Best Practice & Research Clinical Endocrinology & Metabolism 25 (2011) 207–220

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16

Genetics of obesity and overgrowth syndromes

Matthew A. Sabin, FRACP, PhD, Dr. a,*, George A. Werther, FRACP, MD,Professor a, Wieland Kiess, MD, Professor b

aMurdoch Childrens Research Institute, Royal Children’s Hospital & University of Melbourne, Melbourne, AustraliabHospital for Children and Adolescents, Department of Women and Child Health, University Hospitals, University of Leipzig, Germany

Keywords:ObesityOvergrowthGeneticSyndromesStature

* Corresponding author. Department of EndocrinVictoria 3052, Australia. Tel.: þ61 3 9345 5951; fax

E-mail address: matt.sabin@rch.org.au (M.A. Sa

1521-690X/$ – see front matter � 2010 Elsevier Ltdoi:10.1016/j.beem.2010.09.010

Childhood overweight and obesity is highly prevalent withinsociety. In the majority of individuals, weight gain is the result ofexposure to an ‘obesogenic’ environment, superimposed ona background of genetic susceptibility brought about by evolu-tionary adaptation. These individuals tend to be tall in childhoodwith a normal final adult height, as opposed to those who have anunderlying 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 beextremely problematic and yet it is imperative that cliniciansremain alert, as identification of a genetic diagnosis has majorimplications for the individual, family and potential offspring.Alongside this, the recognition of new genetic mutations in thisarea is furthering our knowledge on the important mechanismsthat regulate childhood growth and body composition. This reviewdescribes the genetic syndromes associated with obesity andovergrowth.

� 2010 Elsevier Ltd. All rights reserved.

Introduction

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

ology and Diabetes, Royal Children’s Hospital, Flemington Road, Parkville,: þ61 3 9347 7763.bin).

d. All rights reserved.

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

The last 50 years has also seen the emergence of obesity in adult and paediatric populations, withthe 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 theirpropensity 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 inWesternised countries, it has probably become the commonest reason for referral of children tospecialist services for apparent ‘tall stature and overgrowth’.

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

Genetic variation in the determination of body composition

While final adult height has a strong genetic basis, there is evidence that the regulation of bodyweight and composition also has a high heritability,4 with estimates for the latter being approximately40–70%.5 Numerous genes have been identified through genome wide association studies (GWAS) andcandidate gene approaches that appear to be associated, either directly or indirectly, with the regu-lation of body weight.6 It is likely that, through a process of natural selection, these genes have becomemore prevalent due to the evolutionary advantage that they offer by promoting energy storage tosurvive periods of food deprivation. Within our obesogenic environment, however, these geneticsusceptibility traits are now associated with an increased risk of obesity and associated metabolicdiseases, such as Type 2 diabetes.

The majority of genes identified in monogenic cases of obesity appear to be involved in the centralregulation of energy intake. In this regard, the most strongly replicated candidate gene has been themelanocortin 4 receptor, suggested to be responsible for up to 6% of cases of severe, early-onsetobesity7 and described in more detail below, but also likely contributing to population variations inbody fat, adipose tissue distribution, somemetabolic traits and childhoodweight gain.8 Genes involvedwith energy utilization have also been implicated in common obesity, with replicated associationsshown for genes encoding b-adrenergic receptors 2 and 3, hormone-sensitive lipase, and mitochon-drial uncoupling proteins 1, 2, and 3.9 The FTO gene is another example of a key gene that appears to beresponsible for population-wide variations in body weight and composition,10 and represents just oneof many genes identified in recent times.11 This is a rapidly progressing field of research, in terms ofboth the identification of new genes and the role that they play in both adult and early-onset weightgain.12–14 The challenge now, however, is to develop specific studies aimed at investigating how thesegenes interact with differing environmental exposures.15

A more complete description of population-based genetics in regards to body weight regulation isbeyond the scope of this text.

Pleiotropic obesity syndromes

Several conditions have obesity as a central component of their clinical phenotype. Thesesyndromes are usually associatedwith 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, BardetBiedl syndrome, cases with deletions of 6q16, 1p36, 2q37 and 9q34, maternal uniparental disomy ofchromosome 14, fragile X syndrome and Börjeson–Forssman–Lehman syndrome.16 A full description of

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these conditions, where obesity comprises just one aspect of a much wider phenotype, is summarisedin Table 1.

