Best Practice & Research Clinical Endocrinology & Metabolism

Vol. 19, No. 3, pp. 359374, 2005

doi:10.1016/j.beem.2005.04.004
available online at http://www.sciencedirect.com

3
Genetic and hereditary aspects of childhood
obesity
I. Sadaf Farooqi*
Wellcome Clinician Scientist Fellow
University Departments of Medicine and Clinical Biochemistry, Box 232, Addenbrookes Hospital,
Cambridge CB2 2QQ, UK

Genetic factors are involved in the regulation of body weight and in determining individual
responses to environmental factors such as diet and exercise. The identification and
characterization of monogenic obesity syndromes have led to an improved understanding of
the precise nature of the inherited component of severe obesity and has had undoubted medical
benefits, whilst helping to dispel the notion that obesity represents an individual defect in
behaviour with no biological basis. For individuals at highest risk of the complications of severe
obesity, such findings provide a starting point for providing more rational mechanism-based
therapies, as has successfully been achieved for one disorder, congenital leptin deficiency.
Key words: genes; leptin; melanocortin.

The rising prevalence of childhood and adult obesity can be explained in part by changes
in our environment over the last 30 years, in particular the unlimited supply of
convenient, highly palatable, energy-dense foods, coupled with a lifestyle typified by low
levels of physical activity. However, obesity represents the archetypal complex
multifactorial disease and arises as a result of behavioural, environmental, and genetic
factors which may influence individual responses to diet and physical activity.
There is considerable evidence to suggest that, like height, weight is a heritable trait.1
Traditionally the most favoured model for separation of the genetic component of
variance is based on studies of twins, as monozygotic co-twins share 100% of their
genes and dizygotes 50% on average. Overall, data from twin and adoption studies are
consistent with a genetic contribution for body mass index (BMI) of between 40 and
70%.2 It is clear that different individuals have a certain genetic propensity to store
excessive caloric intake as fat. In a classic study, Bouchard and Tremblay3 overfed pairs
of monozygotic twins by 10%. Different sets of twins showed remarkable differences in
* Tel.:C44 1223 762 634; Fax: C44 1223 762 657.
E-mail address: ifarooqi@hgmp.mrc.ac.uk.

1521-690X/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved.

360 I. S. Farooqi

the degree to which these calories were stored as fat, but the tendency toward
increased adiposity within each set of twins was remarkably similar, indicating that
genetic factors determine an individuals susceptibility to gain weight in a given
environment. Although the role of genes in the regulation of body fat is now
established, it is safe to assume that the rising prevalence of obesity has not been due to
a recent change in the genetics of the Western world. The propensity for obesity must
have been in our midst for a long time, only to emerge recently on a large scale as a
result of changes in the environment, in particular the availability and composition of
food and reduced requirement for physical exertion. It is very likely that the ability to
store fat in times of nutritional abundance was a positive trait selected over many
thousands of years of human evolution.
The identification of the polygenic determinants of adiposity across the general
human population has been challenging and has had limited success thus far.4 However,
as is the case with other human phenotypes, the study of extreme human phenotypes
with Mendelian patterns of inheritance has been illuminating in a number of ways. In this
review, I will focus on the recent advances that have been made through the study of
patients with obesity syndromes that display a Mendelian pattern of inheritance. These
single gene disorders include the classical pleiotropic obesity syndromes, where
affected patients are usually identified as a result of their association with additional
phenotypes such as mental retardation or other developmental abnormalities. More
recently several monogenic disorders resulting from disruption of the leptin
melanocortin pathway have been identified. In these disorders, severe obesity of
early onset is itself the predominant presenting feature, although often accompanied by
characteristic patterns of neuroendocrine dysfunction.

