The molecular and genetic basis of fibroblast growth factor receptor 3 disorders: The achondroplasia family of skeletal dysplasias, Muenke craniosynostosis, and Crouzon syndrome with acanthosis nigricans

Achondroplasia, the most common form of short-limbed dwarfism in humans, oc curs between 1 in 15,000 and 40,000 Live births. More than 90% of cases are sporadic and there is, on average, an increased paternal age at the time o f conception of affected individuals. More then 97% of persons with achondr oplasia have a Gly380Arg mutation in the transmembrane domain of the fibrob last growth factor receptor (FGFR) 3 gene. Mutations in the FGFR3 gene also result in hypochondroplasia, the lethal thanatophoric dysplasias, the rece ntly described SADDAN (severe achondroplasia with developmental delay and a canthosis nigricans) dysplasia, and two craniosynostosis disorders: Muenke coronal craniosynostosis and Crouzon syndrome with acanthosis nigricans. Re cent evidence suggests that the phenotypic differences may be due to specif ic alleles with varying degrees of ligand-independent activation, allowing the receptor to be constitutively active. Since the Gly380Arg achondroplasia mutation was recognized, similar observa tions regarding the conserved nature of FGFR mutations and resulting phenot ype have been made regarding other skeletal phenotypes, including hypochond roplasia, thanatophoric dysplasia, and Muenke coronal craniosynostosis. The se specific genotype-phenotype correlations in the FGFR disorders seem to b e unprecedented in the study of human disease. The explanation for this hig h degree of mutability at specific bases remains an intriguing question.