Prevalence and Complications of Single-Gene and Chromosomal Disorders in Craniosynostosis

<jats:sec><jats:title>OBJECTIVES:</jats:title><jats:p>We describe the first cohort-based analysis of the impact of genetic disorders in craniosynostosis. We aimed to refine the understanding of prognoses and pathogenesis and to provide rational criteria for clinical genetic testing.</jats:p></jats:sec><jats:sec><jats:title>METHODS:</jats:title><jats:p>We undertook targeted molecular genetic and cytogenetic testing for 326 children who required surgery because of craniosynostosis, were born in 1993–2002, presented to a single craniofacial unit, and were monitored until the end of 2007.</jats:p></jats:sec><jats:sec><jats:title>RESULTS:</jats:title><jats:p>Eighty-four children (and 64 relatives) had pathologic genetic alterations (86% single-gene mutations and 14% chromosomal abnormalities). The FGFR3 P250R mutation was the single largest contributor (24%) to the genetic group. Genetic diagnoses accounted for 21% of all craniosynostosis cases and were associated with increased rates of many complications. Children with an initial clinical diagnosis of nonsyndromic craniosynostosis were more likely to have a causative mutation if the synostoses were unicoronal or bicoronal (10 of 48 cases) than if they were sagittal or metopic (0 of 55 cases; P = .0003). Repeat craniofacial surgery was required for 58% of children with single-gene mutations but only 17% of those with chromosomal abnormalities (P = .01).</jats:p></jats:sec><jats:sec><jats:title>CONCLUSIONS:</jats:title><jats:p>Clinical genetic assessment is critical for the treatment of children with craniosynostosis. Genetic testing of nonsyndromic cases (at least for FGFR3 P250R and FGFR2 exons IIIa/c) should be targeted to patients with coronal or multisuture synostoses. Single-gene disorders that disrupt physiologic signaling in the cranial sutures often require reoperation, whereas chromosomal abnormalities follow a more-indolent course, which suggests a different, secondary origin of the associated craniosynostosis.</jats:p></jats:sec>