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The diagnosis of fibrodysplasia ossificans progressiva is missed or delayed because of its insidious precursors, especially in uncharacteristic cases. Fibrodysplasia ossificans progressiva, which mostly displayed the mutation c.617G > A, p.R206H, is characterized by congenital malformation of the great toe and progressive extra-skeletal ossification of ligaments, tendons and muscles. The mutation c.774G > C, p.R258S (HGVS: NC_000002.11:g.158626896 C > G) in activin A receptor type I is an infrequent etiology of fibrodysplasia ossificans progressiva and can present different clinical features. Awareness of these multiple clinical features will help endocrinologists in the early diagnosis of fibrodysplasia ossificans progressiva. We report a case of fibrodysplasia ossificans progressiva with the activin A receptor type I mutation c.774G > C, p.R258S, which was diagnosed before its ossifying period., (© 2024. The Author(s).)

Rationale: Myositis ossificans (MO) is characterized by benign heterotopic ossificans in soft tissues like muscles, which can be classified into nonhereditary MO and fibrodysplasia ossificans progressiva (FOP). Nonhereditary MO is characterized by ossification of the soft tissues after acute or repetitive trauma, burns, or surgical intervention. FOP is a rare and crippling disease characterized by congenital malformation of the big toe and heterotopic ossification in muscle. The majority of FOP's musculoskeletal traits are associated with dysregulated chondrogenesis. The diagnosis is mainly based on clinical manifestation, imaging examination, and genetic analysis. There is still no effective treatment to cure or slow its progression. The best approach remains early diagnosis, conservative drug treatment, and injury prevention to avoid local ossification., Patient Concerns: A 34-year-old male presented at our hospital because of trismus caused by ossification of the masseter muscle. In addition, he had serious stiffness and multiple bony masses throughout the body, which led to limited movement., Diagnoses: Based on the clinical manifestation of movement restriction, characteristic radiographic images of ossification of soft tissues, the genetic test showing a heterozygous molecule (c.974G > C, p.G325A) of the activin A receptor type I, the patient was diagnosed as FOP complicated with localized MO in masseter after trauma and infection., Interventions: The patient underwent the surgical resection of ossification in the masseter muscle, he was instructed to insist on mouth-opening exercises and take glucocorticoids and nonsteroidal anti-inflammatory medications after surgery., Outcomes: The symptoms of trismus are relieved, and eating can be basically achieved after surgery, while the symptoms of trismus recurred 2 years later., Lessons: Although FOP has unique clinical manifestations, its diagnosis may be difficult because of its rarity. Gene analysis is the main standard for diagnosis, while patients with different genotypic variations may show different clinical symptoms. Therapeutic interventions are still supportive and preventive, and surgery is not recommended except under certain circumstances., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Fibro-osseous pseudotumor of the digits is a benign tumour closely related to myositis ossificans. It is a rare lesion seldom reported in the literature. We report the case of a 33-year-old woman with lancinating pain in the first phalanx of the second finger of the right hand, associated with inflammation. The histopathological examination of the surgical excision biopsy of the lesion revealed a spindle-shaped proliferation within a sclerosing, hyaline, and osteoid stroma. In our observation, immunohistochemistry and molecular biology are the main elements that helped to establish the diagnosis and eliminate the various differential diagnoses, despite a non-specific histopathological aspect., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Myositis ossificans, a benign tumor composed of spindle cells and osteoblasts, can clinically and radiologically mimic osteosarcoma. While recognition and accurate diagnosis of myositis ossificans can be a challenge, this is critical as it may allow a conservative surgical approach to maximize functional outcomes. Herein, we present a patient with surface myositis ossificans confirmed genetically by the presence of COL1A1::USP6 gene fusion, along with a literature review. Due to the enhanced visualization of the bone matrix, computed tomography (CT) imaging may be a superior imaging modality to magnetic resonance (MR) imaging. Staged biopsies with samples obtained from the periphery and center of the lesions may allow pathologists to discern the zonal distribution histologically. Furthermore, immunohistochemistry fluorescence in situ hybridization and molecular testing can aid in the distinction of myositis ossificans from mimics. Because of their resemblance to other bone tumors, these cases of myositis ossificans highlight the importance of a multidisciplinary approach integrating clinical, radiologic, and pathologic analysis and involving serial imaging, sampling, and judicious use of ancillary immunohistochemical and molecular testing., (© 2024 Scandinavian Societies for Pathology, Medical Microbiology and Immunology.)

