Prevalence and complications of single-gene and chromosomal disorders in craniosynostosis.
OBJECTIVE
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.
Wilkie
Andrew O M
AO
Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK. awilkie@hammer.imm.ox.ac.uk
Byren
Jo C
JC
Hurst
Jane A
JA
Jayamohan
Jayaratnam
J
Johnson
David
D
Knight
Samantha J L
SJ
Lester
Tracy
T
Richards
Peter G
PG
Twigg
Stephen R F
SR
Wall
Steven A
SA
D002869:Chromosome Aberrations; D003398:Craniosynostoses / Q000453:epidemiology* / Q000235:genetics* / Q000601:surgery; D020732:Cytogenetic Analysis; D005091:Exons / Q000235:genetics; D030342:Genetic Diseases, Inborn / Q000453:epidemiology* / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008967:Molecular Biology / Q000379:methods; D019635:Neurosurgical Procedures / Q000379:methods; D017354:Point Mutation / Q000235:genetics*; D015995:Prevalence; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics*; D019651:Plastic Surgery Procedures / Q000379:methods; D015398:Signal Transduction / Q000235:genetics
C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3