GENETIC DISRUPTION OF THE LEPTINMELANOCORTIN PATHWAY

RESULTS IN MONOGENIC HUMAN OBESITY
Energy homeostasis involves the integration of longer-term afferent signals from fat
(leptin) and pancreatic b cells (insulin) and short-term, meal-related afferent
signals from the gut, including inhibitors of feeding (peptide YY, PYY; glucagon-like
peptide-1, GLP-1; and cholecystekinin, CCK), and the stimulator of feeding (ghrelin).5
These inputs are integrated within the brain and regulate food intake, energy
expenditure, energy partitioning and neuroendocrine status, including reproduction
and growth (Figure 1).
The adipocyte-derived hormone leptin circulates in proportion to body fat content,
crosses the bloodbrain barrier, interacts with receptors on neurons known to
influence energy balance, and exerts long-acting effects to reduce adiposity by
decreasing appetite and increasing thermogenesis.6 Attention has focused on identifying
the molecular events that lie downstream of the leptin receptor in key hypothalamic
target neurons. In particular, neurons within the hypothalamic arcuate nucleus (Arc) act
as primary sensors of alterations in energy stores to control appetite and energy
homeostasis. Pro-opiomelanocortin (POMC) neurons produce the anorectic peptide
a-MSH (a-melanocyte stimulating hormone) together with CART (cocaine- and
amphetamine-related transcript), whilst a separate group expresses the orexigens
neuropeptide Y (NPY) and agouti-related protein (AGRP).7 AGRP is a hypothalamic
neuropeptide that is a potent melanocortin-3 receptor (MC3R) and melanocortin-4
receptor (MC4R) antagonist. Activation of the NPY/AGRP neurons increases food

Genetic and hereditary aspects of childhood obesity 361

DOWNSTREAM NEURONS
+ Food intake

Food intake

Y1R
MC4R

GnRH

NPY/AGRP

LEPTIN RECEPTORS

MC3R

vv

Y4R

HYPOTHALAMUS

POMC/CART

Y1R

GHSR

LEPTIN
RECEPTORS

GHRELIN

INSULIN
LEPTIN

ADIPOSE TISSUE

Figure 1. The leptinmelanocortin pathway. GnRH, gonadotropin-releasing hormone; Y1R, Y4R,

neuropeptide Y1/Y4 receptor; MC3R, MC4R, melanocortin-3/4 receptor; POMC, pro-opiomelanocortin;
NPY/AGRP, neuropeptide Y/agouti-related protein; GHSR, growth hormone secretagogue receptor.

intake and decreases energy expenditure, whereas activation of the POMC neurons
decreases food intake and increases energy expenditure.8 The long isoform of the
leptin receptor is highly expressed on these arcuate neurons, and leptin regulates these
two neuronal populations in a reciprocal manner. From the arcuate, these two
populations of neurons project to other brain areas, which contain second-order
neurons expressing neuropeptides involved in energy homeostasis. In particular, there
are extensive projections to several hypothalamic regions, including the lateral
hypothalamus (LH) and the paraventricular nucleus (PVN).9 Cell bodies within the LH
contain the potent orexigenic peptide, melanin-concentrating hormone (MCH), and
neurons of the PVN express thyrotropin-releasing hormone (TRH) and corticotrophinreleasing hormone (CRH), highlighting a link between the pathways regulating energy
homeostasis and neuroendocrine circuits.9
The fact that many aspects of the normal physiological response to starvation are
abrogated by the administration of leptin10 strongly suggests that one of the major roles
of leptin is to signal the transition from a state of nutritional adequacy to that of
starvation, and this, rather than the prevention of obesity, is likely to be the major
physiological role of leptin.11
Congenital leptin deficiency
In 1997 we reported two severely obese cousins (an 8-year-old girl weighing 86 kg and a
2-year-old boy weighing 29 kg) from a highly consanguineous family of Pakistani origin.12
Despite their severe obesity, both children had undetectable levels of serum leptin and

