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JBJS Case Connector Oct 2023A 5-year-old boy presented with multiple bony swellings in the dorsal spine region, restricted left shoulder movement, and a previous misdiagnosis of hereditary multiple...
CASE
A 5-year-old boy presented with multiple bony swellings in the dorsal spine region, restricted left shoulder movement, and a previous misdiagnosis of hereditary multiple exostoses (HMEs) resulting in unnecessary excision of the right scapular lesion. Clinical examination revealed hallux valgus, brachydactyly, and limited neck movement. Radiography and computed tomography confirmed a diagnosis of fibrodysplasia ossificans progressiva (FOP).
CONCLUSION
This case report underscores the importance of accurate diagnosis and differentiation between FOP and HME. Hallux valgus, brachydactyly, and restricted neck movement suggested FOP. It is paramount for orthopaedic surgeons to exclude rare disorders before performing any interventions. Biopsies or resections of bone formation areas should be avoided for patients with FOP.
Topics: Male; Humans; Child, Preschool; Myositis Ossificans; Hallux Valgus; Brachydactyly; Radiography; Tomography, X-Ray Computed
PubMed: 37797171
DOI: 10.2106/JBJS.CC.23.00327 -
Nature Medicine Oct 2023Fibrodysplasia ossificans progressiva (FOP) is a rare disease characterized by heterotopic ossification (HO) in connective tissues and painful flare-ups. In the phase 2... (Randomized Controlled Trial)
Randomized Controlled Trial
Fibrodysplasia ossificans progressiva (FOP) is a rare disease characterized by heterotopic ossification (HO) in connective tissues and painful flare-ups. In the phase 2 LUMINA-1 trial, adult patients with FOP were randomized to garetosmab, an activin A-blocking antibody (n = 20) or placebo (n = 24) in period 1 (28 weeks), followed by an open-label period 2 (28 weeks; n = 43). The primary end points were safety and for period 1, the activity and size of HO lesions. All patients experienced at least one treatment-emergent adverse event during period 1, notably epistaxis, madarosis and skin abscesses. Five deaths (5 of 44; 11.4%) occurred in the open-label period and, while considered unlikely to be related, causality cannot be ruled out. The primary efficacy end point in period 1 (total lesion activity by PET-CT) was not met (P = 0.0741). As the development of new HO lesions was suppressed in period 1, the primary efficacy end point in period 2 was prospectively changed to the number of new HO lesions versus period 1. No placebo patients crossing over to garetosmab developed new HO lesions (0% in period 2 versus 40.9% in period 1; P = 0.0027). Further investigation of garetosmab in FOP is ongoing. ClinicalTrials.gov identifier NCT03188666 .
Topics: Adult; Humans; Myositis Ossificans; Positron Emission Tomography Computed Tomography; Ossification, Heterotopic
PubMed: 37770652
DOI: 10.1038/s41591-023-02561-8 -
Biomolecules Sep 2023Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder characterized by progressive disabling heterotopic ossification (HO) at extra-skeletal...
Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder characterized by progressive disabling heterotopic ossification (HO) at extra-skeletal sites. Here, we developed adeno-associated virus (AAV)-based gene therapy that suppresses trauma-induced HO in FOP mice harboring a heterozygous allele of human () while limiting the expression in non-skeletal organs such as the brain, heart, lung, liver, and kidney. AAV gene therapy carrying the combination of codon-optimized human ACVR1 (ACVR1) and artificial miRNAs targeting Activin A and its receptor ACVR1 ablated the aberrant activation of BMP-Smad1/5 signaling and the osteogenic differentiation of skeletal progenitors. The local delivery of AAV gene therapy to HO-causing cells in the skeletal muscle resulted in a significant decrease in endochondral bone formation in mice. These mice showed little to no expression in a major AAV-targeted organ, the liver, due to liver-abundant miR-122-mediated repression. Thus, AAV gene therapy is a promising therapeutic strategy to explore in suppressing HO in FOP.
Topics: Animals; Humans; Mice; Activin Receptors, Type I; Activins; Dependovirus; Myositis Ossificans; Osteogenesis
PubMed: 37759764
DOI: 10.3390/biom13091364 -
Indian Journal of Pediatrics Sep 2023To evaluate the natural history and to highlight the possible masqueraders causing diagnostic delay and iatrogenic interventions in Fibrodysplasia Ossificans Progressiva...
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.
