Arch Dis Child 2000;83:31–34 31

RECENT ADVANCES Arch Dis Child: first published as 10.1136/adc.83.1.31 on 1 July 2000. Downloaded from

Recent advances in the of severe childhood

I Sadaf Farooqi, Stephen O’Rahilly

Abstract for age and sex, has increased by approx. 40% is becoming a global (to 11% in the 6–11 year age group).4 The ris- epidemic. Twin studies suggest a herit- ing prevalence of obesity can be explained in ability of fat mass, and disorders of energy part by changes in our environment over the balance that arise from genetic defects last 30 years, in particular the unlimited supply have been identified. In the past three of convenient, highly palatable, energy dense years, five single disorders resulting foods, coupled with a lifestyle typified by low in early onset obesity have been charac- physical activity. However, obesity represents terised. The discovery of these genetic the archetypal complex multifactorial disease defects has biological and clinical impli- and arises as a result of behavioural, environ- cations which are greater than the rarity mental, and genetic factors which may influ- of the individual diseases might suggest. ence individual responses to diet and physical (Arch Dis Child 2000;83:31–34) activity.

Keywords: obesity; genetic defect Evidence for a genetic influence Twin studies suggest a heritability of fat mass Childhood obesity is rapidly emerging as a glo- (fraction of the age adjusted phenotypic variance accounted for by genetic factors) of bal epidemic. Its immediate adverse eVects between 40% and 70% with a concordance of include orthopaedic complications, sleep ap- 1 0.7–0.9 between monozygotic twins compared noea, and psychosocial disorders. As obese 56 to 0.35–0.45 between dizygotic twins. While http://adc.bmj.com/ children are more likely to become obese these associations may in part be explained by adults,2 we may expect to see profound public sharing the same childhood environment, a health consequences as a result of the emer- number of studies have described a closer rela- gence in later life of associated co-morbidities tion between the weights of adoptees and their such as non-insulin dependent diabetes melli- biological parents rather than their adoptive tus, ischaemic heart disease, and stroke. The parents.7 These genetic influences are not con- true prevalence of obesity in childhood is diY- fined to the extremes of obesity, but exert their cult to determine as there is as yet no eVect across the whole range of body weight on September 30, 2021 by guest. Protected copyright. internationally accepted definition of patho- and are consistent with a polygenic inheritance logical adiposity in the paediatric age group. A of fat mass. range of methods are available which allow quite accurate measurement of total body fat; WHICH ? however, none of these are widely available A number of families with rare pleiotropic and/or easily applicable to the clinical situation. obesity syndromes have been studied by Body weight is reasonably well correlated with linkage analysis and chromosomal loci for body fat but is also highly correlated with Cohen’s syndrome,8 Alström’s syndrome,9 and height, and children of the same weight but at least four for Bardet–Biedl syndrome10–12 diVerent heights can have widely diVering have been mapped so far, although the precise amounts of adiposity. In adults, BMI (body molecular defects are not yet known. However, 2 University mass index; weight (kg) divided by height recent studies of genetic syndromes of obesity Departments of (m2)) correlates reasonably well with more spe- in rodents have provided several novel insights Medicine and Clinical cific measurements of body fat. In children the Biochemistry, Box 157, into molecules which may be involved in Addenbrooke’s relation between BMI and body fat varies con- energy homoeostasis. The rodent single gene Hospital, Cambridge siderably with age and with pubertal matura- obesities represent complex admixtures of the CB2 2QQ, UK tion. However, useful centile charts relating key mechanisms that are involved in the devel- I S Farooqi BMI to age have now been published in several opment of an obese phenotype, namely an S O’Rahilly countries.3 increase in energy intake, relative decrease in Correspondence to: In the 10 years between the National Health energy expenditure, or preferential partitioning Dr Farooqi and Nutrition Examination Survey of ingested energy to fat storage. In the past two email: (NHANES) II (1976–1980) and NHANES III years we and others have begun to identify [email protected] (1988–1991) the prevalence of overweight in human disorders of energy balance that arise Accepted 5 April 2000 the USA, based on body mass index corrected from genetic defects in these or similar 32 Farooqi, O’Rahilly

