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A Limited Repertoire of Mutations of the Luteinizing Hormone (LH) Receptor Gene in Familial and Sporadic Patients with Male LH-Independent Precocious Puberty¹

Departments of Human Genetics (H.K., M.v.R., E.C.M.M., H.G.B.) and Pediatrics (B.J.O.), University Hospital, 6500 HB Nijmegen, The Netherlands; the Department of Endocrinology and Reproduction, Erasmus University (J.W.M.M., M.V.-P., A.P.N.T.), 3000 DR Rotterdam, The Netherlands; the Department of Pediatrics, University Hospital (J.M.W.), Leiden, The Netherlands; the Department of Pediatrics, Sophia Children’s Hospital (S.L.S.D.), 30156 Rotterdam, The Netherlands; the Department of Pediatrics, Free University (H.A.D.-v.d.W.), 1081 HV Amsterdam, The Netherlands; the Department of Pediatrics (M.P.-A.), Hospital General de Galacia 15705 Santiago de Compostella, Spain; the Department of Pediatrics, University Hospital (F.D.L.), 90123 Messina, Italy; Hospital Materna-Infantil (N.P.), 08035 Barcelona, Spain; Department of Pediatrics, University of Leeds (J.M.H.B.), Leeds, United Kingdom; Wilhelmina Children’s Hospital (M.J.), 3501 CA Utrecht, The Netherlands; the Department of Pediatrics, Emory University (J.S.P., H.A.L.), Atlanta, Georgia 30322; the Department of Pediatrics, University of Mississippi Medical Center (G.W.M.), Jackson, Mississippi 39216; the Department of Pediatrics, University of Dusseldorf (W.E.), 40225 Dusseldorf, Germany; and the Department of Pediatrics, University Hospital Pisa (G.S.), 56125 Pisa, Italy

Address all correspondence and requests for reprints to: Dr. H. G. Brunner, Department of Human Genetics, University Hospital Nijmegen, Postbox 9101, 6500 HB Nijmegen, The Netherlands. E-mail: h.brunner{at}antrg.azn.nl

Herein, we report mutation analysis of the LH receptor gene in 17 males with LH-independent precocious puberty, of which 8 were familial and 9 had a negative family history. A total of 7 different mutations (all previously reported) were detected in 12 patients. Among 10 European familial male-limited precocious puberty (FMPP) patients who had a LH receptor gene mutation, none had the Asp⁵⁷⁸Gly mutation, which is responsible for the vast majority of cases in the U.S. The restricted number of activating mutations of the LH receptor observed in this and other studies of FMPP strongly suggests that an activating phenotype is associated with very specific sites in the receptor protein. Clinical follow-up of the 5 patients who did not have LH receptor mutations shows that such cases most likely do not have true FMPP. LH receptor mutation analysis provides a sensitive tool for distinguishing true FMPP from other causes of early-onset LH-independent puberty in males.

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