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BACKGROUND: Inflammation is a major driver of heterotopic ossification (HO), a condition of abnormal bone growth in a site that is not normally mineralized. PURPOSE OF REVIEW: This review will examine recent findings on the roles of inflammation and the immune system in fibrodysplasia ossificans progressiva (FOP). FOP is a genetic condition of aggressive and progressive HO formation. We also examine how inflammation may be a valuable target for the treatment of HO. Rationale/Recent findings: Multiple lines of evidence indicate a key role for the immune system in driving FOP pathogenesis. Critical cell types include macrophages, mast cells, and adaptive immune cells, working through hypoxia signaling pathways, stem cell differentiation signaling pathways, vascular regulatory pathways, and inflammatory cytokines. In addition, recent clinical reports suggest a potential role for immune modulators in the management of FOP. FUTURE PERSPECTIVES: The central role of inflammatory mediators in HO suggests that the immune system may be a common target for blocking HO in both FOP and non-genetic forms of HO. Future research focusing on the identification of novel inflammatory targets will help support the testing of potential therapies for FOP and other related conditions.

Fibrodysplasia ossificans progressiva (FOP) is an extremely rare autosomal dominant disorder characterized by congenital skeletal malformation and progressive heterotopic ossification. In the oral and maxillofacial region, deformity of the temporomandibular joint is a common feature of FOP, as well as restricted mouth opening derived from heterotopic ossification in the masticatory muscles. Since surgical procedures are generally not recommended because of the risk of flare-ups and increased heterotopic ossification, reports of tooth extractions and their outcomes in patients with FOP are limited. The present article reports the long-term oral outcomes of three Japanese patients with FOP, in whom the teeth were deliberately extracted to avoid the risk of oral inflammation causing further heterotopic ossification. The extractions were conducted under local or general anesthesia, and healing of sockets was nonproblematic with the formation of new bone. Undesirable events, including progression of heterotopic ossification in the oral and maxillofacial region and further restriction of mouth opening, were not apparent. The extractions also alleviated the existing inflammation, contributing to maintaining their oral hygiene. These cases suggest that deliberate planning and judicious surgery could induce favorable healing after tooth extractions in patients with FOP, leading to long-term stability of their oral health status. [ABSTRACT FROM AUTHOR]

Single case studies of extraordinary disease resilience may provide therapeutic insight into conditions for which no definitive treatments exist. An otherwise healthy 35-year-old man (patient-R) with the canonical pathogenic ACVR1R206H variant and the classic congenital great toe malformation of fibrodysplasia ossificans progressiva (FOP) had extreme paucity of post-natal heterotopic ossification (HO) and nearly normal mobility. We hypothesized that patient-R lacked a sufficient post-natal inflammatory trigger for HO. A plasma biomarker survey revealed a reduction in total matrix metalloproteinase-9 (MMP-9) compared to healthy controls and individuals with quiescent FOP. Whole exome sequencing identified compound heterozygous variants in MMP-9 (c.59C > T, p.A20V and c.493G > A, p.D165N). Structural analysis of the D165N variant predicted both decreased MMP-9 secretion and activity that were confirmed by enzyme-linked immunosorbent assay and gelatin zymography. Further, human proinflammatory M1-like macrophages expressing either MMP-9 variant produced significantly less Activin A, an obligate ligand for HO in FOP, compared to wildtype controls. Importantly, MMP-9 inhibition by genetic, biologic, or pharmacologic means in multiple FOP mouse models abrogated trauma-induced HO, sequestered Activin A in the extracellular matrix (ECM), and induced regeneration of injured skeletal muscle. Our data suggest that MMP-9 is a druggable node linking inflammation to HO, orchestrates an existential role in the pathogenesis of FOP, and illustrates that a single patient's clinical phenotype can reveal critical molecular mechanisms of disease that unveil novel treatment strategies. [ABSTRACT FROM AUTHOR]

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 impede progress in the broader field of medical research into ultra-rare conditions. [ABSTRACT FROM AUTHOR]

Abstract Background Fibrodysplasia ossificans progressiva (FOP) is an ultrarare and disabling genetic disorder of connective tissue characterized by congenital malformation of the great toes, and progressive heterotopic ossification (HO) in soft connective tissues. A gain-of-function mutation of activin A receptor type I (ACVR1) enables ACVR1 to recognize activin A as an agonist with bone morphogenetic protein (BMP) signalling that leads to HO. Previous studies confirmed that activin A stimulates BMP signalling in vitro and drives HO in mouse models of FOP. However, the roles for BMP4 and BMP6 in FOP are supported only by correlative evidence in vitro. Thus, it remains unclear whether the circulating levels of activin A, BMP4 and BMP6 correlate with flare-ups in FOP patients. Hence, we investigated the protein levels of activin A, BMP4 and BMP6 in the serum of FOP patients. Results We recruited 16 untreated FOP patients and 16 age- and sex- matched healthy control subjects in this study. The 16 FOP patients were retrospectively divided into the flare-up group (n = 8) and remission group (n = 8) depending on whether they had flare-ups or worsening of any joint movement in the last 6 months. The serum activin A, BMP4 and BMP6 levels were detected by enzyme-linked immunosorbent assay. The serum activin A, BMP4 and BMP6 levels were slightly higher in FOP patients (median: 434.05 pg/mL, 459.48 pg/mL and 67.84 pg/mL) versus healthy control subjects (median: 364.14 pg/mL, 450.39 pg/mL and 55.36 pg/mL). However, there were no statistically significant differences between the two groups (p > 0.05 for all items), nor were there significant differences between the flare-up and remission groups of FOP (p > 0.05 for all items). Univariate and multivariate logistic regression analyses showed that age, sex, and serum activin A, BMP4 and BMP6 levels were not related to flare-up in FOP patients. Conclusions There were no significant differences in the serum levels of activin A, BMP4 and BMP6 in FOP patients compared with healthy control subjects. Serum activin A, BMP4 and BMP6 proteins might not be the stimulators for FOP flare-up, and may not be biomarkers for FOP diagnosis.

Abstract Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder associated with increased immune activity and severe, progressive heterotopic ossification. We previously described a cohort of 32 patients with FOP who were either exposed to SARS-CoV-2 or received a COVID-19 vaccine1 and showed that these patients did not develop heterotopic ossification after COVID-19 vaccination. Here, we present additional clinical data from new subjects and additional long-term follow-up from the first cohort. We enrolled 15 new subjects between August 24th, 2021 and May 17th, 2022 and collected additional self-reported outcomes. The larger cohort with 47 individuals encompassing 49 events showed that patients with FOP exhibited no additional change in FOP disease activity or flare activity resulting from COVID-19 infection or after receipt of a SARS-CoV-2 vaccine. Thus, although any vaccination carries a risk of inducing heterotopic ossification in patients with FOP, our results show that patients with FOP who choose to receive a COVID-19 vaccination may be able to tolerate the procedure without a high risk of heterotopic ossification when following the published guidelines.

