Your SlideShare is downloading. ×
Genetic and hereditary aspects of childhood obesity
Upcoming SlideShare
Loading in...5

Thanks for flagging this SlideShare!

Oops! An error has occurred.


Introducing the official SlideShare app

Stunning, full-screen experience for iPhone and Android

Text the download link to your phone

Standard text messaging rates apply

Genetic and hereditary aspects of childhood obesity


Published on

  • Be the first to comment

  • Be the first to like this

No Downloads
Total Views
On Slideshare
From Embeds
Number of Embeds
Embeds 0
No embeds

Report content
Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

No notes for slide


  • 1. Best Practice & Research Clinical Endocrinology & Metabolism Vol. 19, No. 3, pp. 359–374, 2005 doi:10.1016/j.beem.2005.04.004 available online at 3 Genetic and hereditary aspects of childhood obesity I. Sadaf Farooqi* Wellcome Clinician Scientist Fellow University Departments of Medicine and Clinical Biochemistry, Box 232, Addenbrooke’s Hospital, Cambridge CB2 2QQ, UK Genetic factors are involved in the regulation of body weight and in determining individual responses to environmental factors such as diet and exercise. The identification and characterization of monogenic obesity syndromes have led to an improved understanding of the precise nature of the inherited component of severe obesity and has had undoubted medical benefits, whilst helping to dispel the notion that obesity represents an individual defect in behaviour with no biological basis. For individuals at highest risk of the complications of severe obesity, such findings provide a starting point for providing more rational mechanism-based therapies, as has successfully been achieved for one disorder, congenital leptin deficiency. Key words: genes; leptin; melanocortin. The rising prevalence of childhood and adult obesity can be explained in part by changes in our environment over the last 30 years, in particular the unlimited supply of convenient, highly palatable, energy-dense foods, coupled with a lifestyle typified by low levels of physical activity. However, obesity represents the archetypal complex multifactorial disease and arises as a result of behavioural, environmental, and genetic factors which may influence individual responses to diet and physical activity. There is considerable evidence to suggest that, like height, weight is a heritable trait.1 Traditionally the most favoured model for separation of the genetic component of variance is based on studies of twins, as monozygotic co-twins share 100% of their genes and dizygotes 50% on average. Overall, data from twin and adoption studies are consistent with a genetic contribution for body mass index (BMI) of between 40 and 70%.2 It is clear that different individuals have a certain genetic propensity to store excessive caloric intake as fat. In a classic study, Bouchard and Tremblay3 overfed pairs of monozygotic twins by 10%. Different sets of twins showed remarkable differences in * Tel.:C44 1223 762 634; Fax: C44 1223 762 657. E-mail address: 1521-690X/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved.
  • 2. 360 I. S. Farooqi the degree to which these calories were stored as fat, but the tendency toward increased adiposity within each set of twins was remarkably similar, indicating that genetic factors determine an individual’s susceptibility to gain weight in a given environment. Although the role of genes in the regulation of body fat is now established, it is safe to assume that the rising prevalence of obesity has not been due to a recent change in the genetics of the Western world. The propensity for obesity must have been in our midst for a long time, only to emerge recently on a large scale as a result of changes in the environment, in particular the availability and composition of food and reduced requirement for physical exertion. It is very likely that the ability to store fat in times of nutritional abundance was a positive trait selected over many thousands of years of human evolution. The identification of the polygenic determinants of adiposity across the general human population has been challenging and has had limited success thus far.4 However, as is the case with other human phenotypes, the study of extreme human phenotypes with Mendelian patterns of inheritance has been illuminating in a number of ways. In this review, I will focus on the recent advances that have been made through the study of patients with obesity syndromes that display a Mendelian pattern of inheritance. These single gene disorders include the classical pleiotropic obesity syndromes, where affected patients are usually identified as a result of their association with additional phenotypes such as mental retardation or other developmental abnormalities. More recently several monogenic disorders resulting from disruption of the leptin– melanocortin pathway have been identified. In these disorders, severe obesity of early onset is itself the predominant presenting feature, although often accompanied by characteristic patterns of neuroendocrine dysfunction. GENETIC DISRUPTION OF THE LEPTIN–MELANOCORTIN PATHWAY RESULTS IN MONOGENIC HUMAN OBESITY Energy homeostasis involves the integration of longer-term afferent signals from fat (leptin) and pancreatic b cells (insulin) and short-term, meal-related afferent signals from the gut, including inhibitors of feeding (peptide YY, PYY; glucagon-like peptide-1, GLP-1; and cholecystekinin, CCK), and the stimulator of feeding (ghrelin).5 These inputs are integrated within the brain and regulate food intake, energy expenditure, energy partitioning and neuroendocrine status, including reproduction and growth (Figure 1). The adipocyte-derived hormone leptin circulates in proportion to body fat content, crosses the blood–brain barrier, interacts with receptors on neurons known to influence energy balance, and exerts long-acting effects to reduce adiposity by decreasing appetite and increasing thermogenesis.6 Attention has focused on identifying the molecular events that lie downstream of the leptin receptor in key hypothalamic target neurons. In particular, neurons within the hypothalamic arcuate nucleus (Arc) act as primary sensors of alterations in energy stores to control appetite and energy homeostasis. Pro-opiomelanocortin (POMC) neurons produce the anorectic peptide a-MSH (a-melanocyte stimulating hormone) together with CART (cocaine- and amphetamine-related transcript), whilst a separate group expresses the orexigens neuropeptide Y (NPY) and agouti-related protein (AGRP).7 AGRP is a hypothalamic neuropeptide that is a potent melanocortin-3 receptor (MC3R) and melanocortin-4 receptor (MC4R) antagonist. Activation of the NPY/AGRP neurons increases food
