Fibrodysplasia ossificans progressiva, usually called FOP, is a genetic condition in which the body gradually builds a second skeleton on top of the first. Muscles, tendons, and ligaments transform into solid bone after injury, illness, or sometimes for no obvious reason at all, locking joints in place permanently. It affects roughly one in every two million people worldwide, making it one of the rarest diseases known to medicine. The condition’s rarity, combined with its bizarre presentation, means that most doctors will never encounter a single case in their careers, and the people who have it face an extraordinary set of challenges that researchers are only now beginning to address with targeted therapies.
What Happens in FOP
Children with FOP usually look healthy at birth aside from one telltale feature: their big toes are short, angled inward, and malformed. That toe abnormality is present at birth and can be spotted on an X-ray before any other sign of the disease appears.1PubMed Central. The Diversity of the Clinical Phenotypes in Patients With Fibrodysplasia Ossificans Progressiva During the first decade of life, children begin experiencing painful soft-tissue swellings called flare-ups. These episodes can be triggered by falls, muscle injuries, viral illnesses, intramuscular injections, or even prolonged muscle stretching and fatigue.2PubMed Central. Fibrodysplasia ossificans progressiva: clinical and genetic aspects Within weeks to months, the swollen tissue is replaced by mature, structurally normal bone that forms outside the skeleton. The process is called heterotopic ossification, and it is irreversible. Once a joint is bridged by this extra bone, it is fused for life.
The disease tends to follow a predictable geographic pattern on the body, starting in the neck and upper back, moving to the shoulders, then down the trunk and limbs. The diaphragm, tongue, heart, and smooth muscles of the digestive tract are spared, which is why people with FOP can still breathe and eat even as the rest of their body stiffens. But the muscles between the ribs and around the spine are not spared, and their ossification has serious consequences for breathing, which we will come to shortly.
The Genetic Mutation Behind FOP
Virtually every person with classic FOP carries the same single-letter change in a gene called ACVR1 (also known as ALK2). This gene encodes a receptor in the bone morphogenetic protein signaling pathway, a system the body normally uses during skeletal development and fracture repair. The mutation is so specific that it has been described as one of the most highly conserved disease-causing mutations in the human genome.3PubMed Central. Fibrodysplasia ossificans progressiva
The key insight, discovered in the mid-2010s, is that the mutant receptor responds abnormally to a signaling molecule called Activin A. In people without FOP, Activin A actually dampens bone-formation signals through this receptor. But in people with the FOP mutation, the receptor misreads Activin A as a “go build bone” command.4PubMed Central. ACVR1R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A Activin A is released during inflammation and tissue injury, which explains why trauma, surgery, and even viral infections can set off episodes of new bone formation. Research in mouse models has confirmed that Activin A is both necessary and sufficient to drive heterotopic ossification when the mutant receptor is present.5PubMed Central. The obligatory role of Activin A in the formation of heterotopic bone in Fibrodysplasia Ossificans Progressiva
Within the affected tissue, research increasingly points to a specific cell population called fibro-adipogenic progenitors (FAPs) as the main culprits. These cells, which normally help repair injured muscle, instead veer into bone-forming pathways when they carry the mutant receptor. They not only produce bone themselves but create an environment that suppresses normal muscle regeneration.6PubMed Central. Cellular and Molecular Mechanisms of Heterotopic Ossification in Fibrodysplasia Ossificans Progressiva
Why FOP Is So Often Misdiagnosed
The average delay between a child’s first symptoms and a correct FOP diagnosis is disturbingly long, sometimes spanning years. The early swellings can resemble aggressive tumors, infections, or other inflammatory conditions, and FOP is so rare that most clinicians do not think to look for it.7PubMed Central. Fibrodysplasia Ossificans Progressiva: Difficulty in Diagnosis and Management Tragically, some children undergo biopsies of the suspicious lumps, which amounts to the worst possible intervention: cutting into the tissue triggers new bone growth at the biopsy site and can accelerate the disease’s progression.
The malformed great toes are the single most reliable early clue. They are present at birth, before any flare-ups have occurred, and a simple foot X-ray can reveal the characteristic shortening and abnormal shape. Yet this sign is routinely overlooked because pediatricians are not trained to connect a slightly odd-looking toe with a catastrophic bone-formation disorder. Current management guidelines stress that early recognition of the toe malformation, combined with genetic testing for the ACVR1 mutation, is the most important step in preventing iatrogenic harm from unnecessary biopsies and injections.8PubMed Central. Fibrodysplasia ossificans progressiva: diagnosis, management, and therapeutic horizons
Flare-Up Triggers and Prevention
Soft-tissue trauma is the most common trigger for a flare-up, but the list of provocations goes well beyond obvious injuries. A childhood fall on the playground, an intramuscular vaccination (particularly when given in the deltoid muscle), overstretching during physical therapy, and even dental procedures can all set off new bone formation. Viral illnesses pose a significant and under-recognized risk: a survey of FOP patients found that the chance of a flare-up during an influenza-like illness was increased at least threefold compared to baseline, and possibly much more.9PubMed. Influenza-like viral illnesses and flare-ups of fibrodysplasia ossificans progressiva Researchers suspect this happens because viral illness causes muscle inflammation, creating the same local tissue-injury signals that follow a fall or injection.