Background: Inflammation is a major driver of heterotopic ossification (HO), a condition of abnormal bone growth in a site that is not normally mineralized. Purpose of review: This review will examine recent findings on the roles of inflammation and the immune system in fibrodysplasia ossificans progressiva (FOP). FOP is a genetic condition of aggressive and progressive HO formation. We also examine how inflammation may be a valuable target for the treatment of HO. Rationale/Recent findings: Multiple lines of evidence indicate a key role for the immune system in driving FOP pathogenesis. Critical cell types include macrophages, mast cells, and adaptive immune cells, working through hypoxia signaling pathways, stem cell differentiation signaling pathways, vascular regulatory pathways, and inflammatory cytokines. In addition, recent clinical reports suggest a potential role for immune modulators in the management of FOP. Future perspectives: The central role of inflammatory mediators in HO suggests that the immune system may be a common target for blocking HO in both FOP and non-genetic forms of HO. Future research focusing on the identification of novel inflammatory targets will help support the testing of potential therapies for FOP and other related conditions.

Background: Fibrodysplasia ossificans progressiva (FOP) is an ultrarare and disabling genetic disorder of connective tissue characterized by congenital malformation of the great toes, and progressive heterotopic ossification (HO) in soft connective tissues. A gain-of-function mutation of activin A receptor type I (ACVR1) enables ACVR1 to recognize activin A as an agonist with bone morphogenetic protein (BMP) signalling that leads to HO. Previous studies confirmed that activin A stimulates BMP signalling in vitro and drives HO in mouse models of FOP. However, the roles for BMP4 and BMP6 in FOP are supported only by correlative evidence in vitro. Thus, it remains unclear whether the circulating levels of activin A, BMP4 and BMP6 correlate with flare-ups in FOP patients. Hence, we investigated the protein levels of activin A, BMP4 and BMP6 in the serum of FOP patients. Results: We recruited 16 untreated FOP patients and 16 age- and sex- matched healthy control subjects in this study. The 16 FOP patients were retrospectively divided into the flare-up group (n = 8) and remission group (n = 8) depending on whether they had flare-ups or worsening of any joint movement in the last 6 months. The serum activin A, BMP4 and BMP6 levels were detected by enzyme-linked immunosorbent assay. The serum activin A, BMP4 and BMP6 levels were slightly higher in FOP patients (median: 434.05 pg/mL, 459.48 pg/mL and 67.84 pg/mL) versus healthy control subjects (median: 364.14 pg/mL, 450.39 pg/mL and 55.36 pg/mL). However, there were no statistically significant differences between the two groups (p > 0.05 for all items), nor were there significant differences between the flare-up and remission groups of FOP (p > 0.05 for all items). Univariate and multivariate logistic regression analyses showed that age, sex, and serum activin A, BMP4 and BMP6 levels were not related to flare-up in FOP patients. Conclusions: There were no significant differences in the serum levels of activin A, BMP4 and BMP6 in FOP patients compared with healthy control subjects. Serum activin A, BMP4 and BMP6 proteins might not be the stimulators for FOP flare-up, and may not be biomarkers for FOP diagnosis. [ABSTRACT FROM AUTHOR]

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder associated with increased immune activity and severe, progressive heterotopic ossification. We previously described a cohort of 32 patients with FOP who were either exposed to SARS-CoV-2 or received a COVID-19 vaccine1 and showed that these patients did not develop heterotopic ossification after COVID-19 vaccination. Here, we present additional clinical data from new subjects and additional long-term follow-up from the first cohort. We enrolled 15 new subjects between August 24th, 2021 and May 17th, 2022 and collected additional self-reported outcomes. The larger cohort with 47 individuals encompassing 49 events showed that patients with FOP exhibited no additional change in FOP disease activity or flare activity resulting from COVID-19 infection or after receipt of a SARS-CoV-2 vaccine. Thus, although any vaccination carries a risk of inducing heterotopic ossification in patients with FOP, our results show that patients with FOP who choose to receive a COVID-19 vaccination may be able to tolerate the procedure without a high risk of heterotopic ossification when following the published guidelines. [ABSTRACT FROM AUTHOR]

Fibrodysplasia ossificans progressiva (FOP) is a devastating disease of progressive heterotopic bone formation for which effective treatments are currently unavailable. FOP is caused by dominant gain‐of‐function mutations in the receptor ACVR1 (also known as ALK2), which render the receptor inappropriately responsive to activin ligands. In previous studies, we developed a genetic mouse model of FOP that recapitulates most clinical aspects of the disease. In this model, genetic loss of the wild‐type Acvr1 allele profoundly exacerbated heterotopic ossification, suggesting the hypothesis that the stoichiometry of wild‐type and mutant receptors dictates disease severity. Here, we tested this model by producing FOP mice that conditionally overexpress human wild‐type ACVR1. Injury‐induced heterotopic ossification (HO) was completely blocked in FOP mice when expression of both the mutant and wild‐type receptor were targeted to Tie2‐positive cells, which includes fibro/adipogenic progenitors (FAPs). Perinatal lethality of Acvr1R206H/+ mice was rescued by constitutive ACVR1 overexpression, and these mice survived to adulthood at predicted Mendelian frequencies. Constitutive overexpression of ACVR1 also provided protection from spontaneous abnormal skeletogenesis, and the incidence and severity of injury‐induced HO in these mice was dramatically reduced. Analysis of pSMAD1/5/8 signaling both in cultured cells and in vivo indicates that ACVR1 overexpression functions cell‐autonomously by reducing osteogenic signaling in response to activin A. We propose that ACVR1 overexpression inhibits HO by decreasing the abundance of ACVR1(R206H)‐containing signaling complexes at the cell surface while increasing the representation of activin‐A‐bound non‐signaling complexes comprised of wild‐type ACVR1. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). [ABSTRACT FROM AUTHOR]

Abstract Background COVID-19, caused by the SARS-CoV-2 virus, is a severe inflammatory condition. Patients with pre-existing conditions including diabetes, hypertension, and cardiovascular disease are at particularly high risk of complications. Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare and debilitating genetic disorder that is characterized by a pro-inflammatory state, which leads to progressive heterotopic ossification and complications after trauma, including intramuscular vaccinations. To better understand the impact of COVID-19 on patients with FOP, we first examined the social impact of the pandemic using data from the FOP Registry managed by the International FOP Association. We also identified patients with FOP who were exposed to or contracted the SARS-CoV-2 virus, or who received a COVID-19 vaccine, to investigate if patients with FOP were at increased risks of complications from SARS-CoV2 exposure or vaccination. Results Data from 326 individuals in 69 countries in the International FOP Association FOP Connection Registry were examined using patient-reported outcomes measurement information system (PROMIS) global health scale scores. Twenty-six (28.9%) participants aged ≥ 15 years old rated their satisfaction with their social activities and relationships as poor in 2020, which was an increase from 18 (18.9%) in 2019, prior to the SARS-CoV-2 outbreak. Similar trends were noted for physical and mental health in the pediatric population. Frequency of physician visits was not changed, but a larger portion of patients reported missing dental visits in 2020 compared with 2019 (31.5% vs. 41.7%). A second cohort with 32 subjects was tracked after SARS-CoV-2 exposure or vaccination. Ten subjects were positively diagnosed with COVID-19, 15 received a COVID-19 vaccine, and seven had high-risk SARS-CoV-2 exposure but either did not have a confirmed clinical diagnosis or tested negative. Subjects who tested positive for the virus showed no major complications or increased FOP disease activity, though our sample size is very limited. Among the 15 subjects who received a COVID-19 vaccine, using the International Clinical Council on FOP guidelines for prophylaxis with ibuprofen or acetaminophen, only one person experienced flare-like activity at the injection site. Conclusions Patients with FOP showed a significant decrease in social activities that was reflective of the isolation and mobility changes in this debilitated population. In our limited cohort, the majority of the patients with FOP who tested positive for COVID-19 showed no major complications. Also, although limited in sample size, the majority of patients who received a COVID-19 vaccination and followed guidelines from the FOP International Clinical Council tolerated vaccination well. Only one person experiencing flare activity following their injection. Thus, the risks and benefits of COVID-19 vaccination needs to be discussed carefully so as to support informed decisions.

