Best Practice & Research Clinical Endocrinology & Metabolism
Vol. 19, No. 3, pp. 359–374, 2005
available online at http://www.sciencedirect.com
Genetic and hereditary aspects of childhood
I. Sadaf Farooqi*
Wellcome Clinician Scientist Fellow
University Departments of Medicine and Clinical Biochemistry, Box 232, Addenbrooke’s 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
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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 individual’s 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 LEPTIN–MELANOCORTIN 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 blood–brain 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
+ Food intake – Food intake
GnRH MC4R HYPOTHALAMUS
LEPTIN RECEPTORS vv
Y1R v RECEPTORS
Figure 1. The leptin–melanocortin 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 corticotrophin-
releasing 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. Hyperinsulinae-
mia 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 leptin-
deﬁcient 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 levels—alongside features of frank hypothalamic
364 I. S. Farooqi
hypothyroidism—are consistent features will become clear only with the description of
Seven children homozygous or compound heterozygous for mutations in POMC have
been reported.21–23 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 hyper-
phagia 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
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
Prohormone convertase-1 (PC1) deﬁciency
We have previously reported a woman with severe early-onset obesity, hypogonado-
tropic 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 patient—and to a lesser extent in the ﬁrst patient we described—may 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 develop-
mental 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
Bardet–Beidl syndrome has been identiﬁed.31
Bardet–Biedl 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 a-
subunit of a prokaryotic chaperonin.34 Mutations in this gene also cause McKusick–
Kaufman syndrome (hydrometrocolpos, post-axial polydactyly and congenital heart
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 BBS7-
encoded 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.
Albright’s hereditary osteodystrophy
Albright’s 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
Fragile X syndrome
Fragile X syndrome is characterized by moderate to severe mental retardation, macro-
orchidism, 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
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 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 Cohen’s syndrome patients from different ethnic groups.47
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 develop-
mental 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
368 I. S. Farooqi
OBESITY SYNDROMES DUE TO CHROMOSOMAL
The Prader–Willi 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
70–80% 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
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 Prader–Willi 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
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.
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.
Age of onset—use of growth charts and family photographs. Early onset (!5 years of age) suggests a
Duration of obesity—short 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 Cushing’s syndrome. Frequent infections and fatigue may suggest
ACTH deﬁciency due to POMC mutations
Hyperphagia—often 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 delay—milestones, educational history, behavioural disorders. Consider craniophar-
yngeoma or structural causes (often relatively short history) and genetic causes
Visual impairment and deafness can suggest genetic causes
Onset and tempo of pubertal development—onset can be early or delayed in children and adolescents.
Primary hypogonadotropic hypogonadism or hypogenitalism associated with some genetic disorders
Family history—consanguineous 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,
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 Prader–Willi 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 distribution—central distribution with purple striae suggests Cushing’s syndrome. Selective fat
deposition (60%) a feature of leptin and leptin receptor deﬁciency
Dysmorphic features or skeletal dysplasia
Hair colour—red 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
Valgus deformities in severe childhood obesity
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
(continued on next page)
370 I. S. Farooqi
Table 1 (continued)
DNA for molecular diagnosis
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 pseudohypopar-
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
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 counselling—and in some cases
treatment—can 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 ?
Suspect endocrine disorder Suspect genetic syndrome
No Yes Karyotype, methylation studies
Common obesity (see Figure 4)
Figure 3. Algorithm for the assessment of an obese child/adult.
OBESITY WITH DEVELOPMENTAL DELAY
Karyotype, FISH/methylation studies Photophobia/nystagmus
Prader–Willi syndrome Alström’s syndrome
Fragile X syndrome
Retinitis, pigmentosa/retinal dystrophy
Ulnar mammary syndrome
Genetic and hereditary aspects of childhood obesity 371
Simpson Golabi–Behmel type 2
Bardet–Biedl syndrome Short in stature
Polydactyly Recessive Dominant
Hypogonadism in males
AHO BFL syndrome
Cohen syndrome Wilson–Turner syndrome
Characteristic facial features MC4R deficiency
Congenital leptin deficiency Consider:
hypogonadotrophic hypogonadism Leptinreceptor
frequent infections, POMC
central hypothyroidism MC4R
Figure 4. Diagnostic algorithm in monogenic childhood obesity syndromes. BFL, Borjeson–Forssman–Lehmann syndrome; AHO, Albright’s hereditary osteodystrophy;
MC4R, melanocortin-4 receptor; PC-1, prohormone convertase-1; POMC, pro-opiomelanocortin.