Objectives: To evaluate the natural history and to highlight the possible masqueraders causing diagnostic delay and iatrogenic interventions in Fibrodysplasia Ossificans Progressiva (FOP)., Methods: Patient details with suspected FOP were retrieved from the patient registry from 2012 through 2021. Clinical records, X-rays, clinical photographs, and molecular testing results were captured. Follow-up was recorded where available., Results: A total of 16 patients with a clinical diagnosis of FOP were found. Twelve patients with both clinical and molecular records were included in this study. The median age of onset and diagnosis was 1.5 y and 6.5 y respectively with a median diagnostic delay of 3.5 y. The disease course was progressive in ten patients. Seven out of twelve patients were subjected to invasive procedures due to misdiagnosis, which exacerbated their disease progression., Conclusions: Clinical suspicion followed by molecular testing is straightforward for a confirmed diagnosis of FOP. It is not only diagnostic, cost-effective, and saves time but also avoids unnecessary interventions in these patients., (© 2023. The Author(s), under exclusive licence to Dr. K C Chaudhuri Foundation.)

Introduction: A soft tissue aneurysmal bone cyst is an extremely rare tumor. The objective of the article is to present the clinical, radiological, and histopathological features of a very unusual neoplasm of soft tissues., Case Report: A 13-year-old male patient presented a painful, mobile, and rapidly growing mass on the posteromedial aspect of his left knee. Imaging studies revealed a mass that arose from the medial surface of the distal sartorius muscle, with extension to the subcutaneous fat tissue. It was a well-circumscribed solid tumor with a peripheral rim calcification on plain film, computerized tomography, and ultrasound (zonal phenomenon). On magnetic resonance imaging, a heterogenous mass on T1-weighted images (WI) and T2-WI was seen, with a peripheral hypointense rim in both sequences. An outstanding edema on T2-WI extending to the soft tissue and muscles of the medial compartment of the knee was detected. The mass was resected, and the "tumoral mimickers" histopathological and molecular (next-generation sequencing) diagnoses confirmed a soft tissue aneurysmal bone cyst. A follow-up showed that the patient was free of disease 12 months after surgery., Conclusion: Soft tissue aneurysmal bone cyst is a rare tumor. Appropriate clinical and radiological correlation should be performed to differentiate it from other tumor mimickers., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose of the Study: Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant condition that leads to significant disability and morbidity, characterised by the formation of heterotopic hard tissues within connective tissues. The condition has an incidence of approximately one per two million people worldwide. There is no known single effective treatment available for FOP. We report the world's first case of a healthy infant born following in vitro fertilisation (IVF) and preimplantation genetic testing for monogenic disorder (PGT-M) using Karyomapping for FOP., Case Presentation: A 30-year-old Caucasian female with FOP presented with her partner seeking IVF with PGT-M to achieve a healthy pregnancy with an embryo unaffected by FOP., Methods: The couple underwent IVF and PGT-M using Karyomapping as the testing method. A multi-disciplinary team approach was utilised in planning this case, considering the additional risks of oocyte retrieval, pregnancy and childbirth in women with FOP., Main Findings: The oocyte retrieval was covered with a 5-day course of prednisolone to reduce the risk of a localised inflammatory reaction, which could result in subsequent heterotopic ossification. This was subsequently weaned down with reducing doses every two days. The patient underwent uncomplicated oocyte retrieval, yielding 12 mature oocytes. Following intracytoplasmic sperm injection (ICSI), ten zygotes having two pro-nuclei were cultured, and six underwent trophoectoderm biopsy and vitrification 5-6 days after retrieval. PGT-M via Karyomapping revealed four out of six (66.7%) of blastocysts were not carriers of the maternal high-risk FOP allele. In total, the patient had three separate embryo transfers. Pregnancy was achieved following the third frozen embryo transfer, which went to 37 weeks' gestation, and delivered by Caesarean section. The baby was born in excellent condition and is unaffected by FOP., Conclusion: IVF/ICSI and PGT-M using Karyomapping was successfully implemented to identify embryos carrying the high-risk FOP allele resulting in a healthy livebirth., (© 2024. The Author(s).)

