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