title: Genetics of congenital hypogonadotropic hypogonadism in Denmark.
abstract: Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder characterized by incomplete/absent puberty caused by deficiency or defective action of gonadotropin-releasing hormone (GnRH). The phenotypic features of patients with CHH vary from genital hypoplasia and absent puberty to reversal of HH later in life. We examined the genetics and clinical features of CHH in Denmark. Forty-one male patients were screened for mutations in KAL1, FGFR1, FGF8, PROK2, PROKR2, GNRHR, TAC3, TACR3, and KISS1R. CHD7 was screened in two patients with hearing loss. In 12 patients, a molecular genetic cause for CHH was found. Four patients had mutations in KAL1 (C105VfsX13, C53X, ex5-8del, R257X), and five in FGFR1 (G97S, R209C, A512V, R646W, and c.1614C>T, (p.I538I), predicted to affect splicing). All 9 had severe HH (cryptorchidism and/or micropenis), and 2 had cleft lip/palate. One patient with a previously reported homozygous R262Q mutation in GNRHR displayed fascinating temporal variation in his phenotype. Two patients with hearing loss had CHD7 mutations (c.7832_7841del (p.K2611MfsX25) and c.2443-2A>C), confirming that CHH patients with CHARGE syndrome-associated features should be screened for mutations in CHD7.
authors.affiliation: Institute of Biomedicine/Physiology, University of Helsinki, Helsinki, Finland; Children's Hospital, Helsinki University Central Hospital (HUCH), Helsinki, Finland. Electronic address: johanna.tommiska@helsinki.fi.
authors.forename: Johanna
authors.initials: J
authors.lastname: Tommiska
authors.affiliation: Institute of Biomedicine/Physiology, University of Helsinki, Helsinki, Finland; Children's Hospital, Helsinki University Central Hospital (HUCH), Helsinki, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Känsäkoski
authors.affiliation: Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Christiansen
authors.affiliation: Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Jørgensen
authors.affiliation: Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jacob Gerner
authors.initials: JG
authors.lastname: Lawaetz
authors.affiliation: Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Anders
authors.initials: A
authors.lastname: Juul
authors.affiliation: Institute of Biomedicine/Physiology, University of Helsinki, Helsinki, Finland; Children's Hospital, Helsinki University Central Hospital (HUCH), Helsinki, Finland.
authors.forename: Taneli
authors.initials: T
authors.lastname: Raivio
mesh_terms: D004265:DNA Helicases / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D003718:Denmark; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D030342:Genetic Diseases, Inborn / Q000235:genetics; D006801:Humans; D007006:Hypogonadism / Q000235:genetics*; D008297:Male; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics*; D011966:Receptors, LHRH / Q000235:genetics*
chemical_list: C076266:ANOS1 protein, human; D004268:DNA-Binding Proteins; D016326:Extracellular Matrix Proteins; C484844:GNRHR protein, human; D009419:Nerve Tissue Proteins; D011966:Receptors, LHRH; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D004265:DNA Helicases; C491434:CHD7 protein, human
keywords: CHARGE syndrome; Congenital hypogonadotropic hypogonadism; Kallmann syndrome; Puberty