362 I. S. Farooqi

were found to be homozygous for a frameshift mutation in the ob gene (DG133), which
resulted in a truncated protein that was not secreted. We have since identified four
further affected individuals from three other families who are also homozygous for the
same mutation in the leptin gene.13 All the families are of Pakistani origin but not known
to be related over five generations. A large Turkish family carrying a homozygous
missense mutation has also been described.14 All subjects in these families are
characterized by severe early-onset obesity and intense hyperphagia. Hyperinsulinaemia and an advanced bone-age are also common features.13 Some of the Turkish
subjects are adults with hypogonadotropic hypogonadism, although there was some
evidence of a delayed but spontaneous pubertal development in one person.15
We demonstrated that children with leptin deficiency had profound abnormalities in
T-cell number and function, consistent with high rates of childhood infection and a high
reported rate of childhood mortality from infection in obese Turkish subjects.13
Response to leptin therapy
We reported the dramatic and beneficial effects of daily subcutaneous injections of
leptin in reducing body weight (98% of which was fat mass) in three congenitally leptindeficient children.13 All children showed a response to initial leptin doses designed to
produce plasma leptin levels at only 10% of those predicted by height and weight (i.e.
approximately 0.01 mg/kg of lean body mass). Among the most dramatic example of the
effects of leptin was with a 3-year-old boy, severely disabled by gross obesity (weight
42 kg), who now weighs 32 kg (75th centile for weight) after 48 months of leptin
therapy (Figure 2). Similar major effects were seen in three leptin-deficient adults
treated with recombinant human leptin, with an improvement in hyperinsulinaemia and
diabetes in one subject.16
The major effect of leptin was on appetite, with normalization of hyperphagia.17
Leptin therapy reduced energy intake during an 18-MJ ad libitum test meal by up to
84%.13 We were unable to demonstrate a major effect of leptin on basal metabolic rate
or free-living energy expenditure, but as weight loss by other means is associated with a
decrease in basal metabolic rate (BMR), the fact that energy expenditure did not fall in
our leptin-deficient subjects is notable.
The administration of leptin permitted progression of appropriately timed pubertal
development in the single child of appropriate age, induced pubertal development
in adults, and did not cause the early onset of puberty in the younger children,
suggesting that leptin is a permissive factor for the development of puberty in humans.13
Free thyroxine and TSH levels, although in the normal range before treatment, had
consistently increased at the earliest post-treatment time point and subsequently
stabilized at this elevated level. These findings are consistent with evidence from animal
models that leptin influences TRH release from the hypothalamus and from studies
illustrating the effect of leptin deficiency on TSH pulsatility in humans.18
Throughout the trial of leptin administration, weight loss continued in all subjects,
albeit with refractory periods which were overcome by increases in leptin dose. The
families in the UK harbour a mutation, which leads to a prematurely truncated form of
leptin, and thus wild-type leptin is a novel antigen to them. Thus, all subjects developed
anti-leptin antibodies after w6 weeks of leptin therapy, which interfered with
interpretation of serum leptin levels and in some cases were capable of neutralizing
leptin in a bioassay.13 These antibodies are the likely cause of refractory periods
occurring during therapy. The fluctuating nature of the antibodies probably reflects

Genetic and hereditary aspects of childhood obesity 363

Figure 2. Response to leptin therapy in a child with leptin deficiency.

the complicating factor that leptin deficiency is itself an immunodeficient state19, and
administration of leptin leads to a change from the secretion of predominantly Th2 to
Th1 cytokines, which may directly influence antibody production. Thus far, we have
been able to regain control of weight loss by increasing the dose of leptin.
Leptin receptor deficiency
A mutation in the leptin receptor has been reported in one consanguineous family of
Algerian origin with three affected subjects.20 Affected individuals were found to be
homozygous for a mutation that truncates the receptor before the transmembrane
domain. The mutant receptor ectodomain is shed from cells and circulates bound to
leptin. However, the unusually high leptin levels in this family are an artefact of the
particular mutation which results in large amounts of leptin being bound to the
abnormally shed ectodomain. In general, leptin receptor deficiency results in a similar
phenotype to leptin deficiency. Leptin receptor-deficient subjects were also of normal
birth weight but exhibited rapid weight gain in the first few months of life, with severe
hyperphagia and aggressive behaviour when food was denied. Basal temperature and
resting metabolic rate were normal, cortisol levels were in the normal range, and all
individuals were normoglycaemic with mildly elevated plasma insulins similar to those
of leptin-deficient subjects. Leptin receptor-deficient subjects had some unique
neuroendocrine features not seen with leptin deficiency.20 Whether the mild growth
retardation with impaired basal and stimulated growth hormone secretion and
decreased IGF-1 and IGF-BP3 levelsalongside features of frank hypothalamic

