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Syndromes with Obesity 

Syndromes with Obesity
Syndromes with Obesity

Philip L. Beales

and Raoul Hennekam

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A recent edition of the Winter-Baraitser Dysmorphology Database (version 1.0.8; London Medical Databases, London, UK) listed 154 syndromes with generalized obesity, of which at least 100 also featured mental retardation (see Appendix for full list). Some of the better-characterized conditions have been discussed in other chapters; however, there are a few worthy of mention here. For most, either there is little known of their pathogenesis or the underlying genes have yet to be identified. This chapter will categorize these according to their likely genetic etiology.

Autosomal Obesity Syndromes

Biemond 2 Syndrome

Biemond syndrome type 2 (BS2) is regarded as having an autosomal recessive pattern of inheritance and closely resembles Bardet-Biedl syndrome (BBS). Classically, it comprises mental retardation, coloboma, obesity, Polydactyly, hypogonadism, hydrocephalus, and facial dysostosis (Figure 13–1). Since the original description of BS2 (Biemond 1934), there have been many case reports misdiagnosed as BS2 owing to the considerable variability in presentation (see Verloes et al. 1997 for redefinition of many of these cases). Several cases of BBS with additional coloboma have been described but can be distinguished from BS2 by the presence of a retinal dystrophy. Indeed, in the original family described by Biemond, neither of the index cases had obesity but were of short stature and had preaxial Polydactyly (Cavallacci 1939; Klein and Ammann 1969; Prosperi and Ciuffi 1969; Schachat and Maumenee 1982). Of all the subsequently reported cases, all had postaxial Polydactyly and most have obesity. Verloes et al. (1997) proposed a new nosology for BS2 and suggested that purported cases may be divided into (1) BS2 with incidental coloboma; (2) BS2 sensu stricto, a recessively inherited syndrome of hypogenitalism, short stature, coloboma, and preaxial Polydactyly without obesity, from the original report; (3) a “new” dominantly inherited form of colobomatous microphthalmia occasionally associated with obesity, hypogonadism, and mental retardation, with (4) a cytogenetically proven Rubinstein-Taybi syndrome in one case; (5) an unclassifiable, early, lethal familial syndrome resembling Buntinx-Majewski syndrome; and (6) a “new” coloboma-zygodactyly-clefting syndrome. The latter two syndromes may represent chromosomal anomalies.

Figure 13–1. Biemond syndrome type 2 (courtesy of Prof. Alain Verloes, Paris, France).

Figure 13–1. Biemond syndrome type 2 (courtesy of Prof. Alain Verloes, Paris, France).

Carpenter Syndrome

Carpenter syndrome, or acrocephalopolysyndactyly type II, is characterized by preaxial Polydactyly of the feet in conjunction with craniosynostosis and generalized or truncal obesity in older patients (Carpenter 1909; Temtamy 1966). In the hands, there is often brachydactyly and syndactyly. There are often dental anomalies, with retention of milk teeth and hypodontia. It is mentioned here as it is one of the differential diagnoses to consider with Polydactyly, and it is likely that the three sibs reported as cases of Laurence-Moon-Biedl-Bardet syndrome with cardiac defects by McLoughlin et al. (1964) have Carpenter syndrome.

Mutations in RAB23 were recently identified in Carpenter syndrome (Jenkins et al. 2007). Rab proteins are small guanosine triphosphatases (GTPases) of the Ras superfamily involved in the regulation of intracellular membrane trafficking. RAB23 is an essential negative regulator of the Sonic hedgehog (Shh) pathway. The related protein Indian hedgehog is important for bone development, but this is the first time a Shh pathway member has been associated with obesity.

Edwards Syndrome: Pigmentary Retinopathy, Hypogonadism, Glucose Intolerance

Not to be confused with the trisomy disorder bearing the same name, the condition described here must be considered in the differential diagnosis of BBS and Alström syndrome. Although the cardinal features were described as mental retardation, retinitis pigmentosa, and deafness, most patients had hypogonadism and generalized obesity (Edwards et al. 1976). The deafness is sensorineural and seems to develop toward the end of the first decade of life. The visual problem develops earlier, and blindness becomes apparent in childhood. Other features include acanthosis nigricans and gynecomastia but not Polydactyly. The other important feature is an abnormal glucose tolerance with hyperinsulinism.

A second report, by Boor et al. (1993), described two affected siblings with similar features. They also had a slightly coarse face, brachydactyly of the hands and feet, cerebral atrophy, and cataracts. The affected girl had polycystic ovaries. Impaired insulin receptor binding was demonstrated.

It remains to be tested if these conditions are allelic variants of ALMS1 (Alström syndrome) or any of the BBS genes.

Kabuki Syndrome

Kabuki syndrome patients have short stature and a characteristic face, with variable developmental delay and occasionally autism (Ho and Eaves 1997).