molecules. These often result in tion in a splice donor site of the receptor,

morbid obesity in childhood without the devel- which results in loss of the transmembrane and Arch Dis Child: first published as 10.1136/adc.83.1.31 on 1 July 2000. Downloaded from opmental pleiotropic features characteristic of cytoplasmic domains because of exon the recognised syndromes of childhood obesity. skipping.22 There were a number of similarities with the leptin deficient subjects. These sisters Leptin and the were also born of normal birth weight, and The severely obese ob/ob mouse, first described exhibited rapid weight gain in the first few by Ingalls et al in 1950,13 inherits its early onset months of life, with severe hyperphagia and obesity in an autosomal recessive pattern and aggressive behaviour when denied food. Basal weighs three times more than normal mice by temperature and resting metabolic rate were maturity. A decrease in thermogenesis is the normal. In contrast, they had mild growth earliest demonstrable defect; hyperphagia is retardation in early childhood with impaired seen after weaning, followed by the develop- basal and stimulated growth hormone secre- ment of severe obesity caused by the preferen- tion and decreased insulin like growth factor 1 tial deposition of fat. The hyperinsulinaemia, (IGF-1) and IGF-BP3 concentrations. There fasting hyperglycaemia, infertility, thyroid dys- was evidence of hypothalamic hypothyroidism, function, stunted linear growth, and low although as in the leptin deficient subjects, cor- sympathetic tone of ob/ob mice are shared by tisol concentrations were normal and they were another strain of severely obese mice, db/db.In normoglycaemic with mildly raised plasma 1994, Friedman and colleagues cloned and insulins. characterised the ob gene which is expressed Of note, the two Turkish adults with leptin predominantly in white adipose tissue and deficiency and the sisters with mutations in the encodes the 167 amino acid secreted protein, leptin receptor did not undergo pubertal leptin.14 The ob transcript is mutant in both development with biochemical features of strains of ob/ob mice which are leptin deficient hypogonadotropic hypogonadism. In the older as a result. Administration of recombinant lep- of our two patients (a 9 year old girl) it is diY- tin completely reverses their phenotypical cult to confirm hypogonadotropic hypogonad- abnormalities,15–17 but has no eVect in db/db ism as she is clinically prepubertal, but a child mice which harbour a in the cytoplas- with a bone age of 12.5 years would usually mic domain of the leptin receptor,18 abundantly have started to develop some secondary sexual expressed in the hypothalamus. characteristics. While bone age is frequently advanced in obese children, an advance in Human congenital leptin deficiency excess of three years has rarely been reported.23 In man, serum leptin concentrations have been In this instance, advanced bone age could not found, in general, to correlate positively with be attributed to excessive and/or premature indices of obesity.19 We have previously identi- secretion of adrenal or ovarian sex steroids as fied two cousins within a highly consanguine- their plasma concentrations were low and the

