Mutations within or upstream of the basic helix-loop-helix domain of the TWIST gene are specific to Saethre-Chotzen syndrome

Saethre-Chotzen syndrome (ACS III) is an autosomal dominant craniosynostosi s syndrome recently ascribed to mutations in the TWIST gene, a basic helix- loop-helix (b-HLH) transcription factor regulating head mesenchyme cell dev elopment during cranial neural tube formation in mouse. Studying a series o f 22 unrelated ACS III patients, we have found TWIST mutations in 16/22 cas es. Interestingly, these mutations consistently involved the b-HLH domain o f the protein. Indeed, mutant genotypes included frameshift deletions/inser tions, nonsense and missense mutations, either truncating or disrupting the b-HLH motif of the protein. This observation gives additional support to t he view that most ACS III cases result from loss-of-function mutations at t he TWIST locus. The P250R recurrent FGFR 3 mutation was found in 2/22 cases presenting mild clinical manifestations of the disease but 4/22 cases fail ed to harbour TWIST or FGFR 3 mutations. Clinical re-examination of patient s carrying TWIST mutations failed to reveal correlations between the mutant genotype and severity of the phenotype. Finally, since no TWIST mutations were detected in 40 cases of isolated coronal craniosynostosis, the present study suggests that TWIST mutations are specific to Saethre-Chotzen syndro me.