Obesity, genetics and the skin


  • Conflict of interest: GM is a co-editor of Clinical and Experimental Dermatology

Correspondence: Dr George W. M. Millington, Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, NR4 7UY, UK

E-mail: george.millington@nnuh.nhs.uk


The increasing problem of obesity in childhood is recognized as both a short-term and long-term serious public-health concern. Excess body weight may contribute to psychological morbidity; cancers; metabolic, cardiovascular and musculoskeletal disorders; and dermatological conditions. There is increasing recognition of the role of genetic factors in the aetiology of obesity. Although in the vast majority of cases these influences are polygenic, some obese children suffer from monogenic disorders, which may present with obesity alone. However, more often than not, they generally display other syndromic features. Some of these syndromes have a clear cutaneous phenotype, and these conditions will be the focus of this review.


Obesity affects 22 million children under 5 years of age worldwide,[1] reflecting rapid social changes.[2] Obesity leads to diabetes mellitus, fatty liver, hypertension, sleep disturbance, and musculoskeletal[3] and psychological problems.[4] Not everyone becomes obese, so genetic factors may be relevant in the aetiology of obesity, particularly in children. Simple obesity results from a complex combination of multiple genes,[5] environmental factors or gene–environment interactions,[2, 6] and is associated with skin diseases (Table 1).[7]

Table 1. Cutaneous associations of simple obesity
Poor wound healingKeratosis pilaris
StriaeSkin cancer
Skin changes associated with diabetes mellitusHidradenitis suppurativa
Lymphovascular disorders and ulcerationScleroedema
Cutaneous infectionLivedo reticularis
Hyperandrogenism and hirsuitismPilonidal sinus
PsoriasisCutaneous side effects of obesity treatments
Atopic eczemaRarer disorders

Monogenic syndromes of obesity and skin disease

Certain rare monogenic human obesity syndromes exist,[8-10] which lack primary cutaneous features (Table 2). As these conditions result in severe obesity, affected children are all prone to developing the secondary consequences of obesity, including cutaneous problems (Table 1).[7] Several other monogenic obesity syndromes do have specific cutaneous features, and these form the basis for most this review (Table 3).

Table 2. Monogenic obesity syndromes without cutaneous features
Monogenic obesity syndromeChromosome or gene(s) involved InheritanceOther clinical features
  1. AD, autosomal dominant; AR, autosomal recessive; BDNF, brain-derived neurotrophic factor; MORM, mental retardation, truncal obesity, retinal dystrophy, and micropenis; MOMO, macrosomia, obesity, macrocephaly and ocular abnormalities; XR, X-linked recessive.

Leptin deficiencyLEPARHypogonadism, frequent infections, hypoleptinaemia
Leptin receptor deficiencyLEPRARHypogonadism, hyperleptinaemia
Melanocortin-4 receptor deficiencyMC4RADAccelerated growth, tall stature
BDNF deficiencyBDNF, p13p15.3 invADDevelopmental delay, hyperactivity, memory problems, reduced pain sensation
TrkB deficiencyNTRK2ADDevelopmental delay, hyperactivity, memory problems, reduced pain sensation
SIM1 deficiencySIM1, 1p22.16q16.2 translARDevelopmental delay (severe)
Bardet–Biedel syndromeBBS1-16, ARL6, MKKS, MKS1,CEP290ARDevelopmental delay, polydactyly, retinopathy, renal anomalies
Alström syndromeALMS1, 2p13ARPhotophobia and visual disturbance, deafness and nystagmus, dilated cardiomyopathy, severe insulin resistance, pulmonary, hepatic and urological dysfunction
Carpenter syndromeRAB23, 6p11ARCraniosynostosis, polysyndactyly, cardiac defects
Rubinstein–Taybi syndromeCREBBP, 16p13.3 and EP300, 22q13.2ADShort stature, developmental delay, with broad thumbs and great toes. Ocular, cardiac, renal and dental problems
Börjeson–Forssman–Lehman syndromePHF6, Xq27.3XRDevelopmental delay, epilepsy, hypogonadism, facial swelling, narrow palpebral fissures, large ears
SH2B deficiencySH2B, 16p11.2 Copy number variationInsulin resistance, hyperinsulinaemia
MOMO syndrome??ARMacrosomia, macrocephaly, retinal coloboma and nystagmus, downward slant of the palpebral fissures, mental retardation and delayed bone maturation, short stature
Cohen syndromeVPS13B?Developmental delay, down-sloping palpebral fissures, maxillary hypoplasia,, micrognathia, high-arched palate, dental anomalies, short stature, delayed puberty, insulin resistance, retinopathy, neutropenia
MORM syndromeINPP5E, 9q34ARMental retardation, truncal obesity, retinal dystrophy and micropenis
Table 3. Monogenic obesity syndromes with cutaneous features
Obesity syndrome with skin signsChromosome or gene(s) involved InheritanceCutaneous features Other clinical features
  1. AD, autosomal dominant; AR, autosomal recessive; CNS, central nervous system; MOMES (mental retardation, obesity, mandibular prognathism, eye and skin anomalies) syndrome; PTH, parathyroid hormone; XR, X-linked recessive. *Only obese if Cushing syndrome is present; †secondary skin changes.

