Genetic Mutations and Syndromic Craniosynostosis

  • Increasing awareness with increasing testing: The large number of patients with craniosynostosis now being genetically screened has led to the discovery of an increasing number of rare variants, which are either associated with a reduced penetrance of craniosynostosis or are of uncertain pathogenicity. Environmental, most importantly intrauterine, and genetic factors are the most likely reasons for the variable expressivity and reduced penetrance.
  • Growing appreciation of genetic anomalies and features expressed: The classification of various syndromes on the basis of a particular suture involved can be very misleading. Patients with the same genetic condition may suffer synostosis of different sutures, and the specific suture involved is of secondary importance in this context. The overall pattern of anomalies allows the diagnosis of a specific syndrome, and small differences between syndromes with craniosynostosis may sometimes be very important.
  • FGFR2 most commonly involved gene: The prevalence of independent mutations found in different genes is in the order FGFR2 > FGFR3 > TWIST1 > FGFR1. The p.P250R mutation in FGFR3 (Muenke syndrome) is the single most common craniosynostosis mutation observed (37).

Apert syndrome

  • FGFR2 gene: Inheritance is autosomal dominant with a male-to-female ratio of 1:1 and most cases representing new mutations. In 1995 Wilkie et al. discovered two mutations on FGFR2 (26).

Crouzon syndrome

  • FGFR2 gene: Inheritance is again mostly autosomal dominant. In Atkinson’s review, 67% of the cases were inherited, and 33% were new mutations (27). Increased paternal age at the time of conception was a statistically significant factor in new mutations. To date, at least 30 mutations are known, and almost all are located on FGFR2, some identical to those causing Pfeiffer syndrome.

Muenke syndrome

  • FGFR3: This FGFR3-associated coronal synostosis syndrome is a newly recognized autosomal dominant condition. It was first reported as a unique point mutation on FGFR3 by Bellus et al. in 1996 (29). and Muenke et al. in 1997 (28).

Pfeiffer syndrome

  • FGFR1 and FGFR2: Inheritance is autosomal dominant with complete penetrance and variable expressivity (30). Both familial inheritance, including several documented and reported two- and three-generation families, as well as sporadic cases have been noted (31, 32). Muenke et al., Schell et al., and others showed that mutations on FGFR1 and FGFR2 are related to Pfeiffer syndrome (33, 34, 35). Approximately 30 different mutations have been reported to date, and mutations on FGFR2 seem more likely to be associated with severe craniosynostosis, midface hypoplasia, more pronounced ocular proptosis, and broader thumbs.

Saethre-Chotzen syndrome

  • TWIST: Saethre-Chotzen syndrome is caused by mutations in the TWIST gene located on the short arm of chromosome 7 (36).