Fibrodysplasia Ossificans Progressiva A Human Genetic Disorder Of

Leo Migdal

-Dec 5, 2025, 4:39 PM

fibrodysplasia ossificans progressiva a human genetic disorder of

Fibrodysplasia ossificans progressiva (FOP) is a rare human genetic disease in which de novo osteogenesis—a developmental process occurring during embryonic skeletal formation—is induced aberrantly and progressively beginning during early childhood in soft connective tissues. Episodic initiation of spontaneous bone-forming lesions occurs over time, affecting a generally predictable sequence of body locations following a pattern similar to that of the developing embryonic skeleton. The heterotopic (extraskeletal) bone formation in FOP can also be induced by connective tissue injury. At the tissue level, an initial tissue degradation phase is followed by a tissue formation phase during which soft connective tissues are replaced by bone tissue through endochondral osteogenesis. This extraskeletal bone is physiologically normal and develops through the same series of tissue differentiation events that occur during normal embryonic skeletal development. The underlying genetic mutation in FOP alters the signals that regulate induction of cell differentiation leading to bone formation.

In addition to postnatal heterotopic ossification, FOP patients show specific malformations of skeletal elements indicating effects on bone formation during embryonic development as well. Nearly all cases of FOP are caused by the identical mutation in the ACVR1 gene that causes a single amino acid substitution, R206H, in the bone morphogenetic protein (BMP) type I receptor ACVR1 (formerly... This mutation causes mild constitutive activation of the BMP signaling pathway and identifies ACVR1 as a key regulator of cell fate decisions and bone formation, providing opportunities to investigate previously unrecognized functions for this... Clinical features of fibrodysplasia ossificans… Clinical features of fibrodysplasia ossificans progressiva (FOP). The classic clinical phenotype of FOP…

Generalized schematic of the BMP signaling pathway. Type I and type II BMP… Heterotopic ossification in FOP. The initial stages of FOP lesion formation involves inflammation… Fibrodysplasia ossificans progressiva (FOP) is a rare genetic condition where bone gradually replaces muscles and connective tissues. Injury or illness causes new bone growth, which can be painful and lead to a shortened lifespan.

Cleveland Clinic is a non-profit academic medical center. Advertising on our site helps support our mission. We do not endorse non-Cleveland Clinic products or services. Policy Pronunciation for the genetic condition fibrodysplasia ossificans progressiva is “fi-bro-dis-play-see-ah os-sif-eh-cans pro-gres-see-vah.” Cleveland Clinic is a non-profit academic medical center.

Advertising on our site helps support our mission. We do not endorse non-Cleveland Clinic products or services. Policy Fibrodysplasia ossificans progressiva (FOP) is a genetic condition where people are born with bunions and their body’s muscle tissue and connective tissues, like tendons and ligaments, turn into bone on the outside of their... This condition restricts movement and can cause a loss of mobility over time in people diagnosed with the condition. Symptoms of FOP appear during childhood and usually begin at the neck and shoulders before moving to other areas of the body.

Fibrodysplasia ossificans progressiva is a disorder in which muscle tissue and connective tissue such as tendons and ligaments are gradually replaced by bone (ossified), forming bone outside the skeleton (extra-skeletal or heterotopic bone) that... This process generally becomes noticeable in early childhood, starting with the neck and shoulders and proceeding down the body and into the limbs. Extra-skeletal bone formation causes progressive loss of mobility as the joints become affected. Inability to fully open the mouth may cause difficulty in speaking and eating. Over time, people with this disorder may experience malnutrition due to their eating problems. They may also have breathing difficulties as a result of extra bone formation around the rib cage that restricts expansion of the lungs.

Any trauma to the muscles of an individual with fibrodysplasia ossificans progressiva, such as a fall or invasive medical procedures, may trigger episodes of muscle swelling and inflammation (myositis) followed by more rapid ossification... Flare-ups may also be caused by viral illnesses such as influenza. People with fibrodysplasia ossificans progressiva are generally born with malformed big toes. This abnormality of the big toes is a characteristic feature that helps to distinguish this disorder from other bone and muscle problems. Affected individuals may also have short thumbs and other skeletal abnormalities. Fibrodysplasia ossificans progressiva is a very rare disorder, believed to occur in approximately 1 in 1 million people worldwide.

Several hundred cases have been reported. Fibrodysplasia ossificans progressiva (/ˌfaɪbroʊdɪˈspleɪʒ(i)ə ɒˈsɪfɪkænz prəˈɡrɛsɪvə/;[1] abbr. FOP), also called Münchmeyer disease or formerly myositis ossificans progressiva, is an extremely rare connective tissue disease. Fibrous connective tissue such as muscle, tendons, and ligaments ossify into bone tissue. The condition ultimately immobilises sufferers as new bone replaces musculature and fuses with the existing skeleton. This has earned FOP the nickname "stone man disease".[2]

FOP is caused by a mutation of the gene ACVR1, affecting the body's repair mechanism. Fibrous tissue including muscle, tendons, and ligaments ossify, either spontaneously or when damaged by trauma. In many cases, otherwise minor injuries can cause joints to permanently fuse as new bone forms, replacing the damaged muscle tissue. This new bone formation (known as "heterotopic ossification") eventually forms a secondary skeleton progressively restricting the patient's ability to move. Circumstantial evidence suggests that the disease can cause joint degradation separate from its characteristic bone growth.[3] It is a severe, disabling disorder. Bone formed as a result of ossification is identical to "normal" bone, but in improper locations.

