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Obesity Due to Proopiomelanocortin Deficiency: Three New Cases and Treatment Trials with Thyroid Hormone and ACTH4–10

Institute of Pediatric Endocrinology (H.K., H.B., D.S., A.G.), University Children’s Hospital, Charite, Humboldt-University Berlin, D-13353 Berlin, Germany; Medical Center Ljubljana University Children’s Hospital (M.Z.T.), SL-61104 Ljubljana, Slovenia; Atrium Medisch Centrum (P.T.), NL-6401 Heerlen, The Netherlands; and University Children’s Hospital (P.E.M.), Inselspital, CH-3010 Bern, Switzerland

Address correspondence and reprint requests to: Dr. Heiko Krude, Institute of Pediatric Endocrinology, Humboldt-University, Augustenburgerplatz 1, D-13353 Berlin. E-mail: heiko.krude{at}charite.de.

The symptoms of severe early-onset obesity, adrenal insufficiency, and red hair define the proopiomelanocortin (POMC) deficiency syndrome as described so far in two children with complete loss-of-function mutations of the human POMC gene. In POMC deficiency, obesity reflects the lack of POMC-derived peptides as ligands at the melanocortin (MC) MC4 and MC3 receptors, which are expressed in the hypothalamic leptin-melanocortin pathway of body weight regulation. Hypocortisolism and alteration of pigmentation are caused by the lack of POMC-derived peptides at the adrenal MC2 receptor and the skin MC1 receptor, respectively. Here we describe three new cases of complete loss-of-function mutations of the POMC gene. Patients were diagnosed based on the clinical trials of red hair, adrenal insufficiency, and early-onset severe obesity. One previously described translation initiation mutation (C3804A) as well as one new nonsense (A6851T) and two new frame-shift mutations (6996del and 7100 + 2G) were found in homozygosity or compound heterozygosity. The heterozygous parents were found to have high normal or mildly elevated body weight, suggesting a dosage effect of the POMC gene product on weight regulation. To compensate for the lack of hypothalamic melanocortin function, we initiated a trial in the two previously published patients with intranasal ACTH4–10, a melanocortin fragment for which an anorexic effect has been described recently. During 3 months with increasing doses of ACTH4–10, no change of body weight or metabolic rate was observed, suggesting that at least in these two POMC-deficient patients ACTH4–10 is without any compensatory effect. In the same two patients, further investigation revealed a mildly elevated TSH. However, a 1-yr treatment with thyroid hormone did not result in a significant reduction of body weight.

This work was supported by the Deutsche Forschungsgemeinschaft (SFB 577-B3) and Swiss Science Foundation (PEM 32-53714.98).

Abbreviations: BMI-SDS_LMS, Body mass index SDscore according to the least mean square method; CNS, Central nervous system; MCR, melanocortin receptor; PC, prohormone convertase; POMC, proopiomelanocortin.

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