Medical Guidelines For Fibrodysplasia Ossificans Progressiva

Leo Migdal

-Dec 5, 2025, 2:22 PM

medical guidelines for fibrodysplasia ossificans progressiva

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic condition characterized by congenital malformations of the great toes and progressive heterotopic ossification (HO) in specific anatomic patterns. Present management summarized here is focused on early diagnosis, assiduous avoidance of injury and iatrogenic harm, symptomatic amelioration of painful flare-ups, and optimization of residual function. Twenty-one members of the International Clinical Council on FOP (ICC) and seven consultants from 15 countries, chosen for their clinical expertise in FOP, developed this summary statement. Further advances in therapeutics will be based on rigorous clinical trials to assess novel and emerging treatment and prevention strategies. A detailed and updated exploration of the topics outlined in this brief perspective can be found in "The Medical Management of Fibrodysplasia Ossificans Progressiva: Current Treatment Considerations" which can be found on the International... Keywords: ACVR1; BMP signaling pathway; fibrodysplasia ossificans progressiva; guidelines; heterotopic ossification.

© The Author(s) 2025. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research. F.S.K. is a clinical trial investigator for Ashibio, Incyte, Ipsen, and Regeneron and serves in an unpaid capacity on the Medical Registry Advisory Board of the International Fibrodysplasia Ossificans Progressiva Association, the International Clinical Council... M.A.M. is a clinical trial investigator for Ashibio, Incyte, Ipsen, and Regeneron, and serves in an unpaid capacity on the Medical Registry Advisory Board of the International Fibrodysplasia Ossificans Progressiva Association, the International Clinical Council...

G.B. has research grants and conference support from FOP France and Ipsen, is a clinical trial investigator for Incyte, Ipsen, and Regeneron, is a member of the Medical Registry Advisory Board of the IFOPA, of... A.H.B. is a clinical trial investigator for Incyte, Ipsen, and Regeneron. M.B. is a clinical trial investigator for Incyte, Ipsen, and Regeneron.

A.C. is a trustee of The Radiant Hope Foundation. T-J.C. is a clinical trial investigator for Incyte and Ipsen. C.C.: None declared. C.L.D.C.

is a clinical trial investigator for Incyte and Ipsen and a member of the Medical Registry Advisory Board of the IFOPA. P.D. is a consultant for Ipsen, a clinical trial investigator for Incyte, Ipsen, and Regeneron, and a member of the Board of Directors of Tin Soldiers Global and the Noi Ci Siamo Association in Switzerland. R.J.D.: None declared. E.M.W.E. is a clinical trial investigator for STOPFOP, Regeneron, Ipsen, and Incyte, a member of the Medical Registry Advisory Board of the IFOPA, the steering committee of the Amsterdam Bone Center, the European Reference Network...

L.F.: None declared. C.F. is a consultant for Ipsen, Clinical Director for The Special Olympics, a member of the Board of Directors of Tin Soldiers Global, and has received an honorarium from Springer for a presentation. Z.G. is a consultant for the Axdev Group. N.H.

was a clinical investigator for Ipsen. E.C.H. serves in an unpaid capacity on the Medical Registry Advisory Board of the International Fibrodysplasia Ossificans Progressiva Association; the Fibrous Dysplasia Foundation Medical and Scientific Advisory Boards; and the International Clinical Council on FOP. ECH receives support for clinical trials through his institution from Clementia Pharmaceuticals, an Ipsen Company; Ipsen Pharmaceuticals; Ascendis; and āshibio. R.K. is a consultant for Ipsen, Alexion, Kyowa Kirin, UCB, Amgen, and Richter, a member of the Advisory Board of Alexion, Kyowa Kirin, Theramex, a clinical investigator for Alexion, Kyowa Kirin, Incyte, Ipsen, and Regeneron,...

J.K.: None declared. C.E.L.: None declared. V.M.: None declared. R.M. is a consultant for Ipsen. J.C.N.: None declared.

C.S. is a consultant for Ipsen and was a previous clinical trial investigator for Ipsen and Regeneron. E.M.S.: None declared. M.A.Z. was a member of the Clementia/Ipsen Data Safety Monitoring Board (DSMB) during the Palovarotene clinical trials and is currently on the Incyte DSMB. K.Z.

is a clinical trial investigator for Incyte, Ipsen, and Regeneron. R.J.P. is a clinical trial investigator for Ashibio, Incyte, Ipsen, and Regeneron, a member of the Medical Registry Advisory Board of the IFOPA, and a consultant for Incyte, Ipsen, and Regeneron. RJP is a co-inventor for the use of Andecaliximab in conditions of heterotopic ossification. Targets and potential therapies for fibrodysplasia ossificans progressiva. Frederick S.

