Screening of patients with craniosynostosis: molecular strategy.

Craniosynostosis is the premature fusion of calvarial bones leading to an abnormal head shape. The craniosynostosis syndromes are clinically heterogeneous with overlapping features, which make an accurate diagnosis difficult at times. Although the clarification of a genetic lesion does not have a direct impact on patient management in many cases, there is a significant benefit in providing accurate prenatal diagnosis. Genetic counsellors are also able to offer better risk estimates of recurrences to non-manifesting carriers and their extended family members and for affected patients of reproductive age. Advances in gene discovery have shown that craniosynostosis syndromes delineated on clinical bases, with the possible exception of Apert syndrome, are genetically heterogeneous, and mutations have been found in fibroblast growth factor receptors (FGFR) 1, 2, 3 and TWIST. We surveyed 99 craniosynostosis patients at the molecular level and found mutations in 50 of them. Six novel point mutations were identified: three in FGFR2 and three in TWIST. Two Saethre-Chotzen patients with TWIST microdeletions at 7p21 were also found. The other mutations identified have been previously reported. In studying these 99 patients, we developed a diagnostic strategy for craniosynostosis testing, where sequential analysis of recurrent mutations was followed by selective sequencing. This algorithm makes testing of craniosynostosis disorders more efficient and cost-effective.