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Craniosynostosis syndromes

Larry H Hollier, Jr, MD
Section Editors
Leonard E Weisman, MD
Helen V Firth, DM, FRCP, DCH
Deputy Editor
Elizabeth TePas, MD, MS


Craniosynostosis, defined as premature fusion or growth arrest at one or more of the cranial sutures, most commonly occurs sporadically as an isolated defect. In contrast, syndromic craniosynostosis typically involves multiple sutures as part of a larger constellation of associated anomalies.

Syndromes most frequently associated with craniosynostosis include Apert, Crouzon, Pfeiffer, Carpenter, and Saethre-Chotzen [1]. Syndromic craniosynostoses are often sporadic and are the result of de novo autosomal dominant mutations involving fibroblast growth factor receptors (FGFRs) and TWIST genes. Common features of these conditions are skull-base abnormalities, midface hypoplasia, and limb anomalies. The etiology and clinical features of these disorders are reviewed here. The diagnosis and surgical management of nonsyndromic craniosynostosis are discussed separately. (See "Overview of craniosynostosis".)


Apert syndrome (acrocephalosyndactyly type I, MIM #101200) is an autosomal dominant disorder that occurs in 6 to 15.5 out of 1 million livebirths [2-6]. Most cases are sporadic. Mutations in the gene encoding fibroblast growth factor receptor 2 (FGFR2), located on chromosome 10, account for almost all known cases [7,8].

The fibroblast growth factor (FGF) family, which consists of 18 structurally related proteins, plays a central role in the growth and differentiation of mesenchymal and neuroectodermal cells. FGFRs consist of four tyrosine kinases that bind FGF and play a substantial role in signal transduction. FGFRs regulate cranial suture fusion on a macroscopic level. Animal studies suggest that defective FGF signal transduction due to receptor malfunction leads to growth arrest of the cranium as well as the midface [9].

Two common mutations in the exon IIIa of FGFR2 are associated with Apert syndrome [10]. In a mouse model, small hairpin ribonucleic acid (RNA) was used to suppress transcription of the mutant FGFR2 allele. This prevented the development of Apert-like syndrome in the treated mice [11]. Mutations in the FGFR also have been linked to Crouzon [12,13], Pfeiffer, Muenke [14], Jackson-Weiss [15], and Saethre-Chotzen [16] syndromes.

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Literature review current through: Sep 2017. | This topic last updated: Oct 13, 2017.
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