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 leptin–melanocortin
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.
*1. Barsh GS, Farooqi IS & O’Rahilly S. Genetics of body-weight regulation. Nature 2000; 404: 644–651.
2. Maes HH, Neale MC & Eaves LJ. Genetic and environmental factors in relative body weight and human
adiposity. Behavior Genetics 1997; 27: 325–351.
3. Bouchard C & Tremblay A. Genetic effects in human energy expenditure components. International
Journal of Obesity 1990; 14(49–55): 55–58. (discussion 55–8).
4. Comuzzie AG. The emerging pattern of the genetic contribution to human obesity. Best Practice and
Research. Clinical Endocrinology and Metabolism 2002; 16: 611–621.
5. Cummings DE & Schwartz MW. Genetics and pathophysiology of human obesity. Annual Review of
Medicine 2003; 54: 453–471.
6. Friedman JM & Halaas JL. Leptin and the regulation of body weight in mammals. Nature 1998; 395: 763–
*7. Schwartz MW, Woods SC, Porte Jr. D, Seeley RJ & Baskin DG. Central nervous system control of food
intake. Nature 2000; 404: 661–671.
8. Coll AP, Farooqi IS, Challis BG et al. Proopiomelanocortin and energy balance: insights from human and
murine genetics. Journal of Clinical Endocrinology and Metabolism 2004; 89: 2557–2562.
9. Zigman JM & Elmquist JK. Minireview: from anorexia to obesity—the yin and yang of body weight control.
Endocrinology 2003; 144: 3749–3756.
* 10. Ahima RS, Prabakaran D, Mantzoros C et al. Role of leptin in the neuroendocrine response to fasting.
Nature 1996; 382: 250–252.
11. Flier JS. Clinical review 94: what’s in a name? In search of leptin’s physiologic role. Journal of Clinical
Endocrinology and Metabolism 1998; 83: 1407–1413.
* 12. Montague CT, Farooqi IS, Whitehead JP et al. Congenital leptin deﬁciency is associated with severe early-
onset obesity in humans. Nature 1997; 387: 903–908.
* 13. Farooqi IS, Matarese G, Lord GM et al. Beneﬁcial effects of leptin on obesity, T cell hyporesponsiveness,
and neuroendocrine/metabolic dysfunction of human congenital leptin deﬁciency. Journal of Clinical
Investigation 2002; 110: 1093–1103.
14. Strobel A, Issad T, Camoin L et al. A leptin missense mutation associated with hypogonadism and morbid
obesity. Nature Genetics 1998; 18: 213–215.
15. Ozata M, Ozdemir IC & Licinio J. Human leptin deﬁciency caused by a missense mutation: multiple
endocrine defects, decreased sympathetic tone, and immune system dysfunction indicate new targets for
leptin action, greater central than peripheral resistance to the effects of leptin, and spontaneous
correction of leptin-mediated defects. Journal of Clinical Endocrinology and Metabolism 1999; 84: 3686–
16. Licinio J, Caglayan S, Ozata M et al. Phenotypic effects of leptin replacement on morbid obesity, diabetes
mellitus, hypogonadism, and behavior in leptin-deﬁcient adults. Proceedings of the National Academy of
Sciences of United States of America 2004; 101: 4531–4536.
17. Farooqi IS, Jebb SA, Langmack G et al. Effects of recombinant leptin therapy in a child with congenital
leptin deﬁciency. New England Journal of Medicine 1999; 341: 879–884.
18. Flier JS, Harris M & Hollenberg AN. Leptin, nutrition, and the thyroid: the why, the wherefore, and the
wiring. Journal of Clinical Investigation 2000; 105: 859–861.
19. Lord GM, Matarese G, Howard JK et al. Leptin modulates the T-cell immune response and reverses
starvation-induced immunosuppression. Nature 1998; 394: 897–901.
