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

Objective: To determine whether specific mutations within the fibroblast gr owth factor receptor 2 (FGFR2) gene that are associated with Crouzon syndro me can be present in an individual who had been assumed to be "clinically n ormal." Methods: Most mutations responsible for Crouzon syndrome occur in exons III a (U) or IIIc (B) of the FGFR2 gene, which facilitates allelotyping using p olymerase chain reaction (PCR)-mediated mutation analysis. Once a specific mutation was identified in the index case, remaining affected family member s and "clinically normal" first-degree relatives were analyzed in order to correlate genotype with phenotype, Results: A novel missense mutation-a G to T transversion-involving the firs t base of codon 362 was identified in ail Crouzon syndrome-affected family members and in one "clinically normal"-appearing parent following DNA seque ncing of exon B of the FGFR2 gene and specific BstNI restriction fragment l ength polymorphism. Pattern profile analysis demonstrated a consistent coll ection of abnormal cephalometric measurements in the Crouzon-affected famil y members and, to a lesser degree, in the "clinically normal" parent. Conclusion: We have identified a novel missense mutation in the FGFR2 gene that predicts an Ala362Ser substitution shared by all family members affect ed 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 indicat ion of minimal expression of Crouzon syndrome in the "clinically normal"-ap pearing father.