進行性骨化性線維異形成症

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disease of heterotopic ossification (HO) caused by mutations in the activin receptor-like kinase-2 (ALK2) protein, a BMP type I receptor of the TGF-β superfamily. These mutations in the ALK2 receptor alter receptor function, causing activin A, a protein that normally inhibits ALK2 signaling, to aberrantly trigger suppressor of mothers against decapentaplegic 1/5/8 (SMAD1/5/8) signaling, thereby activating the chondroosteogenic pathway and leading to HO. Here we report the initial characterization of BCX9250, an orally available small-molecule inhibitor of ALK2 developed by BioCryst with the potential to treat FOP. Inhibition of ALK2-mediated signaling by BCX9250 was assessed using biochemical binding assays and in vitro activity assays with the mouse myoblast C2C12 cell line. The impact of BCX9250 on HO was investigated using 2 mouse models and an HO recurrence mouse model. BCX9250 has potent inhibitory activity against wild-type ALK2 protein and mutant ALK2 protein associated with FOP. In the ALK2R206H-expressing C2C12 cells, BCX9250 potently inhibited activin A-induced SMAD1 phosphorylation. In the selectivity assays, BCX9250 also potently inhibited several other protein kinases. Oral delivery of BCX9250 significantly reduced HO in 2 mouse models, including the Acvr1R206H knock-in mouse FOP model. BCX9250 also reduced the recurrence of HO after surgical removal of HO, suggesting that ALK2 inhibitors may be beneficial as prophylactic treatments following surgical excision of HO. These results suggest that BCX9250 may be useful for the treatment of FOP.

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic bone disorder associated with considerable clinical, economic, and societal impacts on patients, their caregivers, and the healthcare system. The aim of this study was to update the estimated prevalence of FOP in France, characterize the FOP patient population and impact of the disease, assess associated mortality rates, and quantify healthcare resource utilization and socioeconomic costs for individuals with FOP. An observational, retrospective case-control study was conducted using linked data for individuals with FOP from the French National Rare Diseases Registry and the French National Healthcare System Database (SNDS). Results were compared with the SNDS for a control group of individuals with any disease other than FOP. Prevalence of FOP was estimated at 1.39 per million. Data were available for 77 individuals with FOP and 769 controls without FOP. Of 70 individuals with FOP and a social security number at the index date, 50.0% (n = 35/70) were female, and the mean (SD) age was 25.3 (15.7) yr. Comorbidities were consistently more prevalent in individuals with FOP than in people without FOP. Consultations with general practitioners and non-physician healthcare providers, hospitalizations, and use of medical devices and treatments were significantly greater in individuals with vs without FOP (p < .05 for all). Mean total annual healthcare expenditure was more than 10 times greater in individuals with FOP than those without FOP from a societal perspective (largely driven by outpatient costs) and 14 times greater from a payer perspective. Overall survival was significantly worse in individuals with FOP than in individuals without (p < .0001). Findings from this study reinforce the clinical, economic, and societal impacts associated with FOP. Improving disease awareness and developing new interventions to support a reduction in these impacts should be considered key priorities for the FOP community and healthcare providers.

INTRODUCTION: Heterotopic ossification (HO) is the pathological formation of bone within soft tissues, most commonly following trauma or surgery. Pelvic HO that causes direct mechanical compression of the urinary bladder is exceptionally rare. We present a case that remained asymptomatic for over a decade before causing significant lower urinary tract symptoms. CASE PRESENTATION: A 30-year-old man presented with a 4-month history of dysuria, gross hematuria, and left testicular pain, more than 10 years after a high-energy pelvic fracture. Multimodal imaging revealed an exophytic ossified mass arising from the left pubic ramus and compressing the lateral bladder wall. Histopathology confirmed benign submucosal ossification. Surgical excision achieved complete symptom resolution by postoperative day 10. CLINICAL DISCUSSION: This case illustrates the capacity of traumatic HO to remain clinically silent for years before causing organ compression, with radiological overlap among neoplastic and inflammatory conditions complicating diagnosis. A multidisciplinary orthopedic-urology approach is essential. CONCLUSION: Pelvic HO with bladder compression should be included in the differential diagnosis of bladder masses in patients with a remote history of pelvic trauma. Early recognition and surgical excision restore urinary function.

BACKGROUND: Rare bone diseases comprise a heterogeneous group of complex and disabling conditions. Evidence on age-specific hospitalization patterns and in-hospital outcomes across multiple rare bone diseases is limited. METHODS: Population-based cohort study using national hospitalization data (01/2012-12/2021). Among 11,092,151 hospitalizations, 2,875 admissions of children and adults with rare bone diseases were identified via ICD-10 codes (X-linked hypophosphatemia, osteogenesis imperfecta, fibrous dysplasia, achondroplasia, pseudohypoparathyroidism, fibrodysplasia ossificans progressiva) and compared with 14,375 age-, sex-, and patient-complexity-matched hospitalizations from the general population. RESULTS: Hospitalization patterns differed substantially by disease and age. Patients with X-linked hypophosphatemia had an increased risk of emergency admissions in late adulthood, whereas planned admissions were more frequent in early adulthood among patients with achondroplasia and fibrous dysplasia. Malignancies were diagnosed in 22.7% of patients with X-linked hypophosphatemia, and fractures were the leading cause of hospitalization among patients with osteogenesis imperfecta. Across the rare bone diseases, patients had higher all-cause in-hospital mortality compared with matched controls (RR, 2.26; 95% CI, 1.77 to 2.89), longer hospital stays (median difference, 6 days [IQR 3-13 days]), higher risk of ICU admission (RR, 3.08; 95% CI, 2.78 to 3.40), and higher readmission risk (RR, 1.31, 95% CI, 1.15 to 1.49). CONCLUSIONS: The studied rare bone diseases are associated with distinct, disease-specific hospitalization patterns and substantially worse in-hospital outcomes across the lifespan. This underscores the need for tailored preventive strategies and coordinated, long-term care models for patients with rare bone diseases.