Familial craniosynostosis due to Pro250Arg mutation in the fibroblast growth factor receptor 3 gene.

The craniosynostoses, the premature closure of the cranial sutures, are a common heterogeneous group of disorders, affecting about 1 in 2000 children at birth. About 20% have a distinct syndrome defined on clinical and family grounds. The delineation of these syndromes has become more precise with molecular analysis. Mutations in the fibroblast growth factor receptor 1, 2, 3 loci have been identified in craniosynostosis syndromes such as Pfeiffer, Apert, Crouzon, Crouzon with acanthosis nigricans, JacksonWeiss and Beare-Stevenson. The remainder is isolated non-syndromic craniosynostosis. Recently, a mutation in fibroblast growth factor receptor 3 (FGFR3) gene at chromosome 4 (4pl 6) has been described in individuals with a variable picture of craniosynostosis.I The mutation is at C749G predicting a proline 250 arginine aminoacid substitution in the extracellular domain between the second and third immunoglobulinlike loops. The clinical phenotype ofthis mutation is variable, involving unilateral and bilateral craniosynostosis. Most affected individuals have normal-appearing hands and feet, but on radiological investigations may have short, broad middle phalanges of the fingers, absent or hypoplastic middle phalanges of the toes, carpal and tarsal fusion and cone-shaped epiphyses. Some authors have described mental retardation, apparently unrelated to the management of the craniosynostosis.2 This communication describes a family with the FGFR3 Pro25OArg mutation, in which the clinical phenotype encompasses craniosynostosis, macrocephaly, deafness, delayed development, short fingers and toes and proptosis of the eyes.