Genetic and hereditary aspects of childhood obesity 373
20. Clement K, Vaisse C, Lahlou N et al. A mutation in the human leptin receptor gene causes obesity and
pituitary dysfunction. Nature 1998; 392: 398–401.
* 21. Krude H & Gruters A. Implications of proopiomelanocortin (POMC) mutations in humans: the POMC
deﬁciency syndrome. Trends in Endocrinology and Metabolism 2000; 11: 15–22.
22. Krude H, Biebermann H, Schnabel D et al. Obesity due to proopiomelanocortin deﬁciency: three new
cases and treatment trials with thyroid hormone and ACTH4-10. Journal of Clinical Endocrinology and
Metabolism 2003; 88: 4633–4640.
23. Krude H, Biebermann H, Luck W et al. Severe early-onset obesity, adrenal insufﬁciency and red hair
pigmentation caused by POMC mutations in humans. Nature Genetics 1998; 19: 155–157.
24. Challis BG, Pritchard LE, Creemers JW et al. A missense mutation disrupting a dibasic prohormone
processing site in pro-opiomelanocortin (POMC) increases susceptibility to early-onset obesity through a
novel molecular mechanism. Human Molecular Genetics 2002; 11: 1997–2004.
25. Yeo GS, Farooqi IS, Aminian S et al. A frameshift mutation in MC4R associated with dominantly inherited
human obesity. Nature Genetics 1998; 20: 111–112.
26. Vaisse C, Clement K, Guy-Grand B et al. A frameshift mutation in human MC4R is associated with a
dominant form of obesity. Nature Genetics 1998; 20: 113–114.
* 27. Farooqi IS, Keogh JM, Yeo GS et al. Clinical spectrum of obesity and mutations in the melanocortin 4
receptor gene. New England Journal of Medicine 2003; 348: 1085–1095.
28. Jackson RS, Creemers JW, Ohagi S et al. Obesity and impaired prohormone processing associated with
mutations in the human prohormone convertase 1 gene. Nature Genetics 1997; 16: 303–306.
29. Jackson RS, Creemers JW, Farooqi IS et al. Small-intestinal dysfunction accompanies the complex
endocrinopathy of human proprotein convertase 1 deﬁciency. Journal of Clinical Investigation 2003; 112:
30. O’Rahilly S, Farooqi IS, Yeo GS et al. Minireview: human obesity-lessons from monogenic disorders.
Endocrinology 2003; 144: 3757–3764.
31. Katsanis NAS, Badano JL, Eichers ER et al. Triallelic inheritance in Bardet–Biedl syndrome, a Mendelian
recessive disorder. Science 2001; 293: 2256–2259.
32. Katsanis N. The oligogenic properties of Bardet–Biedl syndrome. Human Molecular Genetics 2004; 13
Spec No. 1: R65–R71.
33. Mykytyn KND, Searby CC, Shastri M et al. Identiﬁcation of the gene (BBS1) most commonly involved in
Bardet–Biedl syndrome, a complex human obesity syndrome. Nature Genetics 2002; 31: 435–438.
34. Katsanis N, Beales PL, Woods MO et al. Mutations in MKKS cause obesity, retinal dystrophy and renal
malformations associated with Bardet–Biedl syndrome. Nature Genetics 2000; 26: 67–70.
35. Badano JL, Ansley SJ, Leitch CC et al. Identiﬁcation of a novel Bardet–Biedl syndrome protein, BBS7, that
shares structural features with BBS1 and BBS2. American Journal of Human Genetics 2003; 72: 650–658.
36. Ansley SJ, Badano JL, Blacque OE et al. Basal body dysfunction is a likely cause of pleiotropic Bardet–Biedl
syndrome. Nature 2003; 425: 628–633.
37. Li JB, Gerdes JM, Haycraft CJ et al. Comparative genomics identiﬁes a ﬂagellar and basal body proteome
that includes the BBS5 human disease gene. Cell 2004; 117: 541–552.
38. Mykytyn K, Braun T, Carmi R et al. Identiﬁcation of the gene that, when mutated, causes the human
obesity syndrome BBS4. Nature Genetics 2001; 28: 188–191.
