Fibrodysplasia ossificans progressiva

Fibrodysplasia ossificans progressiva (FOP), also known as myositis ossificans progressiva or Münchmeyer disease, is an extremely rare and severely disabling genetic disorder of the connective tissue characterized by progressive heterotopic ossification — the formation of bone in muscles, tendons, ligaments, and other soft tissues where bone does not normally exist. FOP is caused by mutations in the ACVR1 gene (also known as ALK2), which encodes a bone morphogenetic protein (BMP) type I receptor. The classic mutation, R206H, accounts for the vast majority of cases. This mutation leads to dysregulated BMP signaling, causing the body's repair mechanism to produce bone tissue instead of normal soft tissue following injury, inflammation, or even spontaneously. The hallmark clinical feature present at birth is malformation of the great toes (shortened, deviated, and sometimes monophalangic), which is observed in virtually all affected individuals and serves as an important early diagnostic clue. During childhood, patients begin to experience episodic flare-ups of painful soft tissue swelling, often triggered by trauma, intramuscular injections, viral illnesses, or surgical procedures. These flare-ups progressively transform skeletal muscles and connective tissues into a second skeleton of heterotopic bone, typically following a characteristic pattern — beginning in the dorsal, axial, cranial, and proximal regions and progressing to the ventral, appendicular, caudal, and distal regions. Over time, this extra-skeletal bone formation leads to progressive immobility, with most patients becoming wheelchair-dependent by the third decade of life. The jaw, spine, and shoulders are commonly affected early, leading to difficulties with eating, breathing, and upper limb movement. There is currently no definitive cure or proven treatment to prevent or reverse heterotopic ossification in FOP. Management is primarily supportive and focuses on avoiding known triggers of flare-ups, including intramuscular injections, biopsies, dental procedures, and falls. Corticosteroids and non-steroidal anti-inflammatory drugs may be used during acute flare-ups to reduce inflammation and pain, though their efficacy in preventing ossification is limited. Surgical removal of heterotopic bone is strictly contraindicated as it invariably leads to explosive new bone growth. Palovarotene, a retinoic acid receptor gamma agonist, received regulatory approval in some countries (including Canada in 2022 and the US in 2023 under the brand name Sohonos) for the treatment of FOP, representing the first disease-specific therapy. Several other investigational therapies targeting the BMP signaling pathway are under clinical development. Genetic counseling is recommended for affected families.

Data sourced from FDA regulatory filings and ClinicalTrials.gov. Updated periodically.

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