  • 3. Genetic and hereditary aspects of childhood obesity 361 DOWNSTREAM NEURONS + Food intake – Food intake Y1R GnRH MC4R HYPOTHALAMUS Y4R NPY/AGRP MC3R POMC/CART LEPTIN RECEPTORS vv v v GHSR v LEPTIN Y1R v RECEPTORS – + + GHRELIN INSULIN LEPTIN ADIPOSE TISSUE Figure 1. The leptin–melanocortin pathway. GnRH, gonadotropin-releasing hormone; Y1R, Y4R, neuropeptide Y1/Y4 receptor; MC3R, MC4R, melanocortin-3/4 receptor; POMC, pro-opiomelanocortin; NPY/AGRP, neuropeptide Y/agouti-related protein; GHSR, growth hormone secretagogue receptor. intake and decreases energy expenditure, whereas activation of the POMC neurons decreases food intake and increases energy expenditure.8 The long isoform of the leptin receptor is highly expressed on these arcuate neurons, and leptin regulates these two neuronal populations in a reciprocal manner. From the arcuate, these two populations of neurons project to other brain areas, which contain second-order neurons expressing neuropeptides involved in energy homeostasis. In particular, there are extensive projections to several hypothalamic regions, including the lateral hypothalamus (LH) and the paraventricular nucleus (PVN).9 Cell bodies within the LH contain the potent orexigenic peptide, melanin-concentrating hormone (MCH), and neurons of the PVN express thyrotropin-releasing hormone (TRH) and corticotrophin- releasing hormone (CRH), highlighting a link between the pathways regulating energy homeostasis and neuroendocrine circuits.9 The fact that many aspects of the normal physiological response to starvation are abrogated by the administration of leptin10 strongly suggests that one of the major roles of leptin is to signal the transition from a state of nutritional adequacy to that of starvation, and this, rather than the prevention of obesity, is likely to be the major physiological role of leptin.11 Congenital leptin deficiency In 1997 we reported two severely obese cousins (an 8-year-old girl weighing 86 kg and a 2-year-old boy weighing 29 kg) from a highly consanguineous family of Pakistani origin.12 Despite their severe obesity, both children had undetectable levels of serum leptin and
  • 4. 362 I. S. Farooqi were found to be homozygous for a frameshift mutation in the ob gene (DG133), which resulted in a truncated protein that was not secreted. We have since identified four further affected individuals from three other families who are also homozygous for the same mutation in the leptin gene.13 All the families are of Pakistani origin but not known to be related over five generations. A large Turkish family carrying a homozygous missense mutation has also been described.14 All subjects in these families are characterized by severe early-onset obesity and intense hyperphagia. Hyperinsulinae- mia and an advanced bone-age are also common features.13 Some of the Turkish subjects are adults with hypogonadotropic hypogonadism, although there was some evidence of a delayed but spontaneous pubertal development in one person.15 We demonstrated that children with leptin deficiency had profound abnormalities in T-cell number and function, consistent with high rates of childhood infection and a high reported rate of childhood mortality from infection in obese Turkish subjects.13 Response to leptin therapy We reported the dramatic and beneficial effects of daily subcutaneous injections of leptin in reducing body weight (98% of which was fat mass) in three congenitally leptin- deficient children.13 All children showed a response to initial leptin doses designed to produce plasma leptin levels at only 10% of those predicted by height and weight (i.e. approximately 0.01 mg/kg of lean body mass). Among the most dramatic example of the effects of leptin was with a 3-year-old boy, severely disabled by gross obesity (weight 42 kg), who now weighs 32 kg (75th centile for weight) after 48 months of leptin therapy (Figure 2). Similar major effects were seen in three leptin-deficient adults treated with recombinant human leptin, with an improvement in hyperinsulinaemia and diabetes in one subject.16 The major effect of leptin was on appetite, with normalization of hyperphagia.17 Leptin therapy reduced energy intake during an 18-MJ ad libitum test meal by up to 84%.13 We were unable to demonstrate a major effect of leptin on basal metabolic rate or free-living energy expenditure, but as weight loss by other means is associated with a decrease in basal metabolic rate (BMR), the fact that energy expenditure did not fall in our leptin-deficient subjects is notable. The administration of leptin permitted progression of appropriately timed pubertal development in the single child of appropriate age, induced pubertal development in adults, and did not cause the early onset of puberty in the younger children, suggesting that leptin is a permissive factor for the development of puberty in humans.13 Free thyroxine and TSH levels, although in the normal range before treatment, had consistently increased at the earliest post-treatment time point and subsequently stabilized at this elevated level. These findings are consistent with evidence from animal models that leptin influences TRH release from the hypothalamus and from studies illustrating the effect of leptin deficiency on TSH pulsatility in humans.18 Throughout the trial of leptin administration, weight loss continued in all subjects, albeit with refractory periods which were overcome by increases in leptin dose. The families in the UK harbour a mutation, which leads to a prematurely truncated form of leptin, and thus wild-type leptin is a novel antigen to them. Thus, all subjects developed anti-leptin antibodies after w6 weeks of leptin therapy, which interfered with interpretation of serum leptin levels and in some cases were capable of neutralizing leptin in a bioassay.13 These antibodies are the likely cause of refractory periods occurring during therapy. The fluctuating nature of the antibodies probably reflects
