title: Heterozygous FGF8 mutations in patients presenting cryptorchidism and multiple VATER/VACTERL features without limb anomalies.
abstract: BACKGROUND
  The acronym VATER/VACTERL association describes the combination of at least three of the following cardinal features: vertebral defects, anorectal malformations, cardiac defects, tracheoesophageal fistula with or without esophageal atresia, renal malformations, and limb defects. Although fibroblast growth factor-8 (FGF8) mutations have mainly found in patients with Kallmann syndrome, mice with a hypomorphic Fgf8 allele or complete gene invalidation display, aside from gonadotropin-releasing hormone deficiency, parts or even the entire spectrum of human VATER/VACTERL association.
  
  
  METHODS
  We performed FGF8 gene analysis in 49 patients with VATER/VACTERL association and 27 patients presenting with a VATER/VACTERL-like phenotype (two cardinal features).
  
  
  RESULTS
  We identified two heterozygous FGF8 mutations in patients displaying either VATER/VACTERL association (p.Gly29_Arg34dup) or a VATER/VACTERL-like phenotype (p.Pro26Leu) without limb anomalies. Whereas the duplication mutation has not been reported before, p.Pro26Leu was once observed in a Kallmann syndrome patient. Both our patients had additional bilateral cryptorchidism, a key phenotypic feature in males with FGF8 associated Kallmann syndrome. Each mutation was paternally inherited. Besides delayed puberty in both and additional unilateral cryptorchidism in one of the fathers, they were otherwise healthy. Serum hormone levels downstream the gonadotropin-releasing hormone in both patients and their fathers were within normal range.
  
  
  CONCLUSIONS
  Our results suggest FGF8 mutations to contribute to the formation of the VATER/VACTERL association. Further studies are needed to support this observation.
authors.affiliation: Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Zeidler
authors.forename: Joachim
authors.initials: J
authors.lastname: Woelfle
authors.forename: Markus
authors.initials: M
authors.lastname: Draaken
authors.forename: Sadaf S
authors.initials: SS
authors.lastname: Mughal
authors.forename: Greta
authors.initials: G
authors.lastname: Große
authors.forename: Alina C
authors.initials: AC
authors.lastname: Hilger
authors.forename: Gabriel C
authors.initials: GC
authors.lastname: Dworschak
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Boemers
authors.forename: Ekkehart
authors.initials: E
authors.lastname: Jenetzky
authors.forename: Nadine
authors.initials: N
authors.lastname: Zwink
authors.forename: Martin
authors.initials: M
authors.lastname: Lacher
authors.forename: Dominik
authors.initials: D
authors.lastname: Schmidt
authors.forename: Eberhard
authors.initials: E
authors.lastname: Schmiedeke
authors.forename: Sabine
authors.initials: S
authors.lastname: Grasshoff-Derr
authors.forename: Stefanie
authors.initials: S
authors.lastname: Märzheuser
authors.forename: Stefan
authors.initials: S
authors.lastname: Holland-Cunz
authors.forename: Mattias
authors.initials: M
authors.lastname: Schäfer
authors.forename: Enrika
authors.initials: E
authors.lastname: Bartels
authors.forename: Kathleen
authors.initials: K
authors.lastname: Keppler
authors.forename: Markus
authors.initials: M
authors.lastname: Palta
authors.forename: Johannes
authors.initials: J
authors.lastname: Leonhardt
authors.forename: Christina
authors.initials: C
authors.lastname: Kujath
authors.forename: Anke
authors.initials: A
authors.lastname: Rißmann
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.forename: Heiko
authors.initials: H
authors.lastname: Reutter
authors.forename: Michael
authors.initials: M
authors.lastname: Ludwig
mesh_terms: D001003:Anal Canal / Q000002:abnormalities*; D054304:Anti-Mullerian Hormone / Q000097:blood; D001483:Base Sequence; D003456:Cryptorchidism / Q000235:genetics*; D017931:DNA Primers / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D004947:Esophagus / Q000002:abnormalities*; D051524:Fibroblast Growth Factor 8 / Q000235:genetics*; D005640:Follicle Stimulating Hormone / Q000097:blood; D040461:Gene Components; D005858:Germany; D006330:Heart Defects, Congenital / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007265:Inhibins / Q000097:blood; D007668:Kidney / Q000002:abnormalities*; D017880:Limb Deformities, Congenital / Q000235:genetics*; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D016133:Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D013131:Spine / Q000002:abnormalities*; D013739:Testosterone / Q000097:blood; D014132:Trachea / Q000002:abnormalities*
chemical_list: D017931:DNA Primers; C496456:FGF8 protein, human; C422364:inhibin B; D051524:Fibroblast Growth Factor 8; D013739:Testosterone; D007265:Inhibins; D054304:Anti-Mullerian Hormone; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone
keywords: FGF8; Kallmann syndrome; VACTERL/VATER association; anorectal malformation; cryptorchidism; fibroblast growth factor; hypergonadotropic hypogonadism