31/07/2021 Fibrodysplasia Ossificans Progressiva - NORD (National Organization for Rare Disorders)

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Fibrodysplasia Ossificans Progressiva

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.

Synonyms of Fibrodysplasia Ossificans Progressiva

FOP
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myositis ossificans progressiva

General Discussion
Fibrodysplasia ossificans progressiva (FOP) is a very 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
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.

Signs & Symptoms

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
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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.

Causes
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.

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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.

Affected Populations

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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).

Related Disorders
Symptoms of the following disorders may be similar to those of fibrodysplasia ossificans progressiva. Comparisons may be
useful for differential diagnosis:

Aggressive juvenile fibromatosis is a condition in which cells called fibroblasts increase in number in tendon, ligament and
other connective tissues. This overgrowth of cells may invade adjacent tissues, causing pain and disability. The resulting
lesions may resemble the tissue swelling associated with FOP. However, individuals with aggressive juvenile fibromatosis
do not have the toe malformation that is associated with FOP nor do they develop heterotopic ossification.

Progressive osseous heteroplasia (POH) is an extremely rare inherited disorder characterized by the abnormal
development of bone in areas of the body where bone is not normally present (heterotopic ossification). Unlike FOP, the
initial bone growth may develop on the surface of the skin (osseous plaques). These areas may become progressively
widespread and come together (coalesce) to form even larger areas of hardened and thickened skin (dermal ossification).
Progressive osseous heteroplasia spreads to deeper levels of the skin and to various muscle, fatty, and connective tissues of
the body. As the disorder continues to progress, the abnormal development of bone may lead to stiffening and limited
movement of affected joints. In severe cases, affected joints may become permanently fixed (ankylosed). In addition, arms
and legs may become malformed and not grow to full length. The genetic basis of progressive osseous heteroplasia is a
heterozygous inactivating mutation in the gene encoding the paternally-inherited allele of the alpha subunit of the
stimulatory G-protein of adenylyl cyclase (GNAS). GNAS mutations have been identified in approximately 70% of affected
individuals. POH is a distinct developmental disorder and belongs to a spectrum of clinical conditions that have the
common feature of ossification of the skin (osteoma cutis). Although skeletal malformations have been noted, individuals
with progressive osseous heteroplasia do not have the toe malformation that is characteristic of FOP. (For more
information on this disorder, choose “Progressive Osseous Heteroplasia” as your search term in the Rare Disease
Database.)

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Diagnosis
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.

Standard Therapies
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, 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.

Investigational Therapies
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.

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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: prpl@cc.nih.gov
Some current clinical trials also are posted on the following page on the NORD website:

https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/

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: shore@pennmedicine.upenn.edu

For clinical questions:

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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: Frederick.Kaplan@pennmedicine.upenn.edu

NORD Member Organizations

International FOP Association
1520 Clay Street
Suite H2
Kansas City, MO 64116 USA
Phone: (407) 365-4194
Email: together@ifopa.org
Website: http://www.ifopa.org

Other Organizations
Genetic and Rare Diseases (GARD) Information Center
PO Box 8126
Gaithersburg, MD 20898-8126
Phone: (301) 251-4925
Toll-free: (888) 205-2311
Website: http://rarediseases.info.nih.gov/GARD/

NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases

Information Clearinghouse
One AMS Circle
Bethesda, MD 20892-3675 USA
Phone: (301) 495-4484
Toll-free: (877) 226-4267
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Email: NIAMSinfo@mail.nih.gov
Website: http://www.niams.nih.gov/

Progressive Osseous Heteroplasia Association

1460 Bolingbrook Drive
Columbus, OH 43228 USA
Phone: (614) 887-7642
Email: Info@pohdisease.org
Website: http://www.pohdisease.org

References
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, DOI:
10.1080/21678707.2020.1751122

Zimmer C. The mystery of the second skeleton. Atlantic Monthly. 2013;311(5): 72-82.
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.
JOURNAL ARTICLES

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.
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
Hsaio 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 [Epub ahead of print],
2018.
Kaplan FS, Al Mukaddam M, Pignolo RJ. Longitudinal patient-reported mobility assessment in fibrodysplasia ossificans
progressiva (FOP). Bone 2018;109:150-161.
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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.
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.
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.
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.
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.
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
Mar;31(3):650-6.
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, 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.
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.

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.

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.
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.
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, Glaser DL, Shore EM, Pignolo RJ, Xu M, Zhang Y, Senitzer D, Forman SJ, Emwerson SG. Hematopoietic stem cell
contribution to ectopic skeletogenesis. J Bone Joint Surg Am. 2007;89:347-357.
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.
Kitterman JA, Kantanie S, Rocke DM, Kaplan FS. Iatrogenic harm caused by diagnostic errors in fibrodysplasia ossificans
progressiva. Pediatrics. 2005;116:e654-61.
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. The medical management of fibrodysplasia ossificans progressiva: current
treatment considerations. Proc Intl. Clin. Council FOP 2019; 1:1-111.
https://www.ifopa.org/international_clinical_council_on_fop Accessed May 20, 2020.

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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.

Years Published
1987, 1990, 1996, 2002, 2006, 2008, 2011, 2014, 2017, 2020

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General Discussion
Signs & Symptoms
Causes
Affected Populations
Related Disorders
Standard Therapies
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https://rarediseases.org/rare-diseases/fibrodysplasia-ossificans-progressiva/#:~:text=Fibrodysplasia ossificans progressiva (FOP) is,%2C tendons%2C and skeletal muscles. 16/17
31/07/2021 Fibrodysplasia Ossificans Progressiva - NORD (National Organization for Rare Disorders)

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