ous family of Pakistani origin with severe obes- physiological basis for this is not clear. http://adc.bmj.com/ ity of early onset: an 8 year old girl weighing 86 Morbid obesity was inherited in an auto- kganda2yearoldboyweighing 29 kg.20 These somal recessive pattern in both leptin and lep- children were noted to be severely hyper- tin receptor families and the absence of morbid phagic, constantly demanding food, with an obesity and normal sexual maturation in the intense drive to eat which was never satisfied. heterozygote parents indicates that the lack of They did not exhibit any of the clinical features one normal allele does not greatly aVect weight suggestive of the recognised childhood obesity regulation or neuroendocrine function. syndromes, had a normal karyotype, thyroid, on September 30, 2021 by guest. Protected copyright. and adrenal function, but were hyperinsulinae- POMC and the melanocortin pathway mic and had an advanced bone age. They were The behavioural and neuroendocrine eVects of found to have undetectable concentrations of leptin are thought to be mediated through its serum leptin and were homozygous for a dele- actions at hypothalamic leptin receptors. The tion of a single guanine nucleotide at codon complex neurochemical systems downstream 133 which results in a truncated protein. Both of leptin that regulate appetite and energy sets of parents were heterozygous for this expenditure and integrate nutritional and mutation in keeping with an autosomal reces- circadian information into endocrine re- sive pattern of inheritance. There was no sponses, are being dissected. Pro- evidence of substantial impairment in basal or opiomelanocortin (POMC) is produced by total energy expenditure and body temperature hypothalamic neurones of the arcuate nucleus was consistently normal, indicating that leptin and is sequentially cleaved by prohormone may be less central to the regulation of energy convertases to yield peptides (including á expenditure in humans than in mice, although melanocyte stimulating hormone, áMSH) that subtle defects of energy expenditure are have been shown to play a role in feeding diYcult to measure. behaviour. Forty per cent of POMC neurones Subsequently Strobel and colleagues have in the arcuate nucleus express the mRNA for described a Turkish family in which three the long form of the leptin receptor, and severely obese siblings were found to be leptin POMC expression is regulated positively by deficient because of a missense mutation in the leptin.24 There is clear evidence in rodents that leptin gene.21 Additionally, Clement and col- áMSH, a melanocortin peptide produced from leagues identified three morbidly obese sisters POMC, acts as a suppressor of feeding behav- with very high serum leptin concentrations iour. The recent description of two unrelated who were found to be homozygous for a muta- German subjects with mutations in POMC Genetics of severe childhood obesity 33

associated with isolated adrenocorticotropic rapidly bred out. Similarly POMC deficiency is

hormone (ACTH) deficiency, red hair pigmen- fatal if unrecognised owing to profound Arch Dis Child: first published as 10.1136/adc.83.1.31 on 1 July 2000. Downloaded from tation, hyperphagia, and severe, early onset cortisol deficiency. In contrast MCR4 defi- obesity confirms the importance of POMC ciency appears to cause a relatively “pure” derived peptides in the regulation of body obesity syndrome with no impairment of early weight in humans.25 The hair, skin, and adrenal viability or reproductive function. phenotype of these subjects is readily under- The discovery of these genetic defects has standable on the basis of the known eVects of biological and clinical implications which are POMC derived peptides in these tissues. Given greater than the rarity of the individual diseases the importance of prohormone convertase 1 might suggest. Firstly, at least one disorder, (PC1) in the proteolytic processing of POMC, namely leptin deficiency, is amenable to it is notable that we have reported a single treatment. Such treatment represents the first, patient with severe early onset obesity to have rationally based, hormone replacement therapy compound heterozygote mutations in the gene for any form of human obesity. Secondly, these encoding PC1.26 In addition to obesity, this disorders establish for the first time that human patient had primary amenorrhoea caused by obesity can result from a simple fault in the hypogonadotropic hypogonadism, massive hy- wiring of the circuits concerned with energy perproinsulinaemia, and impaired adrenal homoeostasis without the need to implicate function.27 complex social and environmental factors. We How does the lack of POMC derived ligands hope that this may help to “destigmatise” obes- lead to obesity? Interestingly, one form of ity and validate it as a medical condition melanocortin receptor (MC4R) is highly ex- deserving of sympathetic handling and worthy pressed in areas of the hypothalamus known to of scientific study. Thirdly, they represent pow- be involved in feeding. Mice in which the MC4 erful confirmation that the growing body of receptor has been disrupted by gene targeting data on the molecular circuitry controlling are hyperphagic, becoming severely obese, appetite and energy balance in rodents is hyperinsulinaemic, and exhibiting increased directly relevant to humans, and provides linear growth, but show no evidence of strong support for the benefits of animal reproductive failure or corticosterone excess.28 research. Fourthly, they provide validation of We have recently described a father and son certain key molecules as potential targets for with hyperphagia, severe early onset obesity pharmacological manipulation. Finally, as the and tall stature, with mutations in MC4R.29 loci encompassing these genes have been found Both were heterozygous for a four base pair to be significantly associated with obesity deletion in the region encoding the fifth of related phenotypes in genome wide scans, they seven transmembrane domains, resulting in a provide important candidate genes for exam- truncated protein. Interestingly, both subjects ination in the more common forms of human were tall, in keeping with the increased linear obesity.33 34