  • 5. Genetic and hereditary aspects of childhood obesity 363 Figure 2. Response to leptin therapy in a child with leptin deficiency. the complicating factor that leptin deficiency is itself an immunodeficient state19, and administration of leptin leads to a change from the secretion of predominantly Th2 to Th1 cytokines, which may directly influence antibody production. Thus far, we have been able to regain control of weight loss by increasing the dose of leptin. Leptin receptor deficiency A mutation in the leptin receptor has been reported in one consanguineous family of Algerian origin with three affected subjects.20 Affected individuals were found to be homozygous for a mutation that truncates the receptor before the transmembrane domain. The mutant receptor ectodomain is shed from cells and circulates bound to leptin. However, the unusually high leptin levels in this family are an artefact of the particular mutation which results in large amounts of leptin being bound to the abnormally shed ectodomain. In general, leptin receptor deficiency results in a similar phenotype to leptin deficiency. Leptin receptor-deficient subjects were also of normal birth weight but exhibited rapid weight gain in the first few months of life, with severe hyperphagia and aggressive behaviour when food was denied. Basal temperature and resting metabolic rate were normal, cortisol levels were in the normal range, and all individuals were normoglycaemic with mildly elevated plasma insulins similar to those of leptin-deficient subjects. Leptin receptor-deficient subjects had some unique neuroendocrine features not seen with leptin deficiency.20 Whether the mild growth retardation with impaired basal and stimulated growth hormone secretion and decreased IGF-1 and IGF-BP3 levels—alongside features of frank hypothalamic
  • 6. 364 I. S. Farooqi hypothyroidism—are consistent features will become clear only with the description of further families. POMC deficiency Seven children homozygous or compound heterozygous for mutations in POMC have been reported.21–23 Initial presentation is in neonatal life with adrenal crisis due to ACTH deficiency (POMC is a precursor of ACTH in the pituitary), and the children have pale skin and red hair due to the lack of MSH action at melanocortin-1 receptors in the skin and hair follicles, although this may be less obvious in children from different ethnic backgrounds (unpublished observations). POMC deficiency results in hyper- phagia and early-onset obesity due to loss of melanocortin signalling at the melanocortin-4 receptor (MC4R). Although, as yet, no specific treatment is available, selective small-molecule MC4R agonists are being developed, and it is likely that these children would be highly responsive to such agents. In addition to homozygotes for complete POMC deficiency, other heterozygous point mutations in the POMC gene might contribute to inherited obesity24, and it is notable that there is a high prevalence of obesity in the heterozygous relatives of children with complete POMC deficiency, suggesting that subtle defects in this system may be sufficient to cause obesity. Melanocortin-4 receptor deficiency In 1998, groups in the UK and France reported families with dominantly inherited associated heterozygous mutations in the MC4 receptor (MC4R).25,26 Since then, multiple different heterozygous MC4R mutations have been reported in obese people from various ethnic groups. The prevalence of such mutations has varied from 0.5 to 1.0% of obese adults to 6% in subjects with severe obesity starting in childhood.27 Although few studies have been performed in unselected populations, estimates based on population-derived cohorts are consistent with a population prevalence of at least one in 2000, suggesting that MC4R deficiency may be commoner than either Prader– Willi syndrome or fragile X syndrome. While some studies have found a 100% penetrance of early-onset obesity in heterozygous probands, others have described obligate carriers who were not obese. Given the large number of potential influences on body weight, it is perhaps not surprising that both genetic and environmental modifiers will have important effects in some pedigrees. Indeed, we have now studied six families in whom the probands were homozygotes, and in all of these the homozygotes were more obese than heterozygotes.27 Thus, co-dominance, with modulation of expressivity and penetrance of the phenotype, is the most appropriate descriptor for the mode of inheritance. We have recently defined the phenotype in 150 patients with MC4R deficiency27 (and personal observations). Affected subjects exhibit hyperphagia, but this is not as severe as that seen in leptin deficiency, although it often starts in the first year of life. Of particular note is the finding that the severity of receptor dysfunction seen in assays in vitro can predict the amount of food ingested at a test meal by the subject harbouring that particular mutation.27 Alongside the increase in fat mass, MC4R-deficient subjects also have an increase in lean mass that is not seen in leptin deficiency and a marked increase in bone mineral density; thus they often appear ‘big-boned’. The accelerated linear growth does not appear to be due to dysfunction of the GH axis and may be a consequence of the disproportionate early hyperinsulinaemia.27
