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Genes Nov 2023Fibrodysplasia ossificans progressiva (FOP) is an enigmatic, ultra-rare genetic disorder characterized by progressive heterotopic ossification, wherein soft connective... (Review)
Review
Fibrodysplasia ossificans progressiva (FOP) is an enigmatic, ultra-rare genetic disorder characterized by progressive heterotopic ossification, wherein soft connective tissues undergo pathological transformation into bone structures. This incapacitating process severely limits patient mobility and poses formidable challenges for therapeutic intervention. Predominantly caused by missense mutations in the gene, this disorder has hitherto defied comprehensive mechanistic understanding and effective treatment paradigms. This write-up offers a comprehensive overview of the contemporary understanding of FOP's complex pathobiology, underscored by advances in molecular genetics and proteomic studies. We delve into targeted therapy, spanning genetic therapeutics, enzymatic and transcriptional modulation, stem cell therapies, and innovative immunotherapies. We also highlight the intricate complexities surrounding clinical trial design for ultra-rare disorders like FOP, addressing fundamental statistical limitations, ethical conundrums, and methodological advancements essential for the success of interventional studies. We advocate for the adoption of a multi-disciplinary approach that converges bench-to-bedside research, clinical expertise, and ethical considerations to tackle the challenges of ultra-rare diseases like FOP and comparable ultra-rare diseases. In essence, this manuscript serves a dual purpose: as a definitive scientific resource for ongoing and future FOP research and a call to action for innovative solutions to address methodological and ethical challenges that impede progress in the broader field of medical research into ultra-rare conditions.
Topics: Humans; Myositis Ossificans; Proteomics; Rare Diseases; Ossification, Heterotopic; Bone and Bones
PubMed: 38136984
DOI: 10.3390/genes14122162 -
Skin Appendage Disorders Dec 2023Bony subungual growths arising on the digital tip are uncommon. Among these, subungual exostosis is a common cause.
INTRODUCTION
Bony subungual growths arising on the digital tip are uncommon. Among these, subungual exostosis is a common cause.
CASE PRESENTATION
We describe a 35-year-old-male patient with a rare occurrence of a fibro-osseus pseudotumor of the digit. It presents with reactive intramembranous ossification, with no continuity with the distal phalanx, helping differentiate it from a subungual exostosis. The patient presented with an asymptomatic subungual growth, lifting up the nail plate distally causing onycholysis. The characteristic clinical, radiological, and histopathological features of the case are described, which helped confirm the diagnosis.
CONCLUSION
Cases with fibro-osseus pseudotumor of the digit reported in literature are reviewed comprehensively. The factors helping differentiate this from the other bony tumors affecting the distal phalanx, including subungual exostosis, myositis ossificans, and osteosarcoma are also highlighted.
PubMed: 38107840
DOI: 10.1159/000532113 -
Scientific Reports Dec 2023Flexion-type pediatric humeral supracondylar fractures are rare, and the reduction technique remains contradictory. A minimally invasive technique using percutaneous...
Flexion-type pediatric humeral supracondylar fractures are rare, and the reduction technique remains contradictory. A minimally invasive technique using percutaneous leverage reduction combined with an external fixator was described to achieve satisfactory reduction and avoid the open reduction in this study. The operation and clinical results of patients treated with this technique were retrospectively compared with traditional closed reduction. From January 2013 to January 2018, children diagnosed with displaced flexion-type humeral supracondylar fractures were included in this study. Patients were treated with closed reduction (Group A) or minimally invasive reduction technique (Group B). The external fixator fixation was then applied. The demographic information, as well as the clinical and functional results of the operation, were retrospectively reviewed and evaluated. There were twenty-two patients, ten in Group A and twelve in Group B. The mean duration of the operation in Group A was more prolonged than Group B (59 min versus 46 min, p < 0.001). No infection, nonunion, myositis ossificans, neurovascular injury or other complications related to the operation were observed by the time the fractures healed. During an average 36 months follow-up time, almost all children achieved good to excellent results except for one fair in Group A according to the MEPS and the Flynn criteria. This study introduced a safe and efficient minimally invasive technique for displaced flexion-type supracondylar humerus fractures. With the assistance of mosquito forceps, this leverage technique might achieve similar satisfactory clinical outcomes as traditional closed reduction but with a shorter surgical duration.
Topics: Child; Humans; Retrospective Studies; Humeral Fractures; External Fixators; Humerus; Fracture Fixation, Internal; Treatment Outcome
PubMed: 38097631
DOI: 10.1038/s41598-023-48158-6 -
Journal of Medical Case Reports Dec 2023Fibrodysplasia ossificans progressiva (FOP) as a rare and heritable disorder with the infrequent genetic transmission of the condition is a catastrophic disorder of...
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.
Topics: Female; Humans; Middle Aged; Myositis Ossificans; Ossification, Heterotopic; Toes; Bone and Bones
PubMed: 38044456
DOI: 10.1186/s13256-023-04253-w -
Skeletal Radiology Jul 2024Aneurysmal bone cyst (ABC) is a rare and usually painful condition, representing about 1% of all bone tumors. A geographical lytic, expansile, and septated radiological...