Fibrodysplasia ossificans progressiva (FOP), a disorder of congenital skeletal malformations and progressive extraskeletal ossification, is the most severe form of heterotopic ossification (HO) in humans. Gain-of-function pathogenic variants in activin A receptor type I (ACVR1), a bone morphogenetic protein (BMP) type 1 receptor, cause FOP by dramatically altering the normal physiologic functions of ACVR1, impacting BMP signaling and other interacting pathways. These alterations affect various systems, including inflammation, innate immunity, hypoxia sensing, wound healing, aging, temperature and mechanical thresholds, pain sensitivity, skeletal growth, diarthrodial joint patterning, joint function and fate, and HO. This article examines the emergent properties of FOP's diverse phenotypes, proposes a schema for targeting these phenotypes, and highlights outstanding questions and knowledge gaps., Competing Interests: Declaration of interests F.S.K. is a clinical trial investigator for Ashibio, Incyte, Ipsen, and Regeneron; a coinventor of a US patent (pending) to the Trustees of the University of Pennsylvania on the use of MMP-9 inhibitors for heterotopic ossification; and a member of the Medical Registry Advisory Board of the IFOPA. E.M.S. declares no competing interests. R.J.P. is a clinical trial investigator for Ashibio, Incyte, Ipsen, and Regeneron; a coinventor of U.S. patent (pending) to the Trustees of the University of Pennsylvania on the use of MMP-9 inhibitors for heterotopic ossification; a member of the Medical Registry Advisory Board of the IFOPA; and a consultant for Incyte, Ipsen, and Regeneron., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: COVID-19, caused by the SARS-CoV-2 virus, is a severe inflammatory condition. Patients with pre-existing conditions including diabetes, hypertension, and cardiovascular disease are at particularly high risk of complications. Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare and debilitating genetic disorder that is characterized by a pro-inflammatory state, which leads to progressive heterotopic ossification and complications after trauma, including intramuscular vaccinations. To better understand the impact of COVID-19 on patients with FOP, we first examined the social impact of the pandemic using data from the FOP Registry managed by the International FOP Association. We also identified patients with FOP who were exposed to or contracted the SARS-CoV-2 virus, or who received a COVID-19 vaccine, to investigate if patients with FOP were at increased risks of complications from SARS-CoV2 exposure or vaccination.Results: Data from 326 individuals in 69 countries in the International FOP Association FOP Connection Registry were examined using patient-reported outcomes measurement information system (PROMIS) global health scale scores. Twenty-six (28.9%) participants aged ≥ 15 years old rated their satisfaction with their social activities and relationships as poor in 2020, which was an increase from 18 (18.9%) in 2019, prior to the SARS-CoV-2 outbreak. Similar trends were noted for physical and mental health in the pediatric population. Frequency of physician visits was not changed, but a larger portion of patients reported missing dental visits in 2020 compared with 2019 (31.5% vs. 41.7%). A second cohort with 32 subjects was tracked after SARS-CoV-2 exposure or vaccination. Ten subjects were positively diagnosed with COVID-19, 15 received a COVID-19 vaccine, and seven had high-risk SARS-CoV-2 exposure but either did not have a confirmed clinical diagnosis or tested negative. Subjects who tested positive for the virus showed no major complications or increased FOP disease activity, though our sample size is very limited. Among the 15 subjects who received a COVID-19 vaccine, using the International Clinical Council on FOP guidelines for prophylaxis with ibuprofen or acetaminophen, only one person experienced flare-like activity at the injection site.Conclusions: Patients with FOP showed a significant decrease in social activities that was reflective of the isolation and mobility changes in this debilitated population. In our limited cohort, the majority of the patients with FOP who tested positive for COVID-19 showed no major complications. Also, although limited in sample size, the majority of patients who received a COVID-19 vaccination and followed guidelines from the FOP International Clinical Council tolerated vaccination well. Only one person experiencing flare activity following their injection. Thus, the risks and benefits of COVID-19 vaccination needs to be discussed carefully so as to support informed decisions. [ABSTRACT FROM AUTHOR]

Genetic variants are vital in informing clinical phenotypes, aiding physical diagnosis, guiding genetic counseling, understanding the molecular basis of disease, and potentially stimulating drug development. Here we describe two families with an ultrarare ACVR1 gain‐of‐function pathogenic variant (codon 375, Arginine > Proline; ACVR1R375P) responsible for a mild nonclassic fibrodysplasia ossificans progressiva (FOP) phenotype. Both families include people with the ultrarare ACVR1R375P variant who exhibit features of FOP while other individuals currently do not express any clinical signs of FOP. Thus, the mild ACVR1R375P variant greatly expands the scope and understanding of this rare disorder. [ABSTRACT FROM AUTHOR]

Abstract Background Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare disorder marked by painful, recurrent flare-ups and heterotopic ossification (HO) in soft and connective tissues, which can be idiopathic or provoked by trauma, illness, inflammation, or surgery. There are currently no effective treatments for FOP, or for patients with FOP who must undergo surgery. Palovarotene, an investigational retinoic acid receptor-γ agonist, offers a potential avenue to prevent HO formation. Case presentation The patient is a 32 year-old male, who at age 29 enrolled in a study evaluating palovarotene to prevent HO formation in FOP. One year after starting palovarotene, he fell resulting in a left intertrochanteric fracture. He underwent intramedullary nailing of the femur shaft with screw placement at the distal femur. After surgery, he received palovarotene at 20 mg/day for 4 weeks, then 10 mg/day for 8 weeks. Imaging 12 weeks after surgery showed new bridging HO at the site of intramedullary rod insertion and distal screw. Nine months after the left hip fracture, the patient had a second fall resulting in a subdural hematoma, left parietal bone fracture, and right intertrochanteric fracture. He underwent intramedullary nailing of the right hip, in a modified procedure which did not require distal screw placement. Palovarotene 20 mg/day was started at fracture occurrence and continued for 4 weeks, then reduced to 10 mg/day for 8 weeks. HO also formed near the insertion site of the intramedullary rod. No HO developed at the right distal intramedullary rod. After each fracture, the patient had prolonged recurrent flare-ups around the hips. Conclusion Surgery is only rarely considered in FOP due to the high risks of procedural complications and potential for inducing HO. This case emphasizes the risks of increased flare activity and HO formation from injury and surgery in patients with FOP. The efficacy of HO prevention by palovarotene could not be assessed; however, our observation that palovarotene can be administered in an individual with FOP following surgery with no negative impact on clinical fracture healing, osteointegration, or skin healing will help facilitate future trials testing the role of palovarotene as a therapy for HO.

