Last updated:
06/26/24
Years published: 1987, 1990, 1996, 2002, 2006, 2008, 2011, 2014, 2017, 2020, 2024
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 an extremely rare genetic 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 leads to stiffness in affected areas, limited movement and eventual fusion (ankylosis) 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 variant in the ACVR1 gene in the bone morphogenetic protein (BMP) signaling 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 endochondral bone formation in connective tissues (heterotopic ossification) usually occurs during early childhood and progresses throughout life. 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 (often referred to as flare-ups) 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 patients, 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 environmental 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, the person 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 people, 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 have 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 have an increased susceptibility to respiratory infection or right sided congestive heart failure due to thoracic insufficiency. Hearing impairment is seen in approximately 50% of affected individuals. Some people with more severe forms of FOP may have hair loss or mild cognitive delay.
Most cases of FOP occur sporadically, and there is a single affected individual within a family. When a familial pattern has been identified, FOP is inherited in an autosomal dominant pattern.
Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) changed gene in the affected individual that is not inherited. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.
In 2006, an international team of researchers led by Eileen M. Shore, PhD and Frederick Kaplan MD at the University of Pennsylvania, published results of research identifying the genetic cause of FOP. The team found that FOP is caused by a change (variant) in the ACVR1 gene in the bone morphogenetic protein (BMP) signaling pathway.
Bone morphogenetic proteins are regulatory proteins important in embryonic skeletal formation and in post-natal repair of the skeleton. The ACVR1 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.
FOP is a very rare inherited connective tissue disorder that was first identified in the 18th century. The prevalence of FOP is estimated to be 1/1,000,000. FOP affects males and females equally, and people from all ethnicities.
Misdiagnosis of FOP is common but can be avoided 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.
Treatment
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. Injections of local anesthetics and stretching of the jaw for dental therapy should be avoided. People with FOP should avoid any situations, such as falls, that may cause blunt trauma, since trauma may cause abnormal bone development. Various viral illnesses including influenza and influenza-like illnesses may provoke flare-ups of the condition.
In 2023, palovarotene (Sohonos), a retinoic acid receptor γ (RARγ) agonist, was approved by the U.S. Food and Drug Administration (FDA) as the first treatment for FOP to reduce extra-skeletal bone formation in adults and children aged 8 years and older for females, and 10 years and older for males.
Preventative (prophylactic) antibiotic therapy may be appropriate to prevent infection in affected individuals with an increased susceptibility to respiratory infections due to progressive mobility impairment.
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. An occupational therapist can help obtain special devices or tools to assist in daily activities.
A team approach for infants diagnosed with FOP is also recommended and may include special social, educational and medical services.
Genetic counseling is recommended for individuals with FOP and their families. Other treatment is symptomatic and supportive.
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:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
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
phone: 215-898-2330
fax: 215-573-2133
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
Tel: 215-294-9145
Fax: 215-222-8854
Email: [email protected]
REVIEW ARTICLES
Pignolo RJ and Kaplan FS. Druggable targets, clinical trial design and proposed pharmacological management in fibrodysplasia ossificans progressiva. Expert Opinion on Orphan Drugs 2020; 8:4, 101-109.
Shore EM, Kaplan FS. Role of altered signal transduction in heterotopic ossification and fibrodysplasia ossificans progressiva. Curr Osteoporosis Rep. 2011;9: 83-88.
Shore EM, Kaplan FS. Inherited human diseases of heterotopic bone formation. Nat Rev Rheumatol. 2010;6: 518-527.
Zimmer C. The mystery of the second skeleton. Atlantic Monthly. 2013;311(5): 72-82.
JOURNAL ARTICLES
Adegbite NS, Xu M, Kaplan FS, Shore EM, Pignolo RJ. Diagnostic and mutational spectrum of progressive osseous heteroplasia (POH) and other forms of GNAS-based heterotopic ossification. Am J Med Genet A. 2008;146A:1788-1796.
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.
Convente MR, Chakkalakal SA, Yang E, Caron RJ, Zhang D, Kambayashi T, Kaplan FS, Shore EM. Depletion of mast cells and macrophages impairs heterotopic ossification in an ACVR1 (R206H) mouse model of fibrodysplasia ossificans progressiva. J Bone Miner Res. 2018; 33: 269-282.