Monogenic obesity syndromes

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

Leptin deficiency and leptin receptor mutations

Leptin is a 16 kDa protein, discovered in 1994,17 that is primarily produced from white adipocytesand is involved in energy homeostasis through the regulation of energy intake and expenditure. Theleptin gene is located at 7q31.3. Mutations in both the leptin gene18 (OMIM#164160) and the receptor19

(OMIM#601007) lead to severe, early-onset obesity with associated uncontrollable hyperphagia.Linear growth is normal in childhood but puberty is often delayed, due to associated hypogonado-trophic hypogonadism, leading to a reduction in final adult height. In 1999, Farooqi et al. demonstrateda role for recombinant leptin therapy in leptin-deficient patients.20 Both conditions are exceptionallyrare and represent only a very small minority of patients with severe, early-onset obesity.

Melanocortin 4 Receptor (MC4R) mutations

The melanocortin 4 receptor is centrally involved in the hypothalamic regulation of satiety, and isencoded for by a gene located at 18q22. Heterozygous and homozygous mutations in MC4R areassociated with early-onset obesity, with the most appropriate descriptor for the mode of inheritancebeing co-dominance with modulation of expressivity and penetrance of the phenotype.21 Hyperphagiais apparent within the first year and, as well as increased fat mass, affected subjects also exhibitincreases in lean body mass and bone density (giving them an appearance of being ‘big boned’).Affected individuals have accelerated linear growth in childhood.

POMC/Prohormone convertase 1

Pro-opiomelanocortin (POMC) is a precursor peptide, coded for by a gene located at 2p23.3, whichundergoes extensive, tissue-specific, post-translational processing. Protein products include ACTH, b- andg-lipotropin, corticotrophin-like intermediate peptide, b-endorphin, and a-, b- and g-melanocyte stim-ulating hormone (MSH). aMSH plays a specific role in the arcuate nucleus of the hypothalamus in theregulation of satiety, as well as stimulating the production of melanin. Individuals with complete POMCdeficiency (OMIM#609734) present early in life with hypocortisolaemia, pale skin and red hair and, withphysiological replacement with glucocorticoids, later marked hyperphagia and obesity.21 POMC hap-loinsufficiency is associated with an increased risk of obesity but has not been described in associationwith severe early-onset obesity. This is in contrast with specific sequence variants in certain melano-cortin peptides (such as b-MSH) which have been identified in some severely obese young children.21

Prohormone convertase 1 (PC1) is involved in the post-translational processing of POMC andcompound heterozygotes for PC1 mutations (OMIM#600955) exhibit severe early-onset obesity inassociation with hypogonadotrophic hypogonadism, postprandial hypoglycaemia, hypocortisolaemia,and to a lesser degree small intestinal dysfunction.22, 23 This phenotype likely represents the widerphysiological role of PC1 in the post-translational processing of proinsulin and proglucagon, as well asPOMC. Finally, common nonsynonymous variants in PC1 also appear to confer a risk of obesity ata population level.24

Other monogenic causes of severe, early-onset obesity

Brain-derived neurotrophic factor (BDNF), as well as a tyrosine kinase receptor that mediates itseffects (called tropomysin-related kinase B (TrkB)), are important in the development, survival anddifferentiation of neurons. They appear important in several processes including memory formation.

Table 1Pleiotropic obesity syndromes.

Syndrome OMIM # Genetic basis Major clinical features

Alstrom 203800 Autosomal recessiveALMS1 gene located at 2p13

� Blindness (progressive cone-rod dystrophy)� Sensorineural hearing loss� Childhood obesity & type2 diabetes mellitus

� Dilated cardiomyopathy(in approx 70%)

� Other - renal failure, pulmonary, hepatic,and urologic dysfunction are often observed,and systemic fibrosis develops with age

Pseudo-hypoparathyroidism

103580 20q13.2 � Short stature� Obesity� Round facies� Subcutaneous ossifications� Brachydactyly & skeletal anomalies� PTH and multiple hormone resistancein those with types 1A and 1C

