Chapter 245

## Abstract

Abstract

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. Treatment consists of craniofacial surgery and neurosurgery, and surgical correction of anomalies of the hands and feet. Anomalies in other organ systems (e.g., respiratory difficulties and others) are treated system by system.

7. The pattern of mutations in FGFR1, FGFR2, and FGFR3, which encode related transmembrane receptor tyrosine kinase proteins, is highly nonrandom. The majority of the craniosynostosis mutations are clustered around the third extracellular immunoglobulin-like domain and are missense substitutions. The recurrent nucleotide transversions causing Apert and Muenke syndromes have the highest mutation rates for transversions currently known in the human genome.

8. Functional studies suggest that these FGFR mutations are activating. Three major mechanisms of activation have been described. The first results in increased affinity for fibroblast growth factors (FGFs), the FGFR ligands. The second is fibroblast growth factor (FGF) independent and promotes covalent or noncovalent receptor dimerization, which is required for activation. Finally, ectopic expression of alternative FGFR splice forms may confer the cell with novel ligand-binding properties.

9. A second important cause of craniosynostosis is heterozygous mutations in TWIST, a transcription factor. In contrast to the FGFR mutations, TWIST mutations appear to result in functional haploinsufficiency and so a wider range of molecular lesions is observed including intragenic mutations, large deletions, and translocations occurring up to 250 kb away from the gene.

10. Growth of the skull and maintenance of suture patency represent a balance between cell division and differentiation. Craniosynostosis mutations provide a genetic means to identify some of the proteins that play a critical role in suture development. This provides a platform for ongoing work to understand the processes of suture biogenesis and the pathophysiology of craniosynostosis mutations.

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