, Jones M, Levinn RL, Menzie CM,
single-minded 1 (SIM1) are associated with severe Jefferson-George KS, et al. Brain-derived neuro-
obesity. J Clin Invest. 2013;123(7):3042–50. trophic factor and obesity in the WAGR syndrome.
147. Bonnefond A, Raimondo A, Stutzmann F, N Engl J Med. 2008;359(9):918–27.
Ghoussaini M, Ramachandrappa S, Bersten DC, 160. Skledar M, Nikolac M, Dodig-Curkovic K,
et al. Loss-of-function mutations in SIM1 contrib- Curkovic M, Borovecki F, Pivac N. Association
ute to obesity and Prader-Willi-like features. J Clin between brain-derived neurotrophic factor
Invest. 2013;123(7):3037–41. Val66Met and obesity in children and adolescents.
148. Nambu JR, Franks RG, Hu S, Crews ST. The single-­ Prog Neuro-Psychopharmacol Biol Psychiatry.
minded gene of Drosophila is required for the 2012;36(1):136–40.
expression of genes important for the development 161. Speliotes EK, Willer CJ, Berndt SI, Monda KL,
of CNS midline cells. Cell. 1990;63(1):63–75. Thorleifsson G, Jackson AU, et al. Association
149. Holder JL Jr, Butte NF, Zinn AR. Profound obesity analyses of 249,796 individuals reveal 18 new
associated with a balanced translocation that disrupts loci associated with body mass index. Nat Genet.
the SIM1 gene. Hum Mol Genet. 2000;9(1):101–8. 2010;42(11):937–48.
150. Michaud JL, Boucher F, Melnyk A, Gauthier F, 162. Thorleifsson G, Walters GB, Gudbjartsson DF,
Goshu E, Levy E, et al. Sim1 Haploinsufficiency Steinthorsdottir V, Sulem P, Helgadottir A, et al.
causes hyperphagia, obesity and reduction of the Genome-wide association yields new sequence vari-
paraventricular nucleus of the hypothalamus. Hum ants at seven loci that associate with measures of
Mol Genet. 2001;10(14):1465–73. obesity. Nat Genet. 2009;41(1):18–24.
182 K.A. Irizarry and A.M. Haqq

163. Tapia-Arancibia L, Rage F, Givalois L, Arancibia 170. Rios M, Fan G, Fekete C, Kelly J, Bates B, Kuehn
S. Physiology of BDNF: focus on hypothalamic func- R, et al. Conditional deletion of brain-derived
tion. Front Neuroendocrinol. 2004;25(2):77–107. neurotrophic factor in the postnatal brain leads
164. Xu B, Goulding EH, Zang K, Cepoi D, Cone RD, to obesity and hyperactivity. Mol Endocrinol.
Jones KR, et al. Brain-derived neurotrophic factor 2001;15(10):1748–57.
regulates energy balance downstream of melanocor- 171. Komori T, Morikawa Y, Nanjo K, Senba E. Induction
tin-­4 receptor. Nat Neurosci. 2003;6(7):736–42. of brain-derived neurotrophic factor by leptin in
165. Unger TJ, Calderon GA, Bradley LC, Sena-Esteves the ventromedial hypothalamus. Neuroscience.
M, Rios M. Selective deletion of Bdnf in the ven- 2006;139(3):1107–15.
tromedial and dorsomedial hypothalamus of adult 172. Liao GY, An JJ, Gharami K, Waterhouse EG,
mice results in hyperphagic behavior and obesity. J Vanevski F, Jones KR, et al. Dendritically targeted
Neurosci. 2007;27(52):14265–74. Bdnf mRNA is essential for energy balance and
166. Nakagawa T, Tsuchida A, Itakura Y, Nonomura T, Ono response to leptin. Nat Med. 2012;18(4):564–71.
M, Hirota F, et al. Brain-derived neurotrophic factor 173. Pelleymounter MA, Cullen MJ, Wellman
regulates glucose metabolism by modulating energy CL. Characteristics of BDNF-induced weight loss.
balance in diabetic mice. Diabetes. 2000;49(3):436–44. Exp Neurol. 1995;131(2):229–38.
167. Tonra JR, Ono M, Liu X, Garcia K, Jackson C, 174. Cao L, Choi EY, Liu X, Martin A, Wang C, Xu
Yancopoulos GD, et al. Brain-derived neurotrophic X, et al. White to brown fat phenotypic switch
factor improves blood glucose control and allevi- induced by genetic and environmental activation
ates fasting hyperglycemia in C57BLKS-Lepr(db)/ of a hypothalamic-adipocyte axis. Cell Metab.
lepr(db) mice. Diabetes. 1999;48(3):588–94. 2011;14(3):324–38.
168. Wang C, Godar RJ, Billington CJ, Kotz CM. Chronic 175. Mattson MP. Energy intake and exercise as determi-
administration of brain-derived neurotrophic factor nants of brain health and vulnerability to injury and
in the hypothalamic paraventricular nucleus reverses disease. Cell Metab. 2012;16(6):706–22.
obesity induced by high-fat diet. Am J Physiol Regul 176. Martin B, Golden E, Carlson OD, Pistell P, Zhou J,
Integr Comp Physiol. 2010;298(5):R1320–32. Kim W, et al. Exendin-4 improves glycemic control,
169. Kernie SG, Liebl DJ, Parada LF. BDNF regulates ameliorates brain and pancreatic pathologies, and
eating behavior and locomotor activity in mice. extends survival in a mouse model of Huntington's
EMBO J. 2000;19(6):1290–300. disease. Diabetes. 2009;58(2):318–28.