612462 Imprinted gene612463 Types 1A and 1C, as well as

pseudopseudohypo-parathyroidism, predominantlyhave obesity in their phenotype

Carpenter 20100 Autosomal recessiveRAB23 gene located at 6p11

� Craniosynostosis� Polysyndactyly� Obesity� Cardiac defects

MOMO 157980 Not known as incidenceapproximates 1 in100 million births

� Macrosomia� Obesity� Macrocephaly� Ocular abnormalities (retinalcoloboma and nystagmus)

Rubinstein-Taybi 180849 Autosomal dominantCREBBP (16p13.3) andEP300 genes (22q13.2)

� Short stature� Moderate to severe intellectualdisability

� Distinctive facial features� Broad thumbs and first toes� Other – eye abnormalities, heart andkidney defects, dental problems, and obesity

Prader-Willi 176270 15q11–13Imprinted sequence

� Hypotonia� Hyperphagia and obesity� Intellectual disability� Short stature,� Hypogonadotropic hypogonadism� Small hands and feet

Bardet–Biedl 209900 Autosomal recessive14 genes identified coding forBBS proteins involved inciliary action

� Obesity� Retinitis Pigmentosa� Polydactyly� Intellectual disability� Hypogonadism� Renal failure

Fragile X 300624 Expansion of CCG repeats onthe X chromosome leading toa failure to express FMR1gene (Xq27.3)

� Intellectual disability� Prominent lower jaw� Large protruding ears� Macroorchidism� Joint hyperextensibility� Can be associated with childhood height/weight overgrowth although final heightusually lower than normal

Börjeson–Forssman–Lehman

301900 X-linked recessivePHF6 gene located at Xq26.3

� Severe intellectual disability� Epilepsy� Hypogonadism� Obesity� Swelling of subcutaneoustissue of face

� Narrow palpebral fissures� Large but not deformed ears

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Interestingly, they also appear involved in the regulation of food intake25 and mutations in the genesencoding these proteins have been described in children with severe early-onset obesity.26,27

With this overlap between body weight regulation and neuronal development, there is now anemerging field of research aimed at the identification of genetic mutations which may be responsiblefor severe obesity in childrenwith associated intellectual disability and/or developmental delay. This isa significant problem28 and, while there is a strong underlying environmental component in many, theidentification of mutations (such as those recently described on chromosome 1629) which may, at leastin part, be responsible for both problems is intriguing.

Tall stature and overgrowth syndromes

Commonly, the clinical evaluation of tall stature in children and adolescents leads to the diagnosis ofa familial or weight-related cause. Other endocrine causes, such as precocious puberty, thyrotoxicosis, ora growth hormone secreting pituitary tumor are fortunately rare.30,31 There is a wide array of distinctgenetic syndromes however which either have overgrowth and/or tall stature as a central feature intheir phenotype, and new syndromes are constantly being recognised.32 In the majority of cases, thespecific underlying molecular mechanisms that underpin the unregulated growth are not clear, andalthough it is possible that alterations in insulin-like growth factor (IGF) signalling represent a commonlink between the different syndromes,33 a clearmolecular classification system still evades us. A recentlyproposed classification system for the evaluation of tall stature and overgrowth is shown in Figure 1.

The following descriptions focus mainly on the underlying genetic causes and a more completedescription of the phenotypic features associated with these conditions is found elsewhere.32 Table 2summarises the genetic basis, and major phenotypic features, for the more common overgrowthsyndromes.

Klinefelter syndrome

Klinefelter syndrome is the most common disorder of sex chromosome aneuploidy and, witha prevalence of 1.09–1.72 cases per 1000 births, represents a small but significant number of boys

Figure 1. Diagnostic flow chart for the differential diagnosis of tall stature and overgrowth syndromes. CCA: Congenital ContracturalArachnodactyly; CNP: C-type natriuretic peptide. Reproduced from Visser et al., Paediatric Endocrinology Reviews 2009.

Table 2Major genetic overgrowth syndromes.