The facial appearance is reminiscent of the makeup worn by Kabuki theater actors and includes an everted lateral one-third of the lower lid, notched eyebrows, long palpebral fissures, and luxuriant eyelashes (Figure 13–2). There is usually a broad nasal tip, prominent earlobes, and a cleft or high-arched palate. The fifth finger is short, and there is persistence of the fetal finger pads. Lower lip pits have been frequently reported (Franceschini et al. 1993; Kokitsu-Nakata et al. 1999; Makita et al. 1999;Shotelersuk et al. 2002). Breast development in female infants and features of ectodermal dysplasia are common (Lerone et al. 1997). Dental anomalies (Mhanni et al. 1999; Matsune et al. 2001), hip dislocation, nail hypoplasia, anal abnormalities, and renal defects have all been described. Cardiac defects occur in about 50% of cases (Hughes and Davies 1994; Digilio et al. 2001). A range of renal anomalies have been reported (Iwama et al. 1987; Ewart-Toland et al. 1998). Epilepsy occurs in 10%-40% of cases (Ogawa et al. 2003; Oksanen et al. 2004). With age, the notched eyebrows tend to fill in, and patients remain short and develop obesity, with relatively large heads and tapering fingers (Shalev et al. 2004). A causal gene has not yet been identified.

Macrosomia, Obesity, Macrocephaly, and Ocular Abnormalities

In 1993, Moretti-Ferreira et al. reported an unrelated boy and girl with similar clinical features of truncal obesity, mental retardation, and ocular abnormalities. The latter included retinal coloboma and nystagmus. One of these cases developed bilateral glaucoma at 8 years of age. The facial features were relatively nonspecific, with hypertelorism, downslanting palpebral fissures, a prominent forehead, and a broad nasal root. A possible third case was reported by Zannolli et al. (2000), describing a 5-year-old girl with mild mental retardation, macrocephaly, severe obesity, ocular abnormalities (right optic disk coloboma and left choroidal coloboma), and recurvation of the femur. However, in contrast to the previous two cases, this latter child had short stature. This condition is often referred to in the literature by its acronym, MOMO.

Rubinstein-Taybi Syndrome

A central characteristic of Rubinstein-Taybi syndrome (RTS) is the presence of broad thumbs, although to make a diagnosis the characteristic craniofacial abnormalities should be present. These are microcephaly, antimongoloid eye slant, hypertelorism, long eyelashes, mild ptosis, posteriorly rotated ears, and a convex nose with the columella protruding below the alae nasi on lateral view (Figure 13–3). The thumbs and halluces are broad or occasionally bifid, with medial deviation. The tips of the other fingers may be spatulate. Many patients have central obesity (Figure 13–3). Up to one-third may have a cardiac anomaly (usually ventricular septal defect, atrial septal defect, or persistent ductal arteriosis) (Stevens and Bhakta 1995). Neural and developmental tumors are common (Miller and Rubinstein 1995; Ihara et al. 1999). Ocular features have been described, including congenital glaucoma, cataracts, corneal abnormalities, colobomas, lacrimal duct obstruction, and retinal abnormalities with an abnormal visual evoked potential (van Genderen et al. 2000).

Figure 13–3. Rubinstein-Taybi syndrome.

Figure 13–3. Rubinstein-Taybi syndrome.

Most cases of RTS appear sporadic. A number of translocations and submicroscopic deletions involving 16p13.3 have been reported (Imaizumi and Kuroki 1991; Lacombe et al. 1992; Tommerup et al. 1992;Breuning et al. 1993; Hennekam et al. 1993; Wallerstein et al. 1997; Bartsch et al. 1999). Later point mutations in CBP were found (Petrij et al. 1995). Deletions have been localized to the CBP gene in around 10% of cases (Blough et al. 2000; Petrij et al. 2000). The CBP gene encodes a protein that binds to the phosphorylated form of the cyclic adenosine monophosphate-response element binding protein (CREB) transcription factor and leads to increased expression of genes containing cAMP-responsive elements.


Holder et al. (2000) reported a girl with early-onset obesity and a de novo balanced translocation between lp22.1 and 6q16.2. Subsequent mapping of the translocation breakpoints revealed disruption to the SIM1 gene on 6q, culminating in separation of the 5' promoter region and the basic helix-loop-helix (bHLH) domain from the 3' period, aryl hydrocarbon receptor, Single-minded (PAS) and putative transcriptional regulation domains. SIM1 is the human homologue of the Drosophila transcription factor Single-minded, containing bHLH and PAS domains. Dimerization of bHLH-PAS proteins is a prerequisite for nuclear translocation, and the specificity of dimerization is partly facilitated by the PAS domains. Thus, separation as in this translocation is likely to lead to a loss of function. The authors postulated that haploinsufficiency of SIM1, possibly acting upstream or downstream of the melanocortin 4 receptor (MC4R) in the paraventricular nucleus (PVN), was responsible for severe obesity in their patient. Supporting evidence for the role of SIM1 in obesity came from the report of Faivre et al. (2002), in which a boy with a Prader-Willi-like phenotype carried a deletion of chromosome 6q16.1-q21, resulting in deletion of SIM1.

