A person living with fibrodysplasia ossificans progressiva (FOP) has a body that gradually builds a second skeleton. Muscles, tendons, and ligaments transform into solid bone over the course of years, locking joints into place and progressively restricting movement. The condition traces to a single mutation in a gene that controls bone formation, and it affects roughly one in every one to two million people worldwide. Because the disease is so rare and its early signs so easily mistaken for other conditions, most patients endure years of misdiagnosis and sometimes harmful medical procedures before anyone identifies what is actually happening.
What Goes Wrong at the Genetic Level
FOP is caused by a mutation in the ACVR1 gene, which encodes a receptor for bone morphogenetic proteins, the signaling molecules that tell cells to build bone. In people with the classic form of FOP, a single amino acid change (known as R206H) makes that receptor hyperactive. Instead of waiting for the normal “build bone” signal, the mutant receptor fires on its own, triggering bone formation in tissues where bone should never exist.1JCI Insight. The fibrodysplasia ossificans progressiva R206H ACVR1 mutation activates BMP-independent chondrogenesis and zebrafish embryo ventralization The mutation is autosomal dominant, meaning a single copy is enough to cause the disease. Most cases arise spontaneously rather than being inherited, because people with FOP rarely have children due to the severity of the condition.2Case Reports in Genetics. Sporadic Fibrodysplasia Ossificans Progressiva in an Egyptian Infant with c.617G > A Mutation in ACVR1 Gene: A Case Report and Review of Literature
Research into the cellular side of the disease has identified a specific cell type, known as fibro/adipogenic progenitors (FAPs), as the main culprit. These cells normally help repair injured muscle, but in FOP, the mutant receptor reprograms them to produce cartilage and then bone instead. Critically, this rogue bone formation depends on a signaling molecule called activin A, which does not normally trigger bone growth through a healthy version of the receptor. That dependence on activin A has become one of the most important targets for new therapies.3PubMed Central. Activin-dependent signaling in fibro/adipogenic progenitors causes fibrodysplasia ossificans progressiva
The Earliest Sign Most Doctors Miss
Babies born with FOP almost always have a distinctive malformation of their big toes: the toes are short, bent inward, and sometimes lack a joint. This feature is present at birth and has been called a “hallmark” of the disease.4Case Reports in Genetics. Sporadic Fibrodysplasia Ossificans Progressiva in an Egyptian Infant with c.617G > A Mutation in ACVR1 Gene: A Case Report and Review of Literature In theory, a careful examination of a newborn’s feet could raise suspicion of FOP before any bone-forming episodes begin. In practice, the toe malformation is usually overlooked or dismissed as a minor anatomical quirk, because almost no physician outside a specialized center has ever seen a case of FOP.
That gap in recognition has devastating consequences. A large international survey found that incorrect diagnoses were given to 87% of individuals with FOP. The most common wrong diagnosis was cancer, assigned to about a third of patients. On average, people saw six different physicians over a span of roughly four years before anyone arrived at the correct diagnosis.5Pediatrics. Iatrogenic Harm Caused by Diagnostic Errors in Fibrodysplasia Ossificans Progressiva That delay would be bad enough on its own, but for FOP patients it creates an additional danger: the diagnostic procedures themselves can trigger new bone formation.
