• Martin Wabitsch, Jan-Bernd Funcke, Julia von Schnurbein, Friederike Denzer, Georgia Lahr, Inas Mazen, Mona El-Gammal, Christian Denzer, Anja Moss, Klaus-Michael Debatin, Peter Gierschik, Vanisha Mistry, Julia M Keogh, I Sadaf Farooqi, Barbara Moepps, and Pamela Fischer-Posovszky.
• Division of Pediatric Endocrinology and Diabetes (M.W., J.-B.F., J.v.S., F.D., C.D., A.M., P.F.-P.), and Department of Pediatrics and Adolescent Medicine (G.L., K.-M.D.), University Medical Center Ulm, 89075 Ulm, Germany; Clinical Genetics Department (I.M., M.E.), National Research Center, Cairo 12311, Egypt; Institute of Pharmacology and Toxicology (P.G., B.M.), University Medical Center Ulm, 89081 Ulm, Germany; and University of Cambridge Metabolic Research Laboratories (V.M., J.M.K., I.S.F.), Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom.
• J. Clin. Endocrinol. Metab. 2015 Sep 1;100(9):3227-30.

ContextCongenital leptin deficiency is a very rare cause of severe early-onset obesity. We recently characterized a mutation in the leptin gene (p.D100Y), which was associated with detectable leptin levels and bioinactivity of the hormone.Case DescriptionWe now describe two siblings, a 9-year-old girl and a 6-year-old boy with severe early-onset obesity and hyperphagia, both homozygous for a c.309C>A substitution in the leptin gene leading to a p.N103K amino acid exchange in the protein and detectable circulating levels of leptin. In vitro experiments in a heterologous cell system demonstrated that the mutated protein was biologically inactive. Treatment with sc recombinant human leptin led to rapid improvement of eating behavior and weight loss.ConclusionsSequencing of the leptin gene may need to be considered in hyperphagic, severely obese children with detectable levels of circulating leptin.

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