NORD gratefully acknowledges Frederick S. Kaplan, MD, Isaac & Rose Nassau Professor of Orthopaedic Molecular Medicine; Chief, Division of Orthopaedic Molecular Medicine and Co-Director, Center for Research in FOP & Related Disorders, The Perelman School of Medicine at The University of Pennsylvania, and Eileen M. Shore, PhD, Cali-Weldon Professor of Orthopaedic Molecular Medicine and Genetics and Co-Director of The Center for Research in FOP & Related Disorders, The Perelman School of Medicine at The University of Pennsylvania, for assistance in the preparation of this report.
Fibrodysplasia ossificans progressiva (FOP) is a very rare inherited connective tissue disorder characterized by the abnormal development of bone in areas of the body where bone is not normally present (heterotopic ossification), such as the ligaments, tendons, and skeletal muscles. Specifically, this disorder causes the body's skeletal muscles and soft connective tissues to undergo a metamorphosis, essentially a transformation into bone, progressively locking joints in place and making movement difficult or impossible. Patients with FOP have malformed big toes that are present at birth (congenital). Other skeletal malformations may occur. The abnormal episodic development of bone at multiple soft tissue sites frequently leads to stiffness in affected areas, limited movement, and eventual ankylosis (fusion) of affected joints (neck, back, shoulders, elbows, hips knees, wrists, ankles, jaw - often in that order).
Episodic flare-ups (inflammatory soft tissue swellings) of FOP usually begin during early childhood and progress throughout life. Most cases of FOP occur as the result of a sporadic new mutation and the genetic mutation that results in this disorder has been identified. FOP is caused by the mutation of a gene (ACVR1) in the bone morphogenetic protein (BMP) pathway, which is important during the formation of the skeleton in the embryo and the repair of the skeleton following birth.
All individuals with classic FOP have malformations of the great toes and, in approximately 50% of patients, the thumbs. These changes in the skeleton are present at birth (congenital) and are the first clinical signs of this disorder. The most common skeletal malformation associated with FOP is a shortened great toe with a malformed distal first metatarsal and a missing or abnormal first phalanx and/or interphalangeal joint. Other malformations of the toes and fingers may include inward turning of the great toe toward the other toes (hallux valgus), abnormally short fingers and toes (microdactyly), and/or permanent fixation of the fifth finger in a bent position (clinodactyly). Other congenital signs of FOP include proximal medial tibial osteochondromas, malformation of the upper part of the spinal column (cervical vertebrae), and an abnormally short broad neck of the bone in the thigh that extends from the knee to the pelvis (femur).
Progressive bone formation in connective tissues (heterotopic ossification) usually occurs during early childhood, and progresses throughout life. The abnormal development of bone may occur spontaneously but often occurs following an episode of soft tissue injury or a viral illness. The first sign of heterotopic ossification is the appearance of firm tender swellings on certain parts of the body, especially the back, neck, and/or shoulders. These soft tissue swellings mature through a cartilage-to-bone (endochondral) pathway to form mature heterotopic bone. The ectopic bone growth usually involves tendons, ligaments, skeletal muscle tissue, and connective tissues such as fascia and aponeuroses. In many cases, pain and stiffness occurs in these areas. On some occasions, a low-grade fever may herald the development of these swellings. Although the swellings eventually regress, they usually harden into mature bone as they decrease in size.
In the affected areas, bone slowly replaces connective tissue. The neck, back, chest, arms, and legs are usually the first areas affected. The disease eventually affects the hips, ankles, wrists, elbows, shoulders, and/or jaw as well as the abdominal wall. In some affected individuals, the progression of bone development may be rapid; in others, the process may be gradual. Even among identical twins, the disease progression may vary greatly, reflecting different environment impacts such as traumatic episodes.
Chronic swelling in various parts of the body is a common physical characteristic of individuals with FOP. Swelling may occur coordinately with the abnormal bone formation that characterizes FOP, or it may occur when recently-formed bone presses on lymphatic vessels, obstructing the flow of tissue fluid. In addition, swelling may also be caused by a lack of pumping action within the hardened (ossified) muscle and can cause blood and tissue fluids to pool in a limb (e.g., arms and/or legs).
Abnormal development of bone eventually leads to stiffness and limited movement of affected joints. If the jaw is involved, affected individuals may have trouble eating and/or speaking. In addition, abnormal development of bone may lead to progressive deformity of the spine including side-to-side (scoliosis) and, in some cases, front-to-back curvature of the spine (kyphosis). As is the case for skeletal bone, the bone that develops in abnormal areas may fracture and then undergo fracture repair. As the disease progresses, individuals with FOP experience increasingly limited mobility that causes problems with balance, difficulty walking and/or sitting, and/or severely restricted movement.
