Genetic analysis of patients with the Saethre-Chotzen phenotype

Saethre-Chotzen syndrome is a common craniosynostosis syndrome characterized by craniofacial and limb anomalies. Intragenic mutations of the TWIST gene within 7p21 have been identified as a cause of this disorder. There is phenotypic overlap with other craniosynostosis syndromes, and intragenic mutations in FGFR2 (fibroblast growth factor receptor 2) and FGFR3 (fibroblast growth factor receptor 3) have been demonstrated in the other conditions. Furthermore, complete gene deletions of TWIST have also been found in a significant proportion of patients with Saethre-Chotzen syndrome. We investigated 11 patients clinically identified as having the Saethre-Chotzen phenotype and 4 patients with craniosynostosis but without a clear diagnosis. Of the patients with the Saethre-Chotzen phenotype, four were found to carry the FGFR3 P250R mutation, three were found to be heterozygous for three different novel mutations in the coding region of TWIST, and two were found to have a deletion of one copy of the entire TWIST gene. Developmental delay was a distinguishing feature of the patients with deletions, compared to patients with intragenic mutations of TWIST, in agreement with the results of Johnson et al. [1998: Am J Hum Genet 63:1282-1293]. No mutations were found for the four patients with craniosynostosis without a clear diagnosis. Therefore, 9 of our 11 patients (82%) with the Saethre-Chotzen phenotype had detectable genetic changes in FGFR3 or TWIST. We propose that initial screening for the FGFR3 P250R mutation, followed by sequencing of TWIST and then fluorescence in situ hybridization (FISH) for deletion detection of TWIST, is sufficient to detect mutations in > 80% of patients with the Saethre-Chotzen phenotype.