Heterotopic ossification (HO) is a debilitating pathology where ectopic bone develops in areas of soft tissue. HO can develop as a consequence of traumatic insult or as a result of dysregulated osteogenic signaling, as in the case of the orphan disease fibrodysplasia ossificans progressiva (FOP). Traumatic HO (tHO) formation is mediated by the complex interplay of signaling between progenitor, inflammatory, and nerve cells, among others, making it a challenging process to understand. Research into the pathogenesis of genetically mediated HO (gHO) in FOP has established a pathway involving uninhibited activin-like kinase 2 receptor (ALK2) signaling that leads to downstream osteogenesis. Current methods of diagnosis and treatment lag behind pre-mature HO detection and progressive HO accumulation, resulting in irreversible decreases in range of motion and chronic pain for patients. As such, it is necessary to draw on advancements made in the study of tHO and gHO to better diagnose, comprehend, prevent, and treat both.

Background: Fibrodysplasia ossificans progressiva (FOP) as a rare and heritable disorder with the infrequent genetic transmission of the condition is a catastrophic disorder of heterotopic ossification (HO) and a cause of extraskeletal bone formation in humans. Given the lack of effective treatment for this disease, the important point is to avoid aggravating factors such as bone biopsy, surgery, and intramuscular injection., Case Presentation: In this report, we present a 52-year-old female patient, Kurdish ethnic, suspected to FOP who had a surgical intervention on the second toe of the right foot, which subsequently, it caused further deterioration of the disease in the person including necrosis and amputation of the distal phalanx of the second toe., Conclusions: Although, based on our investigation and the available scientific evidence, surgery may a cause for faster progression and worsening of the FOP disorder, but its proof requires further studies., (© 2023. The Author(s).)

Background: Fibrodysplasia ossificans progressiva (FOP) is a very rare, severe genetic disorder triggered by a gain-of-function mutation in the ACVR1 gene that codes for the type I bone morphogenetic protein (BMP) receptor ACVR1 (activin A receptor-type 1), also known as ALK2 (activin receptor-like kinase-2). It leads to the onset and progression of heterotopic ossification (HO) in soft and connective tissue. HO is often preceded by episodes of soft tissue swelling or flare-ups. Flare-ups, characteristic of FOP, may be induced by trauma, infection, vaccination, or other medications, as well as surgical procedures or may occur spontaneously. As patients age, they develop severe mobility limitations due to progressive HO formation, including immobility, causing a shortened life expectancy. FOP's first characteristic clinical sign is the congenital malformation of one or both big toes with valgus axis deviation, which is present in almost all patients. To confirm the diagnosis, molecular genetic analysis of the ACVR1 gene is possible., Aim of the Recommendations: This white paper aims to provide an overview of the necessary prerequisites and conditions for the care of patients with FOP and positively contribute to patients with FOP by improving the overall availability of knowledge. To achieve this, relevant aspects of the care of the very rare disease FOP are presented, from the initial diagnosis to the care in regular care based on the authors' knowledge (German FOP network) and the international FOP Treatment Guidelines. The recommendations presented here are addressed to all actors and decision-makers in the health care system and are also intended to inform patients and the public., (© 2023. The Author(s).)