Deirmengian GK, Hebela NM, O’Connell M, Glaser DL, Shore EM, Kaplan FS. Proximal tibial osteochondromas in patients with fibrodysplasia ossificans progressiva. J Bone Joint Surg Am. 2008;90:366-374.
Di Rocco M, Forleo-Neto E, Pignolo RJ, et al. Garetosmab in fibrodysplasia ossificans progressiva: a randomized, double-blind, placebo-controlled phase 2 trial. Nat Med. 2023;29(10):2615-2624. doi:10.1038/s41591-023-02561-8
Gupta RR, Delai PLR, Glaser DL, Rocke DM, Al Mukaddam M, Pignolo RJ, Kaplan FS. Prevalence and risk factors for kidney stones in fibrodysplasia ossificans progressiva. Bone 2018;109: 120-123.
Hatsell SJ, Idone V, Wolken DM, et al. ACVR1R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A. Sci Transl Med. 2015;7(303):303ra137. doi:10.1126/scitranslmed.aac4358
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.
Hsiao EC, DiRocco M, Cali A. Zasloff M, Al Mukaddam M, Pignolo R, Grunwald Z, Netelenbos C, Keen R, Baujat G, Brown MA, Cho T-J De Cunto C, Delai P, Haga N, Morhart R, Scott C, Zhang K, Diecidue RJ, Friedman CS, Kaplan FS, Eekhoff EMW. Special considerations for clinical trials in fibrodysplasia ossificans progressiva. Br J Clin Pharmacol 2019; 85(6): 1199-1207.
Kaplan FS, Al Mukaddam M, Pignolo RJ. Longitudinal patient-reported mobility assessment in fibrodysplasia ossificans progressiva (FOP). Bone 2018;109:150-161.
Kaplan FS, Glaser DL, Shore EM, Pignolo RJ, Xu M, Zhang Y, Senitzer D, Forman SJ, Emerson SG. Hematopoietic stem cell contribution to ectopic skeletogenesis. J Bone Joint Surg Am. 2007;89:347-357.
Kaplan FS, Xu M, Seemann P, et al. 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. doi:10.1002/humu.20868
Kaplan FS, Xu M, Glaser DL Collins F, Connor M, Kitterman J, Sillence D, Zackai E, Ravitsky V, Zasloff M, Ganguly A, Shore EM. Early diagnosis of fibrodysplasia ossificans progressiva. Pediatrics. 2008;121:e1295-e1300.
Kaplan FS, Zasloff MA, Kitterman JA, Shore EM, Hong CC, Rocke DM. Early mortality and cardiorespiratory failure in patients with fibrodysplasia ossificans progressiva. J Bone Joint Surg Am. 2010;92:686-691.
Kitterman JA, Kantanie S, Rocke DM, Kaplan FS. Iatrogenic harm caused by diagnostic errors in fibrodysplasia ossificans progressiva. Pediatrics. 2005;116:e654-61.
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.
Lindborg CM, Al Mukaddam M, Baujat G, Cho TJ, DeCunto CL, Delai PLR, Eekhoff EMW, Haga N, Hsiao EC, Morhart R, de Ruiter R, Scott C, Seemann P, Szczepanek M, Tabarkiewicz J, Pignolo RJ, Kaplan FS. Most fractures treated non-operatively in individuals with fibrodysplasia ossificans progressiva heal with a paucity of flareups, heterotopic ossification, and loss of mobility. Clin Orthop Relat Res. 2023; 481: 2447-2458.
Lounev V, Groppe JC, Brewer N, Wentworth KL, Smith V, Xu M, Schomburg L, Bhargava P, Al Mukaddam M, Hsiao EC, Shore EM, Pignolo RJ, Kaplan FS. MMP-9 deficiency confers resilience in Fibrodysplasia Ossificans Progressiva in a man and mice. J Bone Miner Res. 2024; 39(4): 382-398.
