Genetic and epigenetic influences of twins on the pathogenesis of craniosynostosis: a meta-analysis

Plast Reconstr Surg. 2012 Apr;129(4):945-954. doi: 10.1097/PRS.0b013e31824422a8.


Background: The pathoetiology of craniosynostosis is not well understood. It likely results from a combination of genetic and epigenetic phenomena, such as intrauterine constraint from multiple gestations. Information on craniosynostosis in twins is limited to case reports and series. The authors conducted a systematic review and meta-analysis of the literature to elucidate the genetic and nongenetic influences of twins on the pathogenesis of craniosynostosis.

Methods: PubMed and Ovid databases were reviewed for the key terms "craniosynostosis and twins." Data analyzed included demographical information, incidence rates, concordance, and phenotypic variability. Risk factors for craniosynostosis, concordance, and phenotypic variability were assessed by univariate and multivariate analyses. A case series was presented.

Results: Data were extracted from 34 journal articles, including the authors' five patients, and representing a total of 199 twins with craniosynostosis. Twinning was 2.62 times greater in patients with craniosynostosis (6.29 percent) compared with unaffected controls (2.4 percent; p < 0.0001). Boys were affected more than girls (65.30 versus 34.70 percent, respectively; p < 0.0001). Monozygotic concordance rates were greater than dizygotic (60.90 versus 5.30 percent, respectively; p < 0.0001) but were not 100 percent. Phenotypic variability was present in 62 percent of monozygotic twin sets (p < 0.05).

Conclusions: Increased concordance rates among monozygotic compared with dizygotic twins confirm the genetic role of twins on craniosynostosis. Evidence to support the epigenetic influence of twinning on the pathogenesis of craniosynostosis includes the elevated incidence of twins among a craniosynostotic population compared with unaffected twins in the general population and male gender predominance, as well as monozygotic phenotypic variability and discordance.

Clinical question/level of evidence: Risk, IV.

Publication types

  • Meta-Analysis
  • Review
  • Systematic Review

MeSH terms

  • Craniosynostoses / genetics*
  • Diseases in Twins / genetics*
  • Epigenesis, Genetic*
  • Female
  • Humans
  • Infant
  • Male
  • Twins, Dizygotic
  • Twins, Monozygotic