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Unexpected Endocrine Features and Normal Pigmentation in a Young Adult Patient Carrying a Novel Homozygous Mutation in the POMC Gene

Center of Research on Human Nutrition Ile de France (K.C., B.D., M.M.), Paris, 75013, France; Institut National de la Santé et de la Recherche Médicale, U872 team 7 (K.C., B.D., M.M.), Nutriomique, Cordelier Research Center, Paris, 75006, France; University Pierre et Marie Curie-Paris-6 (K.C.), School of Medicine, Paris, 75006, France; Assistance Publique-Hôpitaux de Paris (AP-HP) (K.C.), Endocrinology and Nutrition Department, Pitié Salpêtrière, Paris, 75013, France; AP-HP, Department of Pediatric Nutrition and Gastroenterology (B.D.), Armand-Trousseau Hospital, Paris, 75012, France; AP-HP, University Paris 7 Diderot (P.C., J.L.), Pediatric Endocrinology Unit, Reference Center for Rare Endocrine Growth Disease, Hôpital Robert Debré, Paris, 75019 France; Department of Chemistry (S.I., K.W.), Fujita Health University School of Health Sciences, Aichi 470-1192, Japan; Department of Genetics (G.S.B.), Stanford University School of Medicine, Stanford, California 94143; and Department of Medicine and Diabetes Research Center (C.V.), University of California San Francisco, San Francisco, California 94305

Address all correspondence and requests for reprints to: Prof. Karine Clément, Endocrinology Department, Pitié-Salpêtrière Hospital, Boulevard de l’Hôpital, 75013 Paris, France. E-mail: karine.clement{at}psl.aphp.fr.

Context: Proopiomelanocortin (POMC) is the precursor to five biologically active peptides, including ACTH produced in the anterior pituitary and -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.

Objective: 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.

Result: 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/m² 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.

Conclusion: 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.