364 I. S. Farooqi

hypothyroidismare consistent features will become clear only with the description of
further families.
POMC deficiency
Seven children homozygous or compound heterozygous for mutations in POMC have
been reported.2123 Initial presentation is in neonatal life with adrenal crisis due to
ACTH deficiency (POMC is a precursor of ACTH in the pituitary), and the children
have pale skin and red hair due to the lack of MSH action at melanocortin-1 receptors in
the skin and hair follicles, although this may be less obvious in children from different
ethnic backgrounds (unpublished observations). POMC deficiency results in hyperphagia and early-onset obesity due to loss of melanocortin signalling at the
melanocortin-4 receptor (MC4R). Although, as yet, no specific treatment is available,
selective small-molecule MC4R agonists are being developed, and it is likely that these
children would be highly responsive to such agents. In addition to homozygotes for
complete POMC deficiency, other heterozygous point mutations in the POMC gene
might contribute to inherited obesity24, and it is notable that there is a high prevalence
of obesity in the heterozygous relatives of children with complete POMC deficiency,
suggesting that subtle defects in this system may be sufficient to cause obesity.
Melanocortin-4 receptor deficiency
In 1998, groups in the UK and France reported families with dominantly inherited
associated heterozygous mutations in the MC4 receptor (MC4R).25,26 Since then,
multiple different heterozygous MC4R mutations have been reported in obese people
from various ethnic groups. The prevalence of such mutations has varied from 0.5 to
1.0% of obese adults to 6% in subjects with severe obesity starting in childhood.27
Although few studies have been performed in unselected populations, estimates based
on population-derived cohorts are consistent with a population prevalence of at least
one in 2000, suggesting that MC4R deficiency may be commoner than either Prader
Willi syndrome or fragile X syndrome.
While some studies have found a 100% penetrance of early-onset obesity in
heterozygous probands, others have described obligate carriers who were not obese.
Given the large number of potential influences on body weight, it is perhaps not
surprising that both genetic and environmental modifiers will have important effects in
some pedigrees. Indeed, we have now studied six families in whom the probands were
homozygotes, and in all of these the homozygotes were more obese than
heterozygotes.27 Thus, co-dominance, with modulation of expressivity and penetrance
of the phenotype, is the most appropriate descriptor for the mode of inheritance.
We have recently defined the phenotype in 150 patients with MC4R deficiency27
(and personal observations). Affected subjects exhibit hyperphagia, but this is not as
severe as that seen in leptin deficiency, although it often starts in the first year of life. Of
particular note is the finding that the severity of receptor dysfunction seen in assays in
vitro can predict the amount of food ingested at a test meal by the subject harbouring
that particular mutation.27 Alongside the increase in fat mass, MC4R-deficient subjects
also have an increase in lean mass that is not seen in leptin deficiency and a marked
increase in bone mineral density; thus they often appear big-boned. The accelerated
linear growth does not appear to be due to dysfunction of the GH axis and may be a
consequence of the disproportionate early hyperinsulinaemia.27

Genetic and hereditary aspects of childhood obesity 365

The high frequency of MC4R mutations in obese humans compared to the rarity of
leptin, leptin receptor and PC1 mutations is probably related to the fact that even
partial loss-of-function mutations in the heterozygous form result in a phenotype and
because the mutations do not appear to interfere with reproductive function and
fertility.
While at present there is no specific therapy for MC4R deficiency, it is highly likely
that these subjects would respond well to pharmacotherapy that overcame the
reduction in the hypothalamic melanocortinergic tone that exists in these patients. As
most patients are heterozygotes with one functional allele intact, it is possible that
small-molecule MC4R agonists might, in future, be excellent candidate drugs for this
disorder.
Prohormone convertase-1 (PC1) deficiency
We have previously reported a woman with severe early-onset obesity, hypogonadotropic hypogonadism, postprandial hypoglycaemia, hypocortisolaemia, and evidence of
impaired processing of POMC and proinsulin who was a compound heterozygote for
PC1 mutations.28 We have recently described the second case of congenital PC1
deficiency: a child who was a compound heterozygote for two loss-of-function
mutations.29 Intriguingly, this patient suffered from severe small-intestinal absorptive
dysfunction as well as the characteristic severe early-onset obesity, impaired
prohormone processing and hypocortisolaemia. The small intestinal dysfunction seen
in this patientand to a lesser extent in the first patient we describedmay be the
result of a failure of maturation of propeptides within the enteroendocrine cells and
nerves that express PC1 throughout the gut.

