Achondroplasia
The most common form of dwarfism (1 in 15,000-40,000 births), caused by a gain-of-function FGFR3 mutation that inhibits bone growth. Vosoritide, a C-type natriuretic peptide analogue, counteracts the FGFR3 signal to increase growth velocity in children. Approved by FDA (2021) and EMA (2021).
Technical Context
FGFR3 gain-of-function mutation (G380R — glycine to arginine at position 380 in the transmembrane domain): constitutive receptor activation → sustained MAPK/ERK signalling in growth plate chondrocytes → inhibited proliferation and premature hypertrophy → shortened long bones, characteristic rhizomelic (proximal) limb shortening, macrocephaly, midface hypoplasia. Inheritance: autosomal dominant, but approximately 80% are new mutations (advanced paternal age is a risk factor). Vosoritide (Voxzogo): 39 amino acid CNP analogue, daily SC injection. Mechanism: NPR-B activation → cGMP → PKG-II → RAF-MEK-ERK pathway inhibition downstream of FGFR3 → restored chondrocyte proliferation and differentiation. Phase III results (ACH-PHITE): annualised growth velocity increased by approximately 1.57 cm/year vs placebo over 52 weeks, sustained through open-label extension. Treatment: initiated in children ≥2 months with open epiphyses, continued until growth plates close. Monitoring: growth velocity, IGF-1, blood pressure (CNP has vasodilatory effects).