進行性骨化性線維異形成症

Fibrodysplasia ossificans progressiva is a rare genetic disorder characterized by progressive heterotopic ossification, which may lead to severe functional impairment. Orofacial involvement can result in marked restriction of jaw movement up to extra-articular temporomandibular ankylosis, severely complicating oral hygiene, diagnostics and dental treatment. This case report describes a 25-year-old male patient with advanced fibrodysplasia ossificans progressiva and complete jaw immobility with a maximum interincisal opening of 0 mm. He presented himself with daily dental pain, poor oral hygiene and recurrent swelling episodes. Conventional dental radiography was not feasible. Computed tomography revealed a permanent dentition except tooth 38, marked crowding and several malpositioned, non-occluding posterior teeth without obvious periapical pathology, marked periodontal bone loss or gross carious lesions. After interdisciplinary planning, including anesthesiologic consultation and expert advice in fibrodysplasia ossificans progressiva care, removal of the posterior teeth was performed to improve oral cleanability, reduce the risk of inflammatory complications in inaccessible posterior regions, facilitate nutrition within the existing limitations and improve emergency access for suction in case of vomiting. Local injection techniques were avoided because of the risk of iatrogenic heterotopic bone formation. The procedure was performed under general anesthesia with awake fibreoptic nasotracheal intubation and standby tracheostomy, using a strict soft-tissue-sparing approach and meticulous avoidance of positioning trauma. The patient was monitored for two nights and recovered without complications. At 11-month follow-up, he remained free of dental pain and recurrent swelling episodes and reported improved food intake with a weight gain of 8 kg. This case highlights the importance of preventive dentistry, strict indication for invasive procedures, multidisciplinary planning, airway preparedness, maximal trauma avoidance and long-term dental follow-up in specialized centers.

Engineered cell therapies present an opportunity for endogenous, site-specific production of therapeutic agents. Fibrodysplasia ossificans progressiva (FOP) is a morbid condition in which patients develop extensive heterotopic bony lesions in response to aberrant sensitivity to Activin A, through a mutation in the type I bone morphogenetic protein (BMP) receptor ACVR1 (ACVR1 R206H). We designed a transposon plasmid containing the transgene encoding ActR2A-Fc, with expression controlled by the BMP-responsive element (BRE), which is pathologically activated upon exposure to Activin A in FOP cells. FOP-derived marrow cells modified with this plasmid exhibited closed-loop functionality, with increased ActR2A-Fc expression upon exposure to Activin A and reduced expression upon its withdrawal. Bone marrow transplantation of labeled engineered FOP marrow cells into FOP mice resulted in the trafficking of engineered cells to sites at risk of FOP and a reduction of heterotopic bony lesions. These data provide proof-of-concept and a blueprint for marrow-derived cell therapies across the disease spectrum.

Fibrodysplasia Ossificans Progressiva (FOP) is a rare genetic disorder caused by gain-of-function mutations in ACVR1/ALK2, leading to progressive heterotopic ossification (HO) through endochondral bone formation. Inflammatory flare-ups often precede new ossification events, but the cellular and molecular mechanisms linking immune responses to progenitor cell fate remain incompletely understood. Here, using a tamoxifen-inducible Acvr1R206H mouse model of FOP and a reproducible muscle injury protocol, we combined single-cell RNA sequencing with in vitro assays to dissect early events during lesion formation. We identified an expansion of macrophages (MPs) and fibro-adipogenic progenitors (FAPs) in FOP mice, with both populations exhibiting inflammatory and osteochondrogenic transcriptional signatures. Cell-cell interaction analysis revealed a self-reinforcing network of cytokine signaling among MPs and a prominent MP-FAP communication axis centred on SPP1. Functional studies confirmed that SPP1 enhanced FAP osteogenic differentiation and that its inhibition partially reversed this phenotype in vitro and attenuated HO in vivo. Our findings highlight the critical role of inflammatory MPs in shaping the fate of resident stromal mesenchymal progenitors (e.g. FAP) and suggest that early immune-stromal interactions set the stage for HO. Targeting this immune-mesenchymal crosstalk may represent a potential complementary strategy for preventing or mitigating disease progression in FOP.

Myositis ossificans (MO) is a benign heterotopic ossification of skeletal muscle, typically resulting from direct trauma. Diagnosing MO confined to deep muscle groups, such as the vastus intermedius, can be challenging, often leading to delayed treatment. We present the case of a 39-year-old amateur athlete who developed a giant MO lesion (10x3 cm) two years following a severe thigh contusion. The patient presented with persistent restriction of hip flexion that outlasted the acute inflammatory phase, while a palpable mass was not identified until the chronic stage, 16 months post-injury, due to the deep anatomical localization. Surgical excision was performed, followed by progressive functional recovery. Passive hip flexion improved to 120° by the fourth postoperative week with only minimal end-range pain, and full painless active hip flexion was observed by the eighth week. At the 12-week follow-up, the patient had resumed straight-line jogging without clinical evidence of recurrence, although intermittent anterior thigh cramps persisted during high-intensity exercise. This case highlights the potential pitfalls of relying solely on physical palpation for deep muscle injuries. In such scenarios, early utilization of ultrasonography (US) may be beneficial for the timely detection of MO, as sonographic findings often precede radiographic evidence. Specifically, US typically reveals a hypoechoic mass in the acute phase, which evolves into a hypoechoic lesion containing hyperechoic foci during the intermediate and late stages of maturation. Early detection may help limit lesion progression and reduce the extent of subsequent surgical morbidity.

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder caused by a dominant mutation in the ACVR1 gene (R206H, 97% of cases), leading to debilitating heterotopic ossification (HO) characterized by abnormal bone growth triggered by inflammatory flare-ups. Here, we report the development of disease-modifying, allele-selective small interfering RNA (siRNA) targeting ACVR1 R206H . Allele selectivity is essential as wildtype ACVR1 is crucial for many functions including skeletal homeostasis and development. When conjugated to docosanoic acid (DCA), administration of the fully modified ACVR1 siRNA, either alone or in combination with an siRNA targeting IL1B (a key regulator of inflammation), results in profound reduction of HO using both responsive (post-trauma) and preventative (pre-trauma) intervention strategies in a murine FOP model. Notably, the combination therapy outperforms modulation of either target alone. We also describe the chemical engineering of a new class of lipophilic divalent siRNAs that target both pathways with a single compound, demonstrating superior muscle accumulation and therapeutic efficacy. siRNA treatment inhibits key signaling pathways (e.g. inflammatory, WNT, Notch, Hedgehog, and TGF-β), within muscle-resident fibroadipogenic progenitors (FAPs), leading to a significant reduction in cartilage, bone, and connective tissue formation. This work establishes a foundation for the development of disease-modifying treatments for FOP and offers a platform for targeting other musculoskeletal disorders involving multi-pathway dysregulation.