• PMID: 17235395
• Gene Name: GNRH1
• Condition: Idiopathic hypogonadotropic hypogonadism (IHH)
• Association: 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 heter
• Mutation: FGFR1 mutation
• Population size: 2
• Population details: 2 families one with Kallmann syndrome (IHH and anosmia) and another with normosmic IHH,
• Sex: Male
• Infertility type: Male infertility
• Associated genes: FGFR1, LHRH factor (NELF), GNRHR
• Other associated phenotypes: Idiopathic hypogonadotropic hypogonadism (IHH)

Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism

Pitteloud N, Quinton R, Pearce S, Raivio T, Acierno J, Dwyer A, Plummer L, Hughes V, Seminara S, Cheng YZ, Li WP, Maccoll G, Eliseenkova AV, Olsen SK, Ibrahimi OA, Hayes FJ, Boepple P, Hall JE, Bouloux P, Mohammadi M, Crowley W.

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. FAU - Pitteloud, Nelly AU - Pitteloud N AD - Reproductive Endocrine Unit of the Department of Medicine and Harvard Reproductive Endocrine Science Centers, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. npitteloud@partners.org FAU - Quinton, Richard AU - Quinton R FAU - Pearce, Simon AU - Pearce S FAU - Raivio, Taneli AU - Raivio T FAU - Acierno, James AU - Acierno J FAU - Dwyer, Andrew AU - Dwyer A FAU - Plummer, Lacey AU - Plummer L FAU - Hughes, Virginia AU - Hughes V FAU - Seminara, Stephanie AU - Seminara S FAU - Cheng, Yu-Zhu AU - Cheng YZ FAU - Li, Wei-Ping AU - Li WP FAU - Maccoll, Gavin AU - Maccoll G FAU - Eliseenkova, Anna V AU - Eliseenkova AV FAU - Olsen, Shaun K AU - Olsen SK FAU - Ibrahimi, Omar A AU - Ibrahimi OA FAU - Hayes, Frances J AU - Hayes FJ FAU - Boepple, Paul AU - Boepple P FAU - Hall, Janet E AU - Hall JE FAU - Bouloux, Pierre AU - Bouloux P FAU - Mohammadi, Moosa AU - Mohammadi M