FOP may eventually result in complete immobilization. Affected individuals may experience progressive pain and stiffness in affected areas, complete fusion of the spine, and/or pain in affected areas of the body caused by abnormal bony growths that compress the nerves in these areas (entrapment neuropathies). As mobility begins to deteriorate, affected individuals may exhibit an increased susceptibility to respiratory infection or right sided congestive heart failure. Hearing impairment is seen in approximately 50% of affected individuals. In some cases of more severe forms of variant FOP, individuals may exhibit hair loss or mild cognitive delay.
Most cases of FOP occur sporadically, with a single affected individual within a family. When a familial pattern has been identified, FOP is inherited as an autosomal dominant trait with complete penetrance.
In April 2006, an international team of researchers led by Eileen M. Shore, PhD and Frederick Kaplan MD of the University of Pennsylvania, published results of research identifying the genetic mutation that causes FOP. The team found that FOP is caused by a mutation of a gene on chromosome 2 (2q23-24) for a receptor in the BMP signaling pathway called ACVR1.
Bone morphogenetic proteins are regulatory proteins important in embryonic skeletal formation and in post-natal repair of the skeleton. The gene identified as the FOP gene encodes a BMP receptor called Activin Receptor Type IA, or ACVR1, one of four known BMP Type I receptors. BMP receptors, located at the cell surface, help determine the fate of the stem cells in which they are expressed by transmitting signals into the cell. The classic clinical FOP presentation is caused by the specific substitution of a particular amino acid (arginine, at position 206) in the ACVR1 protein for another amino acid (histidine). This amino acid substitution induces activation of signaling by the ACVR1 receptor. In 2012, an ACVR1 (Arg206His; R206H) knock-in mouse was reported with a similar phenotype as human FOP. Extremely rare and illustrative phenotypic and genotypic variants of FOP have been reported, but in all patients to date, heterozygous activating mutations are present in the ACVR1 gene.
Chromosomes, present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22, and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome, and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further subdivided into multiple numbered regions (bands), which reflect the location of the thousands of genes that are reside within each chromosome. For example, chromosome 2q23-24 refers to a location from bands 23 and 24 on the long arm of chromosome 2.
Genes are encoded within the chromosomal DNAs that are inherited from the father and the mother. Cells have two copies of each gene (except for some genes encoded by the X and Y chromosomes); one gene copy is inherited from the father and one from the mother. Phenotypic variation (including genetic diseases) is determined by differences in the DNA sequences of the genes that specify a particular trait.
Dominant genetic disorders are caused by abnormal DNA sequence changes in one of the two copies of a given gene. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from an affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.
FOP is a very rare inherited connective tissue disorder that was first identified in the 18th century. Of an estimated 4000 affected individuals worldwide, there are approximately 900 known patients. This disorder affects both genders and all ethnicities.
Malformations of the toes and fingers are often present at birth (congenital); abnormal development of extra-skeletal bone usually begins during early childhood. In some rare cases, onset of abnormal bone growth may not occur until late adolescence or early adulthood. Affected individuals may have periods of time where they are free of new episodes of bone growths. However, new episodes of bone growth may begin at any time for no apparent reason (spontaneously).
Misdiagnosis of FOP is common but can be avoided simply by examining the individual’s toes for the characteristic feature, short great toes. The diagnosis may be confirmed by a thorough clinical evaluation, characteristic physical findings, and sequencing of the ACVR1 gene.
Biopsies should be avoided when FOP is suspected because these tests may result in rapid bone formation in those areas where tissue is removed. Intramuscular injections (e.g., immunizations) must be avoided, and dental therapy should preclude injections of local anesthetics and stretching of the jaw. In addition, individuals should avoid any situations, such as falls, that may cause blunt trauma, since trauma may cause abnormal bone development in most cases. Various viral illnesses including influenza and influenza-like illnesses may provoke flare-ups of the condition.
In affected individuals with an increased susceptibility to respiratory infections due to progressive mobility impairment, steps may be taken to prevent infection, such as preventative (prophylactic) antibiotic therapy.
There are no known effective treatments for FOP but clinical trials are underway. Certain types of drugs have been used to relieve pain and swelling associated with FOP during acute flare-ups (most notably corticosteroids) and non-steroidal anti-inflammatory medication between flare-ups.
