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].
Albright hereditary osteodystrophy
Albright hereditary osteodystrophy (AHO) is an autosomal dominant disorder due to inactivating mutations in GNAS1, the gene encoding Gαs, the G protein that couples receptors to adenylyl cyclase leading to cAMP generation. Heterozygous loss‐of‐function mutations lead to AHO, a disease characterized by short stature, obesity, skeletal defects, and developmental delay. Maternal transmission of GNAS1 mutations leads to AHO plus resistance to several hormones (e.g. parathyroid hormone) that activate Gαs in their target tissues, while paternal transmission leads only to the AHO phenotype. Studies in both mice and humans demonstrate that GNAS1 is imprinted in a tissue‐specific manner, being expressed primarily from the maternal allele in some tissues and biallelically in most other tissues; thus, multihormone resistance occurs only when GNAS mutations are inherited maternally [17]. Patients can present with severe obesity alone; the other classical features can emerge over time in some but not all patients.
Bardet–Biedl syndrome
Bardet–Biedl syndrome (BBS) is a rare (prevalence <1/100,000)