  • 7. Genetic and hereditary aspects of childhood obesity 365 The high frequency of MC4R mutations in obese humans compared to the rarity of leptin, leptin receptor and PC1 mutations is probably related to the fact that even partial loss-of-function mutations in the heterozygous form result in a phenotype and because the mutations do not appear to interfere with reproductive function and fertility. While at present there is no specific therapy for MC4R deficiency, it is highly likely that these subjects would respond well to pharmacotherapy that overcame the reduction in the hypothalamic melanocortinergic tone that exists in these patients. As most patients are heterozygotes with one functional allele intact, it is possible that small-molecule MC4R agonists might, in future, be excellent candidate drugs for this disorder. Prohormone convertase-1 (PC1) deficiency We have previously reported a woman with severe early-onset obesity, hypogonado- tropic hypogonadism, postprandial hypoglycaemia, hypocortisolaemia, and evidence of impaired processing of POMC and proinsulin who was a compound heterozygote for PC1 mutations.28 We have recently described the second case of congenital PC1 deficiency: a child who was a compound heterozygote for two loss-of-function mutations.29 Intriguingly, this patient suffered from severe small-intestinal absorptive dysfunction as well as the characteristic severe early-onset obesity, impaired prohormone processing and hypocortisolaemia. The small intestinal dysfunction seen in this patient—and to a lesser extent in the first patient we described—may be the result of a failure of maturation of propeptides within the enteroendocrine cells and nerves that express PC1 throughout the gut. MONOGENIC HUMAN OBESITY: PLEIOTROPIC SYNDROMES There are about 30 Mendelian disorders with obesity as a clinical feature, often in association with mental retardation, dysmorphic features and organ-specific develop- mental abnormalities (i.e. pleiotropic syndromes)30. Positional genetic strategies have led to the recent identification of several different causative mutations underlying such syndromes; however, in most cases the defective gene product is an intracellular protein that is expressed throughout the body and is of unknown function. As yet, the mechanistic link between such defective gene products and dysregulation of energy balance is obscure, although recently a potential novel molecular mechanism underlying Bardet–Beidl syndrome has been identified.31 Bardet–Biedl syndrome Bardet–Biedl syndrome (BBS) is a rare (prevalence !1/100 000) autosomal recessive syndrome characterized by central obesity (in 75% of patients), mental retardation, dysphormic extremities, retinal dystrophy or pigmentary retinopathy, hypogonadism or hypogenitalism (limited to male patients) and renal abnormalities. BBS is a genetically heterogeneous disorder that is known to map to at least eight loci, seven of which have now been identified at the molecular level.32 Although BBS is usually transmitted as a recessive disorder, some families have exhibited so-called ‘tri-allelic’ inheritance31 where the clinical manifestation of the syndrome requires two mutations in one BBS
  • 8. 366 I. S. Farooqi gene plus an additional mutation in a second, unlinked BBS gene, although no evidence for involvement of the common BBS1 mutation in triallelic inheritance has been found. The BBS1 gene (11q13) is the most commonly mutated in white BBS patients.33 However, the protein does not show any significant similarity with any known protein or protein family, and its function is unknown, as is the case for the protein encoded by the BBS2 gene (16q21), which appears to result in the ‘leanest’ BBS phenotype. A relatively small proportion of BBS families are linked to the BBS3 locus, which has recently been refined (3p13-p12). Families with BBS mapping to BBS6 (20p12) have been found to harbour mutations in MKKS which has sequence homology to the a- subunit of a prokaryotic chaperonin.34 Mutations in this gene also cause McKusick– Kaufman syndrome (hydrometrocolpos, post-axial polydactyly and congenital heart defects). Recently, phylogenetic/genomic approaches have led to the identification of BBS7 (4q27)35 and BBS8 or TTC8 (14q32.11).36 Whilst the function of the BBS7- encoded protein is unknown, mutations in BBS8 have been found in three families and in vitro; BBS8 localizes to centrosomes and basal bodies and interacts with PCM1 (pericentriolar material-1 protein), a protein involved in ciliogenesis.36 Further evidence implicating the BBS genes in the generation of both cilia and flagella was obtained using a comparative genomics approach that subtracted the non-flagellated proteome of Arabidopsis from the shared proteome of the ciliated/ flagellated organisms Chlamydomonas and human.37 Thus, Li and colleagues37 identified BBS5, which localizes to basal bodies in mouse and C. elegans and is necessary for ciliary development. BBS4 (15q22.3-q23) was identified using positional cloning several years ago, although the function of the encoded protein was unclear until recently.38 Kim et al39 showed that BBS4 acts as an adaptor to recruit PCM1 to centrosomal satellites and pathogenic mutations in BBS4 result in PCM1 mislocalization, loss of microtubule anchoring at the centrosome, defects in cytokinesis and apoptosis. Mice lacking the BBS4 protein recapitulate the major components of the human phenotype, including obesity and retinal degeneration, and male Bbs4-null mice do not form spermatozoa flagella.40 However, BBS4 KO mice do develop both motile and primary cilia, demonstrating that BBS4 may be required for cilia formation only in a cell- and developmental stage-specific manner.40 As BBS homologues in C. elegans are expressed exclusively in ciliated neurons and contain regulatory elements for RFX, a transcription factor that modulates the expression of genes associated with ciliogenesis and intraflagellar transport, it is plausible that the obesity phenotype in BBS is due to a failure of formation or function of ciliated hypothalamic neurons. Albright’s hereditary osteodystrophy Albright’s hereditary osteodystrophy (AHO) is an autosomal dominant disorder due to germline mutations in GNAS1 which encodes for a-subunit of the stimulatory G protein (Gsa). Maternal transmission of GNAS1 mutations leads to AHO (short stature, obesity, round facies, brachydactyly and ectopic soft tissue ossification) plus resistance to several hormones (e.g. parathyroid hormone) that activate Gs in their target tissues (pseudohypoparathyroidism type IA), while paternal transmission leads only to the AHO phenotype (pseudopseudohypoparathyroidism).41 Thus, GNAS1 is imprinted in a tissue-specific manner, being expressed primarily from the maternal allele in some tissues and biallelically expressed in most other tissues; thus multi-hormone