Siml is expressed in the developing kidney and central nervous system and is essential for formation of the supraoptic nucleus and PVN of the hypothalamus (Michaud et al. 2000). Previous neuroanatomical and pharmacological studies have implicated the PVN in the regulation of body weight: PVN neurons express MC4R and appear to be physiological targets of α-melanocyte-stimulating hormone (α-MSH), which inhibits food intake (Harris et al. 2001; Kishi et al. 2003; Liu et al. 2003) (see Chapter 6 for details). Sim 1 homozygous mice die perinatally, but haploinsufficiency, as in the case described by Holder et al. (2000), causes early-onset obesity, increased linear growth, hyperleptinemia, and hyperinsulinemia (Michaud et al. 2001). Hyperphagia appears to be the cause of the weight gain without any discernible impact on thermogenesis, in contrast with MC4R- and leptin-dencient mice.

Tyrosine Receptor Kinase B

Recent evidence implicates the brain-derived neurotrophic factor (BDNF) and its receptor, tyrosine receptor kinase B (TrkB, encoded by NTRK2), in the regulation of appetite and energy balance (Kernie et al. 2000). Mice haploin-sufficient for Bdnf or with a brain-specific conditional deletion of Bdnf develop hyperphagia and obesity (Rios et al. 2001; Xu et al. 2003).

It has been shown that BDNF is expressed at high levels in the ventromedial hypothalamus, where its expression is regulated by nutritional state and by MC4R signaling (Xu et al. 2003). Similar to MC4R mutants, mice hypomorphic (~25% expression levels) for the BDNF receptor TrkB showed hyperphagia and excessive weight gain on high-fat diets. Furthermore, BDNF infusion into the brain suppresses the hyperphagia and excessive weight gain observed in MC4R-dencient mice, indicating that TrkB may be a downstream effector of MC4R signaling by which it controls energy balance. BDNF and NTRK2 are therefore good candidates for early-onset obesity. Yeo et al. (2004) screened both these genes in a boy with early-onset obesity, hyperphagia, developmental delay, specific impairment of short-term memory, stereotyped behaviors, and impaired nociception, a phenotype closely resembling the Ntrk2 mouse mutant, revealing a heterozygous de novo missense mutation in NTRK2. Further analysis of cells expressing the highly conserved but mutated tyrosine (Y722C) residue showed markedly impaired BDNF-stimulated mitogen-activated protein kinase phosphorylation, as predicted. The extended phenotype in the index case, which encompasses developmental and neurological deficits, is in keeping with the widespread expression of TrkB throughout the central nervous system, where a role has been proposed in the promotion of neuronal survival and differentiation and the regulation of synaptic function. The nociception deficit in this patient is reminiscent of mutations in the related receptor TrkA, responsible for congenital insensitivity to pain with anhydrosis (Indo et al. 1996).

ULnar-Mammary Syndrome

Ulnar-mammary syndrome (UMS), also known as Pallister or Schinzel syndrome, is characterized by ulnar ray defects with missing digits or postaxial Polydactyly, anal and genitourinary abnormalities, and hypoplasia of the apocrine glands and breasts (Pallister et al. 1976; Schinzel et al. 1987). These are usually accompanied by generalized obesity. Males may have a small penis, delayed puberty, and reduced fertility. Females can have small or absent breasts with hypoplastic nipples. Anal atresia, absent kidneys, uterine malformations, and laryngeal stenosis have been reported. Reduced body odor and axillary sweating are reported in both sexes.

Inheritance is autosomal dominant with variable penetrance. In Schinzel's original family (four affected males in three successive generations), in addition to the major features there were delayed growth and onset of puberty, diminished sexual activity, and pyloric, anal, and subglottic stenoses (Schinzel et al. 1987). Several cases of congenital laryngeal web have described dental anomalies in the form of ectopic upper canines (Gay et al. 1981; Franceschini et al. 1992). The accompanying limb abnormality is quite variable, as illustrated in the report by Gonzalez et al. (1976) of an affected mother and son. Both the mother and the son had postaxial Polydactyly of one hand, and the son had unilateral oligodactyly with absent ulna and hypoplasia of the ipsilateral shoulder girdle. The mother also was lacking one kidney.

In a large Utah family with UMS, Bamshad et al. (1995) identified 33 affected individuals and by linkage analysis demonstrated that the UMS gene mapped to 12q23-q24.1. The same group later discovered that mutations in the TBX3 gene are responsible for UMS (Bamshad et al. 1997). In one family, they demonstrated heterozygosity for a 1 bp deletion that caused a frame shift and premature termination of the TBX3 gene product.

The cause of obesity in UMS is uncertain, and no study has attempted to define this aspect, although Sasaki et al. (2002) performed endocrine studies on two affected brothers. Gonadotropin-releasing hormone stimulation tests indicated low to low-normal gonadotropin responses, and human chorionic gonadotropin stimulation tests showed normal testosterone responses. Supplementation with testosterone was effective, suggesting that mild gonadotropin deficiency may be the primary cause for abnormal external genitalia in UMS.

