Fibrodysplasia Ossificans Progressiva Uptodate

Leo Migdal

-Dec 5, 2025, 3:06 PM

fibrodysplasia ossificans progressiva uptodate

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. Fibrodysplasia ossificans progressiva (FOP) is a rare genetic condition where bone gradually replaces muscles and connective tissues. Injury or illness causes new bone growth, which can be painful and lead to a shortened lifespan.

Cleveland Clinic is a non-profit academic medical center. Advertising on our site helps support our mission. We do not endorse non-Cleveland Clinic products or services. Policy Pronunciation for the genetic condition fibrodysplasia ossificans progressiva is “fi-bro-dis-play-see-ah os-sif-eh-cans pro-gres-see-vah.” Cleveland Clinic is a non-profit academic medical center.

Advertising on our site helps support our mission. We do not endorse non-Cleveland Clinic products or services. Policy Fibrodysplasia ossificans progressiva (FOP) is a genetic condition where people are born with bunions and their body’s muscle tissue and connective tissues, like tendons and ligaments, turn into bone on the outside of their... This condition restricts movement and can cause a loss of mobility over time in people diagnosed with the condition. Symptoms of FOP appear during childhood and usually begin at the neck and shoulders before moving to other areas of the body.

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 Fibrodysplasia ossificans progressiva (FOP) is an enigmatic, ultra-rare genetic disorder characterized by progressive heterotopic ossification, wherein soft connective tissues undergo pathological transformation into bone structures. This incapacitating process severely limits patient mobility and poses formidable challenges for therapeutic intervention. Predominantly caused by missense mutations in the ACVR1 gene, this disorder has hitherto defied comprehensive mechanistic understanding and effective treatment paradigms. This write-up offers a comprehensive overview of the contemporary understanding of FOP's complex pathobiology, underscored by advances in molecular genetics and proteomic studies. We delve into targeted therapy, spanning genetic therapeutics, enzymatic and transcriptional modulation, stem cell therapies, and innovative immunotherapies.

We also highlight the intricate complexities surrounding clinical trial design for ultra-rare disorders like FOP, addressing fundamental statistical limitations, ethical conundrums, and methodological advancements essential for the success of interventional studies. We advocate for the adoption of a multi-disciplinary approach that converges bench-to-bedside research, clinical expertise, and ethical considerations to tackle the challenges of ultra-rare diseases like FOP and comparable ultra-rare diseases. In essence, this manuscript serves a dual purpose: as a definitive scientific resource for ongoing and future FOP research and a call to action for innovative solutions to address methodological and ethical challenges that... Keywords: ACVR1; antisense therapy; bone morphogenetic proteins (BMPs); clinical trial design for ultra-rare diseases; fibrodysplasia ossificans progressiva (FOP); genetic therapy; heterotopic ossification; targeted therapy; ultra-rare disorders. T.Y. is a co-founder and shareholder of OligomicsTx Inc., which aims to commercialize antisense technology.

S.A. declares that this study was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest. Schematic overview of the human ACVR1 gene, its molecular architecture, and mutational landscape… Canonical and aberrant BMP signaling and FOP. The canonical and aberrant activin A-mediated…

Fibrodysplasia Ossificans Progressiva Uptodate

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Author For Correspondence (pingham@ntu.edu.sg) This Is An Open Access Article

All Patients Reported To Date Carry Heterozygous Gain-of-function Mutations In

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