Objectives: To assess the reliability and validity of age-specific versions of the Fibrodysplasia Ossificans Progressiva Physical Function Questionnaire (FOP-PFQ), developed to measure the impact of FOP on physical function and activities of daily living., Methods: FOP-PFQ development included a literature review, two iterative phases of qualitative work involving individuals with FOP, and clinical expert review. The analysis used pooled FOP-PFQ data from an FOP natural history study (NCT02322255), a patient registry (NCT02745158), and phase II trials (NCT02190747; NCT02279095; NCT02979769). Item-level and factor analysis informed item retention and determined factor structure. Reliability was evaluated using Cronbach's alpha and intraclass correlation coefficients. Convergent validity was assessed by comparing scores with age, the Cumulative Analogue Joint Involvement Scale (CAJIS), the Patient-Reported Outcomes Measurement Information System Global Health Scale (PROMIS), and heterotopic ossification (HO) volume. Known-groups validity assessment used age, CAJIS, and HO volume., Results: Factor analysis confirmed a two-factor solution: Mobility and Upper Extremity. Results reflected high internal consistency and were supportive of test-retest reliability; correlation coefficients >0.90 demonstrated FOP-PFQ scores were stable over a one- to three-week period. The majority of scores were moderately (r = 0.30-0.50) to highly (r ≥ 0.50) correlated with CAJIS and HO volume, supporting convergent validity. With the exception of some age-based and functional groups, FOP-PFQ scores were significantly worse in groups with more severe disease, demonstrating known-groups validity., Conclusion: The FOP-PFQ was demonstrated to be a reliable, valid measure that may be responsive to change in individuals with FOP, although some results were inconclusive for pediatric versions., Competing Interests: Declaration of competing interest RJP: Research investigator: Ipsen/Clementia, Regeneron; Advisory board: President of the International Clinical Council on FOP; Chair of the Publications Committee for the IFOPA Registry Medical Advisory Board; MK: Employee of Evidera; JW: Employee of Ipsen; AKK: Employee of Evidera; AA: Employee of Ipsen; FSK: Research investigator: Ipsen/Clementia, Regeneron; Advisory Board: IFOPA Medical Advisory Board; Founder and Past-President of the International Clinical Council on FOP. In April 2019, Ipsen acquired Clementia Pharmaceuticals., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: This paper aims to: (1) document a rare femoral heterotopic ossification (HO), and (2) discuss its aetiology and impact on the individual's locomotion and daily living activities., Materials: Adult female skeleton (SG.14-SK.7) from the village of Constância (Portugal), and dated from the 14th-19th centuries CE., Methods: The biological profile and the macroscopic analysis of the bone changes were assessed using standardized methods., Results: The macroscopic analysis revealed a large bony mass (8 cm length) located immediately inferior to the small trochanter of the right femur. The lesion exhibited a compact, tubular appearance located at the site of attachment of the pectineus muscle. No signs of bone fracture were observed., Conclusions: The morphology of the SG.14-SK.7 femoral lesion is compatible with a probable case of myositis ossificans traumatica (MOT), secondary to acute trauma of the pectineus muscle. The underlying trauma episode, such as random accidental and/or occupation-related injury, is unknown. However, it is highly possible that this self-limiting condition significantly impaired the individual's daily life and mobility., Significance: Evidence of severe acute muscle trauma is a rare finding compared with HO secondary to bone trauma and other minor muscle injuries. Moreover, no cases of MOT affecting the pectineus muscle have been reported in the paleopathological literature to date., Limitations: Although unlikely, a case of neurogenic or burn-related HO cannot be completely disregarded. It was not possible to undertake radiography as part of this study., Suggestions for Further Research: The use of imaging techniques to complement the paleopathological description is advised., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Competing Interests: The authors declare no conflict of interest.