X-Linked Obesity

There is a relatively large group of X-linked disorders, each of which is associated with learning impairment/mental retardation. Many of these may eventually prove to be allelic variants of common genes; therefore, we will concentrate on those conditions for which the evidence points to separate entities. Börjeson-Forssman-Lehmann syndrome is reviewed in Chapter 10.

Ahmad Syndrome

Ahmad et al. (1999) reported a large Pakistani family in which 10 males displayed mental retardation, obesity, hypogonadism, and tapering fingers. Linkage studies mapped the gene to the pericentromeric area Xp11.3-Xq23, encompassing the Wilson-Turner locus. The authors pointed out similarities to Wilson-Turner syndrome but remarked on the absence of gynecomastia in their affected family members.

Atkin-Flaitz Syndrome

Atkin et al. (1985) described a large multigenerational family with 11 moderately to severely retarded males and three mildly retarded females. The affected males were obese, of short stature, and macrocephalic, with large square foreheads, prominent supra-orbital ridges, hyperteloric down-slanting palpebral fissures, a broad nasal tip, and a thick lower lip (Atkin et al. 1985). They had a prominent gap between the upper central incisors and a prominent midline groove of the tongue, but the unaffected brothers also had the central tooth gap.

Clark-Baraitser Syndrome

Clinically, the two brothers first described by Clark and Baraitser (1987) and later the two cousins by Baraitser et al. (1995) each had features similar to Afkin-Flaitz syndrome (above) except they were either tall or of normal height and there was no hypertelorism. Subsequently, four further cases (all male) have been reported, suggesting a minimal set of diagnostic features: obesity, macrocephaly, large forehead, prominent supra-orbital ridges, broad nasal tip, prominent/thick lower lip, gap between upper central incisors, large ears, and behavior problems (de Pina-Neto and de Molfetta 1998; Mendicino et al. 2005; Tabolacci et al. 2005). Interestingly, in the brothers described by Tabolacci et al. (2005), a subtelomeric 22q13 deletion was found and ascribed to germinal mosaicism. The authors of this report suggested that, despite the evidence for X-linked inheritance, each case of Clark-Baraitser syndrome should be screened for a 22q13 deletion.

Fragile X Syndrome

Fragile X syndrome is a common cause of X-linked mental retardation. It is caused by an unstable expansion of a triplet repeat (CGG) in the FMR1 gene, but the exact role of its protein is not yet known. Males (and occasionally females) present with characteristic features: learning difficulties/mental retardation, macrocephaly, large ears with fleshy lobes, a large jaw, and macroorchidism. However, a subphenotype resembling Prader-Willi syndrome has been reported with extreme obesity, a round face, small and broad hands/feet, and regional skin hyperpigmentation (Figure 13–4) (Fryns et al. 1987; de Vries et al. 1993).

Figure 13–4. Fragile X syndrome and obesity (courtesy of Prof. Jean-Pierre Fryns, Leuven, Belgium).

Figure 13–4. Fragile X syndrome and obesity (courtesy of Prof. Jean-Pierre Fryns, Leuven, Belgium).

Mental Retardation, Epilepsy, Hypogonadism, Microcephaly, and Obesity

A syndrome of mental retardation, epilepsy, hypogonadism, microcephaly, and obesity (MEHMO) was described in a large, presumably X-linked family by Steinmuller et al. (1998), where the affected males presented with prenatal-onset microcephaly, short stature, obesity, cryptorchidism, and hypogenitalism. Seizures developed later in infancy, accompanied by severe cognitive impairment and developmental delay. The index case had talipes equinovaras and developed diabetes in the first year. The authors described a characteristic face: chubby with a narrowed forehead, simple ears, large lobes, and a downturned mouth. There was facial telangiectasia. The hands and feet were edematous, with tapering fingers. A fatty liver and thymic hypoplasia were found in one case, who died at 10 months. Using this three-generation family, they were able to map a putative gene locus to Xp21.1–22.13.

A second family was reported in which two brothers presented with microcephaly, obesity, spasticity, hypogenitalism, nystagmus, and difficult behavior (Delozier-Blanchet et al. 1989). They had very similar facial features to the cases of Steinmuller et al. (1998), and the authors postulated that the condition may be a consequence of a metabolic disturbance (DeLozier-Blanchet et al. 1999). One of these brothers died at 4 years of age. In 2002, Leshinsky-Silver et al. reported an infant with probable MEHMO and evidence of a mitochondrial electron transport chain defect. Electron microscopy revealed abnormal and enlarged mitochondria and lipid storage.

Shashi Syndrome

A large four-generation North American family with X-linked mental retardation and characteristic facial dysmorphism segregating only with males was described by Shashi et al. (2000). The clinical features in the seven living affected males included moderate mental retardation, coarse facies, puffy eyelids, narrow palpebral fissures, prominent supra-orbital ridges, a bulbous nose, prominent lower lip, large ears, obesity, and large testes (Figure 13–5). None of the carrier females had mental retardation; they did display craniofacial dysmorphism intermediate between that of affected and control males. Linkage analysis using polymorphic DNA markers spanning the X chromosome established linkage to Xq26-q27. Shashi et al. (2000) concluded that the features in this family were unique and constituted a new syndrome despite regional overlap with Börjeson-Forssman-Lehmann and Simpson-Golabi-Behmel syndromes and several other X-linked mental retardation loci. Castro et al. (2003) described a second family in which two brothers are thought to have Shashi syndrome and furthermore haplotype analysis was consistent with localization to Xq26-q27.