Abstract Background Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder characterized by extraskeletal heterotopic ossification. It is well recognized that FOP can lead to a devastating condition of disability. However, the mortality rate of FOP patients in China and risk factors for mortality are still largely unclear. Methods We conducted a retrospective research on a cohort of 65 cases of FOP patients in China from 2008 to 2018. We reviewed medical records of these FOP patients to retrieve information such as date of birth/death, gender, clinical features, genotypes and biochemical parameters and analyze the correlation of these parameters with the mortality. Results 92.3% (60/65 cases) patients were classic FOP patients, 3.1% (2/65 cases) were FOP-plus and 4.6% (3/65 cases) were FOP variants. 9 cases of this cohort were dead during the ten-year period, and the overall mortality rate was 13.8%. c.617G > A mutation was confirmed in all non-survivors. In FOP patients≤18 years at diagnosis, non-survivors demonstrated significantly lower blood osteocalcin and alkaline phosphatase levels compared with survivors (P

Sarah Steele was a young woman who lived her whole life with a rare disabling condition, fibrodysplasia ossificans progressiva (FOP), and in a family that include religion professor, clergy woman, and two siblings. Her death in 2017 and subsequent memorial service drew together multiple communities with whom she had been involved, and included reflections by her father, mother, and two siblings. Her father, Richard Steele, and her mother, Marilyn Hair, had both written and published other essays about their journey with Sarah in the Journal of Disability and in others. Bill Gaventa, with the permission and help of the family, summarizes some of the human and theological dimensions of their journey. [ABSTRACT FROM AUTHOR]

Fibrodysplasia ossificans progressiva (FOP) is a rare disease in which heterotopic ossification (HO) is formed in muscles, tendons and ligaments. Traumatic events, including surgery, are discouraged as this is known to trigger a flare-up with risk of subsequent HO. Anesthetic management for patients with FOP is challenging. Cervical spine fusion, ankylosis of the temporomandibular joints, thoracic insufficiency syndrome, restrictive chest wall disease, and sensitivity to oral trauma complicate airway management and anesthesia and pose life-threatening risks. We report a patient with FOP suffering from life-threatening antibiotic resistant bacterial infected ulcers of the right lower leg and foot. The anesthetic, surgical and postoperative challenges and considerations are discussed. In addition, the literature on limb surgeries of FOP patients is systemically reviewed. The 44 year-old female patient was scheduled for a through-knee amputation. Airway and pulmonary evaluation elicited severe abnormalities, rendering standard general anesthesia a rather complication-prone approach in this patient. Thus, regional anesthesia, supplemented with intravenous analgosedation and N2O-inhalation were performed in this case. The surgery itself was securely planned to avoid any unnecessary tissue damage. Postoperatively the patient was closely monitored for FOP activity by ultrasound and [18F]PET/CT-scan. One year after surgery, a non-significant amount of HO had formed at the operated site. The systematic review revealed seventeen articles in which thirty-two limb surgeries in FOP patients were described. HO reoccurrence was described in 90% of the cases. Clinical improvement due to improved mobility of the operated joint was noted in 16% of the cases. It should be noted, though, that follow-up time was limited and no or inadequate imaging modalities were used to follow-up in the majority of these cases. To conclude, if medically urgent, limb surgery in FOP is possible even when general anesthesia is not preferred. The procedure should be well-planned, alternative techniques or procedures should be tested prior to surgery and special attention should be paid to the correct positioning of the patient. According to the literature recurrent HO should be expected after surgery of a limb, even though it was limited in the case described.

Fibrodysplasia ossificans progressiva (FOP) is an autosomal dominant disease, characterized by the formation of heterotopic ossification (HO) in muscles, ligaments, and tendons. Flare-ups, an inflammatory process that often precedes the formation of HO, can occur spontaneously, but trauma is also a common trigger. It is not known whether radiotherapy, especially in higher doses, might cause sufficient trauma or inflammation to trigger a flare-up and subsequent HO in FOP patients. We report the case of a patient undergoing radiotherapy for the treatment of a 1-cm-wide basal cell carcinoma (BCC) of the lower lip. In addition, we present a systematic review of the available literature. Our patient received 54 Gy in 18 fractions with orthovoltage therapy, resulting in a clinical complete response of the tumor. Six months after treatment, there were no signs of HO either clinically or on [18F]NaF PET/CT. The systematic review identified 11 publications describing either radiation treatment in FOP or radiation therapy as a cause of HO in non-FOP patients. Six case reports described the use of radiation in FOP patients for various reasons, including one with a high-dose treatment of a lip BCC using superficial X-ray therapy. The remaining five studies described the use of low-dose radiotherapy to prevent or treat either an FOP flare-up or HO formation. None of these cases showed worsening of disease that could be attributed to the use of radiation therapy. Radiation induced HO in non-FOP patients was rare and occurred in five studies. The largest of these studies suggested that HO was induced after treatment with high doses, resulting in more widespread evidence of tissue damage, potentially being the end result of this damage. In conclusion, available reports suggest no contraindication to radiotherapy in FOP patients; although the number of cases was small, systematic toxicity reports often were not available, and none of the reports described high-dose, high-energy radiation treatment at locations such as muscle and joint regions.

Fibrodysplasia ossificans progressiva (FOP) is a rare disease in which heterotopic ossification (HO) is formed in muscles, tendons and ligaments. Traumatic events, including surgery, are discouraged as this is known to trigger a flare-up with risk of subsequent HO. Anesthetic management for patients with FOP is challenging. Cervical spine fusion, ankylosis of the temporomandibular joints, thoracic insufficiency syndrome, restrictive chest wall disease, and sensitivity to oral trauma complicate airway management and anesthesia and pose life-threatening risks. We report a patient with FOP suffering from life-threatening antibiotic resistant bacterial infected ulcers of the right lower leg and foot. The anesthetic, surgical and postoperative challenges and considerations are discussed. In addition, the literature on limb surgeries of FOP patients is systemically reviewed. The 44 year-old female patient was scheduled for a through-knee amputation. Airway and pulmonary evaluation elicited severe abnormalities, rendering standard general anesthesia a rather complication-prone approach in this patient. Thus, regional anesthesia, supplemented with intravenous analgosedation and N2O-inhalation were performed in this case. The surgery itself was securely planned to avoid any unnecessary tissue damage. Postoperatively the patient was closely monitored for FOP activity by ultrasound and [18F]PET/CT-scan. One year after surgery, a non-significant amount of HO had formed at the operated site. The systematic review revealed seventeen articles in which thirty-two limb surgeries in FOP patients were described. HO reoccurrence was described in 90% of the cases. Clinical improvement due to improved mobility of the operated joint was noted in 16% of the cases. It should be noted, though, that follow-up time was limited and no or inadequate imaging modalities were used to follow-up in the majority of these cases. To conclude, if medically urgent, limb surgery in FOP is possible even when general anesthesia is not preferred. The procedure should be well-planned, alternative techniques or procedures should be tested prior to surgery and special attention should be paid to the correct positioning of the patient. According to the literature recurrent HO should be expected after surgery of a limb, even though it was limited in the case described. [ABSTRACT FROM AUTHOR]