Introduction: Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare, severely disabling, autosomal dominant, congenital disease characterized by progressive multi-focal heterotopic ossification (HO) of skeletal muscle, ligaments, tendons, and fascia. Past FOP studies have focused on the clinical aspects of the disease; therefore, there is a paucity of qualitative research on the patient experience. Our objective was to better understand the experience of children and adolescents living with FOP from their and their parents' perspectives., Methods: We conducted a qualitative research study comprising in-depth, open-ended interviews with children and adolescents with FOP and their parents. Semi-structured interviews were conducted via phone call or Microsoft Teams with parent-child dyads (n = 11), adolescents (n = 6), and two clinicians. Children/adolescents and their parents were asked open-ended questions to elicit their daily experience of FOP., Results: Concepts were organized into two major themes: symptoms of FOP and the impact of FOP on daily life. Symptoms of FOP reported by children/adolescents, parents, and clinicians were pain, swelling, redness, and stiffness. Functional impacts of flares and FOP in general included accommodations, mobility, activities of daily living, daily activities, and social activities. Impacts were attributed to the difficulties children and adolescents faced living with a disease that prohibited common activities., Conclusions: This research documented the experience of children and adolescents with FOP and its effects on their daily lives. It provides a conceptual model for further exploration of the symptoms and impacts important to children and adolescents with FOP and their parents. Children and adolescents and their parents offered novel insights into life with the disease that have not previously been discussed in published literature. Future studies should build upon our conceptual model to create a holistic view of the patient experience of FOP, to inform clinical practice, and the assessment of the patient experience in clinical trials for the disease., (© 2022. The Author(s).)

Background: Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare, disabling genetic disorder characterized by congenital malformations of the great toes and progressive heterotopic ossification of soft and connective tissues. Assiduous attention to the unmet needs of this patient community is crucial to prevent potential iatrogenic harm and optimize care for individuals with FOP., Objective: To gather international expert opinion and real-world experience on the key challenges for individuals with FOP and their families, highlight critical gaps in care, communication, and research, and provide recommendations for improvement., Methods: An international group of expert clinicians, patients and patient advocates, caregivers and representatives from the international FOP community participated in a virtual, half-day meeting on 22 March 2021 to discuss the key unmet needs of individuals with FOP., Results: Individuals with FOP often face the frustration of long diagnostic journeys, the burden of self-advocacy and the navigation of novel care pathways. Globally, patients with FOP are also confronted with inequities in access to diagnosis and specialist care, and consequently, unequal access to registries, clinical trials, and essential support from patient associations. Organizations such as the International FOP Association, the International Clinical Council on FOP, and national FOP organizations work to provide information, facilitate access to expert clinical guidance, nurture patient empowerment, fund FOP research and/or foster meaningful collaborations with the research community. The non-profit Tin Soldiers Global FOP Patient Search program aims to identify and provide a pathway to diagnosis and care for individuals with FOP, particularly in underserved communities. Such global initiatives and the increasingly widespread use of telemedicine and digital platforms offer opportunities to improve vital access to care and research., Conclusions: This multi-stakeholder perspective highlights some of the unmet needs of individuals with FOP and their families. Regional and international organizations play an important role in improving the quality of life of those they reach in the global FOP community. However, globally, fundamental issues remain around raising awareness of FOP among healthcare professionals, identifying individuals with FOP, reducing time to diagnosis, and ensuring access to best practice in care, support, and clinical research. Medical writing support was industry-sponsored., (© 2022. The Author(s).)

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., (© 2022. The Author(s).)

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; ACVR1 R375P ) responsible for a mild nonclassic fibrodysplasia ossificans progressiva (FOP) phenotype. Both families include people with the ultrarare ACVR1 R375P variant who exhibit features of FOP while other individuals currently do not express any clinical signs of FOP. Thus, the mild ACVR1 R375P variant greatly expands the scope and understanding of this rare disorder., (© 2021 Wiley Periodicals LLC.)

