Unexpected endocrine features and normal pigmentation in a young adult patient carrying a novel homozygous mutation in the POMC gene.

Abstract

Proopiomelanocortin (POMC) is the precursor to five biologically active peptides, including ACTH produced in the anterior pituitary and alpha-MSH produced in the hypothalamus. Mutations that inactivate the POMC gene have been described in children, causing a pleiotropic syndrome that includes secondary hypocortisolism, severe obesity, and variable changes in skin and hair pigmentation. We describe a female patient of North African ancestry, homozygous for a frameshift mutation in the POMC gene (6922InsC) that impairs the production of all melanocortin peptides, and that is associated with novel clinical features. Repeated clinical investigations from birth to age 18 yr are presented. ACTH deficiency was diagnosed at birth. Hyperphagia and obesity became apparent before 2 yr of age and rapidly progressed [body mass index (BMI) Z-score, +7 sd at 2 yr, +9.7 sd at 13 yr; BMI, 50 kg/m(2) at 18 yr). At puberty, the patient developed alterations in the somatotropic, gonadotropic, and thyroid axes necessitating hormonal replacement. Surprisingly, there were no obvious pigmentary features; neither the hair color nor measurements of skin reflectance distinguished between the patient and unaffected family members. However, chemical analysis of hair pigment revealed increased production of both pheomelanin and eumelanin. Molecular genetic abnormalities of POMC should always be considered in patients with early onset adrenal insufficiency and obesity, even in the presence of normal pigmentation and multiple pituitary hormone anomalies.