Syndrome OMIM # Genetic basis Major clinical features

Klinefelter syndrome Supplementary Xchromosome(s)

� Tall stature� Androgen deficiency and pubertal delay� Gynaecomastia� Variable cognitive/behavioural problemswith difficulties in language, problemsolving and planning

� Risk of germ cell tumors, breast cancerand osteoporosis

Marfan syndrome 154700 FBN-1 gene at 15q21.1 � Tall stature� Arachnodactyly� Scoliosis� Hyperextensible joints� Ectopia lentis and other ocular problems� Risk of aortic root dilatation and valveprolapse

Homocystinuria 236200 CBS gene at 21q22.3 � Similar to Marfan syndrome butintellectualdisability, and predisposition tothromboembolic events

Beckwith–Wiedemannsyndrome

130650 Dysregulation of imprintedgenes at 11p15.5

� Neonatal macrosomia � postnatalovergrowth with organomegaly

� Hyperinsulinaemic hypoglycaemia� Abdominal wall defects� Macroglossia� Midface hypoplasia� Anterior linear earlobe creases and helicalear pits

� Hemihypertrophy� Increased risk of embryonal tumors

Simpson–Golabi–Behmel syndrome

312870 GPC3 gene at Xq26.2 � Pre- and postnatal overgrowth, withorganomegaly

� Tall stature� Characteristic dysmorphic features� Supernumerary nipples� Hand anomalies� Speech delay� Cardiac anomalies� Risk of embryonal cancers

Sotos syndrome 117550 NSD-1 gene at 5q35.2–35.3 � Generalised pre- and postnatal overgrowth� ‘Triangular-shaped’ facies� Neonatal hypotonia and feeding problems� Macrocephaly� Intellectual disability

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presenting with tall stature. It is caused by the addition of one or more supplementary X chromosome(s) to the usual allocation of two sex chromosomes, resulting in 47,XXY or, less commonly, 48,XXXY;48,XXYY; 49,XXXXY or 46,XY/47, XXY mosaicism.32,34 Affected boys usually exhibit tall stature inassociation with features of androgen deficiency and pubertal delay. The addition of an extra Xchromosome(s) often results from non-disjunction occurring either during meiotic divisions inparental gametogenesis or in early mitotic divisions.32 In a study of 39 47,XXY males, 53% of this non-disjunction appeared attributable to paternal meiosis I errors, 34% to maternal meiosis I errors, 9% tomaternal meiosis II errors and 3% to a post-zygotic mitotic error.35 How the supernumerary X chro-mosome leads to the Klinefelter phenotype is unclear, although longer CAG repeats of the androgenreceptor36 and/or an overdosage of the short stature homeobox (SHOX) gene37 are both plausibleexplanations. Most studies report little influence governed by parent of origin for the supplementary Xchromosome,32 although a paternally-derived supernumerary X chromosome may be associated withlonger CAG repeats of the androgen receptor and slightly later onset of puberty.38 Furthermore,

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increased paternal age appears more likely in cases where the supplementary X chromosome isinherited from the father, while maternal age is also significantly higher in the maternally derivedcases due to a meiotic I error.39

Marfan syndrome and related disorders

Marfan syndrome (OMIM#154700) is a connective tissue disorder arising from pathogenic muta-tions in the fibrillin (FBN-1) gene, located at 15q21.1. Mode of inheritance is autosomal dominant,although 25% of cases arise from de novomutations. Themajority aremissensemutations located in thecalcium-binding epidermal growth factor (cb-EGF) or transforming growth factor b (TGF-b) bindingprotein like domains.32 FBN-1 encodes a large extracellular matrix protein which is responsible for theassembly and elasticity of connective tissue through polymerisation intomicrofibrils. This is thought tolargely explain the connective tissue features of the condition seen in the skin, cardiovascular systemand eye, while an interactionwith latent TGF-b binding protein-1 (TGFb-1) may be responsible, at leastin part, for some of the skeletal aspects of the condition including tall stature.32

FBN-1 gene mutations, as well as missense mutations of the TGFb receptor subtypes 1 and 2, havebeen reported in other related conditions including ectopia lentis, Shprintzen–Goldberg craniosy-nostosis, familial thoracic aortic aneurysms and dissections (TADD), and Weill–Marchesani syndromeas well as those with Marfan syndrome type II (also known as Loeys–Dietz syndrome) who displayskeletal as well as cardiovascular Marfanoid complications but who lack ocular involvement.40,41

