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Fibrodysplasia Ossificans Progressiva Diagnosis Wiley Online Library

Leo Migdal
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fibrodysplasia ossificans progressiva diagnosis wiley online library

Corresponding Author: Frederick S. Kaplan, M.D. Isaac & Rose Nassau Professor of Orthopaedic Molecular Medicine The University of Pennsylvania School of Medicine Department of Orthopaedic Surgery Silverstein Two Hospital of the University of Pennsylvania 3400 Spruce Street Philadelphia, Pennsylvania 19104... Fibrodysplasia ossificans progressiva (FOP), a rare and disabling genetic condition characterized by congenital malformations of the great toes and progressive heterotopic endochondral ossification (HEO) which is the most catastrophic of HEO disorders in humans. Flare-ups of FOP are episodic; immobility is cumulative. Heterozygous activating mutations in activin receptor IA/activin-like kinase-2 (ACVR1/ALK2), a bone morphogenetic protein (BMP) type I receptor, exist in all sporadic and familial cases of FOP.

The discovery of the FOP gene established a critical milestone in our understanding FOP, and revealed a highly conserved therapeutic target in the BMP signaling pathway. This discovery has advanced efforts to develop novel therapies for this disabling disorder of tissue metamorphosis. While effective treatment for FOP will likely be based on interventions that modulate overactive ACVR1/ALK2 signaling, or that specifically block postnatal HEO, current management is focused on early diagnosis, assiduous avoidance of injury or... Keywords: fibrodysplasia ossificans progressiva, heterotopic ossification, activin receptor IA/activin-like kinase-2 (ACVR1/ALK2), BMP signaling Fibrodysplasia ossificans progressiva (FOP) is a rare and disabling disorder with a worldwide prevalence of approximately one in two million individuals. There is no ethnic, racial, gender, or geographic predisposition [1, 2].

Two clinical features define classic FOP: malformations of the great toes and progressive heterotopic endochondral ossification (HEO) in characteristic anatomic patterns. Individuals with FOP appear normal at birth except for malformations of the great toes that are present in all classically affected individuals. During the first decade of life, most children with FOP develop episodic, painful inflammatory soft tissue swellings (or flare-ups). While some flare-ups regress spontaneously, most transform soft connective tissues including aponeuroses, fascia, ligaments, tendons, and skeletal muscles into mature heterotopic bone. Ribbons, sheets, and plates of heterotopic bone replace skeletal muscles and connective tissues through a process of endochondral ossification that leads to an armament-like encasement of bone and permanent immobility. Minor trauma such as intramuscular immunizations, mandibular blocks for dental work, muscle fatigue, blunt muscle trauma from bumps, bruises, falls, or influenza-like viral illnesses can trigger painful new flare-ups of FOP leading to progressive...

Surgical removal of heterotopic bone provokes explosive and painful new bone growth. Correspondence: E Marelise W Eekhoff, Department of Internal Medicine section Endocrinology, Amsterdam UMC location Vrije Universiteit Amsterdam, De Boelelaan 1117, Amsterdam, the Netherlands, Tel +31 204440588, Email emw.eekhoff@amsterdamumc.nl Received 2022 Jan 29; Accepted 2022 Apr 2; Collection date 2022. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms.

Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Fibrodysplasia ossificans progressiva (FOP), sometimes known as myositis ossificans progressiva, is an ultra-rare disease in which bone is formed in muscular tissue, tendons and ligaments. This is known as heterotopic ossification (HO). FOP is caused by a heterozygous mutation in the highly conserved ACVR1/ALK2 gene which affects about 1 in 1.5–2 million individuals. At birth, patients with the predominant R206H mutation only exhibit a bilateral hallux valgus.

During childhood, heterotopic bone formation develops in a typical pattern, affecting the axial muscles first before appendicular body parts are involved. HO can start spontaneously but is often elicited by soft tissue trauma or medical procedures. After soft tissue injury, an inflammatory process called a flare-up can start, followed by the formation of HO. HO leads to a limited range of motion, culminating in complete ankylosis of nearly all joints. As a result of HO surrounding the thorax, patients often suffer from thoracic insufficiency syndrome (TIS). TIS is the most common cause of a limited life expectancy for FOP patients, with a median life expectancy of 56 years.

