Molecular genetics of craniosynostotic syndromes

This article reviews recent molecular genetic findings in autosomal dominant craniosynostotic syndromes. A mutation in the homeotic gene MSX2 was the first genetic defect identified in an autosomal dominant primary craniosynostosis, i.e. in craniosynostosis type 2 (Boston type). In the more common syndromes of Crouzon, Pfeiffer, Jackson-Weiss, and Apert, mutations were found in the gene coding for fibroblast growth factor receptor (FGFR) 2. Less frequently, mutations are observed in FGFR1 and FGFR3 in some cases of Crouzon and Pfeiffer syndrome. The mutations identified in FGFR2 are located in exons 5 and 7 of the gene that code for immunoglobulin (Ig)-like chain III and the region linking Ig II and Ig III of the receptor. These domains of the receptor are important for ligand binding. Apart from Apert syndrome, identical mutations are found in the clinically distinct syndromes of Crouzon, Pfeiffer, and Jackson-Weiss. Furthermore, the same gene defect can result in a highly variable phenotype even within one family. Therefore, the clinically distinct craniosynostotic syndromes are extremes of a spectrum of craniofacial abnormalities and not nosologic entities. In Saethre-Chotzen syndrome, the gene coding for transcription factor TWIST is mutated. The disease genes identified in craniosynostotic syndromes to date either regulate transcription or are required for signal transduction and play a central role in the development of the calvarial sutures.