How Medical Care Itself Can Cause Harm
When a child with undiagnosed FOP develops a painful soft-tissue swelling on the neck or back, the natural medical response is to biopsy it. In FOP, cutting into a swelling is among the worst things you can do. The trauma of the biopsy triggers new bone to grow at the surgical site, causing permanent loss of mobility that would not have occurred otherwise. In the same survey, two-thirds of patients underwent unnecessary biopsies, and about half reported permanent mobility loss directly caused by invasive medical procedures.6Pediatrics. Iatrogenic Harm Caused by Diagnostic Errors in Fibrodysplasia Ossificans Progressiva A separate study of seven children found that three had undergone invasive diagnostic procedures that worsened their condition before FOP was recognized.7PubMed Central. Early diagnosis of fibrodysplasia ossificans progressiva
This pattern of iatrogenic harm is one of the cruelest features of FOP. The disease punishes the very instinct that normally drives good medicine: investigate, intervene, fix. For FOP patients, the safest route is often to do as little as possible, and that principle extends well beyond biopsies. Intramuscular injections, including routine childhood vaccinations delivered into muscle, can provoke bone formation at the injection site. General anesthesia poses its own challenges because the disease can fuse the jaw, stiffen the neck, and severely restrict the chest wall, making intubation dangerous or impossible.8PubMed Central. General anesthesia in fibrodysplasia ossificans progressive: a case report and clinical review
What Triggers Flare-Ups
The bone-forming episodes of FOP, called flare-ups, tend to begin in the first decade of life. They typically start as painful, warm soft-tissue swellings that can be mistaken for tumors or infections. Over days to weeks, the swollen area progresses through a sequence resembling embryonic bone development: inflammation gives way to cartilage, which then mineralizes into mature bone. Once that bone forms, it is permanent.
Soft-tissue trauma is the most recognized trigger. Falls, bumps, surgical incisions, and even aggressive physical therapy can set off a flare-up.9PubMed Central. Fibrodysplasia ossificans progressiva: clinical and genetic aspects But trauma is not the only cause. A survey of FOP patients and families found that influenza-like viral illnesses increased the risk of a flare-up at least threefold. The connection was first noticed in two half-sisters who both experienced severe flare-ups during confirmed influenza B infections, and the broader survey data strongly supported the link.10Clinical Orthopaedics and Related Research. Influenza-like Viral Illnesses and Flare-ups of Fibrodysplasia Ossificans Progressiva Fatigue, muscular overstretch, and even emotional stress have also been reported as triggers, though trauma and infection remain the best documented.
Not every flare-up produces new bone. A post hoc analysis of placebo-treated patients in a clinical trial found that only about a quarter of patient-reported flare-ups resulted in detectable new bone at the site of the flare.11Oxford Academic (Journal of Bone and Mineral Research). Characterization of flare-ups and impact of garetosmab in adults with fibrodysplasia ossificans progressiva: a post hoc analysis of the randomized, double-blind, placebo-controlled LUMINA-1 trial Still, the flare-ups that do produce bone tend to produce a lot of it. In that same analysis, patients who experienced flare-ups accumulated a median of about 3.8 cubic centimeters of new bone over 28 weeks, while those without flare-ups accumulated none. The most common symptoms during flare-ups were pain and joint stiffness, each reported by about 88% of patients who flared.
How Bone Formation Spreads Through the Body
FOP does not strike randomly. New bone tends to appear first in the upper back, neck, and shoulders, then gradually moves down and outward toward the limbs. This pattern mirrors the sequence in which the embryonic skeleton develops, a striking parallel that researchers have noted for decades.12WIREs Developmental Biology. Fibrodysplasia ossificans progressiva: a human genetic disorder of extraskeletal bone formation, or—how does one tissue become another? In practical terms, this means that FOP patients often lose shoulder and spinal mobility before they lose movement in their hips and knees. Many children develop visible ridges of bone across the upper back by their teenage years.
Certain tissues resist the process entirely. The diaphragm, the tongue, the heart, and the smooth muscle of the digestive tract are spared. The eye muscles are also protected, a feature that has intrigued researchers studying why some muscles resist various dystrophic conditions.13PubMed Central. Sparing of Extraocular Muscle in Aging and Muscular Dystrophies: A Myogenic Precursor Cell Hypothesis The reason for these exemptions is not fully understood but likely relates to differences in the precursor cell populations within those tissues. For patients, the sparing of the diaphragm and heart means that internal organ function remains relatively intact even as the external body becomes increasingly rigid.
The Cardiopulmonary Bottleneck
Despite the sparing of the diaphragm itself, the chest wall is not exempt. As bone forms across the muscles between the ribs and along the spine, the ribcage gradually loses its ability to expand. This creates what clinicians call thoracic insufficiency syndrome: the lungs cannot inflate fully, carbon dioxide builds up, and the heart has to work harder to move blood through compressed lung tissue. Thoracic insufficiency was the most common cause of death in a study of FOP mortality, responsible for about 54% of deaths at a median age of 42. Pneumonia accounted for another 15% of deaths, at a median age of 40.14PubMed Central. Early mortality and cardiorespiratory failure in patients with fibrodysplasia ossificans progressiva The vulnerability to pneumonia is partly mechanical: when you cannot cough effectively because your chest wall is fused, clearing a lung infection becomes much harder.