  • 9. Genetic and hereditary aspects of childhood obesity 367 resistance occurs only when Gsa mutations are inherited maternally.42 Some sporadic cases occur in which patients with a phenotype similar to AHO have a deletion of chromosome 2q37. Fragile X syndrome Fragile X syndrome is characterized by moderate to severe mental retardation, macro- orchidism, large ears, macrocephaly, prominent jaw (mandibular prognathism), and high-pitched jocular speech. In 1991, the molecular cloning of the fragile X locus revealed unstable expansions of a CGG trinucleotide repeat located in the FMR1 (fragile X mental retardation) gene.43 The CGG repeat is polymorphic in the normal population, with alleles of 6 to about 50 CGGs. Large expansions of the repeat (from 230 to O1000 CGGs) are seen in affected patients, with moderate expansions (from 60 to about 200 CGGs) that are unmethylated found in normal transmitting males and in the majority of clinically normal carrier females. Although the exact function of FMRP is not known, it may play a role in the regulation of transport, stability or translation of some messenger RNAs.44 Borjeson–Forssman–Lehmann syndrome Borjeson, Forssman and Lehmann described a syndrome characterized by moderate to severe mental retardation, epilepsy, hypogonadism, and obesity with marked gynaecomastia. Mutations in a novel, widely expressed zinc-finger gene plant homeodomain (PHD)-like finger (PHF6) have been identified in affected families45, although the functional properties of this protein remain unclear. Cohen syndrome Cohen syndrome is an autosomal recessive disorder characterized by mental retardation, microcephaly, characteristic facial features and progressive retinochoroidal dystrophy that is over-represented in the Finnish population, although cases have been reported worldwide.46 The genetic locus for Cohen syndrome was mapped to chromosome 8q, and a novel gene, COH1, in this locus was shown to carry mutations in many Cohen’s syndrome patients from different ethnic groups.47 ¨ Alstrom syndrome ¨ Alstrom syndrome is a homogeneous autosomal recessive disorder that is characterized by childhood obesity associated with hyperinsulinaemia, chronic hyperglycaemia and neurosensory deficits.48 Subsets of affected individuals present with additional features such as dilated cardiomyopathy, hepatic dysfunction, hypothyroidism, male hypogonadism, short stature and mild to moderate develop- mental delay.49 Mutations in a single gene, ALMS1, have been found to be responsible for all cases of Alstrom syndrome so far characterized.50 The ALMS1 ¨ protein has no signal sequences or transmembrane regions, suggesting an intracellular localization.
  • 10. 368 I. S. Farooqi OBESITY SYNDROMES DUE TO CHROMOSOMAL REARRANGEMENTS Prader–Willi syndrome The Prader–Willi syndrome (PWS) is characterized by diminished fetal activity, hypotonia, mental retardation, short stature, hypogonadotropic hypogonadism and obesity, and is the most common syndromal cause of human obesity with an estimated prevalence of about one in 25 000 births and a population prevalence of one in 50 000.51 The syndrome is caused by lack of the paternal segment 15q11.2-q12, either through deletion of the paternal ’critical’ segment (75%) or through loss of the entire paternal chromosome 15 with presence of two maternal homologues (uniparental maternal disomy) in approximately 22% of patients. Deletions, which account for 70–80% of cases, can be visualized by standard prometaphase banding examination, and parental differences in DNA methylation allow for the diagnosis of the remainder of cases of maternal uniparental disomy where cytogenetic examinations yield normal results.52 Within the 4.5 Mb PWS region in 15q11-q13, where there is a lack of expression of paternally imprinted genes, several candidate genes have been studied and their expression shown to be absent in the brains of PWS patients. These include necdin and small nuclear ribonucleoprotein polypeptide N (SNRPN). More recent reports have suggested that other non-expressed genes may include the ring zinc finger 127 polypeptide gene, the MAGE-like 2 gene and the Prader–Willi critical region 1 gene; however, the precise role of these genes and the mechanisms by which they lead to a pleiotropic obesity syndrome remain elusive.51 One suggested mediator of the obesity phenotype in PWS patients is the enteric hormone ghrelin, which is implicated in the regulation of meal-time hunger in rodents and humans and is also a potent stimulator of growth hormone secretion. Several groups have shown that children and adults with PWS have fasting plasma ghrelin levels that are 4.5-fold higher in PWS subjects than in equally obese controls and thus may be implicated in the pathogenesis of hyperphagia in these patients.53,54 Sim-1 A girl has been reported with hyperphagia and early-onset obesity and a balanced translocation between 1p22.1 and 6q16.2, which would be predicted to disrupt the SIM-1 gene on 6q. The Drosophila single-minded (sim) gene is a regulator of neurogenesis, and in the mouse Sim-1 is expressed in the developing central nervous system, is essential for formation of the supraoptic and paraventricular (PVN) nuclei which express the melanocortin-4 receptor; mice heterozygous for loss-of-function mutations in Sim-1 are obese.55 A number of patients with obesity, hypotonia and developmental delay in association with interstitial chromosome 6q deletions have been described56, although whether this syndrome can be attributed to SIM-1 is unclear. WAGR The WAGR syndrome (Wilms tumour, anorexia, ambiguous genitalia and mental retardation) is one of the best-studied contiguous gene syndromes associated with chromosomal deletions at 11p13, the location of the WT1 gene.57 Some patients with