Background: Myositis ossificans progressiva (MOP) is a low prevalence hereditary connective tissue disease (1:2,000,000 habitants). It is characterized by heterotopic ossification with an uncertain behavior that has been exceptionally related to neoplasms. The objective was to know the coexistence of MOP with neoplasms of mesodermal origin, so that they can be considered in the diagnosis of other patients, as well as formulate hypotheses to clarify their association., Clinical Case: 27-year-old female with right gluteal and ischitiobial muscle pain that increased with exercise, without remission with analgesics until limiting the mobility of both extremities. A bone series was requested where areas of heterogeneous radiolucency were evidenced in the region of, both, thighs and pelvis in an irregular manner, similar to bone density, which was compatible with the ultrasound and tomographic findings; we concluded that they were images of myositis ossificans of the hip. The patient reported gastric symptoms and an endoscopy was requested, which histopathologically reported diffuse gastric carcinoma with signet ring cells; cabinet images showed an ovarian tumor., Conclusion: MOP is a low prevalence disease, which is why its knowledge and suspicion are essential for the diagnosis. We found little literature that involves the three entities; therefore, their pathophysiology and understanding is limited. Regarding MOP, at this moment there is no curative treatment; however, an accurate diagnosis allows to start rehabilitation in a timely manner with an improvement in the quality of life., (© 2022 Revista Medica del Instituto Mexicano del Seguro Social.)

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare progressive genetic disease effecting one in a million individuals. During their life, patients with FOP progressively develop bone in the soft tissues resulting in increasing immobility and early death. A mutation in the ACVR1 gene was identified as the causative mutation of FOP in 2006. After this, the pathophysiology of FOP has been further elucidated through the efforts of research groups worldwide. In 2015, a workshop was held to gather these groups and discuss the new challenges in FOP research. Here we present an overview and update on these topics., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 de Ruiter, Smilde, Pals, Bravenboer, Knaus, Schoenmaker, Botman, Sánchez-Duffhues, Pacifici, Pignolo, Shore, van Egmond, Van Oosterwyck, Kaplan, Hsiao, Yu, Bocciardi, De Cunto, Longo Ribeiro Delai, de Vries, Hilderbrandt, Jaspers, Keen, Koolwijk, Morhart, Netelenbos, Rustemeyer, Scott, Stockklausner, ten Dijke, Triffit, Ventura, Ravazzolo, Micha and Eekhoff.)

Background: Fibrodysplasia Ossificans Progressiva (FOP) is a rare autosomal dominant disease characterized by congenital malformation of the great toes and progressive heterotopic ossification of soft tissues leading to cumulative disability. The genetic cause of FOP are mutations in the ACVR1 gene that encodes a type I receptor of Bone Morphogenetic Proteins. The most recurrent mutation in FOP patients is R206H affecting the Glycine-Serine rich domain and causing the hyper-activation of the receptor and the responsivity to the non-canonical ligand, Activin A. In the present study, we described a 3-years old child with early and highly suggestive clinical features of FOP who was found negative for the recurrent p.R206H substitution., Methods: Molecular screening of the whole ACVR1 coding sequence and functional characterization in transfection-based assays., Results and Conclusions: We identified a novel, de novo variant in the fifth ACVR1 coding exon (NM_001111067.4:c.772A>T; NP_001104537.1:p.(R258W)). This substitution, never reported in association with FOP, affects a conserved arginine residue in the kinase domain of the protein. In silico analysis predicted the pathogenicity of this substitution, demonstrated by in vitro assays showing that the p.R258W ACVR1 mutated receptor acquires the ability to transduce the aberrant Activin A-mediated signaling, as observed for the gene variants associated with FOP., (© 2021 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Fibrodyplasia ossificans progressiva (FOP) is a rare hereditary disease, which has a variable course characterized by occasional flare-ups of heterotopic ossification (HO) in soft tissues that are followed by swelling, stiffness, pain and warmth. Here, we report for the first time a case of a 45-year-old female patient with known FOP recovering from COVID-19 with disease progression potentially linked with the viral illness. In December 2020 the patient contracted a mild form of COVID-19 infection without need for hospital admission. Since January 2021, the patient felt unwell, with occasional abdominal pain which progressively intensified. In March 2021 she presented with new onset of HO, complaining of pain, swelling and thickening sensation in the lower abdomen and left part of the neck. Computerized tomography (CT) and cytokine analysis were performed. CT scan revealed new heterotopic bone formation in multiple soft tissue areas of the neck indicating clear radiological progression. Radiotherapy, which has proven to be an efficient tool to control HO in this patient, was not able to halt HO formation after COVID-19 infection. Cytokine analysis of a plasma sample obtained during a flare-up after COVID-19 infection showed a significantly elevated pro-inflammatory cytokines compared to a flare-up panel prior to infection. Of the 23 analyzed levels of cytokines, a staggering number of 21 were above normal levels. This case is the first confirmation of uncontrolled post-COVID-19 effects in a FOP patient, which manifested with flare-ups followed by progressive HO, possibly caused by a thus far, never described form of post-COVID syndrome.

