have suggested a heritability of 0.70 for men and 0.66 for women [7], whilst a heritability of 0.61 was observed in a cohort of UK twins [8]. In a meta‐analysis of results derived from Finnish, Japanese and American archival twins, Allison observed similar correlations [9]. In addition, Price and Gottesman have shown that these correlations did not differ significantly between twins reared apart and twins reared together, and between twins reared apart in relatively more similar (i.e. with relatives) versus less similar environments [8].
Familial resemblance in food intake has been reported in parents and their children [10], although the extent to which this is genetically determined is unclear. Twin data suggest that there are notable genetic influences on overall food intake, size and frequency of meals. Bouchard and Tremblay have shown that about 40% of the variance in resting metabolic rate, thermic effect of food, and energy cost of low to moderate‐intensity exercise may be explained by inherited characteristics [11]. In addition, significant familial resemblance for level of habitual physical activity has been reported in a large cohort of healthy female twins [12].
Pleiotropic obesity syndromes
The assessment of children with severe obesity and indeed adults should be directed at screening for potentially treatable endocrine and neurological conditions and identifying genetic conditions so that appropriate genetic counseling and, in some cases, treatment can be started. Clinically, it remains useful to categorize the genetic obesity syndromes as those with dysmorphism and/or developmental delay and those without these features (Tables 4.1 and 4.2). There are more than 30 Mendelian disorders with obesity as a clinical feature but often associated with learning difficulties, dysmorphic features, and organ‐specific developmental abnormalities (i.e. pleiotropic syndromes). For a comprehensive list of syndromes in which obesity is a recognized part of the phenotype, see Online Mendelian Inheritance in Man (OMIM), www.ncbi.nlm.nih.gov/omim.
Prader–Willi syndrome
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