Beal’s syndrome (Congenital Contractural Arachnodactyly) and Lujan–Fryns syndrome deservespecific mention as they have overlapping features with Marfan syndrome, but are due to mutationsaffecting the fibrillin 2 (FBN-2) gene located at 5q23.3 in the former, andmutations in either theMED12gene or UPF3B gene on the X chromosome in the latter.32

Homocystinuria

Homocystinuria (OMIM#236200) shares similar phenotypic features with Marfan syndrome, withthe addition of central nervous systemmanifestations including intellectual disability and an increasedrisk of psychiatric disorders. It is inherited in an autosomal recessive manner and is due tomutations inthe cystathionine b-synthase (CBS) gene located at 21q22.3. This deficiency leads to abnormalities innormal amino acidmetabolism, with elevated plasma levels of total homocysteine andmethionine anddecreased levels of cystathionine and cysteine. Elevated concentrations of homocysteine have beenshown to interact with FBN-1 (the gene affected in Marfan syndrome), perhaps explaining the over-lapping features of these 2 conditions.32 Ninety-two different disease-associated mutations have beenidentified in the CBS gene with most being missense mutations. The two most frequently encounteredare the pyridoxine-responsive I278T and the pyridoxine-nonresponsive G307S mutations, withmutations due to deaminations of methylcytosines representing 53% of all point substitutions in thecoding region of the CBS gene.42

Beckwith–Wiedemann syndrome

Beckwith–Wiedemann syndrome (BWS; OMIM#130650) is characterised by neonatal macrosomiaand/or postnatal overgrowth, abdominal wall defects and macroglossia, as well as other featuresincluding midface hypoplasia, anterior linear earlobe creases, hemihypertrophy, and embryonaltumors.32 Clinical variability may be due to somatic mosaicism.43 It has been estimated to occur inapproximately 1 in 13700 newborns,44 although these data are over 30 years old and there may also beethnic differences in frequency. Approximately 85% of patients with BWS have sporadic mutations,with the rest showing an autosomal inherited pattern with preferential maternal transmission.32

The genetic basis of BWS is complex and is based on defects in imprinting at 11p15.5. Mostmammalian autosomal genes are expressed from a balance of both maternally and paternal copies ofa chromosome pair. Some genes however are expressed monoallelically in a ‘parent of origin’ specificmanner, in a process termed genomic imprinting. This is primarily controlled by epigenetic mecha-nisms (which are extrinsic to changes in primary nucleotide sequence), including DNA methylation,

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histone modification, and noncoding RNAs. The BWS phenotype results from dysregulation ofimprinted genes at 11p15.5 by several different mechanisms including specific duplications, trans-locations/inversions, microdeletions, DNA methylation changes at the imprinting centres, uniparentaldisomy (where both copies of the gene are inherited from one parent), and mutations in an imprintedgene called CDKN1C. The imprinted genes at 11p15.5 are divided into two domains. Domain 1 containsthe genes IGF-II (a paternally expressed fetal growth factor) and H19 (a maternally expressed genecontaining noncoding RNA). Domain 2 contains several imprinted genes, including maternallyexpressed KCNQ1 and CDKN1C, as well as paternally expressed KCNQ1OT1. In essence, a disturbance ofthis differentially regulated gene-expression profile is responsible for BWS, as shown in Figure 2.32,43