Background: Progressive fibrodysplasia ossificans is a rare genetic disease with heterozygous mutations (autosomal dominant inheritance) in the ACVR1 gene, which causes progressive heterotopic ossification in muscles, tendons, and ligaments, usually secondary to trauma. The ossification foci generate pain, joint ankyloses, and restricted movement. Congenital shortening and medial deviation first metatarsal of the foot is a distinctive feature. This report aimed to present an educational value case of a patient with clinical, imaging, and molecular diagnosis of progressive fibrodysplasia ossificans, recognized as a rare condition that severely affects the quality of life., Case Report: We present the case of a 6-year-old female patient with lumps in the right scapular and dorsal region, progressive joint rigidity, and short first metatarsal medially deviated since birth. By imaging studies, we established the diagnosis of progressive fibrodysplasia ossificans. Sanger sequencing of ACVR1 reported c.617G>A (p.Arg206His)., Conclusions: Confirmation of the diagnosis allowed genetic counseling, including a comprehensive explanation of the disease's natural history and measures to prevent its rapid progression.

Aims: USP6 rearrangement underpins self-limiting fibroblastic/myofibroblastic neoplasms, including nodular fasciitis (NF), myositis ossificans (MO), aneurysmal bone cyst (ABC), and related variants. The aim of this study was to characterise UPS6 and fusion partners in order to delineate the clinicopathological, genetic and bone-forming features in such lesions of soft tissue (ST)., Methods and Results: Break-apart fluorescence in-situ hybridisation (FISH) validated USP6 rearrangement in 31 of 35 NF [comprising three of three fasciitis ossificans (FO) cases, seven of eight cellular variant of fibroma of tendon sheath (C-FTS), four of six MO, three of three ST-ABC, and two of two fibro-osseous pseudotumours of digits (FOPD)]. As determined with FISH and reverse transcription polymerase chain reaction, MYH9-USP6 was the commonest fusion in four C-FTS and 20 NF, including one intravascular case and two infantile (one retroperitoneal) cases. The presence of MYH9-USP6 confirmed the diagnosis of two NFs> 50 mm with prominent ischaemic necrosis. COL1A1-USP6 was predominant in ossifying lesions, including all FO, MO, ST-ABC and FOPD with identified partner genes, and was also present in non-ossifying head and neck NF (HN-NF) and C-FTS in two cases each. A cervical NF of a 14-month-old girl harboured the novel COL1A2-USP6. Ossifying lesions showed considerable genetic and morphological overlaps. Sharing COL1A1-USP6, FO and FOPD showed similar central or haphazard bone matrix deposition. Besides zonation of outward bone maturation, four COL1A1-USP6-positive MO had incipient to sieve-like pseudocysts reminiscent of ST-ABC., Conclusion: MYH9-USP6 is present in some C-FTS and most NF, including rare variants, but is unrelated to bone formation. All bone-forming USP6-rearranged lesions adopt COL1A1 as the 5' partner, indicating close genetic kinships. However, COL1A1/COL1A2 also contributes to the pathogenesis of minor subsets of non-ossifying USP6-rearranged HN-NF and C-FTS., (© 2020 John Wiley & Sons Ltd.)

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 management strategies. 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 hope of a cure. 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., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2020. Published by The Company of Biologists Ltd.)