Figure 13–5. Shashi syndrome (courtesy of Dr. Vandana Shashi, Winston-Salem, NC, USA).

Figure 13–5. Shashi syndrome (courtesy of Dr. Vandana Shashi, Winston-Salem, NC, USA).

Simpson-Golabi-Behmel Syndrome

Simpson-Golabi-Behmel syndrome is characterized by a large head with coarse features, thickened lips, a wide mouth, a large tongue, a husky voice, a high arched palate, malposition of the teeth, a prominent jaw, a short neck, and hepatosplenomegaly. It is often associated with postaxial Polydactyly, high birth weight, tall stature, supernumerary nipples, mental retardation, and obesity (Figure 13–6) (Simpson et al. 1975; Behmel et al. 1984).

Figure 13–6. Simpson-Golabi-Behmel syndrome (courtesy of Dr. Pablo Lapunzina, Madrid, Spain).

Figure 13–6. Simpson-Golabi-Behmel syndrome (courtesy of Dr. Pablo Lapunzina, Madrid, Spain).

In 1984, Golabi and Rosen reported in four children a syndrome associated with prenatal macrosomia, postnatal enlargement of the liver and spleen, severe mental retardation, postaxial Polydactyly, and early death. Some cases had a Meckel diverticulum and large cystic kidneys. Hypoplastic fingernails, particularly of the index fingers, seem to be a characteristic feature.

The gene was eventually mapped to Xq25-q27, supported by a report of a balanced X;l translocation (Xq26;lq12) (Orth et al. 1994; Punnett 1994; Xuan et al. 1994). Deletions were later demonstrated in the extracellular proteoglycan glypican 3 (GPC3), which complexes with insulin-like growth factor II (Pilia et al. 1996). Further deletions have been documented, highlighting the likelihood of heterogeneity, although no mutation has been found in GPC4 (Lindsay et al. 1997; Veugelers et al. 2000).

Wilson-Turner Syndrome

Wilson et al. (1991) described a three-generation family in which the 14 affected males had mental retardation, obesity, gynecomastia, speech difficulties, emotional lability, tapering fingers, and small feet. Many of the features resembled those of Börjeson-Forssman-Lehmann syndrome, but none of the patients developed hypermetropia or cataracts in later life, nor did any have large earlobes (Wilson et al. 1991). Furthermore, linkage studies indicated gene localization close to the centromere (Xp21.1-q22), well outside the region containing PHF6, mutations in which are responsible for Börjeson-Forssman-Lehmann syndrome.

Commenting on the report by Vasquez et al. (1979), Frezal (1992) suggested that these patients may have Wilson-Turner syndrome.

Chromosomal Anomalies and Imprinting Disorders Associated with Obesity

In this section we briefly discuss the association of chromosomal aberrations with obesity. The Prader-Willi syndrome common deletion of the paternal segment of 15q11.2-q12 is discussed in Chapter 12.

Deletion 1 p36

A subgroup of patients with monosomy lp36 has been reported with significant obesity often associated with hyperphagia (D'Angelo et al. 2006). Typically, the lp36 terminally deleted patients have feeding difficulties in infancy, developmental delay, hypotonia, growth retardation, epilepsy, deafness, clefting abnormalities, hypermetropia, structural heart defects, and dilated cardiomyopathy. Facially, there is a gestalt comprising micro- and/or brachycephaly, deep-set eyes, flat nasal bridge and nose, pointed chin, thickened ear helices, and asymmetrical ears. The obese subgroup appears to have a smaller and more interstitial deletion with softer features.

Deletion 2q37

In 1995, reports of patients with a phenotype resembling Albright hereditary osteodystrophy (discussed in Chapter 7) began to emerge, each of whom had a deletion of one copy of 2q37.3 (Phelan et al. 1995; Wilson et al. 1995).

Although there was considerable variation, there was a typical facial gestalt comprising a round face with deep-set eyes, bulbous nasal tip, thin vermilion border of the lips, and sparse hair (Figure 13–7). Obesity was occasionally present. Seizures and mild cognitive impairment appeared to be a feature of the condition. Recently, molecular and cytogenetic analyses of a further five patients narrowed the deleted interval down to a 3 Mb region encompassing the G protein-coupled receptor 35 (GPR35), glypican 1 (GPC1), and serine/threonine protein kinase 25 (STK25) genes (Polityko et al. 2004; Shrimpton et al. 2004).

Figure 13–7. 2q37 deletion syndrome.

Figure 13–7. 2q37 deletion syndrome.

