Prevalence and Complications of Single-Gene and Chromosomal Disorders in Craniosynostosis -- Wilkie et al. 126 (2): e391 -- Pediatrics

Published online July 19, 2010
PEDIATRICS Vol. 126 No. 2 August 2010, pp. e391-e400 (doi:10.1542/peds.2009-3491) This Article
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ARTICLES

Prevalence and Complications of Single-Gene and Chromosomal Disorders in Craniosynostosis
Andrew O. M. Wilkie, DM, FRCPa,b,c, Jo C. Byren, MRCGPb, Jane A. Hurst, FRCPc, Jayaratnam Jayamohan, FRCSb, David Johnson, DM, FRCSb, Samantha J. L. Knight, DPhild,e, Tracy Lester, PhDf, Peter G. Richards, FRCSb, Stephen R. F. Twigg, DPhila, Steven A. Wall, FRCSb

a Weatherall Institute of Molecular Medicine,
d National Institute for Health Research Biomedical Research Centre, and
e Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; and
b Oxford Craniofacial Unit, John Radcliffe Hospital, and
c Department of Clinical Genetics and
f Genetics Laboratories, Churchill Hospital, Oxford Radcliffe Hospitals National Health Service Trust, Oxford, United Kingdom

OBJECTIVES
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.

METHODS
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.

RESULTS
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).

CONCLUSIONS
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.

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Key Words: craniosynostosis • coronal synostosis • FGFR2 • FGFR3 • TWIST1 • Muenke syndrome

Abbreviations: CGH = comparative genomic hybridization • CI = confidence interval
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Accepted Apr 19, 2010.
Prevalence and Complications of Single-Gene and Chromosomal Disorders in Craniosynostosis -- Wilkie et al. 126 (2): e391 -- Pediatrics