Achondroplasia is the most common form of genetic disproportionate short stature or dwarfism with an incidence of 1 in 20 000. It is caused by a recurrent mutation (G380R) in FGFR3, which encodes the transmembrane protein fibroblast growth factor receptor type 3, activating the FGFR3 signalling pathway in the absence of its FGF ligand. This disrupts both endochondral and intramembranous ossification, causing a number of bone modelling abnormalities with secondary complications. These include limb shortening with an impact upon the activities of daily living and functionality, macrocephaly with ventriculomegaly, stenosis of the foramen magnum, thoracolumbar kyphosis, lumbar spinal stenosis, chronic otitis media and obstructive sleep apnoea. Additional health considerations are of a propensity towards obesity, chronic pain and degenerative joint disease. Management has always been conservative and anticipatory, with a multidisciplinary input required to alleviate and prevent these complications. Understanding of the underlying molecular mechanism has allowed exploitation of the FGFR3 pathway to develop potential medicinal treatments for achondroplasia. These treatments include long and short-acting C-natriuretic peptide and other therapies that modify the effects of the activated FGFR3 pathway, such as an FGFR3 decoy and an anti-FGFR3 antibody. Here these different strategies will be explored, along with the anticipated effect upon individuals with achondroplasia. The possible application of these strategies in managing other rare diseases will also be discussed.
27 - 29 Sep 2018
European Society for Paediatric Endocrinology