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J Clin Invest.
Published online 2007 January 18. doi: 10.1172/JCI29884.

Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism

Nelly Pitteloud,1 Richard Quinton,2,3 Simon Pearce,2,4 Taneli Raivio,1 James Acierno,1 Andrew Dwyer,1 Lacey Plummer,1 Virginia Hughes,1 Stephanie Seminara,1 Yu-Zhu Cheng,2,4 Wei-Ping Li,2,4 Gavin Maccoll,5 Anna V. Eliseenkova,6 Shaun K. Olsen,6 Omar A. Ibrahimi,6 Frances J. Hayes,1 Paul Boepple,1 Janet E. Hall,1 Pierre Bouloux,5 Moosa Mohammadi,6 and William Crowley1

1Reproductive Endocrine Unit of the Department of Medicine and Harvard Reproductive Endocrine Science Centers, Massachusetts General Hospital, Boston, Massachusetts, USA. 2Department of Endocrinology and 3Royal Victoria Infirmary, School of Clinical Medical Sciences, and 4Institute for Human Genetics, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom. 5Department of Endocrinology, Royal Free Hospital, London, United Kingdom. 6Department of Pharmacology, New York University School of Medicine, New York, New York, USA.

Address correspondence to: Nelly Pitteloud, Reproductive Endocrine Unit, BHE 5, Massachusetts General Hospital, Boston, 02114 Massachusetts, USA. Phone: (617) 724-1830; Fax: (617) 726-5357; E-mail: npitteloud@partners.org.

Received July 27, 2006; Accepted November 27, 2006.

 
Abstract

Idiopathic hypogonadotropic hypogonadism (IHH) due to defects of gonadotropin-releasing hormone (GnRH) secretion and/or action is a developmental disorder of sexual maturation. To date, several single-gene defects have been implicated in the pathogenesis of IHH. However, significant inter- and intrafamilial variability and apparent incomplete penetrance in familial cases of IHH are difficult to reconcile with the model of a single-gene defect. We therefore hypothesized that mutations at different IHH loci interact in some families to modify their phenotypes. To address this issue, we studied 2 families, one with Kallmann syndrome (IHH and anosmia) and another with normosmic IHH, in which a single-gene defect had been identified: a heterozygous FGF receptor 1 (FGFR1) mutation in pedigree 1 and a compound heterozygous gonadotropin-releasing hormone receptor (GNRHR) mutation in pedigree 2, both of which varied markedly in expressivity within and across families. Further candidate gene screening revealed a second heterozygous deletion in the nasal embryonic LHRH factor (NELF) gene in pedigree 1 and an additional heterozygous FGFR1 mutation in pedigree 2 that accounted for the considerable phenotypic variability. Therefore, 2 different gene defects can synergize to produce a more severe phenotype in IHH families than either alone. This genetic model could account for some phenotypic heterogeneity seen in GnRH deficiency.