Pignolo R.J., Baujat G, Brown MA, DeCunto C, DiRocco M, Hsiao EC, Keen R, Al Mukaddam M, LeQuan Sang K-H, Wilson A, White B, Grogan DR, Kaplan FS. Natural history of fibrodysplasia ossificans progressiva: cross-sectional analysis of annotated baseline phenotypes. Orphanet J. Rare Diseases 2019; 14: 98. https://doi.org/10.1186/s13023-019-1068-7
Pignolo RJ, Baujat G, Brown MA, De Cunto C, Hsiao EC, Keen R, Al Mukaddam M, Le Quan Sang K-H, Wilson A, Marino R, Strahs A, Kaplan FS. The natural history of fibrodysplasia ossificans progressiva: A prospective, global 36-month study. Genetics in Medicine. https://doi.org/10.1016/j.gim. 2022.08.013
Pignolo RJ, Durbin-Johnson BP, Rocke DM, Kaplan FS. Joint -specific risk of impaired function in fibrodysplasia ossificans progressiva (FOP). Bone 2018; 109:124-133.
Pignolo RJ, Bedford-Gay C Liljesthröm M Durbin-Johnson BP, Shore EM , Rocke DM , Kaplan FS. The natural history of flare-ups in fibrodysplasia ossificans progressiva (FOP): a comprehensive global assessment. J Bone Miner Res. 2016;31(3):650-6.
Pignolo RJ, Hsiao EC, Al Mukaddam M, Baujat G, Berglund SK, Brown MA, Cheung AM, DeCunto C, Delai P, Haga N, Kannu P, Keen R, Le Quan Sang, Mancilla EE, Marino R, Strahs A, Kaplan FS. Reduction of new heterotopic ossification (HO) in the open-label phase 3 MOVE trial of palovarotene for fibrodysplasia ossificans progressiva (FOP). J Bone Miner Res. 2023; 38(3): 381-394.
Shen Q, Little SC, Xu M, Haupt J, Ast C, Katagiri T, Mundlos S, Seemann P. Kaplan FS, Mullins MC, Shore EM. The fibrodysplasia ossificans progressiva R206H ACVR1 mutation activates BMP-independent chondrogenesis and zebrafish embryo ventralization. J Clin Invest. 2009;119(11):3462-3472.
Shore EM, Xu M, Feldman GJ, Fenstermacher DA, Cho T-J, Choi IH, Connor JM, Delai P, Glaser DL, Le Merrer M, Morhart R, Rogers JG, Smith R, Triffitt JT, Urtizberea JA, Zasloff M, Brown MA, Kaplan FS. A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nature Genetics. 2006;38:525-527.
Towler OW, Shore EM, Kaplan FS. Skeletal malformations and developmental arthropathy in individuals who have fibrodysplasia ossificans progressiva. Bone 2020 Jan;130:115116. doi: 10.1016/j.bone.2019.115116. Epub 2019 Oct 23.
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; 31(9):1652-65.
Wang H, Shore EM, Pignolo RJ, Kaplan FS. Activin A amplifies dysregulated BMP signaling and induced chondro-osseous differentiation of primary connective tissue progenitor cells in patients with fibrodysplasia ossificans progressiva (FOP). Bone 2018;109: 218-224.
INTERNET
Kaplan FS, Al Mukaddam M, Baujat G, Brown M, Cali A, Cho T-J, Crowe C, DeCunto C, Delai P, Diecidue, R, Di Rocco M, Eekhoff EMW, Friedman C, Grunwald Z, Haga N. Hsiao E, Keen R, Kitterman J, Levy C, Morhart R, Netelenbos C, Scott C, Shore EM, Zasloff M, Zhang K, Pignolo RJ. Proc Intl. Clin. Council The medical management of fibrodysplasia ossificans progressiva: current treatment considerations. FOP 2021 ; 1:1-128. https://www.iccfop.org/dvlp/wp-content/uploads/2021/08/guidelines-aug-2021.pdf Accessed May 16, 2024.
Fibrodysplasia Ossificans Progressiva; FOP. Online Mendelian Inheritance in Man (OMIM). Entry No:135100. Last Updated 11/07/2022. Available at: http://omim.org/entry/135100 Accessed May 16, 2024.
Akesson LS, Savarirayan R. Fibrodysplasia Ossificans Progressiva. 2020 Jun 11 [Updated 2023 May 11]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK558090/ Accessed May 16, 2024.
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