Genetics of Craniosynostosis: Genes, Syndromes, Mutations and Genotype-Phenotype Correlations

Abstract

Craniosynostosis is a very heterogeneous group of disorders, in the etiology of which genetics play an important role. Chromosomal alterations are important causative mechanisms of the syndromic forms of craniosynostosis accounting for at least 10% of the cases. Mutations in 7 genes are unequivocally associated with mendelian forms of syndromic craniosynostosis: FGFR1, FGFR2, FGFR3, TWIST1, EFNB1, MSX2 and RAB23. Mutations in 4 other genes, FBN1, POR, TGFBR1 and TGFBR2, are also associated with craniosynostosis, but not causing the major clinical feature of the phenotype or with an apparently low penetrance. The identification of these genes represented a great advance in the dissection of the genetics of craniosynostosis in the last 15 years, and today they explain the etiology of about 30% of the syndromic cases. The paucity in the identification of genes associated with this defect has partly been due to the rarity of familial cases. In contrast, very little is known about the molecular and cellular factors leading to nonsyndromic forms of craniosynostosis. Revealing the molecular pathology of craniosynostosis is also of great value for diagnosis, prognosis and genetic counseling. This chapter will review (1) the chromosomal regions associated with syndromic forms of the malformation, (2) the genes in which a large number of mutations have been reported by independent studies (FGFR1, FGFR2, FGFR3, TWIST1 and EFNB1) and (3) the molecular mechanisms and genotype-phenotype correlations of such mutations.

Activation of the IGF1 pathway mediates changes in cellular contractility and motility in single-suture craniosynostosis

“…Indeed, the interplay between IGF1 and Wnt or Fgf signaling pathways has been suggested to contribute to the pathogenesis of craniosynostosis (ten Berge et al, 2008;Behr et al, 2010;Maruyama et al, 2010). For example, a number of mutations, including in the FGFR3, TGFBR1 and TGFB3 genes, have been associated with syndromic forms of the disease (Passos-Bueno et al, 2008;Cunningham et al, 2011). The Notch signaling pathway has also been linked to craniosynostosis as a result of its association with tissue boundary formation, which is important during the patterned growth of the skull (Yen et al, 2010).…”

Role of FGFR2-signaling in the pathogenesis of acne

“…52 Apert syndrome (MIM 101200) results from specific heterozygous missense mutations at two adjacent residues of the FGFR2 gene, Ser252Trp or Pro253Arg, predicted to lie in the linker region between D2-and D3-immunoglobulin-like regions of the FGFR2-ligand binding domain (Fig. 2).…”

Diagnosis of infant synostotic and nonsynostotic cranial deformities: a review for pediatricians

“…- 11 Mutations in 7 genes (namely, FGFR1, FGFR2, FGFR3, TWIST1, EFNB1, MSX2 and RAB23) are unequivocally associated with Mendelian forms of syndromic craniosynostosis 911 In contrast, the genetic etiology of nonsyndromic craniosynostosis remained poorly understood until very recently 911 In the last years, epidemiologic and phenotypic studies clearly demonstrate that nonsyndromic craniosynostosis is a complex and heterogeneous condition supported by a strong genetic component accompanied by environmental factors that contribute to the pathogenesis network of this birth defect 9…”

“…- 11 In contrast, the genetic etiology of nonsyndromic craniosynostosis remained poorly understood until very recently 911 In the last years, epidemiologic and phenotypic studies clearly demonstrate that nonsyndromic craniosynostosis is a complex and heterogeneous condition supported by a strong genetic component accompanied by environmental factors that contribute to the pathogenesis network of this birth defect 910 In fact, rare mutations in FGFRs, TWIST1, LRIT3, ALX4, IGFR1, EFNA4, RUNX2, and FREM1 have been reported in a minor fraction of patients with nonsyndromic craniosynostosis 9…”