  • 11. Genetic and hereditary aspects of childhood obesity 369 Table 1. Assessment of the obese child/adult. History Age of onset—use of growth charts and family photographs. Early onset (!5 years of age) suggests a genetic cause Duration of obesity—short history suggests endocrine or central cause A history of damage to the CNS (e.g. infection, trauma, haemorrhage, radiation therapy, seizures) suggests hypothalamic obesity with or without pituitary growth hormone deficiency or pituitary hypothyroidism. A history of morning headaches, vomiting, visual disturbances, and excessive urination or drinking also suggests that the obesity may be caused by a tumour or mass in the hypothalamus A history of dry skin, constipation, intolerance to cold, or fatigue suggests hypothyroidism. Mood disturbance and central obesity suggests Cushing’s syndrome. Frequent infections and fatigue may suggest ACTH deficiency due to POMC mutations Hyperphagia—often denied, but sympathetic approach needed, and specific questions such as waking at night to eat, demanding food very soon after a meal suggest hyperphagia. If severe, especially in children, suggests a genetic cause for obesity Developmental delay—milestones, educational history, behavioural disorders. Consider craniophar- yngeoma or structural causes (often relatively short history) and genetic causes Visual impairment and deafness can suggest genetic causes Onset and tempo of pubertal development—onset can be early or delayed in children and adolescents. Primary hypogonadotropic hypogonadism or hypogenitalism associated with some genetic disorders Family history—consanguineous relationships, other children affected, family photographs useful. Severity may differ due to environmental effects Treatment with certain drugs or medications. Glucocorticoids, sulfonylureas, MAOIs, oral contraceptives, risperidone, clozapine Examination Document weight and height compared to normal centiles. Calculate BMI and WHR (in adults). In children, obtain parental heights and weights where possible Head circumference if clinically suggestive Short stature or a reduced rate of linear growth in a child with obesity suggests the possibility of growth hormone deficiency, hypothyroidism, cortisol excess, pseudohypoparathyroidism, or a genetic syndrome such as Prader–Willi syndrome Obese children and adolescents are often tall (on the upper centiles); however, accelerated linear growth (height sds O2) is a feature of MC4R deficiency Body fat distribution—central distribution with purple striae suggests Cushing’s syndrome. Selective fat deposition (60%) a feature of leptin and leptin receptor deficiency Dysmorphic features or skeletal dysplasia Hair colour—red hair (if not familial) may suggest mutations in POMC in white Caucasians Pubertal development/secondary sexual characteristics. Most obese adolescents grow at a normal or excessive rate and enter puberty at the appropriate age; many mature more quickly than children with normal weight, and bone age commonly is advanced. In contrast, growth rate and pubertal development are diminished or delayed in growth hormone deficiency, hypothyroidism, cortisol excess, and a variety of genetic syndromes. Conversely, growth rate and pubertal development are accelerated in precocious puberty and in some girls with PCOS Acanthosis nigricans Valgus deformities in severe childhood obesity Investigations Fasting and 2-hour post glucose and insulin levels. Proinsulin if PC-1 deficiency considered Fasting lipid panel for detection of dyslipidaemia Thyroid function tests Serum leptin if indicated Karyotype (continued on next page)
  • 12. 370 I. S. Farooqi Table 1 (continued) DNA for molecular diagnosis Bone age Growth hormone (GH) secretion and function tests, when indicated Assessment of reproductive hormones, when indicated Serum calcium, phosphorus, and parathyroid hormone levels to evaluate for suspected pseudohypopar- athyroidism MRI scan of the brain with focus on the hypothalamus and pituitary, when clinically indicated ACTH, adrenocorticotropic hormone; POMC, pro-opiomelanocortin; MAOI, monoamine oxidase inhibitor; BMI, body mass index; WHR, waist to hip circumference ratio; MC4R, melanocortin-4 receptor; PC-1, prohormone convertase-1. WAGR syndrome and obesity have been reported with deletions of chromosome 11p14-p12.58 SUMMARY Obesity is a complex phenotype, and the assessment of obese patients should be directed at screening for potentially treatable endocrine conditions and identifying genetic conditions so that appropriate genetic counselling—and in some cases treatment—can be instituted (Table 1). Classically, patients affected by these obesity syndromes have been identified as a result of their association with mental retardation, dysmorphic features and/or other developmental abnormalities. For the purposes of History, family history, examination Suspect syndromal obesity ? No yes Suspect endocrine disorder Suspect genetic syndrome No Yes Karyotype, methylation studies Common obesity (see Figure 4) consider : cushing's, hypothyroidism GH deficiency Endocrine testing Neuroimaging Figure 3. Algorithm for the assessment of an obese child/adult.
  • 13. OBESITY WITH DEVELOPMENTAL DELAY Yes No Karyotype, FISH/methylation studies Photophobia/nystagmus yes No Positive Negative Prader–Willi syndrome Alström’s syndrome Fragile X syndrome Dysmorphia/skeletal abnormalities Retinitis, pigmentosa/retinal dystrophy yes No Ulnar mammary syndrome Yes No Genetic and hereditary aspects of childhood obesity 371 Simpson Golabi–Behmel type 2 Bardet–Biedl syndrome Short in stature Polydactyly Recessive Dominant Hypogonadism in males Yes No Renal abnormalities Leptin level AHO BFL syndrome Cohen syndrome Wilson–Turner syndrome Characteristic facial features MC4R deficiency Microcephaly PC1 deficiency Absent Present Congenital leptin deficiency Consider: hypogonadotrophic hypogonadism Leptinreceptor frequent infections, POMC central hypothyroidism MC4R Figure 4. Diagnostic algorithm in monogenic childhood obesity syndromes. BFL, Borjeson–Forssman–Lehmann syndrome; AHO, Albright’s hereditary osteodystrophy; MC4R, melanocortin-4 receptor; PC-1, prohormone convertase-1; POMC, pro-opiomelanocortin.
