Navigating The Complex Landscape Of Fibrodysplasia Ossificans

Leo Migdal

-Dec 5, 2025, 3:56 PM

navigating the complex landscape of fibrodysplasia ossificans

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… You have full access to this open access article Fibrodysplasia ossificans progressiva (FOP; OMIM #135100) is a rare genetic disorder characterized by congenital malformation of the great toes and progressive heterotopic ossification of soft tissues.

To date, the disease has been linked to 15 pathogenic variants in the ACVR1 gene, which encodes a type I receptor for bone morphogenetic proteins. Most patients with FOP carry a recurrent single-nucleotide substitution (c.617G>A; p.Arg206His) in the ACVR1 gene. The genotype–phenotype correlations for atypical pathogenic variants of ACVR1 are poorly understood. In this study, we report the largest population of Polish patients affected by FOP and analyze their phenotypes and genotypes. We screened the whole ACVR1 coding sequence of 16 patients affected by FOP to confirm the presence of pathogenic variants. Thirteen individuals carried the classic pathogenic variant (p.Arg206His) and had a classic or FOP-plus phenotype.

In agreement with the findings of previous studies, one patient with a p.Gly356Asp pathogenic variant had a variant FOP phenotype. We point to an unusual phenomenon in two patients who carried atypical pathogenic variants (p.Gly356Asp and p.Arg258Ser) and displayed a classic FOP phenotype. Our study extends the understanding of FOP’s genotype–phenotype correlation, suggesting that classic FOP phenotypes are associated with non-classic pathogenic variants. We also summarize the recent advances in drug development for this condition. Therefore, the study may be valuable for clinicians consulting patients with FOP. Avoid common mistakes on your manuscript.

Fibrodysplasia ossificans progressiva (FOP; OMIM #135100) is a rare, autosomal dominant disorder characterized by heterotopic bone formation (heterotopic ossification, HO) in the connective tissue and skeletal muscles. HO is preceded by inflammatory swelling of soft tissues, known as flare-ups, and leads to progressive ankylosis of joints, resulting in restricted movement. Although flare-ups occur intermittently, the resulting disability accumulates over time. Consequently, most individuals with FOP require wheelchairs by their third decade of life. The prevalence of FOP is estimated to be 0.88 in 1 million people, regardless of race, geographic predisposition, and gender (Pignolo et al. 2013, 2021).

The classic clinical features of the disease are progressive HO and a congenital, bilateral malformation of the great toes, i.e., hallux valgus, deformity of the first metatarsal, and monophalangism. Other symptoms include a broad, short femoral neck, hearing loss, proximal medial tibial osteochondromas, cervical vertebrae fusions, thumb malformations, dental abnormalities, cardiopulmonary complications, and neurologic dysfunction (Kaplan et al. 2009). FOP is classified into three groups based on clinical criteria: the classic phenotype, which has two major clinical features, i.e., malformed great toes and progressive HO, and the other common FOP symptoms in >... 2009). The average life expectancy of patients with FOP is 56 years, and death is often due to cardiorespiratory complications of thoracic insufficiency syndrome (Pignolo et al.

2021). Treatment, including glucocorticoids and nonsteroidal anti-inflammatory drugs, focuses on symptomatic relief (Smilde et al. 2022). FOP results from pathogenic variants in the ACVR1 gene. This gene encodes activin receptor type- 1 (ACVR1), a receptor of the bone morphogenetic protein (BMP) signaling pathway, which is crucial for the development of the skeletal system. ACVR1 belongs to the transforming growth factor-beta receptor (TGFBR1) family and forms a tetrameric complex at the cell membrane in conjunction with type II receptors.

Both types of receptors contain three common domains: a ligand-binding domain, a transmembrane domain, and a serine/threonine kinase domain. Additionally, type I receptors have the glycine-serine (GS) domain (Fig. 1), the site for transferring phosphorylation from a type II receptor to a type I receptor (Wrana et al. 1994). In this process, the 12 kDa FK506-binding protein (FKBP12) represses the kinase activity of type I receptors by binding to the unphosphorylated GS domain. The pathogenic variant in the ACVR1 gene induces hyperactivity of the ACVR1 receptor in response to ligands and, in turn, triggers the phosphorylation of the GS domain, leading to structural alterations within the domain.

