Fibrodysplasia ossificans progressiva (FOP) is a genetic condition in which the body’s soft tissues, including muscles, tendons, and ligaments, gradually turn into bone. It is one of the rarest diseases known, affecting roughly 0.65 per million people in North America and even fewer in other regions. The extra bone forms outside the normal skeleton, locking joints into place and progressively restricting movement over a person’s lifetime.
What Causes FOP
FOP is caused by a mutation in the ACVR1 gene, which controls a receptor involved in bone growth signaling. In a healthy body, this receptor responds only to specific bone-building signals. The FOP mutation changes the receptor so it also responds to a completely different molecule called Activin-A, one that normally has nothing to do with bone formation. When Activin-A binds to the altered receptor, it triggers the same bone-building pathway that the body uses during normal skeletal development.
Making matters worse, the body’s usual safety mechanisms can’t shut this process down. Normally, when bone-building signals fire, the body produces molecules that act as brakes. But the abnormal signaling triggered by Activin-A in FOP sits outside those feedback loops, so it continues unchecked. The result is bone forming in places it was never meant to be: through muscle tissue, across joints, and along tendons. This process is called heterotopic ossification.
Only one copy of the mutated gene is needed to cause the disease. Most cases arise from a new, spontaneous mutation rather than being inherited from a parent.
The Earliest Sign: Malformed Big Toes
Nearly all people with FOP are born with shortened, inward-turning big toes. This is visible at birth and is the single most distinguishing feature of the condition. Because FOP is so rare, many doctors never encounter it, and this toe abnormality is the key clue that should prompt early recognition. Unfortunately, nearly 90% of FOP patients worldwide are initially misdiagnosed with other conditions like tumors, fibromatosis, or bone growths. About 67% undergo unnecessary diagnostic procedures, including biopsies, which can trigger new bone formation and make the disease worse.
How the Disease Progresses
FOP follows a predictable geographic pattern through the body. Bone formation typically begins in the upper back, neck, and shoulders during early childhood, then moves outward and downward over time toward the arms, hips, and legs. The pattern runs from the spine toward the limbs, and from the head downward.
Progression happens through episodes called flare-ups. These often involve painful, rapidly appearing soft tissue swelling that can last days to weeks before the tissue calcifies into solid bone. About 61% of all flare-ups occur spontaneously, with no identifiable trigger. When there is a trigger, the most common causes are physical injury, viral infections, and overuse of muscles. Intramuscular injections, including vaccines delivered into muscle, caused a flare-up in about 25% of patients surveyed, and over 84% of those injection-triggered flare-ups resulted in permanent new bone formation.
Each flare-up is essentially irreversible. Once the new bone forms, it becomes a permanent part of the body, fusing joints and restricting movement. Over years and decades, this accumulation of extra bone can lock the jaw, freeze the spine, and immobilize the limbs.
Why Surgery Makes Things Worse
One of the most counterintuitive aspects of FOP is that surgery to remove the extra bone almost always causes more bone to grow. The trauma of cutting through tissue triggers exactly the kind of inflammatory response that sets off new heterotopic ossification, often at the surgical site and sometimes in areas far from it. Biopsies of FOP lesions are never indicated for the same reason. Elective amputations are also never recommended. Even spinal surgery to correct curvature has been shown to worsen the disease, with bone continuing to grow despite the procedure.
Impact on Breathing
The most serious medical consequence of FOP involves the chest. As bone forms around the ribs, spine, and the muscles between them, the rib cage becomes rigid and unable to expand normally during breathing. This is called thoracic insufficiency syndrome, and it develops in all people with FOP to some degree.
Lung function testing shows that even young children with FOP already have reduced lung capacity. In one study, forced vital capacity (a measure of how much air you can fully exhale) was below 80% of predicted values in every patient tested, including the youngest at age seven. The rigid chest wall also prevents full exhalation, trapping air in the lungs. Over time, this progressive loss of breathing capacity becomes life-threatening.
Life Expectancy
The median lifespan for people with FOP is estimated at 56 years, based on international data. The most common cause of death is cardiorespiratory failure from thoracic insufficiency syndrome, accounting for 54% of deaths at a median age of 42. Pneumonia is the second most common cause, responsible for 15% of deaths at a median age of 40. Both are directly tied to the progressive restriction of the chest wall and declining lung function.
Treatment Options
For decades, there was no approved treatment for FOP. That changed with the approval of palovarotene (brand name Sohonos), the first drug specifically developed for the condition. Palovarotene works by interfering with the pathway that converts cartilage into bone, targeting one of the key steps in heterotopic ossification.
In clinical trials, patients treated with palovarotene showed roughly a 50% to 56% reduction in the volume of new bone forming each year compared to untreated patients, depending on the statistical model used. The drug does not remove bone that has already formed, but it can slow the accumulation of new bone over time.
The most common side effects are related to skin dryness: dry skin (affecting about 53% of patients), dry lips (34%), and rashes (19%). Other frequent side effects include joint pain, upper respiratory infections, and headaches. These are consistent with the drug’s mechanism, which is related to vitamin A signaling and affects skin and mucous membranes.
Living With FOP
Day-to-day management of FOP centers on avoiding triggers that could set off flare-ups. This means being cautious about falls and physical trauma, avoiding intramuscular injections (vaccines can often be given under the skin instead), and being vigilant about infections. Dental care requires special consideration because jaw involvement is common and standard procedures can provoke ossification. Any medical professional treating someone with FOP needs to understand that routine interventions, from blood draws to minor procedures, carry risks that don’t apply to other patients.
Mobility aids become necessary as joints progressively lock. Most people with FOP eventually use a wheelchair, though the timeline varies widely depending on which joints are affected and how frequently flare-ups occur. Because the disease is so rare, connecting with organizations like the International FOP Association can help families find experienced specialists and access current treatment options.