Fibrodysplasia Ossificans Progressiva

Fibrodysplasia Ossificans Progressiva is caused by a gain-of-function mutation in the ACVR1 gene encoding Activin A Type I Receptor (ALK2), a bone morphogenetic protein (BMP) Type I receptor. Over 99% of FOP cases involve the same mutation (c.617G>A, p.R206H). This mutation causes constitutive ALK2 signaling and inappropriate BMP pathway activation in response to cellular stress. This leads to ectopic bone formation in soft tissues. The disease manifests as periodic flare-ups of inflammation in muscles, tendons, and connective tissues, which progressively transform into bone. FOP typically begins in early childhood with inflammatory swelling, warmth, and tenderness in muscles and soft tissues. These flare-ups are often triggered by physical trauma (even minor), infections, surgery, or stress, though spontaneous flare-ups also occur. Over weeks to months, the inflamed tissue hardens and transforms into bone through endochondral ossification. This ectopic bone formation progressively restricts joint motion and mobility. The condition affects axial muscles first (neck, trunk), then spreads to proximal limb muscles and eventually to distal muscles. Most FOP patients are wheelchair-dependent by their 20s and require assistance with basic functions. Life expectancy is reduced, with median survival approximately 55 years, often from restrictive lung disease due to ossification of chest wall and respiratory muscles.