Rationale: Fibrodysplasia ossificans progressiva (FOP) is rare genetic disease featuring progressive heterotopic ossification of soft tissues of the musculoskeletal system which leads to severe disability and premature death. Recognition of this disease is important since invasive diagnostic procedures can promote disease progression. However, despite its distinctive clinical manifestations, diagnosis can be difficult because of its rarity PATIENT CONCERNS:: A 20-year-old woman was referred to rheumatology clinic for management of "ankylosing spondylitis". The patent had begun to have hard subcutaneous nodules when she was 1 year old, and subsequently developed hip joint pain and flexion contractures of knees and hips leading to disability., Diagnoses: Based on characteristic bilateral great toe deformities and radiographic images of ossification of soft tissues, a clinical diagnosis of FOP was made. This was confirmed by genetic test showing a heterozygous mutation (c.G617A) of the activin receptor 1A gene (ACVR1)., Interventions: The patient was treated symptomatically and with supportive measures, and her condition remained stable., Lessons: Diagnosis of FOP can be difficult, despite its distinctive clinical manifestations, because of its rarity. Recognition of this disease is important to avoid invasive diagnostic procedures which can promote progression.

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.

Background: Fibrodysplasia ossificans progressiva (FOP) is a rare and disabling heritable connective tissue disease that is difficult to treat. This study seeks to explore the clinical characteristics, clinical manifestations, treatment and prognosis of FOP to provide a clinical basis for its early diagnosis and treatment., Methods: Twenty-six children with FOP were retrospectively analyzed in terms of their onset, clinical manifestations, auxiliary examinations and treatment., Results: Among the 26 cases, the youngest age of manifestation of mass was 8 days after birth, and the average age was 3 years and 2 months. The peak age was 2-5 years old. Inflammatory mass and toe-finger deformity are the main early clinical manifestations of the disease. These inflammatory masses often lead to hard osteogenic deposits that initially mainly involve the central axis, such as the neck (22/26, 84.6%), back (20/26, 76.9%), and head (13/26, 50%). Toe-finger deformity mainly manifests as symmetrical great toe deformity, or short and deformed thumb and little finger. The diagnosis of FOP requires typical clinical manifestations or ACVR1 gene detection. The main therapeutic drugs for FOP include glucocorticoids and non-steroidal anti-inflammatory drugs. Although not compliant with the recommended medical management of FOP, in our clinical practice children with uncontrollable illness could be treated using a variety of immunosuppressive agents in combination., Conclusions: FOP is a rare autosomal dominant heritable disease. The main clinical manifestations observed in this study were recurrent inflammatory mass and toe-finger deformity. If the diagnosis and treatment are not performed in a timely manner, serious complications are likely to affect the prognosis. Therefore, early diagnosis and active treatment should be performed.

Background: Fibrodysplasia ossificans progressiva (FOP) is the most catastrophic form of heterotopic ossification, due to ongoing intracellular signaling through the bone morphogenic protein pathway. The paroxysmal appearance of inflammatory lumps and elevated inflammatory markers during flares, suggest that FOP is an auto-inflammatory disease. Based on evidence, demonstrating a role for interleukin-1β (IL-1β) in other forms of heterotopic ossification, we hypothesized that treating FOP patients with anti-IL-1 agents could help lower the rate of FOP paroxysms and/or limit the symptoms and residual lesions., Case Presentation: A 13.5-year-old Arab boy was diagnosed with FOP. Treatment with anti-inflammatory drugs did not change the disease course. New lumps appeared in a rate of approximately one every 8 days. Treatment with the anti-IL-1 agents anakinra and canakinumab resulted in significantly lower rate of paroxysms (every 22-25 days, of which almost all involved only 2 existing lumps), as well as shorter duration. High levels of IL-1β were found in the patient's plasma samples, collected during a paroxysm that appeared 8 weeks after the last canakinumab dose. In contrast, IL-1β plasma levels were undetectable in the previous three plasma samples, obtained while he was treated with anti-IL-1 agents., Conclusions: Our data demonstrate the efficacy of anti-IL-1 agents in the treatment of a patient with FOP. Results showing the marked increase in IL-1β plasma levels during a paroxysm support a role for IL-1β in the pathogenesis of FOP and further provide the rationale for the use of anti-IL-1 agents in FOP treatment.