A novel FGFR2 gene mutation in Crouzon syndrome associated with apparent nonpenetrance

To determine whether specific mutations within the fibroblast growth factor receptor 2 (FGFR2) gene that are associated with Crouzon syndrome can be present in an individual who had been assumed to be "clinically normal."

Most mutations responsible for Crouzon syndrome occur in exons IIIa (U) or IIIc (B) of the FGFR2 gene, which facilitates allelotyping using polymerase chain reaction (PCR)-mediated mutation analysis. Once a specific mutation was identified in the index case, remaining affected family members and "clinically normal" first-degree relatives were analyzed in order to correlate genotype with phenotype.

A novel missense mutation--a G to T transversion--involving the first base of codon 362 was identified in all Crouzon syndrome-affected family members and in one "clinically normal"-appearing parent following DNA sequencing of exon B of the FGFR2 gene and specific BstNI restriction fragment length polymorphism. Pattern profile analysis demonstrated a consistent collection of abnormal cephalometric measurements in the Crouzon-affected family members and, to a lesser degree, in the "clinically normal" parent.

We have identified a novel missense mutation in the FGFR2 gene that predicts an Ala362Ser substitution shared by all family members affected by Crouzon syndrome and by a "clinically normal"-appearing father. These data support nonpenetrance of Crouzon syndrome when the diagnosis is based on clear clinical findings. Only through cephalometry was there an indication of minimal expression of Crouzon syndrome in the "clinically normal"-appearing father.