Crouzon syndrome affects suture development and is not associated with limb abnormalities, whereas Pfeiffer syndrome and Jackson-Weiss syndrome are characterized by both craniosynostosis and broad medially displaced toes

Mutations in fibroblast growth factor receptor (FGFR) 2 are responsible for several clinically distinct craniosynostosis syndromes in humans (Naski and Ornitz, 1998; Ornitz and Marie, 2002; Wilkie, 1997). These syndromes share a common feature; premature fusion of at least one of the cranial sutures. However, craniosynostosis syndromes also have distinct facial features and some have characteristic limb and joint abnormalities and central nervous system dysfunction. Crouzon syndrome affects suture development and is not associated with limb abnormalities, whereas Pfeiffer syndrome and Jackson-Weiss syndrome are characterized by both craniosynostosis and broad medially displaced toes (Jabs et al., 1994; Rutland et al., 1995). In contrast, Apert syndrome patients develop coronal synostosis, severe bony and soft tissue syndactyly with associated joint fusion, and often have mental retardation (Cohen, 2000). The unique features of craniosynostosis syndromes probably reflect differences in the mechanism by which FGFR activity is altered by specific missense mutations (Wilkie, 1997). Four FGFR tyrosine kinases bind with varying affinity and specificity to a family of 22 FGF ligands (Ornitz and Itoh, 2001). Ligand binding specificity is regulated by specific sequences in the extracellular region and by the alternative splicing of exons encoding the carboxyl-terminal half of immunoglobulin (Ig) domain III. Alternative splicing of Fgfr2 is tissue specific, resulting in epithelial variants (b splice forms) and mesenchymal variants (c splice forms) (Miki et al., 1992; Naski and Ornitz, 1998; Orr-Urtreger et al., 1993). Ligand binding studies demonstrate that mesenchymally expressed ligands such as FGF7 and 10, activate FGFR2b, whereas FGF2, 4, 6, 8 and 9 activate FGFR2c (Ornitz and Itoh, 2001; Ornitz et al., 1996). The majority of missense mutations in FGFR2 result in some ligand-independent dimerization, phosphorylation and constitutive receptor signaling. Interestingly, a single missense mutation which causes Apert syndrome (P252R or S253W in FGFR2) abolishes its ability to discriminate between epithelially and mesenchymally expressed FGF ligands, providing an explanation for the increased severity of Apert syndrome compared to other craniosynostosis syndromes resulting from mutations in FGFR2 (Anderson et al., 1998; Yu et al., 2000; Yu and Ornitz, 2001). Gain-of-function mutations in FGFR3 result in three related dwarfing chondrodysplasia syndromes; hypochondroplasia, 3063 Development 130, 3063-3074 © 2003 The Company of Biologists Ltd doi:10.1242/dev.00491