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.