Achondroplasia: from genotype to phenotype

Abstract

This review focuses on the rheumatological features of achondroplasia, which is the most common skeletal dysplasia and the most frequent cause of short-limbed dwarfism. It is inherited in an autosomal dominant manner but results in the majority of cases of de novo mutations. The disease is related to a mutation in the fibroblast growth factor receptor-3 (FGFR3) gene encoding one member of the FGFR subfamily of tyrosine kinase receptors, which results in constitutive activation of the receptor. Biochemical studies of FGFR3 combined with experiments in knock-out mice have demonstrated that FGFR3 is a negative regulator of chondrocytes proliferation and differentiation in growth plate. This mutation induces a disturbance of endochondral bone formation. The diagnosis of achondroplasia is based on typical clinical and radiological features including short stature, macrocephaly with frontal bossing, midface hypoplasia and rhizomelic shortening of the limbs. The most common rheumatological complications of achondroplasia are medullar and radicular compressions due to spinal stenosis and deformities of the lower limbs. Current treatment and future therapies are discussed.