MONOGENIC HUMAN OBESITY: PLEIOTROPIC SYNDROMES

There are about 30 Mendelian disorders with obesity as a clinical feature, often in
association with mental retardation, dysmorphic features and organ-specific developmental abnormalities (i.e. pleiotropic syndromes)30. Positional genetic strategies have
led to the recent identification of several different causative mutations underlying such
syndromes; however, in most cases the defective gene product is an intracellular
protein that is expressed throughout the body and is of unknown function. As yet, the
mechanistic link between such defective gene products and dysregulation of energy
balance is obscure, although recently a potential novel molecular mechanism underlying
BardetBeidl syndrome has been identified.31
BardetBiedl syndrome
BardetBiedl syndrome (BBS) is a rare (prevalence !1/100 000) autosomal recessive
syndrome characterized by central obesity (in 75% of patients), mental retardation,
dysphormic extremities, retinal dystrophy or pigmentary retinopathy, hypogonadism or
hypogenitalism (limited to male patients) and renal abnormalities. BBS is a genetically
heterogeneous disorder that is known to map to at least eight loci, seven of which have
now been identified at the molecular level.32 Although BBS is usually transmitted as a
recessive disorder, some families have exhibited so-called tri-allelic inheritance31
where the clinical manifestation of the syndrome requires two mutations in one BBS

366 I. S. Farooqi

gene plus an additional mutation in a second, unlinked BBS gene, although no evidence
for involvement of the common BBS1 mutation in triallelic inheritance has been found.
The BBS1 gene (11q13) is the most commonly mutated in white BBS patients.33
However, the protein does not show any significant similarity with any known protein
or protein family, and its function is unknown, as is the case for the protein encoded by
the BBS2 gene (16q21), which appears to result in the leanest BBS phenotype. A
relatively small proportion of BBS families are linked to the BBS3 locus, which has
recently been refined (3p13-p12). Families with BBS mapping to BBS6 (20p12) have
been found to harbour mutations in MKKS which has sequence homology to the asubunit of a prokaryotic chaperonin.34 Mutations in this gene also cause McKusick
Kaufman syndrome (hydrometrocolpos, post-axial polydactyly and congenital heart
defects).
Recently, phylogenetic/genomic approaches have led to the identification of BBS7
(4q27)35 and BBS8 or TTC8 (14q32.11).36 Whilst the function of the BBS7encoded protein is unknown, mutations in BBS8 have been found in three families
and in vitro; BBS8 localizes to centrosomes and basal bodies and interacts with
PCM1 (pericentriolar material-1 protein), a protein involved in ciliogenesis.36
Further evidence implicating the BBS genes in the generation of both cilia and
flagella was obtained using a comparative genomics approach that subtracted the
non-flagellated proteome of Arabidopsis from the shared proteome of the ciliated/
flagellated organisms Chlamydomonas and human.37 Thus, Li and colleagues37
identified BBS5, which localizes to basal bodies in mouse and C. elegans and is
necessary for ciliary development.
BBS4 (15q22.3-q23) was identified using positional cloning several years ago,
although the function of the encoded protein was unclear until recently.38 Kim et al39
showed that BBS4 acts as an adaptor to recruit PCM1 to centrosomal satellites and
pathogenic mutations in BBS4 result in PCM1 mislocalization, loss of microtubule
anchoring at the centrosome, defects in cytokinesis and apoptosis. Mice lacking the
BBS4 protein recapitulate the major components of the human phenotype, including
obesity and retinal degeneration, and male Bbs4-null mice do not form spermatozoa
flagella.40 However, BBS4 KO mice do develop both motile and primary cilia,
demonstrating that BBS4 may be required for cilia formation only in a cell- and
developmental stage-specific manner.40 As BBS homologues in C. elegans are expressed
exclusively in ciliated neurons and contain regulatory elements for RFX, a transcription
factor that modulates the expression of genes associated with ciliogenesis and
intraflagellar transport, it is plausible that the obesity phenotype in BBS is due to a
failure of formation or function of ciliated hypothalamic neurons.
Albrights hereditary osteodystrophy
Albrights hereditary osteodystrophy (AHO) is an autosomal dominant disorder due to
germline mutations in GNAS1 which encodes for a-subunit of the stimulatory G
protein (Gsa). Maternal transmission of GNAS1 mutations leads to AHO (short
stature, obesity, round facies, brachydactyly and ectopic soft tissue ossification) plus
resistance to several hormones (e.g. parathyroid hormone) that activate Gs in their
target tissues (pseudohypoparathyroidism type IA), while paternal transmission leads
only to the AHO phenotype (pseudopseudohypoparathyroidism).41 Thus, GNAS1 is
imprinted in a tissue-specific manner, being expressed primarily from the maternal allele
in some tissues and biallelically expressed in most other tissues; thus multi-hormone