Figure 2. (a) Schematic representation of the chromosome 11p15.5 imprinted region that is functionally divided into two domains.In the distal domain 1 are two imprinted genes, H19 and insulin-like growth factor 2 (1GF2). IGF2 is a paternally expressed fetalgrowth factor and H19 is a noncoding RNA. The H19-associated imprinting center (IC1) is usually methylated on the paternalchromosome and unmethylated on the maternal chromosome. Normally, the H19 gene is expressed from the maternal allele andIGF2 from the paternal allele. Domain 2 contains several imprinted genes, including KCNQ1, KCNQ1OT1, and CDKN1C. A differentiallymethylated region (IC2) contains the promoter for KCNQ1OT1, a paternally expressed noncoding transcript that regulates in cis theexpression of the maternally expressed imprinted genes in domain 2. Two examples of imprinting alterations leading to Beckwith–Wiedemann syndrome (BWS) are shown in (b1) and (b2). (b1) IC1 gain of methylation in BWS is found inapproximately 5% ofpatients and leads to biallelic expression of IGF2. (b2) Loss of methylation at the KvDMR differentially methylated region (IC2) isfound in 50% of BWS patients. This epigenetic alteration leads to reduced expression of CDKN1C. Red corresponds to preferentialmaternal allelic expression, blue corresponds to preferential paternal allelic expression. Filled rectangles indicate expressed genesand empty rectangles indicate non-expressed gene. Lollipops correspond to methylated sites. Reproduced fromWeksberg et al, 2010by permission from Nature Publishing Group.

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BWS patients generally exhibit a length andweight at birth of>75th centile, with higher percentilesachieved through childhood and adolescence,45 and although there is sparse evidence in the literatureto support this claim, final height is usually within the normal range.43 Further discussion of the finergenetic control of BWS, as well as clinical findings, genotype/phenotype correlations, genetic testing,and management of individuals with this condition can be found in a recent review by Weksberg,Shuman and Beckwith.43

Simpson–Golabi–Behmel syndrome

Simpson–Golabi–Behmel syndrome (SGBS; OMIM#312870) is caused by defects of the glypican 3(GPC3) gene at Xq26.2.32 Glypicans are a family of heparan sulfate proteoglycans that are bound to thecell surface by a glycosyl–phosphatidylinositol anchor. They appear to play a critical role in the regu-lation of morphogenesis.46 There is some evidence that non-functional GPC3 may lead to increasedIGF2 signalling, although this is not certain and other defects in cellular signalling, such as thoseinvolving Wnt or fibroblast growth factors, may be responsible for the clinical features.32 It is associ-ated with pre- and postnatal overgrowth, as well as an array of clinical features including characteristicdysmorphic facies, supernumerary nipples, hand anomolies and speech delay in the majority.32 Thereis also an increased risk of associated cardiac anomalies,47 as well as an increased risk of developingembryonal cancers.48 Phenotype is highly variable, ranging from very mild cases in female carriers toan early lethal form in affected boys.32 GPC3 abnormalities include microdeletions which affecta variable number of exons, deletions of the whole gene, and intragenic point mutations, althoughphenotypic expression correlates poorly with genotype.32 Final adult height is usually >97th centile.49

Interestingly, the dysregulated growth seen in SGBS has been utilised to study factors associatedwith adipogenesis and lipogenesis, using in-vitro cultures of preadipocytes from a patient with thiscondition.50

Sotos syndrome

Sotos syndrome (OMIM#117550) is probably the likeliest syndrome to be considered in the clinicalevaluation of a child with a possible overgrowth syndrome. It is caused by haploinsufficiency in thenuclear receptor binding SET domain protein-1 (NSD-1; location 5q35.2–35.3) in approximately 60–90% of cases, although genome wide SNP array analysis suggest that other sites (including pathogeniccopy number variants on chromosomes 10, 14, 15 and the X chromosome) may also be responsible insome individuals.51 It is inherited in an autosomal dominant manner although the majority of affectedindividuals exhibit de novo mutations.32 Incidence is estimated at 1 in 15,000.52 The main cause ofmutations include intragenic point mutations, whole-gene microdeletions and exon deletions of NSD-1, which occur in approximately 85%, 10% and 5% of cases (although there is wide ethnic variation inthese proportions).32

Clinical features include characteristic ‘triangular-shaped’ facies, alongside generalised overgrowthand macrocephaly, as well as intellectual disability, neonatal hypotonia and feeding problems in thenewborn period. Accelerated growth is apparent from early childhood, with almost universaladvancement in bone age, although final adult height is not affected.53

Weaver syndrome

In 1974, Weaver et al. described a syndrome of accelerated growth and osseous maturation, unusualcraniofacial appearance with a hoarse and low-pitched cry, hypertonia, and camptodactyly(OMIM#277590). Clinical features overlap with Sotos syndrome, although there appear to be distinctdifferences in facial appearances, risk of malignancy (elevated in Sotos, but not in Weaver), and degreeof dental maturation (advanced in Sotos and not thought to be affected in Weaver syndrome).54 Thegenetic basis of Weaver syndrome has not been identified, although some have reported NSD-1mutations in Weaver syndrome patients,55,56 highlighting the high degree of overlap between the twosyndromes.

