Saethre-Chotzen syndrome (ACS III) is an autosomal dominant craniosynostosis 
syndrome recently ascribed to mutations in the TWIST gene, a basic 
helix-loop-helix (b-HLH) transcription factor regulating head mesenchyme cell 
development during cranial neural tube formation in mouse. Studying a series of 
22 unrelated ACS III patients, we have found TWIST mutations in 16/22 cases. 
Interestingly, these mutations consistently involved the b-HLH domain of the 
protein. Indeed, mutant genotypes included frameshift deletions/insertions, 
nonsense and missense mutations, either truncating or disrupting the b-HLH motif 
of the protein. This observation gives additional support to the view that most 
ACS III cases result from loss-of-function mutations at the 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 failed to harbour TWIST or FGFR 3 
mutations. Clinical re-examination of patients 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 syndrome.