Extremely Variable Phenotype with Different Mutations at a Single Codon in the FGFR2 Gene. |[dagger]| 801

Craniostenosis syndromes are a group of developmental disorders which has recently been classified based on mutations in a family of genes named fibroblast growth hormone receptor genes (FGFR2 1,2,3). Mutations in the FGFR genes may manifest themselves in overlapping and variable phenotypes as reported in Crouzon, Pfeiffer, and Apert syndromes. An especially severe case of craniostenosis with multiple congenital anomalies resulting in early demise is described. The findings of cloverleaf skull, profound proptosis, radioulnar synostosis, broad thumbs and great toes, led to a clinical diagnosis of Pfeiffer syndrome, type 2. However, the many overlapping findings combined with the abnormal urogenital sinus could also suggest Antley-Bixler syndrome. Chromosomal studies revealed a normal female karyotype. Molecular studies were performed on the known mutation-bearing regions of the FGFR2 gene in order to determine whether a mutation in this gene was responsible for the severity of this infant's anomalies. The patient was found to have a G to T mutation at codon 290 exon 7 of the FGFR2 gene leading to a substitution of a cysteine for the normal tryptophan at this locus. This is the third mutation characterized at this codon; therefore, this locus appears to be a mutational hotspot in the gene. The introduction of an additional cysteine into a region characterized by immunoglobulin-type loops maintained by cysteine S-S crosslinking may provide a rational explanation for the severity of the clinical findings of this infant and insight into the structure and function of the protein.