Genetic and hereditary aspects of childhood obesity 367

resistance occurs only when Gsa mutations are inherited maternally.42 Some sporadic
cases occur in which patients with a phenotype similar to AHO have a deletion of
chromosome 2q37.
Fragile X syndrome
Fragile X syndrome is characterized by moderate to severe mental retardation, macroorchidism, large ears, macrocephaly, prominent jaw (mandibular prognathism), and
high-pitched jocular speech. In 1991, the molecular cloning of the fragile X locus
revealed unstable expansions of a CGG trinucleotide repeat located in the FMR1
(fragile X mental retardation) gene.43 The CGG repeat is polymorphic in the normal
population, with alleles of 6 to about 50 CGGs. Large expansions of the repeat (from
230 to O1000 CGGs) are seen in affected patients, with moderate expansions (from 60
to about 200 CGGs) that are unmethylated found in normal transmitting males and in
the majority of clinically normal carrier females. Although the exact function of FMRP is
not known, it may play a role in the regulation of transport, stability or translation of
some messenger RNAs.44
BorjesonForssmanLehmann syndrome
Borjeson, Forssman and Lehmann described a syndrome characterized by moderate to
severe mental retardation, epilepsy, hypogonadism, and obesity with marked
gynaecomastia. Mutations in a novel, widely expressed zinc-finger gene plant
homeodomain (PHD)-like finger (PHF6) have been identified in affected families45,
although the functional properties of this protein remain unclear.
Cohen syndrome
Cohen syndrome is an autosomal recessive disorder characterized by mental
retardation, microcephaly, characteristic facial features and progressive retinochoroidal
dystrophy that is over-represented in the Finnish population, although cases have been
reported worldwide.46 The genetic locus for Cohen syndrome was mapped to
chromosome 8q, and a novel gene, COH1, in this locus was shown to carry mutations
in many Cohens syndrome patients from different ethnic groups.47
Alstrom syndrome
Alstrom syndrome is a homogeneous autosomal recessive disorder that is
characterized by childhood obesity associated with hyperinsulinaemia, chronic
hyperglycaemia and neurosensory deficits.48 Subsets of affected individuals present
with additional features such as dilated cardiomyopathy, hepatic dysfunction,
hypothyroidism, male hypogonadism, short stature and mild to moderate developmental delay.49 Mutations in a single gene, ALMS1, have been found to be
responsible for all cases of Alstrom syndrome so far characterized.50 The ALMS1
protein has no signal sequences or transmembrane regions, suggesting an
intracellular localization.

