Absence of Syndactyly Associated With the Common Apert FGFR2 S252W Mutation: A Clinical Report and Likely Molecular Explanation

ABSTRACTApert syndrome is a recognizable craniofacial condition characterized by craniosynostosis, hypertelorism, exorbitism, midface hypoplasia, and complex symmetrical bony and cutaneous ‘mitten’ syndactyly of all four limbs. Around 98% of affected patients have one of two heterozygous missense variants in the FGFR2 gene, encoding either p.(Ser252Trp) (S252W) or p.(Pro253Arg) (P253R). We report a patient with unicoronal craniosynostosis and near normal limbs, in whom we unexpectedly identified a heterozygous FGFR2 S252W variant. Her mother, who had no history suggestive of craniosynostosis and only mild brachydactyly, was also found to carry the variant. We discuss evidence that the presence of a second novel FGFR2 p.(Gly261Arg) missense variant, identified in cis in both patients, could explain the mild phenotype. A similar mechanism may be responsible for occasional reports of Pfeiffer syndrome associated with a common Apert genotype, for which no molecular mechanism has been elucidated previously. Our findings provide further insight into the mechanism of the severe syndactyly that is usually characteristic of Apert syndrome.