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ABSTRACT

  • Craniosynostosis, the premature fusion of one or several sutures of the skull, is one of the commonest craniofacial anomalies at birth with a prevalence of 1 in 2100 to 3000. The shape of the skull is altered depending on which of the sutures are fused prematurely.

  • The etiology of craniosynostosis is heterogeneous. Isolated occurrence with unknown etiology is common, mostly affecting the sagittal suture. Syndromic craniosynostosis has been described in over 100 syndromes which have been delineated based on the suture involvement (most commonly the coronal sutures), craniofacial anomalies, associated limb and other organ system involvement, and inheritance pattern (autosomal dominant and recessive, and X-linked). The clinical features of 27 of the most distinct and important clinical entities associated with craniosynostosis are tabulated.

  • The classical craniosynostosis syndromes are inherited in an autosomal dominant fashion and include Apert (MIM 101200), Pfeiffer (MIM 101600), Saethre-Chotzen (MIM 101400), and Crouzon (MIM 123500) syndromes. They were originally described as separate clinical entities with Apert and sporadic Pfeiffer syndrome generally tending to be more severe than Crouzon and Saethre-Chotzen syndrome.

  • Recently, the molecular bases of these classical disorders, a new common craniosynostosis syndrome (Muenke syndrome (MIM 134934)), and several of the rare craniosynostosis syndromes have been identified. Pfeiffer syndrome is heterogeneous and due to heterozygous mutations in fibroblast growth factor receptor (FGFR) genes 1 and 2. Heterozygous mutations in FGFR2 also cause Apert, Crouzon, Jackson-Weiss (MIM 123150), and Beare-Stevenson (MIM 123790) syndromes. Muenke syndrome was newly defined by a specific mutation in FGFR3, which corresponds to an amino acid substitution equivalent to one change in Apert syndrome in FGFR2 and in Pfeiffer syndrome in FGFR1. Crouzon syndrome with acanthosis nigricans is due to a mutation in FGFR3. Cytogenetic deletions and translocations involving 7p21.1 and various heterozygous mutations in the human/mouse gene symbols for a transcription factor originally named in Drosophila. (TWIST) gene, which maps to this region, cause Saethre-Chotzen syndrome. A missense mutation of the fibrillin-1 (FBN1) gene was identified in a single patient with Shprintzen-Goldberg syndrome (MIM 182212), which is probably genetically heterozygous. Lastly, a specific heterozygous mutation in the human/mouse gene symbols for the MSH (MSX2)(Drosophila) homeobox homolog 2 (MSX2) gene, which has only been observed in a single family, causes Boston-type craniosynostosis (MIM 123101), the first craniosynostosis syndrome in which the genetic etiology was identified.

  • The diagnosis of craniosynostosis syndromes is by clinical examination aided by radiographic imaging of the skull, hands, and feet. Mutation analysis has enabled refinement of this classification by highlighting the etiologic similarities of some disorders (for example, Crouzon and Pfeiffer syndromes due to mutations of FGFR2), whilst clinically similar phenotypes can result from mutations in different genes (for example FGFR3 and TWIST). Molecular analysis also enables the identification of mildly affected carrier parents as well as early prenatal diagnosis.

  • Treatment consists of craniofacial surgery and neurosurgery, and surgical correction of anomalies of the hands and feet. Anomalies in other organ systems ...

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