Because of these triggers, people with FOP and their families live with an extraordinary level of vigilance. Children are typically advised against contact sports, intramuscular injections (vaccines should be given subcutaneously when possible), and even routine blood draws from certain sites. When a significant soft-tissue injury does occur, clinical guidelines recommend a short, high-dose course of corticosteroids, specifically prednisone at roughly 2 mg/kg daily for four days, started as soon as possible after the injury to dampen the inflammatory cascade before it can trigger bone formation.10PubMed Central. Medical guidelines for fibrodysplasia ossificans progressiva The same corticosteroid protocol is recommended for active flare-ups, though it does not reverse bone that has already formed.
How FOP Affects the Lungs
One of the most dangerous aspects of FOP is its effect on breathing. As bone forms in the muscles between the ribs and around the spine, the chest wall gradually loses its ability to expand. This creates what doctors call restrictive lung disease: the lungs themselves may be healthy, but they cannot inflate fully because the chest cage has stiffened. A study tracking lung function in FOP patients found that five out of six had reduced total lung capacity, and in some cases the decline began in childhood and continued into early adulthood.11PubMed Central. Deterioration of pulmonary function: An early complication in Fibrodysplasia Ossificans Progressiva Respiratory failure related to chest-wall restriction is one of the leading causes of death in people with FOP, typically by middle age.
Monitoring lung function early and regularly is now considered important even in patients who do not yet feel short of breath, because the decline can be gradual enough to go unnoticed until it becomes severe. The data suggest that the steepest drop may occur during childhood and adolescence, with some stabilization later, though the evidence on long-term trajectories is still limited by small sample sizes.
The Jaw Problem and Anesthesia Risks
Many people with FOP develop ossification of the muscles around the jaw joint, leading to ankylosis of the temporomandibular joint. When the jaw fuses, it cannot open at all or opens only a few millimeters, making eating, dental care, and especially anesthesia profoundly difficult. Case reports describe patients who can only take in liquefied food through the small remaining gap between their teeth.12PubMed. A description of two surgical and anesthetic management techniques used for a patient with fibrodysplasia ossificans progressiva
If surgery is unavoidable, standard intubation through the mouth is often impossible. Anesthesiologists must instead use fiber-optic techniques through the nose, threading a breathing tube under visual guidance through ossified and narrowed airways.13PubMed Central. General anesthesia in fibrodysplasia ossificans progressive: a case report and clinical review Even minor surgical procedures carry the added risk that tissue manipulation will spark a new flare-up. For these reasons, surgery in FOP patients is treated as a last resort, and when it is performed, the least invasive approach possible is favored.
Pain and Emotional Health
FOP is not just a disease of immobility. Pain is a constant companion for many patients, and not only during active flare-ups. Data from an international FOP registry found that while moderate to severe pain was reported by over half of patients during flare-ups, roughly a third to over half of patients also experienced similar pain levels during periods with no active flare-up at all.14PubMed Central. Longitudinal Evaluation of Pain, Flare‐Up, and Emotional Health in Fibrodysplasia Ossificans Progressiva This chronic baseline pain is something that clinicians and caregivers sometimes underestimate because the disease’s drama tends to cluster around visible flare-up episodes.
The emotional toll is steep. Among patients reporting moderate to severe pain, roughly half to three-quarters reported anxiety, depression, or irritability. Even during periods of low pain, more than a third reported emotional difficulties. The severity of pain was significantly linked to worse emotional health, worse physical functioning, and lower overall quality of life, regardless of whether a flare-up was active.15PubMed Central. Longitudinal Evaluation of Pain, Flare‐Up, and Emotional Health in Fibrodysplasia Ossificans Progressiva Separate research measuring quality of life confirmed that physical functioning was the dimension most severely affected, with pain scores consistently low.16PubMed Central. Quality of life of patients with fibrodysplasia ossificans progressiva
Palovarotene, the First Approved Treatment
For decades, management of FOP was purely supportive: avoid triggers, treat flare-ups with corticosteroids, and preserve whatever mobility remained. That changed with the development of palovarotene, a synthetic retinoid (a compound related to vitamin A) designed to block the pathway that converts cartilage into bone during heterotopic ossification. Palovarotene works downstream of the ACVR1 mutation, interrupting the ossification process at a later step rather than correcting the signaling defect itself.
