Saethre-Chotzen syndrome : cranofacial anomalies caused by genetic changes in the TWIST gene

In this thesis, one of the most frequently occurring and most variable craniosynostosis syndromes was investigated; Saethre-Chotzen syndrome. Craniosynostosis is the premature obliteration of cranial sutures in the developing embryo. It can also occur in the first few months of life. Saethre-Chotzen syndrome is, besides craniosynostosis, characterized by specific facial and limb abnormalities, of which the most frequently reported are ptosis, prominent crus helicis, cutaneous syndactyly of digit 2 and 3 on both hands and feet, and broad halluces. Saethre-Chotzen syndrome has been linked to the TWIST gene on chromosome 7p21.1. Mutations in and variably sized deletions of this gene can be found in patients with clinical features of Saethre-Chotzen syndrome. The latter, TWIST deletions, often also include part of the surrounding chromosome 7p and are reported to be associated with mental retardation. In Saethre-Chotzen patients, in whom neither a mutation nor a deletion of TWIST had been found, the FGFR3 P250R mutation was in some cases detected. This mutation has specifically been linked to Muenke syndrome that is characterized by unior bicoronal synostosis and slight facial dysmorphology. However, a Saethre-Chotzen like phenotype can also result from this mutation. Because of the possible overlap of Saethre-Chotzen with Muenke syndrome, these syndromes were studied in order to provide clinical criteria that discriminate between the two (chapter 4). Many phenotypic features occur in both syndromes. In addition, although unicoronal synostosis occurs slightly more frequently in Muenke syndrome, unicoronal and bicoronal synostosis are seen in both syndromes. The discrimination between Saethre-Chotzen and Muenke is often not made easily and the associated genes, TWIST and FGFR3, respectively, are simultaneously tested for pathogenic mutations. Discrimination between the genetic defects involved in each of these syndromes is important since different genetic defects have different physical and mental outcomes.