fibrodysplasia ossificans progressiva

Fibrodysplasia ossificans progressiva (FOP) is a severely disabling connective-tissue disorder in which muscles, tendons, and other soft tissues gradually turn into bone outside the normal skeleton. Variants in the ACVR1 gene, which encodes a receptor involved in bone morphogenetic protein signaling, disrupt normal regulation of bone formation and drive this process. The condition is present from birth, with distinctive big-toe malformations often providing the earliest clue, but most complications emerge during childhood and adolescence as extra-skeletal bone accumulates. FOP affects fewer than one in a million people worldwide, making it one of the least common genetic conditions encountered in clinical practice. Both males and females can be affected, and the disorder runs a lifelong course that requires careful, individualized management.

FOP has several hallmark features that help distinguish it from other conditions. At birth, nearly all individuals show abnormal great toes, such as a short, inward-turned hallux or fusion of the first metatarsal bone. During early childhood, episodes of painful soft-tissue swelling called flare-ups lead to heterotopic ossification, meaning bone forms within muscles, ligaments, and other connective tissues where it does not belong. Over time, this extra bone locks major joints, limiting neck movement first and then progressively restricting the shoulders, spine, hips, and limbs. Although FOP is primarily a musculoskeletal condition, it affects multiple body systems. Skeletal complications include spinal rigidity, fused cervical vertebrae, hip dysplasia, and an increased risk of fractures. Respiratory problems may arise when the rib cage becomes stiff, and some individuals experience respiratory insufficiency. Hearing impairment, alopecia, and osteochondromas of long bones are reported in a portion of patients. Laboratory testing often shows chronically elevated alkaline phosphatase levels, reflecting active bone formation. Flare-ups can be triggered by seemingly minor trauma such as intramuscular injections, falls, or surgical procedures, so preventive care is critical. Not all individuals experience every feature, and severity varies considerably from person to person.

FOP is caused by pathogenic variants in the ACVR1 gene. ACVR1 encodes a cell-surface receptor that normally helps regulate bone growth. When altered, the receptor signals too strongly, causing ordinary connective tissues to transform into bone. The disorder is inherited in an autosomal dominant pattern, meaning one altered copy of ACVR1 is sufficient to cause symptoms. An affected parent has a 50 percent chance of passing the variant to each child. While the genetic change leads to disease in nearly everyone who carries it, the degree of impairment can differ greatly, a phenomenon known as variable expressivity. Families are strongly encouraged to meet with a genetic counselor to discuss inheritance, testing options for relatives, and family-planning considerations.

Currently, management focuses on supportive care and symptom control, as no disease-modifying therapy is yet approved. Avoiding intramuscular injections, aggressive dental work, and other sources of soft-tissue injury reduces the risk of flare-ups. During active episodes, individualized medical therapy may lessen pain and swelling, and gentle range-of-motion exercises help maintain whatever mobility is possible without forcing joints. Long-term management relies on a multidisciplinary team that often includes orthopedists, pulmonologists, physical and occupational therapists, rehabilitation specialists, and genetic counselors. Regular surveillance is an essential part of care, helping to identify complications such as spinal curvature or declining lung function before they become serious. Surgical removal of heterotopic bone is generally avoided because the procedure itself can trigger further ossification. Patients and families should review all treatment decisions with clinicians who have experience in FOP.

FOP is a lifelong condition marked by periods of relative stability punctuated by flare-ups that can cause sudden loss of mobility. The extent and pace of progression differ significantly among individuals, and even siblings with the same genetic change may have different courses. Many people eventually require wheelchairs or other mobility aids, and respiratory complications are a major health concern when the chest wall becomes rigid. Outcomes described in medical literature continue to evolve as standards of care improve. Families often find it helpful to connect with specialized centers and experienced clinicians to optimize monitoring and early intervention. Genetic counseling, disease-specific support groups, and patient registries can provide additional resources and help guide future planning.

Several clinical trials are currently investigating new treatments aimed at slowing or preventing heterotopic bone formation in FOP. These studies explore approaches that target the overactive ACVR1 signaling pathway as well as other mechanisms involved in inflammation and bone growth. Individuals interested in clinical trials can search ClinicalTrials.gov or consult their care team about eligibility.