Fibrodysplasia Ossificans Progressiva Cleveland Clinic

Leo Migdal

-Dec 5, 2025, 3:55 PM

fibrodysplasia ossificans progressiva cleveland clinic

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 (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 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. Author for correspondence (pingham@ntu.edu.sg) This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly... Heterotopic ossification (HO) is a disorder characterised by the formation of ectopic bone in soft tissue. Acquired HO typically occurs in response to trauma and is relatively common, yet its aetiology remains poorly understood.

Genetic forms, by contrast, are very rare, but provide insights into the mechanisms of HO pathobiology. Fibrodysplasia ossificans progressiva (FOP) is the most debilitating form of HO. All patients reported to date carry heterozygous gain-of-function mutations in the gene encoding activin A receptor type I (ACVR1). These mutations cause dysregulated bone morphogenetic protein (BMP) signalling, leading to HO at extraskeletal sites including, but not limited to, muscles, ligaments, tendons and fascia. Ever since the identification of the causative gene, developing a cure for FOP has been a focus of investigation, and studies have decoded the pathophysiology at the molecular and cellular levels, and explored novel... Based on the established role of BMP signalling throughout HO in FOP, therapeutic modalities that target multiple levels of the signalling cascade have been designed, and some drugs have entered clinical trials, holding out...

A potential role of other signalling pathways that could influence the dysregulated BMP signalling and present alternative therapeutic targets remains a matter of debate. Here, we review the recent FOP literature, including pathophysiology, clinical aspects, animal models and current management strategies. We also consider how this research can inform our understanding of other types of HO and highlight some of the remaining knowledge gaps. KEY WORDS: Bone morphogenetic protein, ACVR1, Fibrodysplasia ossificans progressiva, Heterotopic ossification, Inflammation Summary: Fibrodysplasia ossificans progressiva is a rare disease characterised by progressive heterotopic bone formation. Here, we present a comprehensive summary of the recent literature on this debilitating condition and discuss approaches to solving this clinical puzzle.

Fibrodysplasia Ossificans Progressiva (FOP) is a rare genetic disorder characterized by the abnormal transformation of soft tissues into bone, a process known as heterotopic ossification. This condition typically begins in childhood with painful episodes of soft tissue swelling, which can lead to the gradual formation of an additional skeleton that restricts movement and results in significant immobility. The underlying cause of FOP is a mutation in the ACVR1 gene, which affects bone morphogenetic protein (BMP) signaling pathways, leading to excessive bone formation inappropriately triggered by tissue injury or inflammation. One distinctive feature of FOP is a malformation of the great toe present at birth, which can aid in diagnosis. Although there is currently no cure for FOP, management focuses on alleviating symptoms and providing supportive care for associated disabilities. Patients often face a range of complications, including joint immobility and respiratory issues, with a significantly reduced average life expectancy of around 45 years.

Awareness of the condition is crucial, as misdiagnosis can occur, and certain medical interventions may exacerbate the symptoms. Also known as: FOP; myositis ossificans progressiva Definition Fibrodysplasia ossificans progressiva (FOP) is a very rare genetic condition in which muscle, tendons, and ligaments are transformed into bone. This process of heterotopic ossification, meaning the development of normal bone in abnormal places, leads to the formation of a second ectopic skeleton that immobilizes the joints and severely restricts movement. Most cases of FOP are sporadic and result from a new gene mutation. FOP is inherited as an autosomal dominant trait.

Only a few multigenerational families exist, due to the low reproductive fitness. Though patterns are difficult to discern due to the rarity of the disease, FOP occurs more often in females than in males. FOP is characterized by a progressive transformation of skeletal muscle and connective tissue into ectopic bone. This process of one tissue type being transformed into another is a clinical feature unique to FOP. It is similar to the formation of bone in the developing fetus and during the healing of a fracture. This normal process, called endochondral ossification, involves the formation of bone from a cartilage model.

In FOP, this same process occurs in the wrong places and at the wrong time. Progenitor cells in connective tissue and skeletal muscle are transformed into endochondral bone to form a second skeleton. This process of heterotopic ossification occurs in similar anatomic and temporal patterns to that seen in the fetus, beginning in the head, neck, and shoulders and progressing caudally to the hips and distally through... It characteristically spares the face, eyes, heart, and tongue. Heterotopic ossification is also induced by tissue injury and inflammation. Edited by: Gianluca Testa, Università degli Studi di Catania, Italy

Reviewed by: Emilia Severin, Carol Davila University of Medicine and Pharmacy, Romania; Marco Sapienza, University of Catania, Italy *Correspondence: Peng Liu, l_p@jlu.edu.cn This article was submitted to Pediatric Orthopedics, a section of the journal Frontiers in Pediatrics Received 2022 Jun 29; Accepted 2022 Jul 28; Collection date 2022. First prospective study to assess the association of fibrodysplasia ossificans progressive (FOP) flare-ups and extra-skeletal bone growth (heterotopic ossification or HO) with functional impairment PARIS, France, 28 September 2022 – Ipsen (Euronext: IPN; ADR: IPSEY) today announced the publication of its Natural History Study (NHS) of FOP in Genetics in Medicine, the official journal of the American College...

This is the first time a global, prospective, longitudinal evaluation of FOP has been carried out, with data collected over a period of 36 months. Findings demonstrated the debilitating impact and progressive nature of the disease, with the greatest progression of new heterotopic ossification (HO; or bone growth that takes place outside of the normal skeletal system in joints... “Natural history studies are essential to understanding ultra-rare diseases with high unmet need like FOP, increasing our knowledge around the natural course of disease, diagnoses, monitoring techniques, potential biomarkers and new outcome measures,” said... Robert Pignolo, Professor of Geriatric Medicine, Mayo Clinic, USA. “This is the first study of its kind following the progression of FOP over three years. These results demonstrate the significant impact of the disease on people living with FOP.

Furthermore, it will facilitate the evaluation of meaningful endpoints in the development of new therapies, which are critically needed for individuals with FOP.” Results from the NHS demonstrated at month 36, across the whole study population, a mean of 2.6 body regions with new HO; this was highest (3.9) in those aged between two and eight years... However, although individuals aged 25 – 65 years had the lowest new HO volume at annual visits, approximately 70% continued to accumulate new HO across the duration of the study. These data confirmed the progressive nature of FOP with characteristic patterns of growth, starting in younger individuals initially across the upper and mid-torso, progressing into hip and lower-leg regions, and with accumulation of HO... The assessment of flare-ups showed, 82 (71.9%) individuals experienced a total of 229 flare-ups, most commonly in the upper back (17.9%), hip (14.8%) and shoulder (10.9%). Individuals between the ages of two and eight years, were most likely to report more than one flare-up throughout the study duration.

For those who experienced flare-ups, the most common symptoms were pain and soft tissue swelling. Imaging at the site of the flare-up revealed HO occurring at the time of the flare-up, with many individuals going on to experience new HO in the following 12 weeks.1

Fibrodysplasia Ossificans Progressiva Cleveland Clinic

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