Kaplan Mona Al Mukaddam Genevieve Baujat Alberto Hidalgo Bravo Matthew Brown Amanda Cali Tae-Joon Cho Corrie Crowe Carmen L. De Cunto Patricia L. R. Delai Robert J. Diecidue, Thomas Jefferson UniversityFollow Elisabeth Marelise W Eekhoff Lisa Friedlander Clive S. Friedman Zvi Grunwald, Thomas Jefferson UniversityFollow Nobuhiko Haga Edward C.

Hsiao Richard Keen Joseph A. Kitterman Charles Levy Vrisha Madhuri Rolf Morhart J. Coen Netelenbos Christiaan Scott Eileen M. Shore Michael Zasloff Keqin Zhang Robert J. Pignolo This article is the author’s final published version in JBMR Plus, Volume 9, Issue 11, 2025, Article number ziaf150.

The published version is available at https://doi.org/10.1093/jbmrpl/ziaf150. Copyright © The Author(s) 2025. Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic condition characterized by congenital malformations of the great toes and progressive heterotopic ossification (HO) in specific anatomic patterns. Present management summarized here is focused on early diagnosis, assiduous avoidance of injury and iatrogenic harm, symptomatic amelioration of painful flare-ups, and optimization of residual function. Twenty-one members of the International Clinical Council on FOP (ICC) and seven consultants from 15 countries, chosen for their clinical expertise in FOP, developed this summary statement. Further advances in therapeutics will be based on rigorous clinical trials to assess novel and emerging treatment and prevention strategies.

A detailed and updated exploration of the topics outlined in this brief perspective can be found in "The Medical Management of Fibrodysplasia Ossificans Progressiva: Current Treatment Considerations" which can be found on the International... Kaplan, Frederick S.; Al Mukaddam, Mona; Baujat, Genevieve; Hidalgo Bravo, Alberto; Brown, Matthew; Cali, Amanda; Cho, Tae-Joon; Crowe, Corrie; De Cunto, Carmen L.; Delai, Patricia L. R.; Diecidue, Robert J.; Eekhoff, Elisabeth Marelise W; Friedlander, Lisa; Friedman, Clive S.; Grunwald, Zvi; Haga, Nobuhiko; Hsiao, Edward C.; Keen, Richard; Kitterman, Joseph A.; Levy, Charles; Madhuri, Vrisha; Morhart, Rolf; Netelenbos, J. Coen; Scott, Christiaan; Shore, Eileen M.; Zasloff, Michael; Zhang, Keqin; and Pignolo, Robert J., "Medical Guidelines for Fibrodysplasia Ossificans Progressiva" (2025). Department of Oral and Maxillofacial Surgery Faculty Papers. Paper 8.https://jdc.jefferson.edu/omsfp/8

FOP is an autosomal dominant genetic disorder marked by congenital malformations of the great toes and progressive HO in specific anatomic patterns. Early diagnosis is critical, as the disease manifests with episodic, painful inflammatory soft tissue swellings called flare-ups, which often lead to irreversible heterotopic bone formation through endochondral ossification. Minor trauma—including intramuscular injections, dental procedures, muscle fatigue, and viral illnesses—can precipitate flare-ups, underscoring the need for careful medical management to avoid iatrogenic harm (Pignolo et al., 2025)[1]. Clinically, the diagnosis of FOP is suggested by the presence of malformed great toes and progressive HO. Confirmatory diagnosis requires genetic testing revealing pathogenic gain-of-function variants in the ACVR1 gene, encoding a bone morphogenetic protein (BMP) type I receptor. Approximately 97% of individuals with classic FOP harbor the recurrent ACVR1R206H variant, while others possess different ACVR1 mutations with variable phenotypes (Kaplan et al., 2025)[1].

The discovery of ACVR1 mutations has propelled the development of targeted therapies aimed at inhibiting aberrant BMP signaling, a central pathogenic mechanism in FOP (Shore et al., 2006). Clinical management emphasizes early diagnosis, avoidance of trauma and invasive procedures, symptomatic treatment of flare-ups, and preservation of function. Most patients experience progressive disability, wheelchair dependence by the third decade, and a median life expectancy of approximately 56 years due to complications such as thoracic insufficiency syndrome (Kaplan et al., 2010)[1]. Flare-ups in FOP are inflammatory episodes that often precede heterotopic bone formation. Prompt identification and treatment are essential to mitigate progression. Corticosteroids, particularly prednisone at 2 mg/kg/day for 4 days initiated within 24 hours of flare-up onset, are recommended for flare-ups involving major joints, limbs, jaw, and submandibular regions.

For axial flare-ups (chest/back), corticosteroids are less effective; NSAIDs or COX-2 inhibitors may be used cautiously for symptomatic relief while avoiding narcotics (Kaplan et al., 2025)[1]. Prophylactic corticosteroids are advised following significant soft tissue trauma and invasive procedures such as dental surgeries to prevent flare-ups. Prednisone dosing for prophylaxis is 1-2 mg/kg/day for 3-4 days post-trauma or procedure. Minor bumps or bruises do not warrant corticosteroid use. Local application of cool packs and NSAIDs assist with inflammation and pain management (Pignolo et al., 2025)[1].

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