Prevalence and complications of single-gene and chromosomal disorders in craniosynostosis

Abstract

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.

FIGURE 1

Referrals of craniosynostosis to the Oxford Craniofacial Unit by year of birth and final diagnostic category. Note the increased referral of non-syndromic craniosynostosis after the revised service definition issued by the National Specialist Commissioning Advisory Group in 1998 (arrow).

FIGURE 2

The proportion of children with different types of craniosynostosis analysed by final diagnosis. A, Non-syndromic cases (left) and all cases (right) were analysed for children born in the years 1998-2002, to minimise bias from under-ascertainment of non-syndromic cases. B, Proven genetic cases, analysed for all birth years (1993-2002). Dashed line indicates categorical overlap in patient with combined TWIST1 deletion and chromosome translocation. Numbers in square brackets after gene names indicate the number of different mutations identified in that gene.

FIGURE 3

Number of major craniofacial procedures for children followed up for completed half years (up to age 5 years) or whole years (above age 5 years), for ages with n≥5 children in a given category. A, all children, analysed by final diagnosis. B, selected children in the proven genetic category have been subdivided according to whether they had mutations in FGFR2, FGFR3 (P250R), TWIST1 or a chromosome abnormality, and compared to all cases without a laboratory genetic diagnosis (other syndrome and non-syndromic categories combined). Error bars indicate standard error of the mean. Note the change in the age scale at 5 years.