  • 14. 372 I. S. Farooqi clinical assessment, it remains useful to categorize the genetic obesity syndromes as those with and without associated developmental delay (Figures 3 and 4). More recently several new monogenic disorders, resulting from disruption of the leptin–melanocortin signalling pathway, have been identified. In these disorders, obesity itself is often the predominant presenting feature, although often accompanied by characteristic patterns of neuroendocrine dysfunction. REFERENCES *1. Barsh GS, Farooqi IS & O’Rahilly S. Genetics of body-weight regulation. Nature 2000; 404: 644–651. 2. Maes HH, Neale MC & Eaves LJ. Genetic and environmental factors in relative body weight and human adiposity. Behavior Genetics 1997; 27: 325–351. 3. Bouchard C & Tremblay A. Genetic effects in human energy expenditure components. International Journal of Obesity 1990; 14(49–55): 55–58. (discussion 55–8). 4. Comuzzie AG. The emerging pattern of the genetic contribution to human obesity. Best Practice and Research. Clinical Endocrinology and Metabolism 2002; 16: 611–621. 5. Cummings DE & Schwartz MW. Genetics and pathophysiology of human obesity. Annual Review of Medicine 2003; 54: 453–471. 6. Friedman JM & Halaas JL. Leptin and the regulation of body weight in mammals. Nature 1998; 395: 763– 770. *7. Schwartz MW, Woods SC, Porte Jr. D, Seeley RJ & Baskin DG. Central nervous system control of food intake. Nature 2000; 404: 661–671. 8. Coll AP, Farooqi IS, Challis BG et al. Proopiomelanocortin and energy balance: insights from human and murine genetics. Journal of Clinical Endocrinology and Metabolism 2004; 89: 2557–2562. 9. Zigman JM & Elmquist JK. Minireview: from anorexia to obesity—the yin and yang of body weight control. Endocrinology 2003; 144: 3749–3756. * 10. Ahima RS, Prabakaran D, Mantzoros C et al. Role of leptin in the neuroendocrine response to fasting. Nature 1996; 382: 250–252. 11. Flier JS. Clinical review 94: what’s in a name? In search of leptin’s physiologic role. Journal of Clinical Endocrinology and Metabolism 1998; 83: 1407–1413. * 12. Montague CT, Farooqi IS, Whitehead JP et al. Congenital leptin deficiency is associated with severe early- onset obesity in humans. Nature 1997; 387: 903–908. * 13. Farooqi IS, Matarese G, Lord GM et al. Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. Journal of Clinical Investigation 2002; 110: 1093–1103. 14. Strobel A, Issad T, Camoin L et al. A leptin missense mutation associated with hypogonadism and morbid obesity. Nature Genetics 1998; 18: 213–215. 15. Ozata M, Ozdemir IC & Licinio J. Human leptin deficiency caused by a missense mutation: multiple endocrine defects, decreased sympathetic tone, and immune system dysfunction indicate new targets for leptin action, greater central than peripheral resistance to the effects of leptin, and spontaneous correction of leptin-mediated defects. Journal of Clinical Endocrinology and Metabolism 1999; 84: 3686– 3695. 16. Licinio J, Caglayan S, Ozata M et al. Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults. Proceedings of the National Academy of Sciences of United States of America 2004; 101: 4531–4536. 17. Farooqi IS, Jebb SA, Langmack G et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. New England Journal of Medicine 1999; 341: 879–884. 18. Flier JS, Harris M & Hollenberg AN. Leptin, nutrition, and the thyroid: the why, the wherefore, and the wiring. Journal of Clinical Investigation 2000; 105: 859–861. 19. Lord GM, Matarese G, Howard JK et al. Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature 1998; 394: 897–901.
  • 15. Genetic and hereditary aspects of childhood obesity 373 20. Clement K, Vaisse C, Lahlou N et al. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 1998; 392: 398–401. * 21. Krude H & Gruters A. Implications of proopiomelanocortin (POMC) mutations in humans: the POMC deficiency syndrome. Trends in Endocrinology and Metabolism 2000; 11: 15–22. 22. Krude H, Biebermann H, Schnabel D et al. Obesity due to proopiomelanocortin deficiency: three new cases and treatment trials with thyroid hormone and ACTH4-10. Journal of Clinical Endocrinology and Metabolism 2003; 88: 4633–4640. 23. Krude H, Biebermann H, Luck W et al. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nature Genetics 1998; 19: 155–157. 24. Challis BG, Pritchard LE, Creemers JW et al. A missense mutation disrupting a dibasic prohormone processing site in pro-opiomelanocortin (POMC) increases susceptibility to early-onset obesity through a novel molecular mechanism. Human Molecular Genetics 2002; 11: 1997–2004. 25. Yeo GS, Farooqi IS, Aminian S et al. A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nature Genetics 1998; 20: 111–112. 26. Vaisse C, Clement K, Guy-Grand B et al. A frameshift mutation in human MC4R is associated with a dominant form of obesity. Nature Genetics 1998; 20: 113–114. * 27. Farooqi IS, Keogh JM, Yeo GS et al. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. New England Journal of Medicine 2003; 348: 1085–1095. 28. Jackson RS, Creemers JW, Ohagi S et al. Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nature Genetics 1997; 16: 303–306. 