Background: Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder characterized by extraskeletal heterotopic ossification. It is well recognized that FOP can lead to a devastating condition of disability. However, the mortality rate of FOP patients in China and risk factors for mortality are still largely unclear. Methods: We conducted a retrospective research on a cohort of 65 cases of FOP patients in China from 2008 to 2018. We reviewed medical records of these FOP patients to retrieve information such as date of birth/death, gender, clinical features, genotypes and biochemical parameters and analyze the correlation of these parameters with the mortality. Results: 92.3% (60/65 cases) patients were classic FOP patients, 3.1% (2/65 cases) were FOP-plus and 4.6% (3/65 cases) were FOP variants. 9 cases of this cohort were dead during the ten-year period, and the overall mortality rate was 13.8%. c.617G > A mutation was confirmed in all non-survivors. In FOP patients≤18 years at diagnosis, non-survivors demonstrated significantly lower blood osteocalcin and alkaline phosphatase levels compared with survivors (P < 0.05), and spearman correlation and logistic regression analysis indicated that serum osteocalcin and alkaline phosphatase levels were negatively correlated with the mortality. Furthermore, the receiver-operating characteristic curve analysis showed serum osteocalcin had the largest area under the curve of 0.855 among four biochemical parameters, and serum osteocalcin < 65.9 ng/ml displayed a good capacity to discriminate the non-survivors from survivors in FOP patients aged 18 years and younger at diagnosis. Conclusions: Our findings showed that the mortality rate of FOP was 13.8% in China. Serum OC level was negatively correlated with the mortality in Chinese FOP patients ≤18 years at diagnosis. [ABSTRACT FROM AUTHOR]

Background: Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare disorder marked by painful, recurrent flare-ups and heterotopic ossification (HO) in soft and connective tissues, which can be idiopathic or provoked by trauma, illness, inflammation, or surgery. There are currently no effective treatments for FOP, or for patients with FOP who must undergo surgery. Palovarotene, an investigational retinoic acid receptor-γ agonist, offers a potential avenue to prevent HO formation.Case Presentation: The patient is a 32 year-old male, who at age 29 enrolled in a study evaluating palovarotene to prevent HO formation in FOP. One year after starting palovarotene, he fell resulting in a left intertrochanteric fracture. He underwent intramedullary nailing of the femur shaft with screw placement at the distal femur. After surgery, he received palovarotene at 20 mg/day for 4 weeks, then 10 mg/day for 8 weeks. Imaging 12 weeks after surgery showed new bridging HO at the site of intramedullary rod insertion and distal screw. Nine months after the left hip fracture, the patient had a second fall resulting in a subdural hematoma, left parietal bone fracture, and right intertrochanteric fracture. He underwent intramedullary nailing of the right hip, in a modified procedure which did not require distal screw placement. Palovarotene 20 mg/day was started at fracture occurrence and continued for 4 weeks, then reduced to 10 mg/day for 8 weeks. HO also formed near the insertion site of the intramedullary rod. No HO developed at the right distal intramedullary rod. After each fracture, the patient had prolonged recurrent flare-ups around the hips.Conclusion: Surgery is only rarely considered in FOP due to the high risks of procedural complications and potential for inducing HO. This case emphasizes the risks of increased flare activity and HO formation from injury and surgery in patients with FOP. The efficacy of HO prevention by palovarotene could not be assessed; however, our observation that palovarotene can be administered in an individual with FOP following surgery with no negative impact on clinical fracture healing, osteointegration, or skin healing will help facilitate future trials testing the role of palovarotene as a therapy for HO. [ABSTRACT FROM AUTHOR]

Fibrodysplasia ossificans progressiva (FOP) is an autosomal dominant disease, characterized by the formation of heterotopic ossification (HO) in muscles, ligaments, and tendons. Flare-ups, an inflammatory process that often precedes the formation of HO, can occur spontaneously, but trauma is also a common trigger. It is not known whether radiotherapy, especially in higher doses, might cause sufficient trauma or inflammation to trigger a flare-up and subsequent HO in FOP patients. We report the case of a patient undergoing radiotherapy for the treatment of a 1-cm-wide basal cell carcinoma (BCC) of the lower lip. In addition, we present a systematic review of the available literature. Our patient received 54 Gy in 18 fractions with orthovoltage therapy, resulting in a clinical complete response of the tumor. Six months after treatment, there were no signs of HO either clinically or on [18F]NaF PET/CT. The systematic review identified 11 publications describing either radiation treatment in FOP or radiation therapy as a cause of HO in non-FOP patients. Six case reports described the use of radiation in FOP patients for various reasons, including one with a high-dose treatment of a lip BCC using superficial X-ray therapy. The remaining five studies described the use of low-dose radiotherapy to prevent or treat either an FOP flare-up or HO formation. None of these cases showed worsening of disease that could be attributed to the use of radiation therapy. Radiation induced HO in non-FOP patients was rare and occurred in five studies. The largest of these studies suggested that HO was induced after treatment with high doses, resulting in more widespread evidence of tissue damage, potentially being the end result of this damage. In conclusion, available reports suggest no contraindication to radiotherapy in FOP patients; although the number of cases was small, systematic toxicity reports often were not available, and none of the reports described high-dose, high-energy radiation treatment at locations such as muscle and joint regions. [ABSTRACT FROM AUTHOR]

Fibrodysplasia Ossificans Progressiva (FOP) is an ultra-rare but debilitating disorder characterized by spontaneous, progressive, and irreversible heterotopic ossifications (HO) at extraskeletal sites. FOP is caused by gain-of-function mutations in the Activin receptor Ia/Activin-like kinase 2 gene (Acvr1/Alk2), with increased receptor sensitivity to bone morphogenetic proteins (BMPs) and a neoceptor response to Activin A. There is extensive literature on the skeletal phenotypes in FOP, but a much more limited understanding of non-skeletal manifestations of this disease. Emerging evidence reveals important cardiopulmonary and neurologic dysfunctions in FOP including thoracic insufficiency syndrome, pulmonary hypertension, conduction abnormalities, neuropathic pain, and demyelination of the central nervous system (CNS). Here, we review the recent research and discuss unanswered questions regarding the cardiopulmonary and neurologic phenotypes in FOP.

Fibrodysplasia ossificans progressiva (FOP) is a genetic disease characterized by heterotopic ossification (HO). The disease is caused by a mutation in the activin receptor type 1 (ACVR1) gene that enhances this receptor's responsiveness to Activin‐A. Binding of Activin‐A to the mutated ACVR1 receptor induces osteogenic differentiation. Whether Activin‐A also affects osteoclast formation in FOP is not known. Therefore we investigated its effect on the osteoclastogenesis‐inducing potential of periodontal ligament fibroblasts (PLF) from teeth of healthy controls and patients with FOP. We used western blot analysis of phosphorylated SMAD3 (pSMAD3) and quantitative polymerase chain reaction to assess the effect of Activin‐A on the PLF. PLF‐induced osteoclast formation and gene expression were studied by coculturing control and FOP PLF with CD14‐positive osteoclast precursor cells from healthy donors. Osteoclast formation was also assessed in control CD14 cultures stimulated by macrophage colony‐stimulating factor (M‐CSF) and receptor activator of nuclear factor kappa‐B ligand (RANK‐L). Although Activin‐A increased activation of the pSMAD3 pathway in both control and FOP PLF, it increased ACVR1, FK binding protein 12 (FKBP12), an inhibitor of DNA binding 1 protein (ID‐1) expression only in FOP PLF. Activin‐A inhibited PLF mediated osteoclast formation albeit only significantly when induced by FOP PLF. In these cocultures, it reduced M‐CSF and dendritic cell‐specific transmembrane protein (DC‐STAMP) expression. Activin‐A also inhibited osteoclast formation in M‐CSF and RANK‐L mediated monocultures of CD14+ cells by inhibiting their proliferation. This study brings new insight on the role of Activin A in osteoclast formation, which may further add to understanding FOP pathophysiology; in addition to the known Activin‐A‐mediated HO, this study shows that Activin‐A may also inhibit osteoclast formation, thereby further promoting HO formation. Fibrodysplasia ossificans progressiva (FOP) is a genetic disease characterized by heterotopic bone formation induced by enhanced responsiveness to Activin‐A. Activin‐A inhibits periodontal ligament fibroblasts‐mediated osteoclast formation in healthy donors and in patients with FOP. This inhibitory effect is probably mediated via a direct effect on the osteoclast precursors. [ABSTRACT FROM AUTHOR]