growth seen in MC4R knockout mice, but had http://adc.bmj.com/ no other endocrine abnormalities. A French Postscript family described by Vaisse and colleagues with The authors welcome enquires regarding obesity associated with a mutation in MC4R biochemical and genetic studies of patients have no obvious defect in resting energy with severe early onset obesity. The criteria for 30 expenditure. MC4R, therefore, represents the inclusion in these studies is a BMI >4 SD first locus at which mutations are associated above the age related mean3 and an onset of with dominantly inherited morbid obesity in obesity before 10 years of age. man, a finding that is consistent with the on September 30, 2021 by guest. Protected copyright. observation that mice heterozygous for a null 1 Dietz WH. Health consequences of obesity in youth: child- MC4R allele exhibit weight gain intermediate hood predictors of adult disease. Pediatrics 1998:101:518– 25. to that seen in wild type and homozygous 2 Guo SS, Roche AF, Chumlea WC, Gardner JD, Siervogel mutant littermates. An increasing number of RM. The predictive value of childhood body mass index values for overweight at age 35 y. Am J Clin Nutr 1994;59: obese families with MC4R mutations are now 810–19. being described (Gu et al,31 Hinney et al,32 and 3 Cole TJ, Freeman JV, Preece MA. Body mass index reference curves for the UK, 1990. Arch Dis Child 1995;73: our unpublished observations) making it the 25–9. commonest known genetic cause of human 4 Troiano RP, Flegal KM. Overweight children and adolescents: description, epidemiology and demographics. obesity. Pediatrics 1998;101:497–504. 5 Stunkard AJ, Foch TT, Hrubec Z. A twin study of human obesity. JAMA 1986;256:51–4. Conclusions 6 Borjeson M. The aetiology of obesity in children. Acta Pae- In the past three years, five single gene diatr Scand 1976;65:279–87. 7 Stunkard AJ, Sorensen TIA, Hanis C, et al. An adoption disorders resulting in early onset obesity have study of human obesity. N Engl J Med 1986;314:193–6. been characterised. Two of these, leptin recep- 8 Kondo I, Hamabe J, Yamamoto K, Niikawa N. Exclusion mapping of the Cohen syndrome gene from the Prader- tor and PC1, have been restricted to single Willi syndrome locus. Clin Genet 1990;38:422–6. families. Three families with mutations in 9 Russell-Eggitt IM, Clayton PT, CoVey R, Kriss A, Taylor DS, Taylor JF. Alstrom syndrome. Report of 22 cases and POMC or leptin have been described. Muta- literature review. Ophthalmology 1998;105:1274–80. tions in the MC4R appear to be a more 10 Beales PL, Warner AM, Hitman GA, Thakker R, Flinter FA. Bardet-Biedl syndrome: a molecular and phenotypic common cause of obesity, perhaps because study of 18 families. J Med Genet 1997;34:92–8. heterozygotes are clinically aVected and there- 11 Bruford EA, Riise R, Teague PW, et al. Linkage mapping in 29 Bardet-Biedl syndrome families confirms loci in fore only one mutational event is required. chromosomal regions 11q13, 15q22.3-q23, and 16q21. Additionally, mutations in leptin, the leptin Genomics 1997;41:93–9. receptor, and PCI adversely aVect reproduc- 12 Young TL, Penney L, Woods MO, et al. A fifth locus for Bardet-Biedl syndrome maps to chromosome 2q31. Am J tion and therefore would be expected to be Hum Genet 1999;64:900–4. 34 Farooqi, O’Rahilly

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