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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 10 4821-4826
Copyright © 2004 by The Endocrine Society

CLINICAL CASE SEMINAR

Congenital Leptin Deficiency Due to Homozygosity for the {Delta}133G Mutation: Report of Another Case and Evaluation of Response to Four Years of Leptin Therapy

William T. Gibson, I. Sadaf Farooqi, Mary Moreau, Alex M. DePaoli, Elizabeth Lawrence, Stephen O’Rahilly and Rebecca A. Trussell

University Department of Clinical Biochemistry, Cambridge Institute for Medical Research, Addenbrooke’s Hospital (W.T.G., I.S.F., S.O.), Cambridge, United Kingdom CB2 2XY; Department of Pediatric Endocrinology, Alberta Children’s Hospital (M.M., R.A.T.), Calgary, Alberta, Canada T2T 5C7; and Amgen, Inc. (A.M.D., E.L.), Thousand Oaks, California 91320-1799

Address all correspondence and requests for reprints to: Dr. William T. Gibson, University Department of Clinical Biochemistry, Cambridge Institute for Medical Research, Addenbrooke’s Hospital, Cambridge, United Kingdom CB2 2XY. E-mail: wtgibson{at}cmmt.ubc.ca (or sorahill{at}hgmp.mrc.ac.uk).

Congenital leptin deficiency is a rare, but treatable, cause of severe early-onset obesity. To date, two United Kingdom families of Pakistani origin carrying a frameshift/premature stop mutation, c.398delG ({Delta}133G), and one Turkish family carrying a missense mutation, c.313C>T (Arg105Trp), have been described. Affected subjects are homozygotes and manifest severe obesity and hyperphagia accompanied by metabolic, neuroendocrine, and immune dysfunction. The effects of recombinant leptin therapy have been reported in three children with the {Delta}133G mutation, and in all cases this has led to a dramatic resolution of clinical and biochemical abnormalities. We now report a Canadian child, of Pakistani origin but unrelated to the previously reported subjects, presenting with severe hyperphagia and obesity, who was found to be homozygous for the {Delta}133G mutation. In this child, 4 yr of therapy with sc injections of recombinant leptin provided additional evidence for the sustained beneficial effects of leptin replacement on fat mass, hyperinsulinemia, and hyperlipidemia. In addition, leptin administration corrected abnormal thyroid biochemistry and allowed the withdrawal of T4 treatment, providing additional support for the role of leptin in the regulation of the human hypothalamic-pituitary-thyroid axis.




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