Management is focused on preventing soft-tissue injury that can provoke flare-ups. This includes prevention of iatrogenic damage by biopsies, intramuscular injections and surgery. Anti-inflammatory medication is often started when a flare-up occurs but has a poor basis of evidence. Several forms of potential treatment for FOP are being researched in clinical trials. Progression of the disease is monitored using CT and 18F-NaF PET/CT combined with functional assessments. Patients are regularly evaluated for frequently occurring complications such as restrictive lung disease.

Here, we review the current management, monitoring and treatment of FOP. Keywords: fibrodysplasia ossificans progressiva, heterotopic ossification, activin A receptor type 1, treatment strategies Corresponding author: Frederick S. Kaplan, Isaac and Rose Nassau Professor of Orthopaedic Molecular Medicine, The Perelman School of Medicine at the University of Pennsylvania, Department of Orthopaedic Surgery, 3737 Market Street – Sixth Floor, Philadelphia, PA 19104, United... Received 2025 Aug 4; Revised 2025 Sep 5; Accepted 2025 Sep 9; Collection date 2025 Nov. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited.

For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. 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: fibrodysplasia ossificans progressiva, heterotopic ossification, BMP signaling pathway, ACVR1, guidelines Research output: Contribution to journal › Review article › peer-review Fibrodysplasia ossificans progressiva (FOP), a rare and disabling genetic condition characterized by congenital malformations of the great toes and progressive heterotopic endochondral ossification (HEO) which is the most catastrophic of HEO disorders in humans. Flare-ups of FOP are episodic; immobility is cumulative. Heterozygous activating mutations in activin receptor IA/activin-like kinase-2 (ACVRI/ ALK2), a bone morphogenetic protein (BMP) type I receptor, exist in all sporadic and familial cases of FOP.

The discovery of the FOP gene established a critical milestone in our understanding of FOP, and revealed a highly conserved therapeutic target in the BMP signaling pathway. This discovery has advanced efforts to develop novel therapies for this disabling disorder of tissue metamorphosis. While effective treatment of FOP will likely be based on interventions that modulate overactive ACVR1/ALK2 signaling, or that specifically block postnatal HEO, current management is focused on early diagnosis, assiduous avoidance of injury or... Research output: Contribution to journal › Review article › peer-review T1 - Fibrodysplasia ossificans progressiva T2 - diagnosis, management, and therapeutic horizons.

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.

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Corresponding Author: Frederick S. Kaplan, M.D. Isaac & Rose Nassau

Corresponding Author: Frederick S. Kaplan, M.D. Isaac & Rose Nassau Professor of Orthopaedic Molecular Medicine The University of Pennsylvania School of Medicine Department of Orthopaedic Surgery Silverstein Two Hospital of the University of Pennsylvania 3400 Spruce Street Philadelphia, Pennsylvania 19104... Fibrodysplasia ossificans progressiva (FOP), a rare and disabling genetic condition charac...

The Discovery Of The FOP Gene Established A Critical Milestone

The discovery of the FOP gene established a critical milestone in our understanding FOP, and revealed a highly conserved therapeutic target in the BMP signaling pathway. This discovery has advanced efforts to develop novel therapies for this disabling disorder of tissue metamorphosis. While effective treatment for FOP will likely be based on interventions that modulate overactive ACVR1/ALK2 signal...

Two Clinical Features Define Classic FOP: Malformations Of The Great

Two clinical features define classic FOP: malformations of the great toes and progressive heterotopic endochondral ossification (HEO) in characteristic anatomic patterns. Individuals with FOP appear normal at birth except for malformations of the great toes that are present in all classically affected individuals. During the first decade of life, most children with FOP develop episodic, painful in...

Surgical Removal Of Heterotopic Bone Provokes Explosive And Painful New

Surgical removal of heterotopic bone provokes explosive and painful new bone growth. Correspondence: E Marelise W Eekhoff, Department of Internal Medicine section Endocrinology, Amsterdam UMC location Vrije Universiteit Amsterdam, De Boelelaan 1117, Amsterdam, the Netherlands, Tel +31 204440588, Email emw.eekhoff@amsterdamumc.nl Received 2022 Jan 29; Accepted 2022 Apr 2; Collection date 2022. This...

Non-commercial Uses Of The Work Are Permitted Without Any Further

Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Fibrodysplasia ossificans progressiva (FOP), sometimes known as myositis ossificans progressiva, is an ultra-rare di...