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Fibrodysplasia ossificans progressive (FOP) is an ultra-rare genetic disorder that is caused by a mutation in the ACVR1 gene and provokes severe heterotopic ossification. Since flares of the disease are associated with inflammation, it is assumed that JAK inhibitors can control active FOP due to blocking multiple signaling pathways. Aim of Study: To assess the safety and efficacy of tofacitinib in patients with FOP refractory to standard of care treatment. Material and Methods: In the retrospective observation study we included information about 13 genetically confirmed FOP patients who were treated with tofacitinib 5 mg twice a day. All patients initially failed treatment with NSAIDs, corticosteroids, and bisphosphonates. We evaluated the patients 12 months before the beginning of their treatment with tofacitinib and continued evaluating to at least 12 months of their tofacitinib treatment period. Results: In 7 boys (54%) and six girls (46%) tofacitinib was prescribed at the age of 10.2 (ranged 2.2–19.6) years. Onset age was 1.5 (ranged 0.1-6.0) years. Main clinical features were malformed great toes (n = 13; 100%), short malformed thumbs (n = 9; 69%), peripheral osteochondromas (n = 9; 69%), abnormalities of the cervical spine (n = 13; 100%), multiple heterotopic ossifications (n = 13; 100%). The mean diagnostics delay was 44 (range: 1; 165) months. During the trial, the median (25%; 75%) frequency of flares decreased from 10 (6; 12) during 12 months before the baseline to 0 (0; 2) in the following 12 months and 0 (0; 0) in 24 months of treatment. There were no deteriorations of the CAJIS index during the study, except for only one patient whose CAJIS index deteriorated by 1 point. Improvement in the range of motion in the large joints was noted in 31% of patients. NSAID, oral and intravenous corticosteroids were successfully decreased from 100%; 61.5%, and 15.4% (baseline) to 46.2%, 7.7%, and 0% (12 months) and 22.2%, 0%, and 0% (24 months), consequently. The drug tolerance was good. No severe adverse events were registered. Conclusion: Tofacitinib is a highly efficient, well-tolerated option that may prevent FOP flares. Further studies of the therapeutic potential of JAK-kinase inhibitors in FOP patients are needed. [ABSTRACT FROM AUTHOR]

A 2-year-and-10-month-old boy presented with multiple masses in the neck and chest for over 3 months. The child had a history of unstable walking, with hard lumps visible at the injury sites after falls, which would resolve on their own. Following a recent injury, a mass was discovered in the posterior neck, protruding above the skin surface and accompanied by limited joint movement. Gradually, new masses were found on the left side of the neck, back near the scapular lower angle, in the scapular fossa, and along the left axillary midline. Magnetic resonance imaging examination showed diffuse low signal on T1-weighted images and high signal on T2-weighted images in the bilateral posterior neck and back muscles two months ago. A CT scan revealed muscle swelling, with areas of patchy low density and multiple nodular high-density ossifications within some muscles. Genetic testing results indicated a mutation in the ACVR1 gene, leading to the final diagnosis of progressive ossifying myositis in this patient. This article summarizes the etiology, diagnosis, and treatment of one case of progressive ossifying myositis, providing a reference for clinicians.

Fibrodysplasia ossificans progressive (FOP) is an extremely rare noninflammatory disease that involves heterotrophic bone formation after tissue injury. Diagnosis of FOP is based on clinical suspicion for children presenting with bilateral hallux valgus and acute soft tissue swelling after trauma. Genetic analysis for mutation of the ACVR1 gene is considered a confirmatory test. We present 2 children with FOP that were diagnosed at seven years and twenty months of age respectively. The first patient presented with acute tissue swelling over the back and an incidental finding of hallux valgus. Genetic study revealed heterozygous c617G>A mutation in exon 4 of the ACVR1 gene suggestive of FOP. She had several relapses, and management pitfalls are highlighted. This first case alerted early diagnosis of FOP in a twenty- month-old boy with bilateral hallux valgus. [ABSTRACT FROM AUTHOR]

Introduction and aim. Progressive ossifying myositis ossifi- cans (FOP) is an extremely rare, genetic disease that leads to disability and premature death. It is inherited in an autosomal dominant fashion, caused by mutations in the ACVR1 gene, which encodes the activin receptor-like kinase ALK2. It is characterized by progressive heterotopic ossification (HO) of the endochondral tissue, skeletal muscles, fascia, tendons and ligaments, and congenital malformations of the big toes, leading to deformities and loss of trunk mobility, joint contractures in the limbs, and limited ability to open the mouth. Material and methods. Suspicion of FOP is diagnosed on the basis of toe malformation and heterotopic ossification, therefore in such cases the diagnosis of FOP should be implemented, based on the presence of a heterozygous pathogenic variant in the ACVR1/ALK2 gene. Analysis of literature. Currently, therapy focuses on the treatment of relapses with glucocorticoids and non-steroidal anti-inflammatory drugs. Taking into account the different stages in the pathogenesis of the disease, it is possible to develop a treatment based on therapy targeted at specific processes. Saracatinib, an ALK2 inhibitor, shows promising results in preclinical models due to the fact that it has shown the ability to inhibit HO and is currently in the second phase of clinical trials. Rapamycin, an immunosuppressive drug, has been shown to slow HO in animal models of FOP. Palovarotene, a Phase 3 drug, by reducing bone morphogenetic protein signaling, may reduce heterotopic bone volume in FOP patients. Garetosmab, an antibody that binds to activin A, blocks its activity, so it can prevent the formation and inhibit the growth of HO. Conclusion. Despite many efforts, there is still no effective and specific treatment for FOP, therefore the cooperation of global centers is very important, which is of key importance in the development of targeted therapy against FOP. [ABSTRACT FROM AUTHOR]

Background: Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disease affecting connective tissue, primarily caused by de novo mutations of the ACVR1 gene. FOP is a disease with congenital malformations of the toes and heterotopic ossification in characteristic patterns that progresses with flare-ups and remissions. Cumulative damage results in disability and, eventually, death. This report aimed to describe a case of FOP to highlight the importance of early diagnosis of this rare condition., Case Report: We describe the case of a 3-year-old female diagnosed with congenital hallux valgus, who initially presented with soft tissue tumors, predominantly in the neck and chest, with partial remission. Multiple diagnostic tests were performed, including biopsies and magnetic resonance imaging, with nonspecific results. We observed ossification of the biceps brachii muscle during evolution. The molecular genetic study found a heterozygous ACVR1 gene mutation that confirmed FOP., Conclusions: Knowledge of this rare disease by pediatricians is critical for an early diagnosis and for avoiding unnecessary invasive procedures that may promote disease progression. In case of clinical suspicion, performing an early molecular study is suggested to detect ACVR1 gene mutations. The treatment of FOP is symptomatic and focused on maintaining physical function and family support., (Copyright: © 2023 Permanyer.)