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

Pediatrics. 2010 Aug;126(2):e391-400. doi: 10.1542/peds.2009-3491. Epub 2010 Jul 19.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chromosome Aberrations
  • Craniosynostoses / epidemiology*
  • Craniosynostoses / genetics*
  • Craniosynostoses / surgery
  • Cytogenetic Analysis
  • Exons / genetics
  • Genetic Diseases, Inborn / epidemiology*
  • Genetic Diseases, Inborn / genetics*
  • Humans
  • Infant
  • Infant, Newborn
  • Molecular Biology / methods
  • Neurosurgical Procedures / methods
  • Plastic Surgery Procedures / methods
  • Point Mutation / genetics*
  • Prevalence
  • Receptor, Fibroblast Growth Factor, Type 3 / genetics*
  • Signal Transduction / genetics

Substances

  • FGFR3 protein, human
  • Receptor, Fibroblast Growth Factor, Type 3