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Pallister–Killian syndrome

Pallister–Killian syndrome (OMIM#601803) is a rare, sporadic syndrome caused by tissue-limitedmosaicism of a supernumerary 12p isochromosome.49 A typical facial appearance includes hyper-telorism, epicanthal folds, sparse eyebrows and eyelashes, short nose with a broad nasal bridge, andunusual lips with ‘cupid-bow’ shaped upper lip and pouting lower lip. This is associated with abnormalpigmentary streaks on the skin, intellectual disability and seizures.49 A normal to increased birth lengthand weight is associated with a postnatal deceleration of the former and acceleration of the latter.49

22q13 deletion syndrome

22q13 deletion syndrome (also known as Phelan–McDermid syndrome; OMIM#606232) is asso-ciated with hypotonia, global developmental delay, normal to accelerated growth, absent to severelydelayed speech, autistic behaviour, and minor dysmorphic features. It represents a contiguous genedeletion syndrome, and haploinsufficiency of the SHANK3 gene (a synaptic scaffolding protein) may beresponsible for at least some of the phenotypic features such as autism.57

Bannayan–Riley–Ruvalcaba syndrome

Bannayan–Riley–Ruvalcaba syndrome (OMIM#153480) is an autosomal dominant disorder, causedby haploinsufficiency of the phosphatase and tensin homolog (PTEN) gene at 10q23.31.32 PTEN inhibitsthe PI3Kinase/AKT pathway, an intracellular signalling pathway critically involved in cell proliferationand survival, as well as inhibiting Focal Adhesion Kinase (FAK) which inhibits cell migration. PTENabnormalities are also responsible for approximately 80% of cases of Cowden syndrome (as well as 20%of cases of Proteus syndrome; a condition of asymmetric and disproportionate overgrowth of bodyparts) and cancer surveillance is therefore required in patients with this condition. Diagnostic criteriainclude macrocephaly, hamartomas and lipomas, and penile macules, while other features includeintellectual disability, hypotonia, joint hypermobility and postnatal overgrowth.32 There is, however,growth deceleration during childhood which leads to a normal final adult height.

Neurofibromatosis type 1

Neurofibromatosis type 1 (NF-1; OMIM#162200) is an autosomal dominant condition affectingapproximately 1 in 2500–3000 individuals. It is caused by heterozygous mutations of the NF-1 gene,located at chromosome 17q11.2, with approximately 50% of mutations arising de novo.58 These de novomutations occur more commonly on the paternally-derived chromosome.59 It has been reported tolead to tall stature in around half of affected individuals,60 although previous reports suggest a greaterproportion actually being shorter than expected at the end of childhood growth.61

The protein product, termed neurofibromin, is thought to act as a tumor suppressor or negativeregulator of cellular growth.58

Clinical phenotype in NF-1 is highly variable across affected individuals. Only around 5% of patientshave an entire, or nearly entire, deletion and these patients display a more severe phenotype, withlarge numbers of neurofibromas, a greater likelihood of cognitive deficiency, increased risk of malig-nancy, and wider and more severe connective tissue involvement.58 A detailed description of theclinical phenotype and diagnostic features is beyond the scope of this text.