Affected individuals may benefit from occupational therapy. Special shoes, braces, and other devices that assist in walking and weight-bearing have been used to help people with FOP. Affected individuals may have their physicians contact an occupational therapist who can help obtain special devices or tools to assist them in daily activities.
Genetic counseling may be of benefit for families with inheritance of FOP. A team approach for infants diagnosed with FOP will also be of benefit and may include special social, educational, and medical services. Other treatment is symptomatic and supportive.
The discovery of the FOP gene and the mutation that causes FOP continues to lead to research on possible ways to treat the underlying cause of the disease itself, and not just its symptoms.
Investigational therapies for FOP include retinoic acid receptor gamma-selective agonists, immunosuppressants, and BMP pathway antagonists.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.
For information about clinical trials being conducted at the National Institutes of Health (NIH) Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
Contacts for additional information about fibrodysplasia ossificans progressiva:
For basic research questions:
Eileen M. Shore, PhD
Professor, Departments of Orthopaedic Surgery and Genetics
Perelman School of Medicine
University of Pennsylvania
309A Stemmler Hall
3450 Hamilton Walk
Philadelphia, PA 19104-6081
email: [email protected]
For clinical questions:
Frederick S. Kaplan, M.D.
Isaac & Rose Nassau Professor of Orthopaedic Molecular Medicine
Chief, Division of Orthopaedic Molecular Medicine
Perelman School of Medicine
The University of Pennsylvania
c/o Department of Orthopaedic Surgery
Penn Musculoskeletal Center – Suite 600
3737 Market Street
Philadelphia, PA 19104
Email: [email protected]
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Lees-Shepard JB, Yamamoto M, Biswas AA, Stoessel SJ, Nicholas SE, Cogswell CA, Devarakonda PM, Schneider MJ Jr, Cummins SM, Legendre NP, Yamamoto S, Kaartinen V, Hunter JW, Goldhamer DJ. Activin-dependent signaling in fibro/adipogenic progenitors causes fibrodysplasia ossificans progressiva. Nat Commun. 2018 Feb 2;9(1):471. doi: 10.1038/s41467-018-02872-2.
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Wang H, Lindborg C, Lounev V, Kim J, McCarrick-Walmsley R, Xu M, Mangiavini L, Groppe J, Shore E, Schipani E, Kaplan F, Pignolo R. Cellular Hypoxia Promotes Heterotopic Ossification by Amplifying BMP Signaling. J Bone Miner Res. 2016 Sep;31(9):1652-65.
Hatsell SJ, Idone V, Wolken DM, Huang L, Kim HJ, Wang L, Wen X, Nannuru KC, Jimenez J, Xie L, Das N, Makhoul G, Chernomorsky R, D’Ambrosio D, Corpina RA, Schoenherr CJ, Feeley K, Yu PB, Yancopoulos GD, Murphy AJ, Economides AN. ACVR1R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A. Sci Transl Med. 2015;Sep 2;7(303):303ra137.
Hino K, Ikeya M, Horigome K, Matsumoto Y, Ebise H, Nishio M, Sekiguchi K, Shibata M, Nagata S, Matsuda S, Toguchida J. Neofunction of ACVR1 in fibrodysplasia ossificans progressiva. PNAS 2015; doi/10.1073/pnas.1510540112.
Chakkalakal SA, Zhang D, Culbert AL, Convente MR, Caron RJ, Wright AC, Maidment AD, Kaplan FS, Shore EM. An Acvr1 Knock-in mouse has fibrodysplasia ossificans progressiva. J Bone Miner Res. 2012; 27:1746-1756.
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Kaplan FS, Xu M, Seemann P, Connor JM, Glaser DL, Carroll L, Delai, P, Xu M, Seemann P, Fastnacht-Urban E, Forman SJ, Gillessen-Kaesbach G, Hoover-Fong J, Köster B, Pauli RM, Reardon W, Zaidi S-A, Zasloff M, Morhart R, Mundlos S, Groppe J, and Shore EM. Classic and atypical fibrodysplasia ossificans progressiva (FOP) phenotypes are caused by mutations in the bone morphogenetic protein (BMP) type I receptor ACVR1. Hum Mutat. 2009;30(3):379-390.
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Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Fibrodysplasia Ossificans Progressiva; FOP. Entry No:135100. Last Updated 09/19/2017. Available at: http://omim.org/entry/135100 Accessed May 20, 2020.
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