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Genetics of obesity and overgrowth syndromes

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Childhood overweight and obesity is highly prevalent within society. In the majority of individuals, weight gain is the result of exposure to an ‘obesogenic’ environment, superimposed on a background of genetic susceptibility brought about by evolutionary adaptation. These individuals tend to be tall in childhood with a normal final adult height, as opposed to those who have an underlying monogenic cause where short stature is more common (although not universal). Identifying genetic causes of weight gain, or tall stature and overgrowth, within this setting can be extremely problematic and yet it is imperative that clinicians remain alert, as identification of a genetic diagnosis has major implications for the individual, family and potential offspring. Alongside this, the recognition of new genetic mutations in this area is furthering our knowledge on the important mechanisms that regulate childhood growth and body composition. This review describes the genetic syndromes associated with obesity and overgrowth.

Introduction

Human growth is a multi-factorial and complex process, involving physiological interplay between nutritional, endocrine, and metabolic factors, on a wider background of variation in genetic traits and environmental exposure. It would therefore seem counterintuitive to expect that children will grow in a highly predictable manner, and yet this is almost universally the case,1 highlighting that the optimal size of all animal species (including humans) is predominantly under genetic control.2

On a statistical basis as many children have short stature as tall stature, and yet short children are disproportionately referred for investigation. While there may be many reasons for this, it likely reflects the psychosocial pressures on those not attaining average heights. A knock-on effect of this skewed referral practice, has been that the study of tall stature and ‘overgrowth’ has perhaps occurred in a less systematic manner than the study of short stature, for which a clear molecular classification system now exists.3

The last 50 years has also seen the emergence of obesity in adult and paediatric populations, with the latter leading to wider variations in patterns of childhood growth. Children with ‘lifestyle-related’ weight gain tend to be taller throughout childhood than genetic potential would predict, but their propensity to an earlier onset of true puberty fortunately leads to minimal effects on final adult height. Despite this, and with overweight and obesity now affecting as many as 1 in every 3 children in Westernised countries, it has probably become the commonest reason for referral of children to specialist services for apparent ‘tall stature and overgrowth’.

Identifying children with a genetic predisposition to tall stature, obesity and/or overgrowth, from those with more straightforward environmental causes, is a difficult task given the prevalence of overweight and obesity in society. This chapter aims to provide an overview of current knowledge relating to the genetics of each, with an emphasis on identification of children that may benefit from further investigation and genetic screening.

Section snippets

Genetic variation in the determination of body composition

While final adult height has a strong genetic basis, there is evidence that the regulation of body weight and composition also has a high heritability,4 with estimates for the latter being approximately 40–70%.5 Numerous genes have been identified through genome wide association studies (GWAS) and candidate gene approaches that appear to be associated, either directly or indirectly, with the regulation of body weight.6 It is likely that, through a process of natural selection, these genes have

Pleiotropic obesity syndromes

Several conditions have obesity as a central component of their clinical phenotype. These syndromes are usually associated with short stature (although not in all syndromes and not in all cases) and include Alstrom syndrome, Albright’s hereditary osteodystrophy (pseudohypoparathyroidism), Carpenter syndrome, MOMO syndrome, Rubinstein–Taybi syndrome, Prader–Willi syndrome, Bardet Biedl syndrome, cases with deletions of 6q16, 1p36, 2q37 and 9q34, maternal uniparental disomy of chromosome 14,

Monogenic obesity syndromes

There are a number of monogenic conditions known to lead to severe, early-onset obesity. These are described in more detail below.

Tall stature and overgrowth syndromes

Commonly, the clinical evaluation of tall stature in children and adolescents leads to the diagnosis of a familial or weight-related cause. Other endocrine causes, such as precocious puberty, thyrotoxicosis, or a growth hormone secreting pituitary tumor are fortunately rare.*30, 31 There is a wide array of distinct genetic syndromes however which either have overgrowth and/or tall stature as a central feature in their phenotype, and new syndromes are constantly being recognised.32 In the