Deletion 6q16.2

Please also refer to SIM1 above, which falls in this deleted interval. In total, five cases of interstitial deletions involving chromosome region 6q16.2 (Turleau et al. 1988; Villa et al. 1995; Gilhuis et al. 2000; Faivre et al. 2002) and one case with a de novo balanced translocation between chromosomes Ip22.1 and 6q16.2 (Holder et al. 2000) have been reported. Patients with this deletion are said to have a Prader-Willi-like habitus with hypotonia, obesity, short extremities, and developmental delay. Varela and colleagues (2005) reviewed the phenotype of all interstitial deletion reports.

Deletion 9q34.3

In a report of two unrelated children with early-onset obesity and hyperphagia, mental retardation, developmental delay, and hypotonia, a de novo terminal deletion of chromosome 9q34.3 was discovered. Each had distinctive facial features, including synophrys, anteverted nares, prognathism, thin upper lip, brachycephaly, short neck and extremities, syndactyly of toes, hypogenitalism and hypospadias, sleep disturbances with repeated night awakenings, stereotypic hand movements, and behavioral difficulties. In a review of 13 other patients with 9q34.3 deletions, only two were reported with obesity. This region contains around 20 genes.

Duplication 3p25.3p26.2

In a single case report, a boy with a duplication of 3p25.3p26.2 developed early-onset severe obesity, mild developmental delay, and tapering digits. Interestingly, this interval contains several obesity-related genes, which include ghrelin, oxytocin receptor, γ-aminobutyric acid (GABA), neurotransmitter transporters (SLC6A1 and SLC6A11), and peroxisome proliferator-activated receptor-γ (PPARG).

Maternal Uniparental Disomy of Chromosome 14

Imprinting occurs during gamete formation and involves gene silencing in oocytes (maternal imprinting) or spermatocytes (paternal imprinting). This normal epigenetic phenomenon plays an important role in determining functional differences in gene expression throughout development, depending on parental origin. Genomic imprinting is typically revealed when both of a chromosome pair are inherited exclusively from a single parent—termed uniparental disomy (UPD)—and results in either overexpression or absence of a parent-specific transcript.

Maternal UPD 14 (mUPD 14) is consistently associated with prematurity, intrauterine growth retardation, low birth weight but later mild truncal obesity, short stature, hypotonia, variable motor and cognitive developmental delay, small hands and feet, skeletal problems, hypercholesterolemia, and precocious puberty (Cotter et al. 1997; Kurosawa et al. 2002). The facial characteristics include a prominent forehead, prominent supra-orbital ridges, short philtrum, and downturned corners of the mouth (Figure 13–8). To date, over 20 cases have been reported.

Figure 13–8. Uniparental disomy 14 (courtesy of Dr. Roel Hordijk, Groningen, the Neherlands).

Figure 13–8. Uniparental disomy 14 (courtesy of Dr. Roel Hordijk, Groningen, the Neherlands).

Wilms Tumor, Aniridia, Ambiguous Genitalia, and Mental Retardation (Deletion/Imprinting of 11 P13)

Three patients with Wilms tumor, aniridia, ambiguous genitalia, and mental retardation (WAGR syndrome) have been reported to have severe early-onset obesity (Marlin et al. 1994; Tiberio et al. 2000; Amor 2002). In two of these cases, food intake was reported to be normal. The last case was associated with hyperphagia and massive binge eating with onset in infancy. The syndrome is caused by variably sized deletions of 11p13 (including the WT1 gene), and it has been proposed that the interval might contain an obesity gene despite the lack of obesity in a study of 40 patients (Turleau et al. 1984). Many genes in the 1 lp13 region are also subject to imprinting.

Down Syndrome

By contrast with the aforementioned disorders, which involve hemizygous deletion of multiple genes, Down syndrome (DS) is most frequently caused by complete or partial trisomy (too many genes) of a critical portion of chromosome 21. It is one of the most common chromosomal abnormalities found in children, and the gross phenotype is readily recognized by most of us. Short stature with obesity is one of the most common associations, with affected women more likely to be morbidly obese than their control counterparts (Melville et al. 2005). Males with DS are more likely to be overweight than matched control males. Obesity in children with DS is a major predisposing factor for obstructive sleep apnea and perhaps pulmonary hypertension (Marcus et al. 1991). Surprisingly little research into the cause of obesity in this group has been published, and furthermore, the results are conflicting. At least two studies suggest that both children and adults with DS have a reduced resting metabolic rate (RMR) compared with controls (Luke et al. 1994; Allison et al. 1995). In sharp disagreement with these former reports, a recent study could find no evidence for reduced RMR in adult patients (Fernhall et al. 2005). It has been postulated that differences in child-feeding practices may play a role in the development of obesity in DS, but this would not account for persistence into adulthood (O'Neill et al. 2005). Some studies show a decrease (or no difference) in overall energy intake in DS individuals, suggesting that activity levels may in fact be lower (Sharav and Bowman 1992; Luke et al. 1996).