Proopiomelanocortin deficiencyPOMCARRed hair, fair (type 1) skinTall stature, hypoadrenalism
Prohormone convertase 1/3 deficiencyPCSK1ARRed hair, fair (type 1) skinPostprandial hypoglycaemia, hypogonadism, elevated proinsulin and 32-33 split proinsulin
Prader–Willi syndrome15q11-q13, SNRPN, NecdinImprintedGeneralised hypopigmentation, acanthosis nigricansDevelopmental delay, hypotonia, short stature, small hands and feet, hypogonadotrophic hypogonadism
McCune–Albright syndrome*GNAS1ImprintedAtypical café-au-lait patches, linear epidermal naevi, pigmentation of the nape of the neckPolyostotic fibrous dysplasia, thyrotoxicosis,† precocious puberty, Cushing's syndrome,† gigantism,† acromegaly,†
Albright hereditary osteodystrophyGNAS1ImprintedSubcutaneous ossification, dimpling over the metacarpo-phalangeal jointsShort stature, skeletal defects and brachydactyly, round facies, multiple hormone resistance (including PTH)
Carney complex*PRKAR1AARLentigines, oral and mucosal pigmentation, multiple blue naevi, schwannomata, café-au-lait macules, breast-duct adenoma, cutaneous and mucosal myxomas, skin tags, lipomas, pilonidal sinusCardiac myxoma, cardiomyopathy, precocious puberty, Cushing syndrome,† gigantism,† acromegaly,† thyroid nodules and carcinoma, prolactinoma, osteochondromyxoma
Fragile X syndrome Xq26.3 Expansion of CGG repeats on X chromosome, leading to failure to express FMR1 geneXRRegional hyperpigmentationDevelopmental delay, prominent mandible, macro-orchidism, large ears, elongated face, hypermobility, muscle hypotonia initially accelerated growth but adult short stature, mitral valve prolapse
MOMES syndrome4q35.1 del, 5p14.3 dupARAtopic eczemaDevelopmental delay, ocular abnormalities, macrocephaly, maxillary hypoplasia, prognathism
Ulnar-mammary syndromeTBX3ADHypohidrosis, nipple hypoplasia to absent breasts, absent axillary hair, nail duplicationMalformed digits, hypogonadism, delayed growth, cardiac-conduction abnormalities, dental abnormalities
Majewski osteodysplastic primordial dwarfism Type IIPCNTARGeneralised hyperpigmentation, freckling, regional hypopigmentation, café-au-lait macules, xerosis, fine sparse hair, polkiloderma, sacral dimplesDelayed growth, bony dysplasia, scoliosis, microcephaly, prominent nose and ears, hypoplastic dentition, developmental delay, CNS aneurysms, risk of haemorrhagic stroke
Coffin–Lowry syndromeCLSXREnlarged lips, lax skinDevelopmental delay, growth retardation, delayed puberty, kyphosis and scoliosis, cervical ribs, pectus carinatum and excavatum, prominent forehead, hypertelorism, downslanting palpebral fissures, prominent and low-set ears, deafness, seizures, ‘drop’ attacks, cardiac problems
Diploid/triploid mosaicismDiploid/triploid mosaicismChromosomal defectTransverse palmar crease, irregular skin pigmentationDevelopmental delay, growth retardation, asymmetrical growth, prominent forehead, micrognathia, low-set ears, hypotonia, precocious puberty, micropenis, cryptorchidism, clinodactyly, syndactyly, narrow and small hands
Prolidase deficiencyPEPDARLeg ulcers, papular erythematous and necrotic lesions, telangiectasiae, pruritis, impetigo-like and eczema-like lesions, photosensitivity, hirsuitismDevelopmental delay, recurrent respiratory infections, hypertelorism, exophthalmos, micrognathia, saddle nose