Clinical trials for orphan diseases are critical for developing effective therapies. One such condition, fibrodysplasia ossificans progressiva (FOP; MIM#135100), is characterized by progressive heterotopic ossification (HO) that leads to severe disability. Individuals with FOP are extremely sensitive to even minor traumatic events. There has been substantial recent interest in clinical trials for novel and urgently‐needed treatments for FOP. The International Clinical Council on FOP (ICC) was established in 2016 to provide consolidated and coordinated advice on the best practices for clinical care and clinical research for individuals who suffer from FOP. The Clinical Trials Committee of the ICC developed a focused list of key considerations that encompass the specific and unique needs of the FOP community – considerations that are endorsed by the entire ICC. These considerations complement established protocols for developing and executing robust clinical trials by providing a foundation for helping to ensure the safety of subjects with FOP in clinical research trials. [ABSTRACT FROM AUTHOR]

Various substitution mutations in ALK2, a transmembrane serine/threonine kinase receptor for bone morphogenetic proteins (BMPs), have been identified in patients with genetic disorders such as fibrodysplasia ossificans progressiva (FOP), diffuse intrinsic pontine glioma (DIPG) and heart defects. In this study, we characterized the ALK2 mutants R258G, G328V and F246Y, which were identified in patients with severe FOP, DIPG and unusual hereditary skeletal dysplasia, respectively. Both R258G and G328V were gain-of-function mutations, but F246Y was equivalent to wild-type ALK2. We also examined the effect of the suppressor FKBP12 on the signal transduction of a further 14 ALK2 mutations associated with FOP and/or DIPG. To varying extents FKBP12 over-expression suppressed the basal signaling induced by thirteen of the ALK2 mutants, whereas PF197-8L was uniquely resistant. In the PF197-8L mutant, the modelled ALK2 residue L197 induced a steric clash with the D36 residue in FKBP12 and dissociated their interaction. The co-expression of BMP type II receptors or stimulation with ligands relieved the suppression by FKBP12 by disrupting the interaction between mutant ALK2 and FKBP12. Taken together, FKBP12 binds to and suppresses mutant ALK2 proteins associated with FOP and DIPG, except for PF197-8L. [ABSTRACT FROM AUTHOR]

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic condition characterized by progressive extra-skeletal ossification leading to cumulative and severe disability. FOP has an extremely variable and episodic course and can be induced by trauma, infections, iatrogenic harms, immunization or can occur in an unpredictable way, without any recognizable trigger. The causative gene is ACVR1, encoding the Alk-2 type I receptor for bone morphogenetic proteins (BMPs). The signaling is initiated by BMP binding to a receptor complex consisting of type I and II molecules and can proceed into the cell through two main pathways, a canonical, SMAD-dependent signaling and a p38-mediated cascade. Most FOP patients carry the recurrent R206H substitution in the receptor Glycine-Serine rich (GS) domain, whereas a few other mutations are responsible for a limited number of cases. Mutations cause a dysregulation of the downstream BMP-dependent pathway and make mutated ACVR1 responsive to a non-canonical ligand, Activin A. There is no etiologic treatment for FOP. However, many efforts are currently ongoing to find specific therapies targeting the receptor activity and the downstream aberrant pathway at different levels or targeting cellular components and/or processes that are important in modifying the local environment leading to bone neo-formation. [ABSTRACT FROM AUTHOR]

Fibrodysplasia Ossificans Progressiva (FOP) is an ultrarare genetic disorder of progressive, disabling heterotopic ossification for which there is presently no definitive treatment. Several recent studies in genetic mouse models of FOP support involvement of the mechanistic target of rapamycin complex 1 (mTORC1) pathway in the pathophysiology of FOP and propose the repurposed use of rapamycin, an inhibitor of mTORC1 signaling in clinical trials for the management of FOP. Here we report two patients with the classic FOP mutation who received rapamycin—one for four months on a compassionate basis for treatment of acute flare-ups of the neck and back that were refractory to corticosteroid therapy—and the other for 18 years for chronic immunosuppression following liver transplantation for intercurrent cytomegalovirus infection. In both patients, FOP progressed despite the use of rapamycin. This report highlights the real-world use of rapamycin in two FOP patients and provides insight into the use of rapamycin in clinical trials for the management of FOP. [ABSTRACT FROM AUTHOR]

Fibrodyplasia ossificans progressiva (FOP) is an ultra-rare genetic condition of heterotopic ossification (HO) that results in progressive loss of joint function, ultimately rendering movement impossible. Death is most commonly the result of thoracic insufficiency syndrome, or complications related to recurrent respiratory infections. There are no current treatments for FOP, but early and emerging clinical trials offer hope for this devastating disease. With the recent reporting of a comprehensive global natural history study, scales to assess joint dysfunction, and a more accurate prediction of joint survival, it is now possible to construct a conceptual framework for the clinical staging of FOP. Based on assessment of FOP features in seven areas, it is possible to assign five clinical stages. FOP features include flare-up activity, body regions affected, thoracic insufficiency, other complications, activities of daily living (ADLs), ambulatory status, and the cumulative joint involvement scale (CAJIS) score. Assessments of these features assign an individual with FOP to early/mild, moderate, severe, profound, or late-stage disease. These criteria seek to be flexible enough to be used by clinicians without reliance on advanced imaging or specialized testing, as well as by investigators involved in research or clinical trial studies who would have these tools available. These staging measures for FOP assess the influence of HO and accelerated joint dysfunction (due to congenital abnormalities) on the ability to perform common functional activities, and thus a delay or lack of progression from one stage to the next represents the ultimate test of efficacy for drug trials. This framework will serve both as a prediction tool for FOP progression as well as a critical opportunity to substantiate therapeutic interventions. The staging system proposed here will permit an accurate assessment of severity to appropriately develop or revise clinical plans of care, define operational research criteria, and identify the effectiveness of interventions. Ultimately, this clinical staging will aid the field in moving toward earlier intervention at a stage where disease-modifying therapies may be most efficacious. [ABSTRACT FROM AUTHOR]