Copy Number Variations

With the advent of new genomewide microarrays such as comparative genome hybridization, a plethora of new copy number changes are being associated with dysmorphic syndromes. Already, at least three studies have indicated an association with obesity, and more are expected. In the study of Krepischi-Santos and colleagues (2006), among nine patients with mental retardation and obesity, two were found to have imbalances; a 14-year-old female with hyperphagia had a 2.7 Mb deletion at 7q22.1–22.3 and a 14-year-old male with an unusual skull shape and hypogonadism had a single clone maternal duplication at Xq28. A further study implicated a supernumerary marker derived from 19q12 to 19q13.2 (partial trisomy 19q) in obesity with insulin resistance (Zung et al. 2007).


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        Appendix. 154 Syndromes with Reported Generalized Obesity—Winter-Baraitser Dysmorphology Database (version 1.0.8, London Medical Databases, London, UK) (2006)

        Achard – arachnodactyly – micrognathia

        Acrocallosal—agenesis corpus callosum, mental retardation, polydactyly

        Albright—pseudo- and pseudopseudohypoparathyroidism

        Alström syndrome

        Aniridia—Wilms tumor/WAGR syndrome

        Aniridia plus

        Atkin 1985—macrocephaly, mental retardation, Coffin-Lowry-like face

        Ayazi (1981)—choroideremia, obesity, deafness

        Bannayan-Riley-Ruvalcaba syndrome

        Bardet-Biedl (Laurence-Moon-Bardet-Biedl) syndrome

        Beckwith-Wiedemann (EMG) syndrome

        Beemer (1988)—ptosis, telecanthus

        Biemond II—obesity, polydactyly, iris coloboma

        Blount disease

        Börjeson-Forssman—Lehmann syndrome—microcephaly, obesity, mental retardation

        Börjeson-Forssman-like syndrome

        Cabezas (2000)—X-linked mental retardation

        Camera syndrome (1993)—obesity

        Carbohydrate-deficient glycoprotein syndrome type Ia

        Carboxypeptidase E deficiency

        Carpenter syndrome—acrocephalopolysyndactyly type II

        Chromosome 13q34—submicroscopic deletion

        Chromosome 14—maternal disomy

        Chromosome 1p36—submicroscopic deletion

        Chromosome 22qter—submicroscopic subtelomeric deletion

        Chromosome 2q37—submicroscopic deletions, Albright—like features

        Chromosome 3p25-26—duplication

        Chromosome 8p23—submicroscopic deletion

        Chromosome 9q22.3—microdeletion

        Chromosome 9q34—submicroscopic deletion

        Chudley (1988)—mental retardation, short stature, obesity, hypogonadism

        Cohen syndrome

        Cole-Hughes (1991)—macrocephaly

        Coloboma—obesity, hypogonadism, mental retardation

        Congenital muscular dystrophy with cataracts and minor brain anomaly

        Costello syndrome


        Deafness—metaphyseal dysplasia

        DeVitto (2005)—overgrowth, cranial hyperostosis, mental retardation

        Devriendt (1996)—alopecia, mental retardation, hypogonadism

        Donnai-Barrow—diaphragmatic hernia, exomphalos, absent corpus callosum

        Duba (1997)—chromosome instability disorder

        Edwards 1976—pigmentary retinopathy, hypogonadism, glucose intolerance

        Elejalde (1977)—acrocephalopolydactylous dysplasia

        Emphysema—genital anomalies, deafness, mental retardation

        Ferlini (1995)—hydrocephalus, Sprengel shoulder, skeletal anomalies

        Frias (1975)—growth deficiency, facial abnormalities, brachydactyly

        Fryns (1988)—mental retardation, macrocephaly, short stature, craniofacial abnormalities

        Fryns—Aftimos—webbed neck, seizures, pachygyria of frontal lobes

        Fryns-Delooz—nasal hypoplasia, sparse hair, obesity, labial hypoplasia, mental retardation

        Furlong (1987)—marfanoid syndrome with craniosynostosis

        Gabrielli (2000)—obesity, cleft lip/palate, growth hormone deficiency, mental retardation

        Glycogen storage disease type 1

        Goldstein (1988)—Sotos-like syndrome

        Growth hormone—releasing receptor mutations

        Gu (1996)—nonspecific X-Linked mental retardation

        Hall syndrome—craniostenosis and Turner phenotype

        Hernandez (1982)—mental retardation, bulbous nose, epilepsy

        Hockey (1986)—X-linked mental retardation, precocious puberty

        Hughes (1985)—dominant “acromegaloid” appearance

        Hypertrichosis, osteodysplasia, cardiomyopathy

        Hypochondroplasia (autosomal recessive)

        Hypothalamic syndrome

        Ichthyosis, hypogonadism, mental retardation (X-linked)

        Insulin resistance, acanthosis nigricans, hypothyroidism, obesity

        Ischiospinal dysostosis

        Jones (1973)—microcephaly, mental retardation, cubitus valgus

        Kabuki makeup syndrome

        Kajantie (2000)—facial asymmetry, obesity, dolicocephaly

        Kallmann syndrome

        Killian/Pallister mosaic syndrome

        Laurence-Moon (see also Bardet-Biedl) syndrome

        Leptin deficiency

        Leptin receptor mutation

        Livedo reticularis, stroke-like episode, cystic kidneys

        Lorenz (1990)—acrocephalosyndactyly, parieto—occipital “encephalocele”

