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The Prader–Willi syndrome (PWS) is the most common syndromal cause of human obesity, with an estimated prevalence of about 1 in 25,000. It is an autosomal dominant disorder caused by deletion or disruption of a paternally imprinted region on the proximal long arm of chromosome 15. The PWS is characterized by diminished fetal activity, hypotonia, failure to thrive in infancy, obesity, learning difficulties, short stature, and hypogonadotropic hypogonadism [13]. Feeding difficulties generally improve by the age of 6 months. From 12 to 18 months onward, uncontrollable hyperphagia results in severe obesity.

Whilst hyperphagia is a dominant feature in PWS subjects, the eating behavior in PWS might be due to decreased satiation as well as increased hunger. One suggested mediator of the obesity phenotype in PWS patients is the stomach‐derived hormone ghrelin, which is implicated in the regulation of mealtime hunger and is also a potent stimulator of growth hormone (GH) secretion. Fasting plasma ghrelin levels are 4.5‐fold higher in PWS subjects than equally obese controls [14].

Table 4.1 Pleiotropic genetic obesity syndromes

Syndrome	Inheritance	Additional clinical features
Prader–Willi	Autosomal dominant	Hypotonia, failure to thrive in infancy, developmental delay, short stature, hypogonadotropic hypogonadism, sleep disturbance, obsessive behavior
Albright’s hereditary osteodystrophy	Autosomal dominant	Short stature in some, skeletal defects, developmental delay, shortened metacarpals; hormone resistance when mutation on maternally inherited allele.
Bardet–Beidl	Autosomal recessive	Syndactyly/brachydactyly/polydactyly, developmental delay, retinal dystrophy or pigmentary retinopathy, hypogonadism, renal abnormalities
Cohen	Autosomal recessive	Facial dysmorphism, microcephaly, hypotonia, developmental delay, retinopathy
Carpenter	Autosomal recessive	Acrocephaly, brachydactyly, developmental delay, congenital heart defects; growth retardation, hypogonadism
Alstrom	Autosomal recessive	Progressive cone‐rod dystrophy, sensorineural hearing loss, hyperinsulinemia, early type 2 diabetes mellitus, dilated cardiomyopathy, pulmonary, hepatic, and renal fibrosis
Tubby	Autosomal recessive	Progressive cone‐rod dystrophy, hearing loss

Table 4.2 Monogenic obesity syndromes affecting the leptin‐melanocortin pathway

Gene affected	Inheritance	Additional clinical features
Leptin	Autosomal recessive	Severe hyperphagia, frequent infections, hypogonadotropic hypogonadism, mild hypothyroidism
Leptin receptor	Autosomal recessive	Severe hyperphagia, frequent infections, hypogonadotropic hypogonadism, mild hypothyroidism
Pro‐opiomelanocortin	Autosomal recessive	Hyperphagia, cholestatic jaundice, or adrenal crisis due to ACTH deficiency, pale skin, and red hair
Prohormone convertase 1	Autosomal recessive	Small bowel enteropathy, postprandial hypoglycemia, hypothyroidism, ACTH deficiency, hypogonadism, central diabetes insipidus
Carboxypeptidase E	Autosomal recessive	—
Melanocortin 4 receptor	Autosomal dominant	Hyperphagia accelerated linear growth
Single‐minded 1	Autosomal dominant	Hyperphagia, accelerated linear growth, speech and language delay, autistic traits
BDNF	Autosomal dominant	Hyperphagia, developmental delay, hyperactivity, behavioral problems including aggression
TrkB	Autosomal dominant	Hyperphagia, speech and language delay, variable developmental delay, hyperactivity, behavioral problems including aggression
SH2B1	Autosomal dominant	Hyperphagia, disproportionate hyperinsulinemia, early type 2 diabetes mellitus, behavioral problems including aggression

Children with PWS display diminished growth, reduced lean mass, increased fat mass, and body composition abnormalities resembling those seen in GH deficiency. Diminished GH responses to various provocative agents, low insulin‐like growth factor‐I levels, and the presence of additional evidence of hypothalamic dysfunction support the presence of true GH deficiency (GHD) in many children with PWS. GH treatment in these children decreases body fat and increases linear growth, muscle mass, fat oxidation, and energy expenditure. In PWS children, therapy with GH significantly improves the rate of growth and final height. Long‐term studies show that the final height is in the average range for age, and GH is now licensed for use in PWS.

Prader–Willi syndrome is caused by deficiency of one or more paternally expressed imprinted transcripts within chromosome 15q11‐q13, a region that includes multiple small nucleolar RNAs (snoRNAs). The molecular pathophysiology of PWS remains unclear, although the expression of oxytocin and brain‐derived neurotrophic factor (BDNF) is reduced in the postmortem brains of PWS patients [15]. Microdeletions of the HBII‐85 snoRNAs in children with PWS provide strong evidence that deficiency of HBII‐85 snoRNAs plays a major role in the key characteristics of the PWS phenotype [16].