In clinical trials, patients who served as their own controls showed reduced new bone formation during the treatment phase compared to their earlier observation period without the drug.17PubMed Central. Palovarotene (Sohonos), a synthetic retinoid for reducing new heterotopic ossification in fibrodysplasia ossificans progressiva: history, present, and future Palovarotene was approved under the brand name Sohonos in Canada in 2022 and later in the United States and Europe, though regulatory paths differed. It is not a cure; it does not reverse existing heterotopic bone, and it must be taken continuously to suppress new episodes. It also comes with notable side effects, including premature growth-plate closure in children, which limits its use in younger patients and has generated debate about the risk-benefit balance in the pediatric population most affected by FOP.
Garetosmab and Targeting Activin A Directly
Because Activin A was identified as the key ligand driving abnormal bone formation through the mutant receptor, blocking it became an obvious drug target. Garetosmab is a monoclonal antibody that neutralizes Activin A. In a phase 1 study in healthy volunteers, it demonstrated an acceptable safety profile with no dose-limiting toxicities.18PubMed Central. Pharmacokinetics and Pharmacodynamics of Garetosmab (Anti-Activin A): Results From a First-in-Human Phase 1 Study
The phase 2 trial in FOP patients told a more nuanced story. The drug did not significantly shrink or deactivate existing heterotopic bone lesions over 28 weeks, which was the original primary endpoint. However, it markedly suppressed the development of new lesions. When patients who had been on placebo crossed over to garetosmab, none of them developed new heterotopic bone, compared to about 41% who had developed new lesions while on placebo.19PubMed Central. Garetosmab in fibrodysplasia ossificans progressiva: a randomized, double-blind, placebo-controlled phase 2 trial That distinction matters: existing bone may be permanent, but preventing new bone from forming could substantially slow the disease’s progression. Development is ongoing.
Experimental Approaches on the Horizon
Several other therapeutic strategies are being explored, each targeting the FOP pathway at a different point. Rapamycin, a drug already used in transplant medicine to suppress the immune system, has shown promise in mouse models of FOP. Continuous treatment reduced both the incidence and severity of heterotopic ossification, and early prophylactic use was more effective than treatment started only after an injury.20PubMed Central. Prophylactic treatment of rapamycin ameliorates naturally developing and episode-induced heterotopic ossification in mice expressing human mutant ACVR1 In a separate rat model of blast-related bone formation (not FOP-specific but mechanistically related), higher doses of rapamycin reduced ectopic bone by roughly 90%.21PubMed Central. Inhibition of Mammalian Target of Rapamycin Signaling with Rapamycin Prevents Trauma-Induced Heterotopic Ossification Human trials in FOP patients are being considered but have not yet reported results.
At the genetic level, researchers are working on antisense oligonucleotides, short synthetic strands of modified DNA designed to silence only the mutant copy of the ACVR1 gene while leaving the normal copy intact. Early laboratory work in cells taken from FOP patients has shown that certain designs can preferentially knock down the mutant gene’s output at both the RNA and protein level without substantially affecting the healthy version.22Molecular Therapy Nucleic Acids. Single-base 2′OMe-modified LNA and MOE gapmers selectively silence ACVR1R206H in fibrodysplasia ossificans progressiva 23PubMed. Allele-Selective LNA Gapmers for the Treatment of Fibrodysplasia Ossificans Progressiva Knock Down the Pathogenic ACVR1(R206H) Transcript and Inhibit Osteogenic Differentiation This approach is still in its preclinical stages, but the concept is elegant: rather than blocking the downstream consequences of the mutation, you silence the mutation itself. The challenge is delivering these molecules to the right tissues at the right time in a living person.
Tracking the Disease With Blood Tests
One of the frustrations of managing FOP has been the lack of a simple way to measure disease activity between flare-ups. Imaging can show bone that has already formed, but it cannot predict when new bone is about to form. Researchers have been looking for blood-based biomarkers that could fill that gap. A case-control study comparing plasma from 40 FOP patients against matched controls identified several promising signals. Two molecules, adiponectin and tenascin-C, were strongly associated with simply carrying the FOP mutation, suggesting they reflect a baseline state of chronic inflammation present even when no flare-up is happening. A third molecule, kallikrein-7, was specifically correlated with active flare-up status.24PubMed. Plasma-Soluble Biomarkers for Fibrodysplasia Ossificans Progressiva (FOP) Reflect Acute and Chronic Inflammatory States
If validated in larger studies, markers like these could serve multiple purposes: flagging flare-ups before they become clinically obvious, helping clinicians decide when to start a corticosteroid burst, and giving clinical trial researchers a way to measure whether a new drug is actually reducing disease activity rather than waiting months for bone to show up on imaging. The picture that emerges from the biomarker research reinforces something that patients have long described: FOP is not a disease of occasional dramatic episodes punctuated by calm. It is a condition of ongoing, low-grade inflammatory activity with periodic spikes, and understanding that chronic dimension may be as important as managing the acute flare-ups.