Biallelic pathogenic variants in POMC can cause combined pituitary hormonal deficiency associated with severe obesity.

Objective: Biallelic variants in the pro-opiomelanocortin gene (POMC) can cause hypocortisolism, hypopigmentation, and early-onset obesity. Following the identification of 2 patients of combined pituitary hormone deficiency (CPHD), we investigated the prevalence of this association among carriers of rare pathogenic or likely pathogenic (P/LP) POMC variants.

Design: This study is a case report and systematic literature review.

Methods: Genetic analysis was conducted in a family with 2 cousins with childhood-onset obesity and CPHD. We assessed CPHD in carriers for biallelic pathogenic POMC variants using data from the literature and Human Gene Mutation Database. Clinical and biological data were collected, including pituitary axis involvement, obesity onset age, and pituitary imaging results.

Results: The 2 cousins, compound heterozygous for POMC variants, developed CPHD following initial hypocortisolism, with subsequent hypothyroidism, growth hormone deficiency, and hypogonadism. Among 41 patients with biallelic POMC variants identified in the literature, 20 had rare homozygous/compound heterozygous P/LP POMC variants and detailed endocrine evaluations. Of these, 40% presented with CPHD, always associated with early-onset severe obesity and hypocortisolism. Growth hormone deficiency was the most frequent (75%), followed by thyrotropic and gonadotropic deficiencies (62.5%). No anomalies were revealed in pituitary imaging. Two patients recovered the gonadotropic axis after treatment with the MC4R agonist.

Conclusion: These findings underscore the potential for CPHD to occur in carriers of biallelic pathogenic POMC variants. Sequencing the full POMC, including coding and regulatory regions, is crucial in CPHD cases, alongside evaluating all pituitary axes in neonatal hypocortisolism. Beyond weight regulation, setmelanotide may modulate hypothalamic-pituitary function, with implications for fertility.