ABSTRACT

Genetic factors play a major role in the regulation of body weight and in the susceptibility to obesity in the population. A subset of people with severe obesity carry rare, highly penetrant genetic variants that can result in severe childhood-onset obesity. Current estimates suggest that up to 20% of children with severe obesity may carry pathogenic chromosomal abnormalities or mutations. The diagnosis of a genetic obesity syndrome can provide information that has value for the patient and their family and may help them deal with the social stigma that comes with severe obesity in childhood. In an increasing number of cases, the finding of a genetic cause for a patient’s obesity can inform clinical care and the use of targeted therapies. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

At a population level, obesity is driven by an increase in the intake of easily available, energy-dense, highly palatable foods and a decrease in physical activity at school/work and in leisure time. However, variation in body mass index (BMI: weight in kg/height in meters squared) within the population is influenced by genetic factors (1,2). Studies in twins and families have shown that food intake, satiety responsiveness (fullness after a fixed meal), basal metabolic rate, the amount of energy utilized during a fixed amount of exercise, and body fat distribution are all heritable traits (3).

Genome-wide association studies (GWAS’s) in large population-based cohorts have identified thousands of common variants (minor allele frequency > 5%) that are associated with BMI and/or obesity (4). While individually each variant often has a small effect on BMI, cumulatively, the effect of millions of common and rare variants can now be combined to compute a polygenic risk score which can predict the development of severe obesity (5). Studies are ongoing to test how such scores might be useful in the clinical setting. Most common obesity associated variants lie in noncoding areas of the genome so identifying the mechanism by which they affect body weight can be challenging. It is interesting to note that most obesity- or BMI-associated variants lie in or near genes which are expressed in the brain and some of these variants have been associated with increased food intake (4,6). In contrast, GWAS associations for body fat distribution/waist-to-hip ratio, mostly seem to be linked to genes expressed in adipose tissue (7).

CLINICAL APPROACH TO DIAGNOSIS OF GENETIC OBESITY SYNDROMES

Rare (less than 1% minor allele frequency), highly penetrant genetic variants in multiple genes have been associated with severe obesity that often presents in childhood. Whilst these disorders are rare, cumulatively up to 20% of children with severe obesity have chromosomal abnormalities or other penetrant rare variants that drive their obesity (8). The assessment of children and adults with severe obesity should be directed at screening for endocrine, neurological, and genetic disorders (9). Important information can be obtained from a detailed family history to identify potential consanguineous relationships, the presence of other family members with severe obesity and those who have had bariatric surgery, and the ethnic origin of family members (Figure 1). The clinical history and examination can then guide the appropriate use of diagnostic tests. For the purposes of clinical assessment, it remains useful to categorize the genetic obesity syndromes as those with and without associated developmental delay.

Figure 1.

Diagnosis of genetic obesity syndromes.

OBESITY SYNDROMES WITHOUT DEVELOPMENTAL DELAY

The adipocyte-derived hormone leptin acts mainly to defend against starvation (10), with a fall in leptin levels (as seen in weight loss, acute caloric restriction or congenital leptin deficiency) causing an increase in food intake and physiological responses that act to restore energy balance (11). In most people, circulating leptin levels correlate closely with fat mass (12), although there is considerable variation in leptin levels at any given BMI, which is as yet unexplained. Leptin signals through the long isoform of the leptin receptor, which is widely expressed in the hypothalamus and other brain regions involved in energy homeostasis (13). In the arcuate nucleus of the hypothalamus (which has a permeable blood-brain barrier), there are several neuronal populations known to be important in weight regulation expressing the leptin receptor. In the fed state, leptin stimulates the expression of pro-opiomelanocortin (POMC), which is processed to generate the melanocortin peptides that, in turn, activate the melanocortin 4 receptor (MC4R) on second-order neurons in the paraventricular nucleus. Leptin also inhibits adjacent neurons containing Agouti-related protein (AgRP), a MC4R antagonist. The integration of these two actions leads to reduced food intake (Figure 2). In the fasted state and with weight loss, a drop in leptin levels reduces the activation state of POMC neurons and increases AgRP signaling to cause an increase in food intake. These hypothalamic pathways interact with other brain centers to affect not just eating behaviors but also energy expenditure.