Proopiomelanocortin and prohormone convertase 1 deficiency

Severe obesity, phototype I skin and red hair[10, 11] are all features of the rare syndromes associated with homozygous mutations in the proopiomelanocortin (POMC) and prohormone convertase 1 (PCCK1) genes, respectively (Fig. 1).[10, 11] POMC and PCCK1 are involved in the same biochemical pathway (Fig. 1).[10, 11] POMC is a propeptide, which produces active peptides via several sequential enzymatic steps (including PCCK1 activity), in a tissue-specific manner, yielding the melanocyte-stimulating hormones (MSHs) corticotrophin (ACTH) and β-endorphin (Fig. 1).[11] The MSHs and ACTH bind to the extracellular melanocortin receptors (MCRs).[11] α-MSH and ACTH bind to the melanocortin 1 receptor (MC1R) to increase pigmentation.[11] Homozygous and heterozygous mutations in MC1R lead to fair skin and red hair in humans, which is also seen with inactivating human POMC mutations.[10, 11] MC1R mutations are associated with increased risk of skin cancer, but POMC single-nucleotide polymorphisms in white populations are not.[7, 11] In the central nervous system, MSH released from POMC neurones binds to the melanocortin 1 receptor (MC4R) in discrete feeding centres, decreasing feeding.[10, 12] Heterozygous mutations in the MC4R gene are associated with severe obesity and tall stature in humans, as with human POMC deficiency.[10, 12]

Figure 1.

Gene structure and post-translational processing of proopiomelanocortin (POMC). POMC in mammals consists of three exons, of which exons 2 and 3 are translated. Prohormone convertases 1 and 2 (PC1/2) break the parent POMC peptide into successively smaller peptides by cleavage at paired dibasic amino acid residues consisting lysine (K) and/or arginine (R). The final products are generated in a tissue-specific manner, for example α-melanocyte-stimulating hormone (MSH) and corticotrophin (ACTH) are not produced by the same cells in the pituitary. They also involve additional enzymatic post-translational modifications, such as the acetylation of α-MSH. The final products include the melanocortins (MSHs and ACTH), β-endorphin (β-end) and corticotropin-like-intermediate peptide (CLIP). There are intermediate peptides whose biological function remains unclear, such as β and γ lipotrophins (β-LPH, γ-LPH).

Humans with PCSK1 deficiency are morbidly obese, with associated glucocorticoid deficiency, hypogonadotropic hypogonadism and postprandial hypoglycaemia.[10] In addition, affected individuals develop severe malabsorption in neonatal life, perhaps as a result of impaired propeptide processing due to lack of PCSK1 within the intestinal hormone-secreting cells.[10] In humans, PCSK1 mutations do not necessarily alter pigmentation, whereas POMC mutations do.[11]

Imprinted gene disorders

Imprinting is the process by which genetic alleles responsible for a phenotype are inherited from one parent only.[13, 14] It is an epigenetic phenomenon resulting from altered DNA methylation, modification of protruding histones, or the effect of noncoding microRNAs on transcription.[13, 14] Prader–Willi syndrome (PWS) is due to inactivation or deletion of a paternally (not maternally) inherited chromosome region, 15q11-q13 (Table 3), leading to severe obesity.[13] Many people with PWS are hypopigmented, but most lack the typical ocular features of albinism.[13] Other cutaneous features of PWS include acanthosis nigricans and decreased pain sensitivity, leading to chronic sores and scars.[13]

G-proteins have either stimulatory (GS) or inhibitory (GI) actions, and transmit extracellular signals received by transmembrane receptors.[13] Each G-protein consists of three subunits.[13] The GNAS1 gene encodes the α subunit of the GS protein, which activates adenyl cyclase, increasing cyclic adenosine monophosphate (cAMP) levels to catalyse further subcellular reactions.[13] Regulation of the GNAS1 genomic region is complex, and is associated with tissue-specific imprinting.[13] All of the diseases in which the GNAS1 gene is mutated have endocrine or skeletal features, and some have quite characteristic cutaneous signs.[13]

McCune–Albright syndrome (MAS) results from a gain-of-function dominant mutation in the GNAS1 gene, expressed in a tissue-specific manner and with the effects of the pathology limited by varying degrees of mosaicism.[13] MAS is characterized by café-au-lait patches or linear epidermal naevi of the skin, polyostotic fibrous dysplasia of bone, and abnormalities of the endocrine system.[13] Pigmentation on the nape of the neck is common.[13] Both bony and pigmentary lesions are characteristically unilateral, stopping sharply at the midline.[13] For a clinical diagnosis, two out of three organs need to be involved (skin, bone, endocrine glands).[13] Obesity is only present if Cushing syndrome (CS) also develops.[13]

Type Ia pseudohypoparathyroidism (also called Albright hereditary osteodystrophy) is characterized by subcutaneous ossifications, brachydactyly, dimpling over the metacarpophalangeal joints, dental abnormalities, resistance to parathyroid hormone and other hormones (lutenizing, thyroid-stimulating and follicle-stimulating hormones), short stature, obesity, round face and developmental delay.[13] It is caused by heterozygous, maternally imprinted loss-of-function mutations in the GNAS1 gene.[13]

