Heterozygous FGF8 mutations in patients presenting cryptorchidism and multiple VATER/VACTERL features without limb anomalies

Birth Defects Res A Clin Mol Teratol. 2014 Oct;100(10):750-9. doi: 10.1002/bdra.23278. Epub 2014 Aug 8.


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.

Conclusion: Our results suggest FGF8 mutations to contribute to the formation of the VATER/VACTERL association. Further studies are needed to support this observation.

Keywords: FGF8; Kallmann syndrome; VACTERL/VATER association; anorectal malformation; cryptorchidism; fibroblast growth factor; hypergonadotropic hypogonadism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anal Canal / abnormalities*
  • Anti-Mullerian Hormone / blood
  • Base Sequence
  • Cryptorchidism / genetics*
  • DNA Primers / genetics
  • Enzyme-Linked Immunosorbent Assay
  • Esophagus / abnormalities*
  • Fibroblast Growth Factor 8 / genetics*
  • Follicle Stimulating Hormone / blood
  • Gene Components
  • Germany
  • Heart Defects, Congenital / genetics*
  • Heterozygote
  • Humans
  • Inhibins / blood
  • Kidney / abnormalities*
  • Limb Deformities, Congenital / genetics*
  • Luteinizing Hormone / blood
  • Male
  • Molecular Sequence Data
  • Mutation / genetics*
  • Polymerase Chain Reaction
  • Sequence Analysis, DNA
  • Spine / abnormalities*
  • Testosterone / blood
  • Trachea / abnormalities*


  • DNA Primers
  • FGF8 protein, human
  • inhibin B
  • Fibroblast Growth Factor 8
  • Testosterone
  • Inhibins
  • Anti-Mullerian Hormone
  • Luteinizing Hormone
  • Follicle Stimulating Hormone

Supplementary concepts

  • VACTERL association