Severe obesity can result from mutations that disrupt key components of the leptin-melanocortin pathway (Figure 2). People with these genetic disorders experience an intense drive to eat (hunger), find food to be highly rewarding, and have impaired fullness (satiety) leading to hyperphagia (increased food intake), resulting in excessive weight gain from early childhood.

Figure 2.

Genes involved in the leptin-melanocortin pathway whose disruption causes obesity.

Pro-opiomelanocortin Deficiency

Due to impaired production of melanocortin stimulating hormone peptides (a/b MSH) and diminished or absent MC4R signaling (Figure 2), homozygous or compound heterozygous mutations in POMC cause hyperphagia and early-onset obesity (29). People deficient in POMC also have pale skin and red or light colored hair due to the lack of signaling of pigment-inducing melanocortin 1 receptors in the skin (29). In the pituitary gland, POMC is the precursor for adrenocorticotrophin (ACTH). As such, complete POMC deficiency presents in neonatal life with features of ACTH and cortisol deficiency: hypoglycemia and cholestatic jaundice requiring long-term corticosteroid replacement therapy (30). Typically, patients with primary or secondary cortisol deficiency present with hypophagia and weight loss, so adrenal insufficiency with hyperphagia in the absence of a structural hypothalamic abnormality should raise suspicion for a POMC defect. POMC deficiency may also impair the timing of puberty, an effect that appears to be mediated by the melanocortin 3 receptor (MC3R) (31).

Complete POMC deficiency can be treated with a melanocortin receptor agonist (setmelanotide) (32) (Figure 3). Heterozygous missense mutations directly affecting the function of POMC peptides have been described (Figure 2) (33). These variants significantly increase obesity risk but are not invariably associated with obesity. The potential efficacy of MC4R agonists in patients with these heterozygous mutations is currently being tested in clinical trials.

Figure 3.

Medical treatment of patients with genetic obesity syndromes. POMC: pro-opiomelanocortin. PCSK1: prohormone convertase-1. MC4R: melanocortin 4 receptor. GLP-1: glucagon receptor-1.

OBESITY SYNDROMES WITH DEVELOPMENTAL DELAY

Prader-Willi Syndrome

Prader-Willi syndrome is an autosomal dominant disorder caused by deletion or disruption of a paternally imprinted region on chromosome 15q11.2-q12 (49). The clinical features of Prader-Willi syndrome (PWS) include diminished fetal activity, hypotonia, and feeding difficulties in infancy followed by hyperphagia, obesity, developmental delay, short stature, hypogonadotropic hypogonadism, and small hands and feet (Figure 4). Children with PWS display diminished growth, reduced lean body mass and increased fat mass. These body composition abnormalities can be explained, in part, by growth hormone (GH) deficiency and improved with growth hormone treatment, which should be started in early childhood.

Figure 4.

Infancy and childhood clinical features of Prader-Willi Syndrome (PWS).

Contained within the 4.5Mb PWS region in 15q11-q13 are silenced paternally imprinted genes and a family of small nucleolar RNAs (snoRNAs) known as the HBII-85 snoRNAs. Small deletions exclusively encompassing these snoRNAs result in the key features of PWS including obesity (Figure 4) (50,51), suggesting that these snoRNAs play a critical role in the development of this syndrome. Histopathological studies on post-mortem brain samples from PWS patients have demonstrated reduced levels of oxytocin expression in the hypothalamus (52) and trials of intranasal administration in PWS are ongoing (53). Brain-derived neurotrophic factor (BDNF) expression is also reduced in PWS, potentially contributing to both the obesity and neurobehavioral features including stereotyped behaviors (54).

FUTURE PERSPECTIVES

The diagnosis of a genetic obesity syndrome can provide information that has diagnostic value for the family to whom genetic counselling can be provided. A genetic diagnosis can help children and their families deal with the social stigma that comes with severe obesity and, in some instances, has prevented children from being taken into care by social services when obesity is blamed on parental neglect. A genetic diagnosis can inform management (many such patients are relatively refractory to weight loss through changes in diet and exercise) and can inform clinical decision-making. For example, bariatric surgery (particularly Roux-en-Y bypass surgery) is contraindicated in many genetic obesity syndromes as it does not reverse the strong hypothalamic drive to eat and continued overeating can be harmful. Importantly, an increasing number of genetic obesity syndromes are now treatable with mechanism-based pharmacologic therapies.

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