Other inherited disorders with cutaneous features and obesity

Carney complex (CC) presents with a range of cutaneous and noncutaneous features, including multiple endocrine neoplasia and cardiac myxomas (Table 3).[15] Obesity develops only if CS forms part of the disease.[15] CC is due to haploinsufficiency of the PRKAR1A gene, which leads to excess cellular cAMP signalling in affected tissues.[15]

Fragile X syndrome is an X-linked recessive condition characterized by developmental delay, obesity, mitral valve prolapse, hypotonia, typical facies, and regional hyperpigmentation.[16, 17] Mutations in the FMR1 gene are characterized by multiple CGG repeats in the promoter region, which block gene transcription.[17]

MOMES (mental retardation, obesity, mandibular prognathism, eye and skin anomalies) syndrome is due to a very rare gene deletion or duplication, probably inherited in a recessive manner.[18, 19] The condition is typified by obesity with atopic eczema and a range of other syndromic features.[18, 19]

Ulnar–mammary syndrome is due to haploinsufficiency of the TBX3 gene.[20-22] In addition to obesity and other syndromic features, cutaneous features include hypohidrosis, amastia, absent axillary hair and nail abnormalities.[20-22]

Majewski osteodysplastic primordial dwarfism type (MOPD) II is caused by homozygous or compound heterozygous mutation in the pericentrin (PCNT) gene on chromosome 21q22.[23] The syndrome is characterized by severe growth retardation along with several other features.[24] The most typical cutaneous features are sparse hair and xerosis at birth.[24] Progressive mottling then develops, with some hypopigmentation and café-au-lait macule formation.[24] Some affected people have extensive freckling.[24]

Coffin–Lowry syndrome (CLS), an X-linked recessive syndrome, is due to a mutation in the CLS locus.[25] The CLS locus encodes ribosomal S6 kinase (RSK)2, which takes part in RAS-mitogen-activated protein kinase signalling.[25] CLS has many cutaneous features, including large lips and lax skin.[26] Female carriers may develop a milder phenotype, which includes obesity and the skin signs described above.[26]

Diploid/triploid mosaicism occurs when, in addition to the normal diploid cell-line in the developing embryo, a second triploid cell-line is present to varying degrees.[27] This can lead to a range of clinical features, typically developmental delay, growth retardation, with asymmetrical growth and obesity.[27] A single palmar crease is typical, and the pigmentary abnormalities can mimic those of hypomelanosis of Ito.[27] Standard karyotyping is normal in 75% of cases.[27] If this diagnosis is suspected, a skin biopsy should be taken to obtain cultured fibroblasts for further karyotyping.[27]

Prolidase deficiency presents with many cutaneous and other syndromic features, but is characterized by early-onset, severe leg ulcers.[28] One case has also been associated with severe, early-onset obesity.[29]


Childhood obesity is an increasing health concern. There is a small number of inherited syndromes characterized by obesity, alone or in combination with other features, including skin disease. The cutaneous features of these latter syndromes are often (but not exclusively) pigmentary in nature. An understanding of the molecular genetics of these disorders may benefit the sciences of both metabolism and dermatology.

What's already known about this topic?

  • Obesity is becoming increasingly common in children.
  • It may have a genetic basis, particularly in this age group, and has severe health implications for the affected child.
  • Both simple obesity and congenital syndromes of obesity are associated with skin diseases.
  • Many of the skin signs associated with congenital obesity syndromes are disorders of pigmentation.
  • Other endocrine problems may be associated with genetic obesity syndromes with cutaneous features.

What does this study add?

  • A classification of the cutaneous problems associated with genetic syndromes of obesity is provided.

CPD questions

Learning objective

The purpose of these questions is to help with understanding the importance of the cutaneous features of inherited childhood obesity syndromes.

Question 1

Worldwide, at the turn of the twenty-first century, how many children under 5 years are obese (approximately)?

  1. 250 000
  2. 2.5 million
  3. 5 million
  4. 25 million
  5. 250 million

Question 2

Which of the following is never associated with generalized hypopigmentation?

  1. POMC deficiency
  2. Prohormone convertase (PCCK)1 deficiency
  3. Type 1a pseudohypoparathyroidism
  4. MC1R mutations
  5. Prader–Willi syndrome

Question 3

Which condition may be associated with Cushing syndrome?

  1. Carney complex
  2. MOPD II
  3. Coffin–Lowry syndrome
  4. POMC deficiency
  5. Prader–Willi syndrome

Question 4

Which condition often presents with café-au-lait macules before other features develop?

  1. Ulnar–mammary syndrome
  2. Prolidase deficiency
  3. Type 1a pseudohypoparathyroidism
  4. Fragile X syndrome
  5. McCune–Albright syndrome

Question 5

Which condition is typically associated with the development of eczema?

  1. Coffin–Lowry syndrome
  2. MOMES syndrome
  3. McCune Albright syndrome
  4. Prader–Willi syndrome
  5. POMC deficiency

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