39. Kim JC, Badano JL, Sibold S et al. The Bardet–Biedl protein BBS4 targets cargo to the pericentriolar
region and is required for microtubule anchoring and cell cycle progression. Nature Genetics 2004; 36:
40. Mykytyn K, Mullins RF, Andrews M et al. Bardet–Biedl syndrome type 4 (BBS4)-null mice implicate Bbs4 in
ﬂagella formation but not global cilia assembly. Proceedings of the National Academy of Sciences of United
States of America 2004; 101: 8664–8669.
41. Weinstein LS, Chen M & Liu J. Gs[alpha] mutations and imprinting defects in human disease. Annales of the
New York Academy of Sciences 2002; 968: 173–197.
42. Weinstein LS, Yu S & Liu J. Analysis of genomic imprinting of Gs alpha gene. Methods in Enzymology 2002;
43. Jin P & Warren ST. New insights into fragile X syndrome: from molecules to neurobehaviors. Trends in
Biochemical Science 2003; 28: 152–158.
44. Hagerman PJ & Hagerman RJ. The fragile-X premutation: a maturing perspective. American Journal of
Human Genetics 2004; 74: 805–816.
374 I. S. Farooqi
45. Lower KM, Turner G, Kerr BA et al. Mutations in PHF6 are associated with Borjeson–Forssman–
Lehmann syndrome. Nature Genetics 2002; 32: 661–665.
46. Cohen Jr. MM, Hall BD, Smith DW et al. A new syndrome with hypotonia, obesity, mental deﬁciency, and
facial, oral, ocular, and limb anomalies. Journal of Pediatrics 1973; 83: 280–284.
47. Chandler KE, Kidd A, Al-Gazali L et al. Diagnostic criteria, clinical characteristics, and natural history of
Cohen syndrome. Journal of Medical Genetics 2003; 40: 233–241.
48. Russell-Eggitt IM, Clayton PT, Coffey R et al. Alstrom syndrome. Report of 22 cases and literature review.
Ophthalmology 1998; 105: 1274–1280.
49. Michaud JL, Heon E, Guilbert F et al. Natural history of Alstrom syndrome in early childhood: onset with
dilated cardiomyopathy. Journal of Pediatrics 1996; 128: 225–229.
50. Collin GB, Marshall JD, Ikeda A et al. Mutations in ALMS1 cause obesity, type 2 diabetes and neurosensory
degeneration in Alstrom syndrome. Nature Genetics 2002; 31: 74–78.
* 51. Goldstone AP. Prader–Willi syndrome: advances in genetics, pathophysiology and treatment. Trends in
Endocrinology and Metabolism 2004; 15: 12–20.
52. Butler M. Prader–Willi syndrome: current understanding of cause and diagnosis. American Journal of
Medical Genetics 35: 319– 1990; 35: 319–332.
53. Haqq AM, Farooqi IS, O’Rahilly S et al. Serum ghrelin levels are inversely correlated with body mass index,
age, and insulin concentrations in normal children and are markedly increased in Prader–Willi syndrome.
Journal of Clinical Endocrinology and Metabolism 2003; 88: 174–178.
54. Cummings DE, Clement K, Purnell JQ et al. Elevated plasma ghrelin levels in Prader Willi syndrome.
Nature Medicine 2002; 8: 643–644.
55. Michaud JL, Boucher F, Melnyk A et al. Sim1 haploinsufﬁciency causes hyperphagia, obesity and reduction
of the paraventricular nucleus of the hypothalamus. Human Molecular Genetics 2001; 10: 1465–1473.
56. Faivre L, Cormier-Daire V, Lapierre JM et al. Deletion of the SIM1 gene [6q16.2] in a patient with a
Prader–Willi-like phenotype. Journal of Medical Genetics 2002; 39: 594–596.
57. Rose EA, Glaser T, Jones C et al. Complete physical map of the WAGR region of 11p13 localizes a
candidate Wilms’ tumor gene. Cell 1990; 60: 495–508.
58. Gul D, Ogur G, Tunca Y & Ozcan O. Third case of WAGR syndrome with severe obesity
and constitutional deletion of chromosome [p12p14]. American Journal of Medical Genetics 2002;