Saethre-Chotzen Syndrome: Clinical and Molecular Genetic Aspects

Saethre-Chotzen syndrome (SCS) is one of the frequent autosomal dominant craniosynostosis syndromes with the following main features: coronal suture fusion resulting in progressive synostosis, dilated parietal foramina, low frontal hairline, hypertelorism, ptosis of upper eyelids, small auricles with prominent anthelical crura, broad or bifid great toe and soft tissue syndactyly, but without primary mental retardation. The most striking difference between FGFR1/2-associated craniosynostoses and SCS is the lack of proptosis due to normally sized orbits in the latter. There is a phenotypic overlap with Muenke syndrome, and the mildest forms of SCS present with only isolated coronal synostosis. SCS shows high penetrance but great variability. It is caused by loss-of-function mutations in the TWIST1 gene on chromosome 7p21. TWIST1 is an important transcription factor and part of a complicated signaling pathway involved in both early embryogenesis and later on in chondroblast and osteoblast differentiation. The mutational spectrum comprises missense mutations located mainly in the basic helix-loop-helix domain, nonsense mutations, small in-frame duplications, and whole gene deletions. About one-third of mutations are de novo. There is no recognizable genotype-phenotype correlation. The main complication is a high rate of elevated intracranial pressure due to progressive synostosis.