While affected individuals are normal weight at birth, POMC deficiency manifests in infancy with rapid weight gain. MSH produced by neurons in the hypothalamus regulates energy homeostasis, including the anorexic effects of leptin, via binding to melanocortin 3 and 4 receptors. MSH deficiency leads to excessive hunger and hyperphagia, and infants with POMC deficiency typically reach weights in the 99th percentile by age 1. Hyperphagic obesity persists into adulthood in affected individuals. Congenital secondary adrenal insufficiency results from loss of adrenocorticotropic hormone (ACTH) signaling in the adrenal cortex, which can lead to hypoglycemia, cholestasis, and hyperbilirubinemia, and is potentially life-threatening if untreated.
Although pigmentation can be variable, individuals with POMC deficiency most commonly have light skin (Fitzpatrick skin phototype I) and red hair because melanin production is impaired by loss of α-MSH signaling through the melanocortin 1 receptor on melanocytes. Hypopituitarism with deficiencies of thyrotropin, growth hormone (GH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) has rarely been reported in association with POMC deficiency.
E66.8 – Other obesity
702949005 – Proopiomelanocortin deficiency syndrome
Differential Diagnosis & Pitfalls
- Melanocortin 1 receptor (MC1R) loss-of-function polymorphisms – The most common cause of the red hair / light skin phototype phenotype.
- Beckwith-Wiedemann syndrome – Also causes early obesity and hypoglycemia, but usually no hyperphagia. Presents with high birth weight and height (macrosomia) and features such as macroglossia, midline abdominal wall defects, nevus flammeus, and preauricular sinuses.
- Prader-Willi syndrome – Also presents with hyperphagia, but is associated with hypotonia, hypogonadism, and intellectual disability.
- Other monogenic obesity syndromes, including melanocortin 4 receptor (MC4R), leptin, and leptin receptor deficiencies.
- Proprotein convertase 1/3 deficiency – Look for other endocrinopathies, diarrhea, and malabsorption.
- Congenital hypopituitarism – Abnormal development of the pituitary gland results from mutations in the prophet of Pit-1 gene (PROP1) or the POU1F1 gene and can present with variable hormonal deficiencies, severity, and age of onset (from childhood to late adulthood).
- Congenital isolated ACTH deficiency – Caused by mutations in TPIT (TBX19), this typically presents as hypoglycemia in neonates.
- Congenital adrenal hyperplasia – Look for hyperpigmentation, genital ambiguity, and adrenal crisis.
- Familial glucocorticoid deficiency – Presents with hyperpigmentation.