Four fibroblast growth receptor genes, FGFR1 to FGFR4, encode receptors for the 18 (or more) fibroblast growth factors. Any of the factors can bind to any of the receptors, although there are preferences. Structurally, the receptors consist of an extracellular region, comprising three immunoglobulinlike domains, a single hydrophobic segment that spans the membrane, and a cytoplasmic tyro-sine kinase domain. Binding of the fibroblast growth factor (FGF) ligand to the extracellular domain activates the intracellular tyrosine kinase domain and initiates a signaling pathway that is involved in cell division and differentiation. Mutations that cause hereditary diseases of the skeleton have been discovered in FGFR1, FGFR2, and FGFR3 but not so far in FGFR4. (The only currently reported variant in FGFR4, G388R, is associated with tumor progression and metastasis.) Different gain-of-function mutations in FGFR1, FGFR2, and FGFR3 lead to two major categories of disease, the craniosynostoses and the chondrodysplasias. Mutation effects are varied, including ligand-free receptor dimerization that results in constitutive receptor signaling, direct activation of the tyrosine kinase, and modulation of the receptor ligand binding affinity or specificity.1


Craniosynostosis results from the premature fusion of the cranial sutures. The shape of the skull is dependent on which sutures are affected and at what stage of development the premature fusion occurs. Most cases of simple craniosynostosis are sporadic, but up to 10% may be hereditary. Differentiation of sporadic from hereditary cran-iosynostosis is very important when assessing recurrence risk. The hereditary craniosynostoses are generally characterized by bilateral coronal craniosynostosis (with the exception of Muenke syndrome) in association with specific facial and more variable hand and foot features that delineate the different syndromes. Some types result in cloverleaf skulls due to the premature fusion of all sutures. The craniosynostoses are usually named after the individuals who described them, and all show autosomal dominant transmission with very high or complete pene-trance. Craniosynostosis may be a feature of a very large number (>150) of other genetic syndromes."Splitters" note the variations between the different named syndromes, whereas "lumpers" see them all as fibroblast growth factor receptor (FGFR)-related craniosynostoses. The molecular genetic evidence currently supports both camps: all have FGFR mutations, but both types of heterogeneity are known, sometimes with the same syndrome caused by mutations in different genes, and sometimes the same mutation is found in patients with different clinical diagnoses.

The chondrodysplasias are characterized by abnormalities in the growth of long bones, and an autosomal dominant inheritance pattern would apply if the diseases were not lethal. The nomenclature for the chondrodysplasias is descriptive of the associated pathology. A rare FGFR-related disorder, osteoglophonic dysplasia, is associated with features of both craniosynostoses and chondrodys-plasias, as well as nonossifying bone lesions that create a hollowed-out appearance of bone on x-ray.

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