• Claudia Zeidler, Joachim Woelfle, Markus Draaken, Sadaf S Mughal, Greta Große, Alina C Hilger, Gabriel C Dworschak, Thomas M Boemers, Ekkehart Jenetzky, Nadine Zwink, Martin Lacher, Dominik Schmidt, Eberhard Schmiedeke, Sabine Grasshoff-Derr, Stefanie Märzheuser, Stefan Holland-Cunz, Mattias Schäfer, Enrika Bartels, Kathleen Keppler, Markus Palta, Johannes Leonhardt, Christina Kujath, Anke Rißmann, Markus M Nöthen, Heiko Reutter, and Michael Ludwig.
• Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany.
• Birth Defects Res. Part A Clin. Mol. Teratol. 2014 Oct 1; 100 (10): 750-9.

BackgroundThe 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.MethodsWe performed FGF8 gene analysis in 49 patients with VATER/VACTERL association and 27 patients presenting with a VATER/VACTERL-like phenotype (two cardinal features).ResultsWe 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.ConclusionOur results suggest FGF8 mutations to contribute to the formation of the VATER/VACTERL association. Further studies are needed to support this observation.© 2014 Wiley Periodicals, Inc.

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