Background Flare-ups of the hips are among the most feared and disabling complications of fibrodysplasia ossificans progressiva (FOP) and are poorly understood. In order to better understand the nature of hip flare-ups in FOP, we evaluated 25 consecutive individuals with classic FOP (14 males, 11 females; 3–56 years old, median age, 17 years old) who presented with acute unilateral hip pain. Results All 25 individuals were suspected of having a flare-up of the hip based on clinical history and a favorable response to a four day course of high-dose oral prednisone. Ten individuals (40%) experienced rebound symptoms of pain and/or stiffness within seven days after discontinuation of prednisone and all ten subsequently developed heterotopic ossification (HO) or decreased mobility of the affected hip. None of the 14 individuals who experienced sustained relief of symptoms following a course of oral prednisone experienced HO or decreased mobility. Incidental radiographic findings at the time of presentation were multifactoral and included osteochondromas of the proximal femur (18/25; 72%), degenerative arthritis (17/25; 68%), developmental hip dysplasia (15/25; 60%), previously existing heterotopic ossification (12/25; 48%), intra-articular synovial osteochondromatosis (8/25; 32%) or traumatic fractures through pre-existing heterotopic bone (1/25; 4%). Conclusions Developmental joint pathology may confound clinical evaluation of hip pain in FOP. The most useful modality for suspecting an ossification-prone flare-up of the hip was lack of sustained response to a brief course of oral prednisone. Evaluation of soft tissue edema by ultrasound or magnetic resonance imaging showed promise in identifying ossification-prone flare-ups and warrants further analysis in prospective studies. [ABSTRACT FROM AUTHOR]

Clinical and laboratory observations strongly suggest that the innate immune system induces flare-ups in the setting of dysregulated bone morphogenetic protein (BMP) signaling in fibrodysplasia ossificans progressiva (FOP). In order to investigate the signaling substrates of this hypothesis, we examined toll-like receptor (TLR) activation and bone morphogenetic protein (BMP) signaling in connective tissue progenitor cells (CTPCs) from FOP patients and unaffected individuals. We found that inflammatory stimuli broadly activate TLR expression in FOP CTPCs and that TLR3/TLR4 signaling amplifies BMP pathway signaling through both ligand dependent and independent mechanisms. Importantly, Evolutionarily Conserved Signaling Intermediate in the Toll Pathway (ECSIT) integrates TLR injury signaling with dysregulated BMP pathway signaling in FOP CTPCs. These findings provide novel insight into the cell autonomous integration of injury signals from the innate immune system with dysregulated response signals from the BMP signaling pathway and provide new exploratory targets for therapeutic approaches to blocking the induction and amplification of FOP lesions. [ABSTRACT FROM AUTHOR]

Signaling of the Bone Morphogenetic Protein (BMP) pathway is influenced by the level of expression of its components, in particular receptors, intracellular molecules and target genes which largely depends on gene transcription. One peculiar aspect of Fibrodysplasia Ossificans Progressiva (FOP) relates to the cell types in which the genetic mutation exerts its effects, then not only those involved in the heterotopic ossification processes but also others that participate in the inflammatory phases preceding and triggering heterotopic ossification. Such effects are in part detectable as variation in gene expression, which is also variably manifesting in term of time of appearance in different phases of the inflammatory or ossification processes. [ABSTRACT FROM AUTHOR]

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare autosomal dominant genetic disorder of heterotopic ossification (HO) characterized by skeletal anomalies and episodic soft tissue swelling (flare-ups) that can transform into heterotopic bone. The progressive development of heterotopic bone and progressive arthropathy leads to significant limitation of mobility. This paper will review various imaging modalities used in evaluating episodic soft tissue swelling (flare-ups), heterotopic bone and skeletal anomalies. Different imaging modalities are required at different stages of the disease. Ultrasound and MRI can be useful for evaluating edema in early stages of a flare-up; MRI being superior to ultrasonography. Plain radiographs and computed tomography (CT) can evaluate heterotopic bone in later stages of HO, but CT scan is better at evaluating presence and the volume of heterotopic bone. Functional imaging demonstrates increased activity at sites of flare-ups, their utility in determining disease progression need to be further evaluated. Cost, radiation exposure, availability of various imaging modalities and the ability of FOP patients to fit in the scanner are all considerations when requesting radiographic tests in a patient with FOP. Future studies are required to determine if early radiographic findings can determine disease progression and response to treatment in this disorder. [ABSTRACT FROM AUTHOR]

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease with a progressive course characterized by episodically local flare-ups, which often but not always leads to heterotopic bone formation (HO). Recently, we showed that [18F]NaF PET/CT may be the first tool to monitor progression of a posttraumatic flare-up leading to new HO, which was demonstrated in a patient with FOP who underwent a maxillofacial surgery. This paper evaluates [18F]NaF PET/CT as a marker of FOP disease activity, comparing its use with other imaging modalities known in literature. In addition, the follow-up of a spontaneous flare-up in a 19-year old patient is presented showing high muscle [18F]NaF uptake in one defined part within the flare-up area after three weeks. During follow-up [18F]NaF PET /CT scan revealed newly formed heterotopic bone but only in this previously active [18F]NaF region. In conclusion, increased muscle [18F]NaF uptake may predict future HO development in FOP patients. At present [18F]NaF PET/CT appears to be a sensitive imaging modality to serve as a noninvasive marker for bone formation and to monitor disease activity during flare-ups in FOP. [ABSTRACT FROM AUTHOR]

Background Fibrodysplasia ossificans progressiva (FOP) is an ultrarare genetic disorder of progressive, disabling heterotopic ossification (HO) for which there is presently no definitive treatment. Research studies have identified multiple potential targets for therapy in FOP, and novel drug candidates are being developed for testing in clinical trials. A complementary approach seeks to identify approved drugs that could be re-purposed for off-label use against defined targets in FOP. One such drug is imatinib mesylate, a tyrosine kinase inhibitor originally developed for use in patients with chronic myeloid leukemia (CML). Imatinib has the desirable effect of attacking multiple targets involved in the early hypoxic and inflammatory stages of FOP flare-ups, including HIF1-α, PDGFRα, c-KIT, and multiple MAP kinases. Results Based on compelling biologic rationale, strong preclinical data, and a favorable safety profile, imatinib has been prescribed on an off-label basis in a non-trial setting in seven children with continuous FOP flare-ups, predominantly in the axial regions, and which were not responsive to standard-of-care regimens. Anecdotal reports in these seven isolated cases document that the medication was well-tolerated with a ubiquitous reported decrease in the intensity of flare-ups in the six children who took the medication. Conclusions These early clinical observations support the implementation of clinical trials in children with uncontrolled FOP flare-ups to determine if imatinib may ameliorate symptoms or alter the natural history of this debilitating and life-threatening disease. [ABSTRACT FROM AUTHOR]

Mesenteric heterotopic ossification (MHO) is very rare and occurs in mid- to late-adulthood, usually in the context of prior abdominal surgery. The mechanisms of MHO are unknown. Here we describe the case of a 72-year-old man with MHO. Standard histological staining revealed that MHO occurred through an endochondral process. By comparison to known mutations in genetic conditions of HO such as fibrodysplasia ossificans progressiva (FOP) and progressive osseous heteroplasia (POH), DNA sequencing analysis demonstrated the presence of a commonly occurring heterozygous synonymous polymorphism (c.690G>A; E230E) in the causative gene for FOP ( ACVR1/ALK2 ). However, no frameshift, missense, or nonsense mutations in ACVR1 , or in the causative gene for POH ( GNAS ), were found. Although genetic predisposition may play a role in MHO, our data suggest that mutations which occur in known hereditary conditions of HO are not the primary cause. [ABSTRACT FROM AUTHOR]

