Fibrodysplasia Ossificans Progressiva · What Is It, Causes, Symptoms, Treatment, and More

Published: Apr 07, 2026

Author: Lily Guo, MD•

Editor: Alyssa Haag, MD•

Editor: Józia McGowan, DO•

Editor: Kelsey LaFayette, DNP, ARNP, FNP-C

Illustrator: Jung Hee Lee, MScBMC

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What is fibrodysplasia ossificans progressiva?

Fibrodysplasia ossificans progressiva (FOP), also known as myositis ossificans progressiva or stoneman syndrome, is a very rare genetic connective tissue disorder characterized by toe malformations at birth, and progressive heterotopic ossification (i.e., abnormal replacement of soft tissue by bone) within connective tissue (e.g., ligaments, skeletal muscle, tendons, fascia) most commonly in the neck, spine, and shoulder. Specifically, toe malformations include hallux valux (i.e., bunion), and a short, deviated first toe that is monophalangic (i.e., one bone as opposed to two). Ossification is the normal process of bone formation, whereas heterotopic ossification results in abnormal bone growth within soft tissue. In those with FOP, heterotrophic ossification tends to occur progressively and episodically over one’s lifetime and can be unpredictable.

Generally, the disorder develops within the first 10 years of life. Unfortunately, abnormal bone growth within connective tissue is inevitable and often leads to individuals being wheelchair bound by the third decade of life, and is ultimately fatal. Fibrodysplasia ossificans progressiva has a worldwide prevalence of approximately one case in 2 million individuals worldwide. No ethnic, racial, or geographic predisposition has been described.

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What causes fibrodysplasia ossificans progressiva?

FOP is most commonly caused by a sporadic (i.e., spontaneous) mutation in the activin receptor 1 (ACVR1) gene on chromosome 2. The most common mutation found in 90% of those with FOP is a substitution of histidine for the amino acid arginine at position 206 of the ACVR1 protein, resulting in defective activin receptor 1 protein. ACVR1 protein is responsible for controlling the growth and development of bones and muscles, including the process of ossification. While most mutations in ACVR1 occur sporadically, there have been cases of FOP where the mutated gene is inherited in an autosomal dominant manner from a parent with FOP (i.e., a single copy of the mutated gene passed from one parent is sufficient to cause disease).

FOP flares also occur intermittently and are commonly caused by biopsies, intramuscular injections, injections for dental procedures, infections (e.g., influenza-like illnesses) and even trauma, like falls.

What are the signs and symptoms of fibrodysplasia ossificans progressiva?

The signs and symptoms of FOP include painful swelling in the connective tissue in various areas of the body, including skeletal muscle, ligaments, tendons, and fascia. This commonly occurs in the back, shoulders, neck, hips, knees, and elbows. Pain and soft tissue swelling associated with FOP are often episodic and cause flares. While some flare-ups spontaneously regress, most turn soft connective tissues into heterotopic bone. Many individuals lose their ability to sit by childhood or adolescence, and then eventually lose the ability to walk or open their mouths resulting in difficulty eating and severe weight loss. Most individuals are wheelchair-bound by the third decade of life.

Over time, ossification of connective tissue can lead to restriction of chest wall movements resulting in right-sided heart failure, pneumonia, and respiratory failure, which are common causes of mortality in those with FOP. Other associated features may include severe scoliosis (i.e., abnormal curvature of the spine), short thumbs, fifth finger clinodactyly (i.e., curvature of the digit), C2-C7 facet joint fusion, tall and narrow vertebral bodies, short broad femoral necks, deafness, baldness, and mild intellectual disability.

How is fibrodysplasia ossificans progressiva diagnosed?

FOP can be diagnosed based on a thorough physical examination and clinical history. Ideally, a diagnosis should be made during the neonatal period to avoid procedures that could trigger ossification, such as a soft tissue biopsy. Recognizing congenital big toe malformations, which are present in almost all cases, is crucial. These toe malformations, along with rapidly appearing soft tissue lesions, can definitively indicate FOP. Clinicians may also ask about a family history of ossification in the case of inherited FOP.

Imaging can be used to aid in diagnosis, including bone scintigraphy, X-ray, computed tomography (CT) scans and magnetic resonance imaging (MRI). Imaging can show ectopic calcification in the soft tissue. Laboratory testing is generally not useful for the diagnosis of FOP since there are no specific changes. Analysis of bone mineral metabolism including calcium, phosphorus, and parathyroid levels are usually normal. Serum alkaline phosphatase, an enzyme derived from bone, and erythrocyte sedimentation rate (ESR), a non-specific marker of inflammation, may be increased, especially during disease flare-ups. Genetic testing looking for a mutation in ACVR1 can confirm the diagnosis.

How is fibrodysplasia ossificans progressiva treated?

Treatment of FOP includes symptomatic management as there is currently no cure. Preventative measures can be taken including reducing the risk of falls and injury and avoiding unnecessary intramuscular injections and injections of local anesthetics (e.g., mandibular blocks). Several medications have been used in symptomatic management of FOP including glucocorticoids (e.g., prednisone, prednisolone), bisphosphonates (e.g., etidronate), nonsteroidal anti-inflammatory medications (e.g., ibuprofen), cyclo-oxygenase-2 inhibitors (e.g., rofecoxib, celecoxib), leukotriene inhibitors (e.g., montelukast, zafirlukast) and mast cell stabilizers (e.g., cromolyn sodium). The United States Food and Drug Administration (FDA) has approved palovarotene, a retinoic acid receptor gamma agonist, for the treatment of FOP in genetic females aged 8 years and older and genetic males aged 10 years and older, with the goal of reducing the amount of new heterotopic ossification. Lastly, surgery to remove heterotopic bone is contraindicated as it can lead to episodes of explosive and painful new bone formation at the surgical site.

What are the most important facts to know about fibrodysplasia ossificans progressiva?

Fibrodysplasia ossificans progressiva (FOP) is a rare connective tissue disorder characterized by progressive heterotopic ossification and congenital toe malformations. Soft tissue including skeletal muscle, tendons, and ligaments are replaced by bone, primarily in the neck, spine, and shoulders. It's caused by mutations in the ACVR1 gene, often occurring sporadically but can be inherited in an autosomal dominant manner. Symptoms include painful swelling and episodic flare-ups leading to severe mobility restrictions. Initial symptoms such as toe malformations are typically seen at birth, with increasing soft tissue swelling that may manifest within the first decade of life. FOP is a progressive disease with most individuals becoming wheelchair bound. Diagnosis is based on physical examination and clinical history, and genetic testing can be used to confirm the diagnosis. Treatment includes symptomatic management and preventative measures to avoid injury.

References

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