A novel mutation, Ala315Ser, in FGFR2: a gene-environment interaction leading to craniosynostosis?

Mutations in the fibroblast growth factor receptor 1, 2 and 3 (FGFR1, -2 an d -3) and TWIST genes have been identified in several syndromic forms of cr aniosynostosis. There remains, however, a significant number of patients wi th non-syndromic craniosynostosis in whom no genetic cause can be identifie d. We describe a novel heterozygous mutation of FGFR2 (943G --> T, encoding the amino acid substitution Ala315Ser) in a girl with non-syndromic unicor onal craniosynostosis. The mutation is also present in her mother and her m aternal grandfather who have mild facial asymmetry but do not have craniosy nostosis. None of these individuals has the Crouzonoid appearance typically associated with FGFR2 mutations. However, the obstetric history revealed t hat the proband was in persistent breech presentation in utero and was deli vered by Caesarean section, at which time compression of the skull was appa rent. We propose that this particular FGFR2 mutation only confers a predisp osition to craniosynostosis and that an additional environmental insult (in this case foetal head constraint associated with breech position) is neces sary for craniosynostosis to occur. To our knowledge, this is the first rep ort of an interaction between a weakly pathogenic mutation and intrauterine constraint, leading to craniosynostosis.