POMC – Obesity due to Pro-opiomelanocortin Deficiency

Pro-opiomelanocortin (POMC) encodes the precursor of adrenocorticotropic hormone (ACTH) and melanocortin peptides, which regulate adrenal function, energy homeostasis, and pigmentation. Biallelic loss-of-function variants in POMC cause a rare autosomal recessive syndrome characterized by ACTH deficiency, early‐onset severe obesity, red hair, and related endocrinopathies.

Patients typically present in infancy with profound hyperphagia and rapid weight gain, secondary adrenal insufficiency manifesting as hypoglycaemia and seizures, and hypopigmentation with red hair. Apneas and central hypothyroidism may also occur as part of the POMC deficiency spectrum.

Autosomal recessive inheritance is supported by reports of 26 probands across more than 20 unrelated families with homozygous or compound heterozygous POMC variants (PMID:33666293). No significant segregation in heterozygous relatives has been observed, consistent with obligate biallelic deficiency.

The variant spectrum includes frameshift, nonsense, splice-donor, and 5′-UTR mutations. A recurrent homozygous c.206del (p.Pro69LeufsTer2) variant has been identified in consanguineous pedigrees (PMID:28739551). Compound heterozygosity for the 5′-UTR splice mutation c.-11C>A and the nonsense p.Trp84Ter has further delineated genotype–phenotype correlations (PMID:23431750)

Functional studies demonstrate that c.-11C>A reduces POMC mRNA levels and allows only ~17% residual translation, while frameshift and nonsense alleles abolish production of bioactive ACTH and α-MSH (PMID:27906547, PMID:12165561). These data confirm haploinsufficiency and loss‐of‐function as the mechanism of disease.

Heterozygous POMC variants alone do not cause monogenic obesity, though carriers may have modestly elevated body mass index, underscoring the necessity of biallelic hits for full POMC deficiency (PMID:37092539).

Taken together, the POMC–POMC deficiency association is classified as Definitive. Genetic diagnosis enables early adrenal replacement and anticipatory obesity management, and emerging melanocortin‐4 receptor agonists hold promise as targeted therapies. Key take-home: Biallelic POMC LoF variants cause a recognizable autosomal recessive syndrome where molecular diagnosis directly informs clinical care.

References

• Journal of paediatrics and child health • 2021 • Proopiomelanocortin deficiency diagnosed in infancy in two boys and a review of the known cases. PMID:33666293
• Genetic counseling (Geneva, Switzerland) • 2012 • Early-onset severe obesity with ACTH deficiency and red hair in a boy: the POMC deficiency. PMID:23431750
• The Journal of clinical endocrinology and metabolism • 2017 • Late Diagnosis of POMC Deficiency and In Vitro Evidence of Residual Translation From Allele With c.-11C>A Mutation. PMID:27906547
• Human molecular genetics • 2002 • A missense mutation disrupting a dibasic prohormone processing site in pro-opiomelanocortin (POMC) increases susceptibility to early-onset obesity through a novel molecular mechanism. PMID:12165561
• Journal of clinical research in pediatric endocrinology • 2018 • A Patient with Proopiomelanocortin Deficiency: An Increasingly Important Diagnosis to Make. PMID:28739551
• Genetics in medicine • 2023 • Heterozygous pathogenic variants in POMC are not responsible for monogenic obesity: Implication for MC4R agonist use. PMID:37092539

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