Best Practice & Research Clinical Endocrinology & Metabolism
16Genetics of obesity and overgrowth syndromes
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
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Cited by (38)
A soy-based probiotic drink modulates the microbiota and reduces body weight gain in diet-induced obese mice
2018, Journal of Functional FoodsCitation Excerpt :The etiology of obesity is represented by endogenous and exogenous factors, which can act at the same time or in isolation. These etiological factors contribute to an increase in adiposity that result in serious health conditions (Eid et al., 2017; Sabin, Werther & Kiess, 2011). The intestinal microbiota composition is one of these etiological factors involved in the development of obesity and insulin resistance, as it influences fat storage, energy capture and it can triggers a systemic inflammation as well as metabolic disorders (Zhang et al., 2012).
A 17-year-old boy with Klinefelter syndrome presenting Marfan syndrome-like clinical features of tall stature, scoliosis, arachnodactyly and subluxation of bilateral elbow joints
2018, Taiwanese Journal of Obstetrics and GynecologyInvestigation of tall stature in children: Diagnostic work-up, review of the main causes
2018, Archives de PediatrieIdentification of a novel de novo nonsense mutation of the NSD1 gene in monozygotic twins discordant for Sotos syndrome
2017, Clinica Chimica ActaCitation Excerpt :After puberty, growth in terms of height tends to normalize, but macrocephaly is typical in both children and adults. Despite the well-defined phenotype, it may be difficult to diagnose, particularly for inexperienced pediatricians due to phenotype variability, lack of a molecular genetic tests and an overlap of clinical features with other overgrowth syndromes (e.g., Weaver syndrome, fragile X syndrome, Bannayan-Riley-Ruvalcaba syndrome, Beckwith-Wiedemann syndrome, and Marfan syndrome) [11,12]. There was no biomarker for Sotos syndrome, and the diagnosis is based on clinical and neuroimaging findings.
Can Macrosomia or Large for Gestational Age Be Predictive of Mucopolysaccharidosis Type I, II and VI?
2016, Pediatrics and NeonatologyCitation Excerpt :Congenital overgrowth is defined by a neonatal weight above the 97th percentile.22 The main differential diagnoses are Sotos syndrome (OMIM 117550), Weaver syndrome (WVS, OMIM 277590), Beckwith-Wiedemann syndrome (BWS, OMIM 130650) and Simpson dysmorphia syndrome (SDYS, Simpson-Golabi-Behmel syndrome, SGBS1, OMIM 312870).5,23–26 Sotos syndrome is an autosomal dominant overgrowth syndrome with four major diagnostic criteria: overgrowth with advanced bone age, macrocephaly, characteristic facial appearance, and developmental delay.27
Burden of Growth Hormone Deficiency and Excess in Children
2016, Progress in Molecular Biology and Translational ScienceCitation Excerpt :Therefore, strict monitoring is essential during patient follow-up. Finally, recent knowledge of monogenic disorders associated with obesity and tall stature, constitutes a new therapeutic challenge.56,71 In conclusion, in the presence of clinical symptoms of overgrowth, an adequate clinical, genetic, and molecular diagnosis should be performed, as not only the possible and most appropriate therapeutic management should be evaluated, but also familial genetic counseling, when applicable.