This alteration results in the detachment of the previously bound FKBP1 A from the GS domain. The phosphorylated ACVR1 type I receptor activates SMAD1/5/9(8) phosphorylation, which binds to SMAD4. The complex translocates to the nucleus, where it activates transcription factors and the expression of BMP target genes (Fig. 2). Consequently, affected patients experience progressive HO of soft connective tissues (Song et al. 2010).

First prospective study to assess the association of fibrodysplasia ossificans progressive (FOP) flare-ups and extra-skeletal bone growth (heterotopic ossification or HO) with functional impairment PARIS, France, 28 September 2022 – Ipsen (Euronext: IPN; ADR: IPSEY) today announced the publication of its Natural History Study (NHS) of FOP in Genetics in Medicine, the official journal of the American College... This is the first time a global, prospective, longitudinal evaluation of FOP has been carried out, with data collected over a period of 36 months. Findings demonstrated the debilitating impact and progressive nature of the disease, with the greatest progression of new heterotopic ossification (HO; or bone growth that takes place outside of the normal skeletal system in joints... “Natural history studies are essential to understanding ultra-rare diseases with high unmet need like FOP, increasing our knowledge around the natural course of disease, diagnoses, monitoring techniques, potential biomarkers and new outcome measures,” said... Robert Pignolo, Professor of Geriatric Medicine, Mayo Clinic, USA.

“This is the first study of its kind following the progression of FOP over three years. These results demonstrate the significant impact of the disease on people living with FOP. Furthermore, it will facilitate the evaluation of meaningful endpoints in the development of new therapies, which are critically needed for individuals with FOP.” Results from the NHS demonstrated at month 36, across the whole study population, a mean of 2.6 body regions with new HO; this was highest (3.9) in those aged between two and eight years... However, although individuals aged 25 – 65 years had the lowest new HO volume at annual visits, approximately 70% continued to accumulate new HO across the duration of the study. These data confirmed the progressive nature of FOP with characteristic patterns of growth, starting in younger individuals initially across the upper and mid-torso, progressing into hip and lower-leg regions, and with accumulation of HO...

The assessment of flare-ups showed, 82 (71.9%) individuals experienced a total of 229 flare-ups, most commonly in the upper back (17.9%), hip (14.8%) and shoulder (10.9%). Individuals between the ages of two and eight years, were most likely to report more than one flare-up throughout the study duration. For those who experienced flare-ups, the most common symptoms were pain and soft tissue swelling. Imaging at the site of the flare-up revealed HO occurring at the time of the flare-up, with many individuals going on to experience new HO in the following 12 weeks.1 Correspondence: Mohammed S Alharthi, Department of Clinical Pharmacy, College of Pharmacy, Taif University, Taif, Saudi Arabia, Email Ms.harthi@tu.edu.sa Received 2025 Apr 29; Accepted 2025 Sep 5; Collection date 2025.

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, v4.0) License (http://creativecommons.org/licenses/by-nc/4.0/). 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) is a rare genetic disorder marked by progressive heterotopic ossification (HO), causing severe disability and reduced life expectancy.

Despite advancements in understanding its pathophysiology, effective treatments remain limited. Promising pharmacological approaches include retinoic acid receptor γ (RARγ) agonists, such as palovarotene, and monoclonal antibodies targeting activin A, like garetosmab. However, the rarity of FOP complicates the generation of robust clinical evidence. This narrative review analysed data from Phase II and III clinical trials on ClinicalTrials.gov, including completed and terminated interventional studies evaluating pharmacological treatments for FOP. Key trial details were systematically extracted and reviewed, including design, interventions, outcomes, and adverse events.

Navigating The Complex Landscape Of Fibrodysplasia Ossificans

People Also Search

Fibrodysplasia Ossificans Progressiva (FOP) Is An Enigmatic, Ultra-rare Genetic Disorder

We Advocate For The Adoption Of A Multi-disciplinary Approach That

Declares That This Study Was Conducted In The Absence Of

To Date, The Disease Has Been Linked To 15 Pathogenic

In Agreement With The Findings Of Previous Studies, One Patient