title: A mutation in the fibroblast growth factor receptor 1 gene causes fully penetrant normosmic isolated hypogonadotropic hypogonadism.
abstract: BACKGROUND
  Kallmann syndrome (KS) consists of idiopathic hypogonadotropic hypogonadism (IHH) and anosmia/hyposmia. Currently, the fibroblast growth factor receptor 1 (FGFR1) gene is the only known autosomal dominant cause of KS, which is also associated with synkinesia, midfacial defects, and dental agenesis.
  
  
  OBJECTIVE
  Mutations in FGFR1 typically demonstrate reduced penetrance, variable expressivity, and until recently have been exclusively identified in families with anosmia. The purpose of this study was to determine whether FGFR1 mutations were present in a unique family with autosomal dominant, fully penetrant, normosmic IHH.
  
  
  METHODS
  The study is a review of detailed clinical findings, dynamic endocrine studies, and performance of a molecular analysis of the FGFR1 gene.
  
  
  METHODS
  The study was carried out in an academic medical center.
  
  
  METHODS
  All four affected individuals have complete IHH with full penetrance but no anosmia/hyposmia, and they have none of the FGFR1-associated anomalies. In addition, no other family member has anosmia. Inverventions: Interventions included detailed phenotype characterization including history, physical exam, smell testing, dynamic pituitary testing, brain imaging, and molecular analysis.
  
  
  METHODS
  Outcome was measured by the determination of the severity of IHH, olfactory function, and sequence of the FGFR1 gene.
  
  
  RESULTS
  The same heterozygous nonsense mutation, Arg622X, was present in all four affected members, but not in three unaffected members or 100 controls. The mutation is predicted to encode a truncated protein or result in nonsense-mediated decay.
  
  
  CONCLUSIONS
  Our findings indicate that mutations in the FGFR1 gene can cause normosmic, fully penetrant, complete IHH with little or no variable expressivity, and without the other FGFR1-associated anomalies typically found in KS.
authors.affiliation: Section of Reproductive Endocrinology, Infertility, and Genetics, Department of Obstetrics and Gynecology, The Medical College of Georgia, 1120 15th Street, Augusta, Georgia 30912-3360, USA.
authors.forename: Ning
authors.initials: N
authors.lastname: Xu
authors.forename: Yu
authors.initials: Y
authors.lastname: Qin
authors.forename: Richard H
authors.initials: RH
authors.lastname: Reindollar
authors.forename: Sandra P T
authors.initials: SP
authors.lastname: Tho
authors.forename: Paul G
authors.initials: PG
authors.lastname: McDonough
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Layman
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D004252:DNA Mutational Analysis; D004200:Diseases in Twins / Q000235:genetics; D005260:Female; D006801:Humans; D007006:Hypogonadism / Q000235:genetics*; D017436:Kallmann Syndrome / Q000235:genetics; D008297:Male; D009154:Mutation; D010375:Pedigree; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics*; D014427:Twins
chemical_list: C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1