The rate of ossified bone growth varies by patient. It is the only known medical condition in which tissue of one organ system changes into that of another.[4] Surgical removal of ossified bone causes the body to "repair" the affected area with additional bone. FOP has no current known cure. However, there are intermittent treatments such as anti-inflammatory drugs. Promising breakthroughs include the approved treatment, Sohonos (palovarotene).

Another promising treatment is Antisense-mediated therapy using allele-selective LNA gapmers. Medical reports describing individuals affected by FOP date back to Dr. Guy Patin in 1692.[5] FOP was originally called myositis ossificans progressiva and was thought to be caused by muscular inflammation (myositis) that caused bone formation.[5] In 1736, London surgeon, John Freke wrote the first... They likewise arise from every rib of his body, and joining together in all parts of his back, as the ramifications of coral do, they make, as it were, a fixed bony pair of... McKusick in 1970 following the discovery that soft tissue other than muscles (e.g. ligaments) were also affected by the disease process.[5]

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder that causes muscles, tendons, and other soft tissues to turn permanently into bone. Extra bone forms across joints making movement difficult and sometimes impossible. This process of ossification continues throughout a patient's life. FOP affects many areas of the body including, but not limited to, the neck, spine, chest, shoulders, elbows, wrists, hips, knees, ankles and jaw. FOP is a progressive disease, which means it typically gets worse as the patient ages. The rate of new bone formation differs for each person, and the disease's progression is generally unpredictable.

FOP is known to affect about 2,500 people globally, across all ethnicities, ages, genders, and races. Because FOP is such a rare disease, experts believe that 80 percent or more of the cases are misdiagnosed and the number of people with FOP may actually be much higher. Experts in both pediatric and adult endocrinology, genetics, orthopedics, orthopedic surgery and rheumatology at UCSF Benioff Children's Hospitals are among the few in the country who readily diagnose and treat FOP. In addition, researchers at UCSF are studying how the disease progresses and working to identify new therapies. One of the nation's best for endocrinology & diabetes care current address: University of San Diego, California, Altman Center for Clinical and Translational Research, 9452 Medical Center Drive, La Jolla, CA 92037

Corresponding Authors: Frederick S. Kaplan, M.D., Chief, Division of Orthopaedic Molecular Medicine, Perelman School of Medicine at the University of Pennsylvania, c/o Department of Orthopaedic Surgery, Penn Musculoskeletal Center - Suite 600, 3737 Market Street, Philadelphia, PA 19104,... Shore, Ph.D., Department of Orthopaedic Surgery, Perelman School of Medicine at the University of Pennsylvania, 309A Stemmler Hall, 3450 Hamilton Walk, Philadelphia, PA 19104-6081, Tel: 215-898-2133; Fax: 215-573-2133, shore@pennmedicine.upenn.edu Fibrodysplasia Ossificans Progressiva (FOP) is an ultra-rare genetic disorder of extraskeletal bone formation, but could appropriately be viewed as a seminal disorder of osteochondrogenesis. Many, if not most, of the musculoskeletal features of FOP are related to dysregulated chondrogenesis including abnormal articular cartilage formation, abnormal diarthrodial joint specification, growth plate dysplasia, osteochondroma formation, heterotopic endochondral ossification (HEO), and... In FOP, causative activating mutations of Activin receptor A type I (ACVR1), a bone morphogenetic protein (BMP) type I receptor, are responsible for the osteochondrodysplasia that impacts developmental phenotypes as well as postnatal features...

Here, we highlight the myriad developmental and postnatal effects on osteochondrogenesis that emanate directly from mutant ACVR1 and dysregulated bone morphogenetic protein (BMP) signaling in FOP. Keywords: Fibrodysplasia ossificans progressiva, bone morphogenetic protein signaling pathway, ACVR1, heterotopic ossification, osteochondrodysplasia, osteochondrogenesis, osteochondroma, arthropathy, growth plate The first verifiable description of fibrodysplasia ossificans progressiva (FOP; MIM 135100) was published in the Philosophical Transaction of the Royal Society of London by John Freke in 1740. One hundred twenty-eight years later, in 1868, the name myositis ossificans progressiva was ascribed to the condition by von Dusch in recognition of the episodic inflammatory flare-ups involving skeletal muscle. During the following decade, the malformation and microdactyly of the great toes were recognized by Frankel and Helferich. For nearly a century, the condition was commonly known as myositis ossificans progressiva (MOP).

The name Fibrodysplasia Ossificans Progressiva (FOP) was proposed by Bauer & Bode in 1940 and adopted by McKusick in 1960 in recognition of the primary connective tissue involvement of tendons, ligaments, fascia and aponeuroses... Fibrodysplasia Ossificans Progressiva is one such condition that changes lives in ways that feel almost unreal, rare, severe, and often misunderstood. People frequently discover it unknowingly, like a child with unusual toe deformities, swelling after a minor fall, or stiffness that doesn’t go away. What begins as small signs often turns out to be one of the rarest fibrodysplasia disease conditions known to medicine. For families living with this reality, awareness, early recognition, and the right support can make all the difference. In FOP, the body’s repair mechanisms become misdirected, causing bone to form where it should never exist, such as within muscles, ligaments, and tendons.

As this extra bone accumulates, it creates a second skeleton that makes movement increasingly difficult. This description aligns with the widely accepted fibrodysplasia ossificans progressiva definition, which explains it as a genetic disorder involving progressive extra-skeletal bone formation. Many fibrodysplasia ossificans progressiva cases begin subtly. Children may appear completely healthy except for a malformed big toe or early stiffness. Because fibrodysplasia is so rare, it is often misdiagnosed, and invasive procedures worsen the condition. This makes awareness of fibrodysplasia ossificans progressiva symptoms crucial for early intervention.

Fibrodysplasia Ossificans Progressiva A Human Genetic Disorder Of

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