Background Genesis of a cartilaginous scaffold is an obligate precursor to bone formation in heterotopic endochondral ossification (HEO). We tested the hypothesis that cartilage-derived retinoic acid-sensitive protein (CD-RAP) can serve as a plasma biomarker for the pre-osseous cartilaginous stage of HEO. Palovarotene, a retinoic acid receptor-gamma (RARγ) agonist, has been proposed as a possible treatment for fibrodysplasia ossificans progressiva (FOP) and is a potent inhibitor of HEO in mouse models. Current drug development for FOP mandates the identification of stage-specific biomarkers to facilitate the evaluation of clinical trial endpoints. Results Here we show in an injury-induced, constitutively-active transgenic mouse model of FOP that CD-RAP levels peaked between day-7 and day-10 during the zenith of histologically-identified chondrogenesis, preceded radiographically apparent HEO, and were diminished by palovarotene. Cross-sectional analysis of CD-RAP levels in plasma samples from FOP patients demonstrated a statistically non-significant trend toward higher levels in the recent flare-up period (three weeks to three months within onset of symptoms). However, in a longitudinal subgroup analysis of patients followed for at least six months after resolution of flare-up symptoms, there was a statistically significant decrease of CD-RAP when compared to levels in the same patients at the time of active or recent exacerbations. Conclusions These data support the further exploration of CD-RAP as a stage-specific biomarker of HEO in FOP. [ABSTRACT FROM AUTHOR]

Background Fibrodysplasia ossificans progressiva (FOP), is caused by mutations in the type I BMP receptor ACVR1 that lead to increased activation of the BMP-pSmad1/5/8 signaling pathway. Recent findings suggest that Activin A (Act A) promiscuously stimulates the bone morphogenetic protein (BMP) signaling pathway in vitro and mediates heterotopic ossification (HO) in mouse models of FOP, but primary data from FOP patient cells are lacking. Objective To examine BMP-pSmad1/5/8 pathway signaling and chondro-osseous differentiation in response to endogenous and exogenous Act A in primary connective tissue progenitor cells [CTPCs; also known as stem cells from human exfoliated deciduous teeth (SHED) cells] from patients with FOP. These cells express the common FOP mutation, ACVR1 (R206H). Results We found that Act A amplifies dysregulated BMP pathway signaling in human FOP primary CTPCs cells through the Smad1/5/8 pathway and induces chondro-osseous differentiation. Amplification of BMP-pSmad1/5/8 signaling was inhibited by Follistatin and by a neutralizing antibody to Activin A. The increased basal pSmad1/5/8 activity, as well as the hypoxia-induced stimulation of FOP CTPCs cells, were BMP4 and Act A independent. Importantly, either BMP4 or Act A stimulated pSmad1/5/8 pathway signaling but BMP4 signaling was not dependent on Activin A and vice versa. Circulating plasma levels of Act A or BMP4 are similar in controls compared to FOP patients, and suggest the potential for an autocrine or paracrine route for pathological signaling. Conclusions The mutated FOP receptor [ACVR1 (R206H)] is hypersensitive to BMP4 and uniquely sensitive (compared to the wild type receptor) to Act A. Both canonical and non-canonical ligands have a synergistic effect on BMP-pSmad1/5/8 signaling in FOP CTPCs and may cooperate to alter the threshold for HO in FOP. Our findings in primary human FOP CTPCs have important implications for the design of clinical trials to inhibit dysregulated BMP pathway signaling in humans who have FOP. [ABSTRACT FROM AUTHOR]

Fibrodysplasia Ossificans Progressiva (FOP) is an inherited disease in which progressive ossification of striated muscles, tendons, ligaments and other connective tissues forming bridges of extra bones across the joints leads to severe disability and there are associated characteristic congenital skeletal malformations. FOP is also known as Stoneman's syndrome. The case we report here is a 23-year-old male with the clinical and radiologic characteristics of FOP.

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic condition characterized by progressive extra-skeletal ossification leading to cumulative and severe disability. FOP has an extremely variable and episodic course and can be induced by trauma, infections, iatrogenic harms, immunization or can occur in an unpredictable way, without any recognizable trigger. The causative gene is ACVR1, encoding the Alk-2 type I receptor for bone morphogenetic proteins (BMPs). The signaling is initiated by BMP binding to a receptor complex consisting of type I and II molecules and can proceed into the cell through two main pathways, a canonical, SMAD-dependent signaling and a p38-mediated cascade. Most FOP patients carry the recurrent R206H substitution in the receptor Glycine-Serine rich (GS) domain, whereas a few other mutations are responsible for a limited number of cases. Mutations cause a dysregulation of the downstream BMP-dependent pathway and make mutated ACVR1 responsive to a non-canonical ligand, Activin A. There is no etiologic treatment for FOP. However, many efforts are currently ongoing to find specific therapies targeting the receptor activity and the downstream aberrant pathway at different levels or targeting cellular components and/or processes that are important in modifying the local environment leading to bone neo-formation.

ABSTRACT Fibrodysplasia ossificans progressiva (FOP), a rare and as yet untreatable genetic disorder of progressive extraskeletal ossification, is the most disabling form of heterotopic ossification (HO) in humans and causes skeletal deformities, movement impairment, and premature death. Most FOP patients carry an activating mutation in a bone morphogenetic protein (BMP) type I receptor gene, ACVR1R206H, that promotes ectopic chondrogenesis and osteogenesis and, in turn, HO. We showed previously that the retinoic acid receptor γ (RARγ) agonist palovarotene effectively inhibited HO in injury-induced and genetic mouse models of the disease. Here we report that the drug additionally prevents spontaneous HO, using a novel conditional-on knock-in mouse line carrying the human ACVR1R206H mutation for classic FOP. In addition, palovarotene restored long bone growth, maintained growth plate function, and protected growing mutant neonates when given to lactating mothers. Importantly, palovarotene maintained joint, limb, and body motion, providing clear evidence for its encompassing therapeutic potential as a treatment for FOP. © 2016 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

The progressive transformation of one organ system into another is a fundamental signature of fibrodysplasia ossificans progressiva (FOP), the most catastrophic form of extraskeletal bone formation in humans. In all affected individuals, FOP is caused by heterozygous missense gain-of-function mutations in Activin receptor A type I (ACVR1), a bone morphogenetic protein (BMP) type I receptor. Loss of autoinhibition of the mutant receptor (mACVR1) results in dysregulated BMP pathway signaling, and is necessary for the myriad developmental features of FOP, but does not appear sufficient to induce the episodic flare-ups that lead to disabling post-natal heterotopic endochondral ossification (HEO) and that are a hallmark of the disease. Post-natal FOP flare-ups strongly implicate an underlying immunological trigger involving inflammation and the innate immune system. Recent studies implicate canonical and non-canonical TGFβ/BMP family ligands in the amplification of mACVR1 signaling leading to the formation of FOP lesions and resultant HEO. BMP and Activin ligands that stimulate mACVR1 signaling also have critical regulatory functions in the immune system. Cross-talk between the morphogenetic and immunological pathways that regulate tissue maintenance and wound healing identifies potential robust therapeutic targets for FOP. Here we review current evidence for an immunological trigger for flare-ups and HEO in FOP, propose a working schema for the pathophysiology of observed phenomena, and highlight outstanding questions under investigation. [ABSTRACT FROM AUTHOR]