Artificial conception

In-vitro fertilisation (IVF) is associated with a small, but significant, increased risk of Beckwith–Wiedemann syndrome and other imprinted disorders.66 Interestingly, a recent report highlighting the lack of long-term growth and metabolic data from IVF-conceived babies, has also shown that IVF babies show an increased height in childhood, along with elevated concentrations of IGF-I, IGF-II and free IGF-I.67 Long-term prospective follow-up is now required to see whether this leads to an

Summary

A wide range of genetic conditions are associated with tall stature, obesity and overgrowth. As yet, a unified molecular classification for these conditions is not known although much is being learnt relating to the important contribution of specific genes, and their coded proteins, in the regulation of childhood growth and body composition. While specific treatments for affected individuals may not be available, the identification of an underlying genetic condition has major implications for

References (71)

  • Kring SI, Holst C, Toubro S, et al. Common variants near MC4R in relation to body fat, body fat distribution, metabolic...
  • A.I. Blakemore et al.

    Is obesity our genetic legacy?

    Journal of Clinical Endocrinology & Metabolism

    (2008)
  • Fawcett KA, Barroso I. The genetics of obesity: FTO leads the way. Trends in Genetics....
  • Vimaleswaran KS, Loos RJ. Progress in the genetics of common obesity and type 2 diabetes. Expert Reviews in Molecular...
  • Scherag A, Dina C, Hinney A, et al. Two new loci for body-weight regulation identified in a joint analysis of...
  • Elks CE, Loos RJ, Sharp SJ, et al. Genetic markers of adult obesity risk are associated with greater early infancy...
  • J. Zhao et al.

    The role of obesity-associated loci identified in genome-wide association studies in the determination of pediatric BMI

    Obesity (Silver Spring)

    (2009)
  • N.J. Wareham et al.

    Epidemiological study designs to investigate gene-behavior interactions in the context of human obesity

    Obesity (Silver Spring)

    (2008)
  • A.P. Goldstone et al.

    Genetic obesity syndromes

    Frontiers of Hormone Research

    (2008)
  • Y. Zhang et al.

    Positional cloning of the mouse obese gene and its human homologue

    Nature

    (1994)
  • C.T. Montague et al.

    Congenital leptin deficiency is associated with severe early-onset obesity in humans

    Nature

    (1997)
  • K. Clement et al.

    A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction

    Nature

    (1998)
  • I.S. Farooqi et al.

    Effects of recombinant leptin therapy in a child with congenital leptin deficiency

    The New England Journal of Medicine

    (1999)
  • I.S. Farooqi

    Monogenic human obesity

    Frontiers of Hormone Research

    (2008)
  • R.S. Jackson et al.

    Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene

    Nature Genetics

    (1997)
  • R.S. Jackson et al.

    Small-intestinal dysfunction accompanies the complex endocrinopathy of human proprotein convertase 1 deficiency

    The Journal of Clinical Investigation

    (2003)
  • M. Benzinou et al.

    Common nonsynonymous variants in PCSK1 confer risk of obesity

    Nature Genetics

    (2008)
  • Cordeira JW, Frank L, Sena-Esteves M, et al. Brain-derived neurotrophic factor regulates hedonic feeding by acting on...
  • J. Gray et al.

    Hyperphagia, severe obesity, impaired cognitive function, and hyperactivity associated with functional loss of one copy of the brain-derived neurotrophic factor (BDNF) gene

    Diabetes

    (2006)
  • G.S. Yeo et al.

    A de novo mutation affecting human TrkB associated with severe obesity and developmental delay

    Nature Neuroscience

    (2004)
  • Maiano C. Prevalence and risk factors of overweight and obesity among children and adolescents with intellectual...
  • E.G. Bochukova et al.

    Large, rare chromosomal deletions associated with severe early-onset obesity

    Nature

    (2010)
  • Verge CF, Mowat D. Overgrowth. Archives of Disease in Childhood....
  • J. Dotsch et al.

    Gs alpha mutation at codon 201 in pituitary adenoma causing gigantism in a 6-year-old boy with McCune–Albright syndrome

    Journal of Clinical Endocrinology & Metabolism

    (1996)
  • R. Visser et al.

    Overgrowth syndromes: from classical to new

    Pediatric Endocrinology Reviews

    (2009)
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