368 I. S. Farooqi

OBESITY SYNDROMES DUE TO CHROMOSOMAL

REARRANGEMENTS
PraderWilli syndrome
The PraderWilli syndrome (PWS) is characterized by diminished fetal activity,
hypotonia, mental retardation, short stature, hypogonadotropic hypogonadism and
obesity, and is the most common syndromal cause of human obesity with an estimated
prevalence of about one in 25 000 births and a population prevalence of one in
50 000.51 The syndrome is caused by lack of the paternal segment 15q11.2-q12, either
through deletion of the paternal critical segment (75%) or through loss of the entire
paternal chromosome 15 with presence of two maternal homologues (uniparental
maternal disomy) in approximately 22% of patients. Deletions, which account for
7080% of cases, can be visualized by standard prometaphase banding examination, and
parental differences in DNA methylation allow for the diagnosis of the remainder of
cases of maternal uniparental disomy where cytogenetic examinations yield normal
results.52
Within the 4.5 Mb PWS region in 15q11-q13, where there is a lack of expression of
paternally imprinted genes, several candidate genes have been studied and their
expression shown to be absent in the brains of PWS patients. These include necdin and
small nuclear ribonucleoprotein polypeptide N (SNRPN). More recent reports have
suggested that other non-expressed genes may include the ring zinc finger 127
polypeptide gene, the MAGE-like 2 gene and the PraderWilli critical region 1 gene;
however, the precise role of these genes and the mechanisms by which they lead to a
pleiotropic obesity syndrome remain elusive.51
One suggested mediator of the obesity phenotype in PWS patients is the enteric
hormone ghrelin, which is implicated in the regulation of meal-time hunger in rodents
and humans and is also a potent stimulator of growth hormone secretion. Several
groups have shown that children and adults with PWS have fasting plasma ghrelin levels
that are 4.5-fold higher in PWS subjects than in equally obese controls and thus may be
implicated in the pathogenesis of hyperphagia in these patients.53,54
Sim-1
A girl has been reported with hyperphagia and early-onset obesity and a balanced
translocation between 1p22.1 and 6q16.2, which would be predicted to disrupt the
SIM-1 gene on 6q. The Drosophila single-minded (sim) gene is a regulator of
neurogenesis, and in the mouse Sim-1 is expressed in the developing central nervous
system, is essential for formation of the supraoptic and paraventricular (PVN) nuclei
which express the melanocortin-4 receptor; mice heterozygous for loss-of-function
mutations in Sim-1 are obese.55 A number of patients with obesity, hypotonia and
developmental delay in association with interstitial chromosome 6q deletions have been
described56, although whether this syndrome can be attributed to SIM-1 is unclear.
WAGR
The WAGR syndrome (Wilms tumour, anorexia, ambiguous genitalia and mental
retardation) is one of the best-studied contiguous gene syndromes associated with
chromosomal deletions at 11p13, the location of the WT1 gene.57 Some patients with

Genetic and hereditary aspects of childhood obesity 369

Table 1. Assessment of the obese child/adult.

History
Age of onsetuse of growth charts and family photographs. Early onset (!5 years of age) suggests a
genetic cause
Duration of obesityshort history suggests endocrine or central cause
A history of damage to the CNS (e.g. infection, trauma, haemorrhage, radiation therapy, seizures) suggests
hypothalamic obesity with or without pituitary growth hormone deficiency or pituitary hypothyroidism. A
history of morning headaches, vomiting, visual disturbances, and excessive urination or drinking also
suggests that the obesity may be caused by a tumour or mass in the hypothalamus
A history of dry skin, constipation, intolerance to cold, or fatigue suggests hypothyroidism. Mood
disturbance and central obesity suggests Cushings syndrome. Frequent infections and fatigue may suggest
ACTH deficiency due to POMC mutations
Hyperphagiaoften denied, but sympathetic approach needed, and specific questions such as waking at
night to eat, demanding food very soon after a meal suggest hyperphagia. If severe, especially in children,
suggests a genetic cause for obesity
Developmental delaymilestones, educational history, behavioural disorders. Consider craniopharyngeoma or structural causes (often relatively short history) and genetic causes
Visual impairment and deafness can suggest genetic causes
Onset and tempo of pubertal developmentonset can be early or delayed in children and adolescents.
Primary hypogonadotropic hypogonadism or hypogenitalism associated with some genetic disorders
Family historyconsanguineous relationships, other children affected, family photographs useful. Severity
may differ due to environmental effects
Treatment with certain drugs or medications. Glucocorticoids, sulfonylureas, MAOIs, oral contraceptives,
risperidone, clozapine
Examination
Document weight and height compared to normal centiles. Calculate BMI and WHR (in adults). In
children, obtain parental heights and weights where possible
Head circumference if clinically suggestive
Short stature or a reduced rate of linear growth in a child with obesity suggests the possibility of growth
hormone deficiency, hypothyroidism, cortisol excess, pseudohypoparathyroidism, or a genetic syndrome
such as PraderWilli syndrome
Obese children and adolescents are often tall (on the upper centiles); however, accelerated linear growth
(height sds O2) is a feature of MC4R deficiency
Body fat distributioncentral distribution with purple striae suggests Cushings syndrome. Selective fat
deposition (60%) a feature of leptin and leptin receptor deficiency
Dysmorphic features or skeletal dysplasia
Hair colourred hair (if not familial) may suggest mutations in POMC in white Caucasians
Pubertal development/secondary sexual characteristics. Most obese adolescents grow at a normal or
excessive rate and enter puberty at the appropriate age; many mature more quickly than children with
normal weight, and bone age commonly is advanced. In contrast, growth rate and pubertal development
are diminished or delayed in growth hormone deficiency, hypothyroidism, cortisol excess, and a variety of
genetic syndromes. Conversely, growth rate and pubertal development are accelerated in precocious
puberty and in some girls with PCOS
Acanthosis nigricans
Valgus deformities in severe childhood obesity
Investigations
Fasting and 2-hour post glucose and insulin levels. Proinsulin if PC-1 deficiency considered
Fasting lipid panel for detection of dyslipidaemia
Thyroid function tests
Serum leptin if indicated
Karyotype
(continued on next page)

