title: Mutations in fibroblast growth factor receptor 1 cause Kallmann syndrome with a wide spectrum of reproductive phenotypes.
abstract: BACKGROUND
  Kallmann's syndrome (KS) is a clinically and genetically heterogeneous disorder consisting of idiopathic hypogonadotropic hypogonadism (IHH) and anosmia. Mutations in KAL1 causing the X-linked form of KS have been identified in 10% of all KS patients and consistently result in a severe reproductive phenotype. KAL1 gene encodes for anosmin-1, a key protein involved in olfactory and GnRH neuronal migration through a putative interaction with FGFR1. Heterozygous mutations in the FGFR1 gene accompanied by a high frequency of cleft palate and other facial dysmorphisms were recently identified in 8% of a large KS cohort, yet the reproductive phenotype of KS patients harboring FGFR1 mutations has not been described.
  
  
  RESULTS
  One hundred and fifty probands with KS (130 males and 20 females) were studied to determine the frequency and distribution of FGFR1 mutations and their detailed reproductive phenotypes. Fifteen heterozygous mutations in unrelated probands were identified. Twelve missense mutations (p.R78C, p.V102I, p.D224H, p.G237D, p.R254Q, p.V273M, p.E274G, p.Y339C, p.S346C, p.I538V, p.G703S and p.G703R) were distributed among the first, second and third immunoglobulin-like domains (D1-D3), as well as the tyrosine kinase domain (TKD). The mutations Y339C and S346C are located in exon 8B and code for the isoform FGFR1c. Additionally, two nonsense mutations (p.T585X and p.R622X) were documented in the TKD of the protein. A wide spectrum of reproductive function was observed among KS probands including: (1) a severe phenotype demonstrated by microphallus, cryptorchidism, no pubertal development, undetectable serum gonadotropins and low serum testosterone (T) and inhibin B; (2) partial pubertal development; (3) the fertile eunuch variant of IHH with normal testicular size and active spermatogenesis with a reversal of HH after T therapy. In addition, we found an even wider spectrum of reproductive function within pedigrees carrying an FGFR1 mutation ranging from IHH to delayed puberty to normal reproductive function (anosmia only or asymptomatic carriers). These observations strongly suggest a role for other genes that modify the phenotype of FGFR1 mutations.
  
  
  CONCLUSIONS
  KS patients and family members carrying an FGFR1 mutation present a broad spectrum of pubertal development in contrast to the almost uniform severe clinical phenotype described in KS subjects with a KAL1 mutation. Additionally, this report implicates the isoform FGFR1c in the pathogenesis of KS.
authors.affiliation: Reproductive Endocrine Unit of the Department of Medicine & National Center for Infertility Research, Bartlett Hall Extension 5, Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114, United States. npitteloud@partners.org
authors.forename: Nelly
authors.initials: N
authors.lastname: Pitteloud
authors.forename: Astrid
authors.initials: A
authors.lastname: Meysing
authors.forename: Richard
authors.initials: R
authors.lastname: Quinton
authors.forename: James S
authors.initials: JS
authors.lastname: Acierno
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Dwyer
authors.forename: Lacey
authors.initials: L
authors.lastname: Plummer
authors.forename: Eric
authors.initials: E
authors.lastname: Fliers
authors.forename: Paul
authors.initials: P
authors.lastname: Boepple
authors.forename: Frances
authors.initials: F
authors.lastname: Hayes
authors.forename: Stephanie
authors.initials: S
authors.lastname: Seminara
authors.forename: Viriginia A
authors.initials: VA
authors.lastname: Hughes
authors.forename: Jinghong
authors.initials: J
authors.lastname: Ma
authors.forename: Pierre
authors.initials: P
authors.lastname: Bouloux
authors.forename: Moosa
authors.initials: M
authors.lastname: Mohammadi
authors.forename: William F
authors.initials: WF
authors.lastname: Crowley
mesh_terms: D000293:Adolescent; D002648:Child; D002972:Cleft Palate / Q000235:genetics; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D006801:Humans; D007006:Hypogonadism / Q000235:genetics; D017436:Kallmann Syndrome / Q000235:genetics*; D008297:Male; D008958:Models, Molecular; D009154:Mutation; D000857:Olfaction Disorders / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D011628:Puberty, Delayed / Q000235:genetics; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics* / Q000502:physiology; D012098:Reproduction / Q000235:genetics* / Q000502:physiology
chemical_list: C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1