A clinical staging framework for FOP describes this cardiopulmonary decline as part of the disease’s late phase, underscoring that respiratory failure is the principal threat to life.15PubMed. Clinical staging of Fibrodysplasia Ossificans Progressiva (FOP) Monitoring lung function over time and aggressively treating respiratory infections are considered central to extending survival, though the options for reversing chest wall restriction are essentially nonexistent once the bone has formed.
Palovarotene and the First Approved Treatment
For most of the disease’s recorded history, there was no specific therapy for FOP. Treatment was limited to short courses of corticosteroids during flare-ups, careful avoidance of trauma, and symptomatic pain management. That changed with the development of palovarotene, a synthetic retinoid that selectively activates a receptor involved in suppressing cartilage-to-bone conversion. In animal models, palovarotene reduced injury-induced and genetic bone formation significantly.16JBMR Plus. Palovarotene (Sohonos), a synthetic retinoid for reducing new heterotopic ossification in fibrodysplasia ossificans progressiva: history, present, and future
Clinical trials in FOP patients showed promising results. In a placebo-controlled phase 2 trial, patients receiving the higher dose of palovarotene developed substantially less new bone than those on placebo over 12 weeks, though the difference did not reach statistical significance in that small study.17PubMed Central. Palovarotene for Fibrodysplasia Ossificans Progressiva (FOP): Results of a Randomized, Placebo-Controlled, Double-Blind Phase 2 Trial Subsequent post hoc analyses across larger phase 2 and phase 3 datasets reported significant reductions in new bone volume during both chronic dosing and flare-up treatment.18PubMed Central. A Narrative Review of Phase II and III Clinical Trials for the Pharmacological Treatment of Fibrodysplasia Ossificans Progressiva (FOP): Efficacy, Safety, and Challenges in Treatment Strategies Palovarotene was approved for FOP in Canada in 2022 and later in other jurisdictions, making it the first approved disease-specific treatment.
The drug carries real risks. Because retinoids affect growth plate cartilage, some younger patients in clinical trials experienced premature growth plate closure, raising concerns about use in children who are still growing.19JBMR Plus. Palovarotene (Sohonos), a synthetic retinoid for reducing new heterotopic ossification in fibrodysplasia ossificans progressiva: history, present, and future Balancing the benefit of reduced bone formation against the risk of stunted skeletal growth is a particularly difficult clinical decision in a disease that overwhelmingly affects children.
Garetosmab and the Activin A Strategy
Because the mutant receptor in FOP is driven by activin A, researchers reasoned that blocking activin A directly might halt the entire bone-forming cascade at its source. Garetosmab is a fully human monoclonal antibody designed to bind activin A and prevent it from activating the FOP-mutant receptor.20Nature Medicine. Garetosmab in fibrodysplasia ossificans progressiva: a randomized, double-blind, placebo-controlled phase 2 trial In a phase 2 trial, garetosmab significantly reduced the proportion of patients experiencing flare-ups compared to placebo: 35% of garetosmab-treated patients had a flare-up over 28 weeks versus 71% on placebo. Flare-ups that did occur were shorter, with a median duration of 15 days on garetosmab compared to 48 days on placebo.21Oxford Academic (Journal of Bone and Mineral Research). Characterization of flare-ups and impact of garetosmab in adults with fibrodysplasia ossificans progressiva: a post hoc analysis of the randomized, double-blind, placebo-controlled LUMINA-1 trial
The activin A approach is conceptually appealing because it targets the ligand that the mutant receptor misinterprets, rather than trying to control downstream consequences after the bone-forming process has already started. Garetosmab remains investigational, and longer-term data on whether sustained activin A blockade can meaningfully slow cumulative bone burden are still being gathered.
