obesity due to pro-opiomelanocortin deficiency

Obesity due to pro-opiomelanocortin deficiency is a genetically determined condition that leads to severe, early-onset obesity, adrenal insufficiency, and distinctive pigmentation features such as red hair and pale skin. It is caused by variants in the POMC gene and follows an autosomal recessive inheritance pattern. This condition is very rare, affecting fewer than 1 in 1,000,000 individuals. It most often presents in childhood, with symptoms that may prompt clinical evaluation at an early age.

The clinical presentation of this condition is marked by hallmark features that include adrenocorticotropic hormone deficiency, decreased circulating cortisol levels, obesity, and increased adipose tissue which are observed in all affected individuals. Many patients also experience polyphagia and may develop childhood-onset truncal obesity, cholestasis, and hypopigmentation of the skin. Other variable features include red hair, failure to thrive, growth delay, hypoglycemic seizures, delayed puberty, hyperinsulinemia, and pituitary hypothyroidism. Not all individuals experience all features, and severity varies considerably.

This condition is caused by pathogenic variants in the POMC gene. The POMC protein plays an important role in regulating energy balance, pigmentation, and adrenal function, and disruptions in its production lead to the characteristic features of the condition. It is inherited in an autosomal recessive pattern, which means that an affected individual has inherited two altered copies of the gene, one from each parent. This condition is more common when parents share a common ancestor, and while each pregnancy in affected families has a 25% chance of resulting in an affected child, genetic counseling is recommended to discuss family planning options.

Currently, management focuses on supportive care and symptom management, as there are no FDA-approved or foundational therapies specifically targeting this condition. Treatment is tailored to the individual and typically involves a multidisciplinary team to address aspects such as adrenal insufficiency and weight management. Regular surveillance is an essential part of long-term care, helping to identify potential complications early and guide adjustments in management. Patients should discuss treatment options with their healthcare team to determine which approaches may be most appropriate for their situation, and genetic counseling is recommended to support affected families.

The long-term outlook for individuals with obesity due to pro-opiomelanocortin deficiency varies considerably and depends on the severity of symptoms as well as access to comprehensive care. With current standards of care, many individuals manage their symptoms into adulthood, although the condition requires lifelong monitoring. Outcomes described in medical literature continue to evolve as standards of care improve. Families often find it helpful to connect with specialists familiar with this condition, and genetic counseling provides valuable guidance for understanding inheritance and planning for the future.

Clinical trials are underway exploring new treatment approaches for this condition. Individuals interested in clinical trials can search ClinicalTrials.gov or consult their care team about eligibility.