Aromatase deficiency

Human aromatase deficiency is a very rare syndrome characterised by congenital estrogen defi-ciency. It is caused by loss-of-function mutations in CYP19A1 at 15q21.1 (OMIM#107910). Estrogenplays a critical role in epiphyseal fusion and individuals with this condition exhibit tall stature, delayedbone maturation, osteopenia/osteoporosis and eunuchoid skeletal proportions. Paradoxically, the tallstature seen in this condition appears to exist in the presence of growth hormone deficiency (whichappears common in affected individuals62), highlighting the important role of estrogens in growth.63

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Other syndromes involving early overgrowth

Nevo syndrome (also termed Ehlers–Danlos syndrome type VIA) is a rare autosomal recessivecondition, characterised by increased perinatal length, talipes calcaneovalgus, kyphoscoliosis, gener-alised hypotonia, oedemamatous palms and soles, and spindle shaped fingers.32 It is caused bymutations in the PLOD1 gene on chromosome 1, which is responsible for hydroxylation of lysyl resi-dues in collagen proteins.64 Whether it represents a true overgrowth syndrome is not clear and,although increased length is apparent at birth with some degree of tall stature in infancy and mid-childhood, final adult height data have not been described.32

Perlman syndrome is a rare, autosomal recessive condition characterised by typical facial features(including a full round face, prominent forehead, deep set eyes and a broad depressed nasal bridge)alongside macrosomia, nephromegaly, hypotonia, and cryptorchidism.49 Most affected infants die inthe neonatal period, some with refractory hypoglycaemia due to hyperplasia of the islets of Langer-hans.49 In those few who survive, the growth pattern quickly falls to normal/below-normal ranges(suggesting that this is not a true overgrowth condition),49 and there is usually profound develop-mental delay and a high risk for the development of Wilms tumor.65 The genetic basis for Perlmansyndrome is currently unknown and continues to be the focus of much interest.65

Vascular anomalies may also lead to overgrowth of certain body regions, such as in Klippel–Tre-naunay syndrome (OMIM#149000) and Parkes Weber syndrome (OMIM#608355), although theseprobably do not represent true ‘overgrowth’ syndromes.

Other conditions recently described which may involve overgrowth include overexpression ofNatriuretic Peptide Precursor C and haploinsufficiency of RNF135.32

Genetic issues relating to conception and prenatal screening

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 thelack of long-term growth andmetabolic data from IVF-conceived babies, has also shown that IVF babiesshow 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 increase in finaladult height, and/or an increased cancer risk in these individuals.

Prenatal screening

The majority of children with an underlying genetic predisposition to obesity will not presentprenatally or in the immediate postnatal period,8,68 even with severe monogenic forms such ascongenital leptin deficiency.69 Likewise, not all infants with overgrowth syndromes will have clear-cutexcessive in-utero growth aiding a prenatal diagnosis. Large for gestational age (LGA) fetuses areusually identified incidentally through routine maternity care and detection should lead to suspicionrelating to accuracy of pregnancy dates, and/or the presence of maternal diabetes. In the absence ofthese, and particularly when there are other associated congenital abnormalities, then considerationshould be given to the possibility of an overgrowth syndrome. In these situations, prenatal diagnosismay difficult but certain ultrasonographic techniques and findings may be helpful.65,70,71 Geneticcounselling in some conditions, such as BWS, requires specific expertise with an understanding of theavailable methods for current prenatal genetic testing for this condition.43

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 learntrelating to the important contribution of specific genes, and their coded proteins, in the regulation ofchildhood growth and body composition. While specific treatments for affected individuals may not be

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available, the identification of an underlying genetic condition has major implications for the indi-vidual and their family, and clinicians should remain alert to possible underlying genetic causes whenassessing patients, and particularly children, with these conditions.

Practice points

� Normal or tall stature is seen in the majority of children with environmental, or lifestyle-related, weight gain.

� Short stature in the setting of obesity should alert the clinician to the possibility of anunderlying hormonal or genetic cause, whilst recognising that some genetic conditions suchas MC4R mutations are associated with tall stature.

� Tall stature or overgrowth, particularly when out of keeping with parental height and in thesetting of associated congenital anomalies, may be an indicator for an underlying geneticcause and should lead to appropriate investigation.

Research agenda

� Many different genetic conditions are associated with obesity and overgrowth and a clearerclassification system is urgently required.

� Further work is needed to more fully understand the impact of environmental exposure onunderlying genetic predispositions. This is difficult, and will necessitate in-depth datacollection across large cohorts of individuals, but is critical to better understand whichindividuals are more likely to gain weight and develop associated co-morbidities.

� Furthering our understanding of the genetic and molecular factors that promote andconstrain growth may lead to the future identification of potential therapeutic options.

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