Gene Therapy and Experimental Approaches
The most ambitious research aims to correct the problem at its root. A gene therapy strategy using adeno-associated virus (AAV) vectors has been tested in preclinical models. The approach combines two tools: a small RNA molecule designed to silence the mutant copy of ACVR1 while leaving the normal copy intact, paired with delivery of an optimized normal version of the gene. In mouse models of FOP, this combined strategy eliminated heterotopic bone formation and, remarkably, allowed normal muscle tissue to regenerate in areas that would otherwise have turned to bone.22Nature Communications. Suppression of heterotopic ossification in fibrodysplasia ossificans progressiva using AAV gene delivery The work is still preclinical, and the leap from mice to humans is always substantial, but the results represent one of the few strategies that addresses the mutation itself rather than its downstream effects.
Other experimental avenues have been more sobering. Rapamycin, an immunosuppressant that showed promise in mouse FOP models by targeting a signaling pathway downstream of the mutation, did not halt disease progression in the two human cases where it was reported. One patient received it for four months during active flare-ups; the other had been on it for 18 years following a liver transplant. FOP progressed in both.23PubMed. Acute and chronic rapamycin use in patients with Fibrodysplasia Ossificans Progressiva: A report of two cases A separate screening study identified a different mTOR-modulating compound that suppressed heterotopic bone formation in laboratory models,24Stem Cell Reports. Phenotypic Screening Identifies an mTOR Signaling Modulator that Suppresses Heterotopic Ossification in Fibrodysplasia Ossificans Progressiva but the disconnect between the rapamycin experience in humans and the mouse data serves as a reminder that preclinical results do not always translate.
Daily Life, Pain, and Emotional Health
Living with FOP means navigating a world designed for bodies that bend. As joints fuse, everyday tasks like dressing, bathing, and eating require increasingly creative adaptations. Data from the International FOP Association’s global registry capture the extent of this: patients report using wheelchairs, adapted utensils, raised toilet seats, and a wide range of other aids and assistive devices as the disease advances.25PubMed. Self-reported baseline phenotypes from the International Fibrodysplasia Ossificans Progressiva Association Global Registry
Pain is a constant companion. Analysis of international FOP registry data found that pain severity was significantly linked to worse emotional health, worse physical health, and lower overall quality of life, regardless of whether a flare-up was happening at the time.26PubMed Central. Longitudinal Evaluation of Pain, Flare‐Up, and Emotional Health in Fibrodysplasia Ossificans Progressiva: Analyses of the International FOP Registry That “regardless of flare-up status” detail matters, because it means the disease imposes a chronic pain burden beyond the acute episodes that get most of the clinical attention. One encouraging finding from quality-of-life research is that mental health and emotional functioning tend to be among the most preserved domains in FOP patients, even as physical function declines steeply.27PubMed Central. Quality of life of patients with fibrodysplasia ossificans progressiva The psychological resilience of people living with FOP is striking, though it should not be mistaken for evidence that the emotional toll is small.
Patient Registries and the Search for Undiagnosed Cases
Because FOP is so rare, traditional clinical-trial infrastructure struggles to accommodate it. Patient registries have become essential. The FOP Connection Registry, launched by the International FOP Association (IFOPA), was designed to build the most comprehensive global dataset on the disease, making it possible to track natural disease history, identify patterns, and accelerate therapy development.28PubMed. The FOP Connection Registry: Design of an international patient-sponsored registry for Fibrodysplasia Ossificans Progressiva
Beyond registries, organizations like the IFOPA, the International Clinical Council on FOP, and the Tin Soldiers Global FOP Patient Search program work to identify undiagnosed individuals, particularly in communities with limited access to genetic testing. Given that the vast majority of cases are misdiagnosed for years, and that a simple examination of a child’s toes could raise the correct suspicion, there is almost certainly a population of people living with FOP who do not yet know the name of their condition.29Orphanet Journal of Rare Diseases. Current challenges and opportunities in the care of patients with fibrodysplasia ossificans progressiva (FOP): an international, multi-stakeholder perspective Finding them before they undergo the biopsies and injections that cause irreversible harm is one of the most urgent practical goals in the FOP community.