PubMed: 37698759
DOI: 10.1007/s12098-023-04843-y -
Journal of Clinical Pharmacology Feb 2024Here, we report the clinical pharmacology data from LUMINA-1 (NCT03188666), a Phase 2 trial that evaluated garetosmab (a monoclonal antibody against activin A) in... (Randomized Controlled Trial)
Randomized Controlled Trial
Here, we report the clinical pharmacology data from LUMINA-1 (NCT03188666), a Phase 2 trial that evaluated garetosmab (a monoclonal antibody against activin A) in patients with fibrodysplasia ossificans progressiva. Forty-four patients were randomly assigned to intravenous 10 mg/kg of garetosmab or placebo every 4 weeks in a double-blind 28-week treatment period, followed by a 28-week open-label treatment period with garetosmab, and subsequent open-label extension. Serum samples were obtained to assess pharmacokinetics (PK), immunogenicity, and bone morphogenetic protein 9 (BMP9). Comparative exposure-response analyses for efficacy and safety were performed with trough concentrations (C ) of garetosmab prior to dosing. Steady-state PK was reached 12-16 weeks after the first dose of garetosmab, with mean (standard deviation) C of 105 ± 30.8 mg/L. Immunogenicity assessments showed anti-garetosmab antibody formation in 1 patient (1/43; 2.3%); titers were low, and did not affect PK or clinical efficacy. Median concentrations of BMP9 in serum were approximately 40 pg/mL at baseline. There were no meaningful differences in PK or BMP9 concentration-time profiles between patients who did and did not experience epistaxis or death. The comparative exposure-response analyses demonstrated no association between C and efficacy or safety. PK findings were consistent with prior data in healthy volunteers and were typical for a monoclonal antibody administered at doses sufficient to saturate target-mediated clearance. There were no trends that suggested patients with higher serum exposures to garetosmab were more likely to experience a reduction in heterotopic ossification or adverse events. Garetosmab is being further evaluated in the Phase 3 OPTIMA trial.
Topics: Humans; Myositis Ossificans; Pharmacology, Clinical; Antibodies, Monoclonal
PubMed: 37694449
DOI: 10.1002/jcph.2344 -
Pediatric Rheumatology Online Journal Aug 2023Fibrodysplasia ossificans progressive (FOP) is an ultra-rare genetic disorder that is caused by a mutation in the ACVR1 gene and provokes severe heterotopic...
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.
Topics: Humans; Myositis Ossificans; Patients; Piperidines; Inflammation; Rare Diseases
PubMed: 37644581
DOI: 10.1186/s12969-023-00856-1 -
Orthopadie (Heidelberg, Germany) Nov 2023Fibrodysplasia 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... (Review)
Review
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.
Topics: Humans; Myositis Ossificans; Mutation; Ossification, Heterotopic; Bone Morphogenetic Proteins; Delivery of Health Care
PubMed: 37603129
DOI: 10.1007/s00132-023-04425-y -
German Medical Science : GMS E-journal 2023Fibrodysplasia ossificans progressiva (FOP) is an autosomal dominant rare disease characterized by foot deformities and concomitant heterotopic ossifications....
Fibrodysplasia ossificans progressiva (FOP) is an autosomal dominant rare disease characterized by foot deformities and concomitant heterotopic ossifications. Theoretically, in the absence of early diagnosis and medication, the patient's outcome will be poor. The patients are usually diagnosed at an early age. Hence, encountering a non-treated and terminal-period patient is rare. Our case was unique because it showed the clinical picture and atypical radiological distribution of a 20-year-old, terminally ill untreated female patient. She had hallux valgus, heterotopic ossifications and multiple osteochondromas that were detected in the right clavicula, the posterior arch of the 9 rib, the bilateral tibia and fibula. Atypically, heterotopic ossifications were not present in the soft tissues of the neck. Hand deformity, cardiac anomaly, or mental retardation was not observed. It was a sporadic case. The presentation with neurological symptoms was also atypical.
Topics: Humans; Female; Young Adult; Adult; Myositis Ossificans; Arthrogryposis; Bunion; Clavicle; Clonal Hematopoiesis
PubMed: 37599859
DOI: 10.3205/000326 -
Journal of Stomatology, Oral and... Dec 2023Myositis ossificans of the temporalis muscle results in a cosmetic problem both before and after treatment because of the preoperative swelling and the postoperative...
Myositis ossificans of the temporalis muscle results in a cosmetic problem both before and after treatment because of the preoperative swelling and the postoperative defect respectively. The authors hypothesized that a patient-specific Polyether-ether ketone implant can be appropriate for immediate obliteration and reconstruction of such defect benefiting from the accuracy of CAD/CAM technology and computer-guided maxillofacial surgery. A Forty-year-old male patient with myositis ossificans affecting the left temporalis muscle was treated with a computer-guided surgical approach, a patient-specific implant was fabricated to obliterate the defect and avoid temporal hollowing using PEEK material. The functional and cosmetic results were satisfactory both immediately and at the 5-year follow-up, except that the skin over the implant was noticed to be stretched after 5 years. Hence, it can be concluded that virtual surgical planning and PEEK patient-specific implants are reliable in the immediate reconstruction of post-surgical temporal hollowing.
Topics: Male; Humans; Adult; Follow-Up Studies; Myositis Ossificans; Plastic Surgery Procedures; Dental Implants; Polyethylene Glycols; Ketones
PubMed: 37567345
DOI: 10.1016/j.jormas.2023.101593