370 I. S. Farooqi

Table 1 (continued)
DNA for molecular diagnosis
Bone age
Growth hormone (GH) secretion and function tests, when indicated
Assessment of reproductive hormones, when indicated
Serum calcium, phosphorus, and parathyroid hormone levels to evaluate for suspected pseudohypoparathyroidism
MRI scan of the brain with focus on the hypothalamus and pituitary, when clinically indicated
ACTH, adrenocorticotropic hormone; POMC, pro-opiomelanocortin; MAOI, monoamine oxidase
inhibitor; BMI, body mass index; WHR, waist to hip circumference ratio; MC4R, melanocortin-4 receptor;
PC-1, prohormone convertase-1.

WAGR syndrome and obesity have been reported with deletions of chromosome
11p14-p12.58

SUMMARY
Obesity is a complex phenotype, and the assessment of obese patients should be
directed at screening for potentially treatable endocrine conditions and identifying
genetic conditions so that appropriate genetic counsellingand in some cases
treatmentcan be instituted (Table 1). Classically, patients affected by these obesity
syndromes have been identified as a result of their association with mental retardation,
dysmorphic features and/or other developmental abnormalities. For the purposes of
History, family history, examination

Suspect syndromal obesity ?

No

yes

Suspect endocrine disorder

Yes

No
Common obesity

Suspect genetic syndrome

Karyotype, methylation studies

(see Figure 4)

consider :
cushing's, hypothyroidism
GH deficiency
Endocrine testing
Neuroimaging
Figure 3. Algorithm for the assessment of an obese child/adult.

OBESITY WITH DEVELOPMENTAL DELAY

Yes

No
Photophobia/nystagmus

Karyotype, FISH/methylation studies

Positive
PraderWilli syndrome
Fragile X syndrome

yes

Negative

No

Alstrms syndrome
Dysmorphia/skeletal abnormalities

Retinitis, pigmentosa/retinal dystrophy

yes
Yes

No

Ulnar mammary syndrome

No

BardetBiedl syndrome
Polydactyly
Hypogonadism in males
Renal abnormalities
Cohen syndrome
Characteristic facial features
Microcephaly

Short in stature
Yes
AHO

Recessive

Dominant

No
BFL syndrome
WilsonTurner syndrome

Leptin level
MC4R deficiency
PC1 deficiency
Absent

Congenital leptin deficiency

hypogonadotrophic hypogonadism
frequent infections,
central hypothyroidism

Present
Consider:
Leptinreceptor
POMC
MC4R

Figure 4. Diagnostic algorithm in monogenic childhood obesity syndromes. BFL, BorjesonForssmanLehmann syndrome; AHO, Albrights hereditary osteodystrophy;
MC4R, melanocortin-4 receptor; PC-1, prohormone convertase-1; POMC, pro-opiomelanocortin.

Genetic and hereditary aspects of childhood obesity 371

Simpson GolabiBehmel type 2

372 I. S. Farooqi

clinical assessment, it remains useful to categorize the genetic obesity syndromes as

those with and without associated developmental delay (Figures 3 and 4). More recently
several new monogenic disorders, resulting from disruption of the leptinmelanocortin
signalling pathway, have been identified. In these disorders, obesity itself is often the
predominant presenting feature, although often accompanied by characteristic patterns
of neuroendocrine dysfunction.

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