Fibroblast Growth Factor Receptor 2 (FGFR2) Mutation Related Syndromic Craniosynostosis

Abstract

Craniosynostosis results from the premature fusion of cranial sutures, with an incidence of 1 in 2,100-2,500 live births. The majority of cases are non-syndromic and involve single suture fusion, whereas syndromic cases often involve complex multiple suture fusion. The fibroblast growth factor receptor 2 (FGFR2) gene is perhaps the most extensively studied gene that is mutated in various craniosynostotic syndromes including Crouzon, Apert, Pfeiffer, Antley-Bixler, Beare-Stevenson cutis gyrata, Jackson-Weiss, Bent Bone Dysplasia, and Seathre-Chotzen-like syndromes. The majority of these mutations are missense mutations that result in constitutive activation of the receptor and downstream molecular pathways. Treatment involves a multidisciplinary approach with ultimate surgical fixation of the cranial deformity to prevent further sequelae. Understanding the molecular mechanisms has allowed for the investigation of different therapeutic agents that can potentially be used to prevent the disorders. Further research efforts are need to better understand screening and effective methods of early intervention and prevention. Herein, the authors provide a comprehensive update on FGFR2-related syndromic craniosynostosis.

Keywords: Craniosynostosis.; Fibroblast Growth Factor Receptor; Mutations, Syndromic.

Figure 1

Schematic representation of FGFR signaling pathway. A typical FGFR gene encodes a tyrosine kinase (TK) receptor. This receptor has an extracellular ligand-binding sites, which are comprised of immunoglobulin-like domains (IgI, IgII and IgIII), transmembrane region and divided intracellular tyrosine kinase domains, TK1 and TK2. The signaling pathway mainly operates through at least 3 distinct pathways. Initiation of RAS/MAPK pathways starts with formation of FRS2 complex and regulates cell proliferation and differentiation. The PI3K/AKT pathway controls cells survival and fate determination after getting initiated by FRS2 complex formation. Activation of PKC pathway started with binding of PLCγ to the activated FGFR and regulates morphogenesis and migration of cells.