        Maclean (2002)—microcephaly, growth hormone deficiency, retinopathy

        Macrocephaly, cutis marmorata telengiectatica congenita

        Macrocephaly, familial

        Macrocephaly, spastic paraplegia

        Macular degeneration—Sotos-like features

        Marshall-Smith syndrome

        Maternal diabetes syndrome

        MC4R mutations and obesity

        McPherson-Clemens—cleft lip and palate, congenital heart defect

        Mégarbané-Cormier-Daire—mental retardation, short stature, joint laxity

        Mental retardation, distal arthrogryposis

        Mental retardation, epileptic seizures, hypogonadism, microcephaly, obesity

        Mental retardation, obesity (X-linked)

        Microcephaly, cutis verticis gyrata, edema

        MMMM syndrome—megalocornea, macrocephaly, mental and motor retardation

        MOMES syndrome—mental retardation, obesity, prognathism

        MOMO syndrome—macrosomia, obesity, macrocephaly, ocular abnormalities

        Moreno (1974)—gigantism, advanced bone age, hoarse cry

        Morgagni-Stewart-Morel syndrome

        MORM syndrome—mental retardation, truncal obesity, retinal dystrophy, micropenis


        Multiple circumferential skinfolds

        Myhre (1981)—growth deficiency, clefting, mental retardation


        Neuhauser (1975)—megalocornea, mental retardation

        Nevo (1974)—overgrowth, hypotonia

        Nguyen (2003) syndrome—mild Smith-Lemli-Opitz following familial hypocholesterolemia

        Obesity, adrenal insufficiency, red hair

        Obesity and SIM1 mutation

        Obesity, tall stature, psychosis, seizures

        Overgrowth syndrome, type Nishimura

        Pashayan (1973)—mental retardation, truncal obesity, webbed neck, blepharophimosis

        Pavone (1996)—hypertrichosis, obesity, brachydactyly, mental retardation

        Perlman syndrome—gigantism with renal dysplasia/tumors

        Pfeiffer—Kapferer—sensorineural deafness, hypospadias, synostoses

        Piussan (1983)—brachydactyly, thumb ankylosis, mental retardation

        Prader—Willi syndrome

        Primrose (1982)—muscle wasting, mental retardation, cataracts, calcified pinnae

        Prolidase deficiency

        Ramsden (2000)—hypertrophied skinfolds

        Rozendaal (2003)—midface hypoplasia, obesity, mental retardation

        Russell—Eggitt (1989)—Leber's amaurosis, cardiomyopathy

        Russman (1985)—macrocephaly, tremor

        Schinzel (1974)—fractures, delayed dentition, rhizomelia (arms)

        Schinzel—Bernasconi—short stature, brachydactyly, small ears

        Scholte (1991)—early balding, patella laxity, acromicria, hypogonadism, mental retardation


        Scott (1969)—short stature, acanthosis nigricans

        Seemanova (1992)—insulin resistance syndrome

        Sengers (1985)—hydrocephaly, obesity, hypogenitalism (X—linked recessive)

        Shashi 2000—X-linked mental retardation

        Sierpinski—Bart (1981)—mental retardation, tapetoretinal degeneration, arachnodactyly

        Simpson—Golabi—Behmel syndrome

        Simpson—Golabi—Behmel syndrome, severe infantile form

        Single central incisor, short stature

        Sinnerbrink and Ades (2004)—mental retardation, deafness, ocular abnormalities, short stature

        Smith—Magenis syndrome

        Sotos syndrome (cerebral gigantism)

        Stevenson (1982)—marfanoid syndrome

        Summitt (1969)—acrocephalosyndactyly

        Tarhan (2004)—mental retardation, polysyndactyly, deafness, facial dysmorphism

        Teebi (1986)—hypogonadotropic hypogonadism, mental retardation, obesity

        Teebi 1989—macrosomia, microphthalmia, cleft palate

        Teebi 1989—overgrowth syndrome

        Moreno (1974)—gigantism, advanced bone age, hoarse cry

        Temtamy (1974)—metaphyseal dysplasia, anetoderma, optic atrophy

        Tetraploid/diploid mosaicism

        Trichomegaly, chorioretinopathy

        Triploid/diploid mosaicism

        Ulnar—mammary (Pallister) syndrome

        Urban 1979—obesity, mental retardation, contractures, genital anomalies

        Vasquez 1979—X-linked hypogonadism, gynecomastia, obesity, mental retardation

        Verloes (1990)—male pseudohermaphroditism, mullerian structures, mental retardation

        Verloes—Lesenfants—obesity, camptodactyly, agenesis of corpus callosum

        Weaver syndrome

        Weiss (1932)—nerve deafness, mental retardation, obesity, hypogenitalism

        Wilson 1991—X-linked mental retardation, gynecomastia, obesity

        X—linked mental retardation, obesity, microcephaly

        Yim (1982)—amelia, hydrocephalus, iris coloboma, cleft lip/palate