29. Jackson RS, Creemers JW, Farooqi IS et al. Small-intestinal dysfunction accompanies the complex endocrinopathy of human proprotein convertase 1 deficiency. Journal of Clinical Investigation 2003; 112: 1550–1560. 30. O’Rahilly S, Farooqi IS, Yeo GS et al. Minireview: human obesity-lessons from monogenic disorders. Endocrinology 2003; 144: 3757–3764. 31. Katsanis NAS, Badano JL, Eichers ER et al. Triallelic inheritance in Bardet–Biedl syndrome, a Mendelian recessive disorder. Science 2001; 293: 2256–2259. 32. Katsanis N. The oligogenic properties of Bardet–Biedl syndrome. Human Molecular Genetics 2004; 13 Spec No. 1: R65–R71. 33. Mykytyn KND, Searby CC, Shastri M et al. Identification of the gene (BBS1) most commonly involved in Bardet–Biedl syndrome, a complex human obesity syndrome. Nature Genetics 2002; 31: 435–438. 34. Katsanis N, Beales PL, Woods MO et al. Mutations in MKKS cause obesity, retinal dystrophy and renal malformations associated with Bardet–Biedl syndrome. Nature Genetics 2000; 26: 67–70. 35. Badano JL, Ansley SJ, Leitch CC et al. Identification of a novel Bardet–Biedl syndrome protein, BBS7, that shares structural features with BBS1 and BBS2. American Journal of Human Genetics 2003; 72: 650–658. 36. Ansley SJ, Badano JL, Blacque OE et al. Basal body dysfunction is a likely cause of pleiotropic Bardet–Biedl syndrome. Nature 2003; 425: 628–633. 37. Li JB, Gerdes JM, Haycraft CJ et al. Comparative genomics identifies a flagellar and basal body proteome that includes the BBS5 human disease gene. Cell 2004; 117: 541–552. 38. Mykytyn K, Braun T, Carmi R et al. Identification of the gene that, when mutated, causes the human obesity syndrome BBS4. Nature Genetics 2001; 28: 188–191. 39. Kim JC, Badano JL, Sibold S et al. The Bardet–Biedl protein BBS4 targets cargo to the pericentriolar region and is required for microtubule anchoring and cell cycle progression. Nature Genetics 2004; 36: 462–470. 40. Mykytyn K, Mullins RF, Andrews M et al. Bardet–Biedl syndrome type 4 (BBS4)-null mice implicate Bbs4 in flagella formation but not global cilia assembly. Proceedings of the National Academy of Sciences of United States of America 2004; 101: 8664–8669. 41. Weinstein LS, Chen M & Liu J. Gs[alpha] mutations and imprinting defects in human disease. Annales of the New York Academy of Sciences 2002; 968: 173–197. 42. Weinstein LS, Yu S & Liu J. Analysis of genomic imprinting of Gs alpha gene. Methods in Enzymology 2002; 344: 369–383. 43. Jin P & Warren ST. New insights into fragile X syndrome: from molecules to neurobehaviors. Trends in Biochemical Science 2003; 28: 152–158. 44. Hagerman PJ & Hagerman RJ. The fragile-X premutation: a maturing perspective. American Journal of Human Genetics 2004; 74: 805–816.
  • 16. 374 I. S. Farooqi 45. Lower KM, Turner G, Kerr BA et al. Mutations in PHF6 are associated with Borjeson–Forssman– Lehmann syndrome. Nature Genetics 2002; 32: 661–665. 46. Cohen Jr. MM, Hall BD, Smith DW et al. A new syndrome with hypotonia, obesity, mental deficiency, and facial, oral, ocular, and limb anomalies. Journal of Pediatrics 1973; 83: 280–284. 47. Chandler KE, Kidd A, Al-Gazali L et al. Diagnostic criteria, clinical characteristics, and natural history of Cohen syndrome. Journal of Medical Genetics 2003; 40: 233–241. 48. Russell-Eggitt IM, Clayton PT, Coffey R et al. Alstrom syndrome. Report of 22 cases and literature review. Ophthalmology 1998; 105: 1274–1280. 49. Michaud JL, Heon E, Guilbert F et al. Natural history of Alstrom syndrome in early childhood: onset with dilated cardiomyopathy. Journal of Pediatrics 1996; 128: 225–229. 50. Collin GB, Marshall JD, Ikeda A et al. Mutations in ALMS1 cause obesity, type 2 diabetes and neurosensory degeneration in Alstrom syndrome. Nature Genetics 2002; 31: 74–78. * 51. Goldstone AP. Prader–Willi syndrome: advances in genetics, pathophysiology and treatment. Trends in Endocrinology and Metabolism 2004; 15: 12–20. 52. Butler M. Prader–Willi syndrome: current understanding of cause and diagnosis. American Journal of Medical Genetics 35: 319– 1990; 35: 319–332. 53. Haqq AM, Farooqi IS, O’Rahilly S et al. Serum ghrelin levels are inversely correlated with body mass index, age, and insulin concentrations in normal children and are markedly increased in Prader–Willi syndrome. Journal of Clinical Endocrinology and Metabolism 2003; 88: 174–178. 54. Cummings DE, Clement K, Purnell JQ et al. Elevated plasma ghrelin levels in Prader Willi syndrome. Nature Medicine 2002; 8: 643–644. 55. Michaud JL, Boucher F, Melnyk A et al. Sim1 haploinsufficiency causes hyperphagia, obesity and reduction of the paraventricular nucleus of the hypothalamus. Human Molecular Genetics 2001; 10: 1465–1473. 56. Faivre L, Cormier-Daire V, Lapierre JM et al. Deletion of the SIM1 gene [6q16.2] in a patient with a Prader–Willi-like phenotype. Journal of Medical Genetics 2002; 39: 594–596. 57. Rose EA, Glaser T, Jones C et al. Complete physical map of the WAGR region of 11p13 localizes a candidate Wilms’ tumor gene. Cell 1990; 60: 495–508. 58. Gul D, Ogur G, Tunca Y & Ozcan O. Third case of WAGR syndrome with severe obesity and constitutional deletion of chromosome [11][p12p14]. American Journal of Medical Genetics 2002; 107: 70–71.