Aneurysmal bone cyst (ABC) is a rare and usually painful condition, representing about 1% of all bone tumors. A geographical lytic, expansile, and septated radiological pattern, with fluid-fluid levels on MRI, is classically displayed. ABC can be a primary bone lesion (70% of patients) or can arise in an underlying condition and is subsequently named "ABC-like changes" (30%). ABC-like changes are more frequently encountered in skeletal segments affected by chondroblastoma, fibrous dysplasia, giant cell tumor, osteoblastoma, non-ossifying fibroma, and osteosarcoma. In this article, we describe the first case of ABC-like changes developed in association with an ultra-rare sclerosing bone disease: melorheostosis. Melorheostosis is characterized by recognizable patterns on radiological studies with a pathological increased bone density and a cortical thickening within the periosteal or endosteal space, usually with a "dripping candle wax" appearance. More rarely, other different radiological patterns can be observed, such as "osteopatia striata-like," "osteoma-like," "myositis ossificans-like," and mixed patterns. Pain and limb hypotrophy are the most common clinical manifestations. We report the case of a Caucasian male with a clinic-radiological diagnosis of melorheostosis (with epiphyseal osteopoikilosis) since the age of twelve. At the age of nineteen, he suffered from increased pain in the proximal right thigh, and the radiological control revealed an expansive septated lesion at the right proximal femoral bone. The diagnosis of ABC-like changes developed in melorheostosis was obtained after CT-guided bone biopsy and confirmed by open-incisional biopsy.
Topics: Humans; Melorheostosis; Male; Bone Cysts, Aneurysmal; Osteopoikilosis; Magnetic Resonance Imaging; Diagnosis, Differential; Epiphyses; Adult; Tomography, X-Ray Computed
PubMed: 38015230
DOI: 10.1007/s00256-023-04529-8 -
BMC Medical Research Methodology Nov 2023The design of clinical trials in rare diseases is often complicated by a lack of real-world translational knowledge. Fibrodysplasia ossificans progressiva (FOP) is an...
BACKGROUND
The design of clinical trials in rare diseases is often complicated by a lack of real-world translational knowledge. Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder characterized by skeletal malformations and progressive heterotopic ossification (HO). Palovarotene is a selective retinoic acid receptor gamma agonist. Here, we describe the methodology of three studies in the palovarotene clinical development program in FOP and discuss insights that could inform future research, including endpoint suitability and the impact of trial design.
METHODS
PVO-1A-001 (NCT02322255) was a prospective, protocol-specified, longitudinal FOP natural history study (NHS). PVO-1A-201 (NCT02190747) was a randomized, double-blind, placebo-controlled phase II trial; PVO-1A-202 (NCT02279095) was its open-label extension. Trial designs, including treatment regimens and imaging assessments, were refined between PVO-1A-201 and PVO-1A-202, and within PVO-1A-202, based on emerging data as the studies progressed. Palovarotene doses were administered using a flare-up treatment regimen (higher dose for 2/4 weeks, followed by lower dose for 4/≥8 weeks; from flare-up onset), with or without accompanying chronic (daily) treatment. Flare-up and disease progression outcomes were assessed, including incidence and volume of new HO during flare-ups and/or annually, as well as other clinical, patient-reported, and exploratory outcomes. Safety was monitored throughout all studies.
RESULTS
Overall, 114 and 58 individuals with FOP were enrolled in the NHS and phase II trials, respectively. Results of the NHS and PVO-1A-201 were published in 2022; complete results of PVO-1A-202 will be publicly available in due course. Together the studies yielded important information on endpoint suitability, including that low-dose whole-body computed tomography was the optimum imaging modality for assessing HO progression annually and that long study durations are needed to detect substantial changes in functional and patient-reported outcomes.
CONCLUSIONS
A flexible clinical development program is necessary for underexplored rare diseases to overcome the many challenges faced. Here, the NHS provided a longitudinal evaluation of FOP progression and interventional trials were based on emerging data. The studies described informed the design and endpoints implemented in the phase III MOVE trial (NCT03312634) and provide a foundation for future clinical trial development.
TRIAL REGISTRATION
NCT02322255 (registered 23/12/2014); NCT02190747 (registered 15/07/2014); NCT02279095 (registered 30/10/2014).
Topics: Humans; Myositis Ossificans; Ossification, Heterotopic; Prospective Studies; Rare Diseases; Randomized Controlled Trials as Topic; Clinical Trials, Phase II as Topic
PubMed: 37957586
DOI: 10.1186/s12874-023-02080-7 -
Rheumatology (Oxford, England) Apr 2024
Topics: Humans; Myositis Ossificans; Mediastinal Cyst
PubMed: 37935436
DOI: 10.1093/rheumatology/kead591 -
International Journal of Surgical... Nov 2023A 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...
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.
PubMed: 37933149
DOI: 10.1177/10668969231208030 -
Imaging Science in Dentistry Sep 2023Fibrodysplasia ossificans progressiva is a rare hereditary disorder characterized by progressive heterotopic ossification in muscle and connective tissue, with few...
Fibrodysplasia ossificans progressiva is a rare hereditary disorder characterized by progressive heterotopic ossification in muscle and connective tissue, with few reported cases affecting the head and neck region. Although plain radiographic findings and computed tomography features have been well documented, limited reports exist on magnetic resonance findings. This report presents 2 cases of fibrodysplasia ossificans progressiva, one with limited mouth opening due to heterotopic ossification of the lateral pterygoid muscle and the other with restricted neck movement due to heterotopic ossification of the platysma muscle. Clinical findings of restricted mouth opening or limited neck movement, along with radiological findings of associated heterotopic ossification, should prompt consideration of fibrodysplasia ossificans progressiva in the differential diagnosis. Dentists should be particularly vigilant with patients diagnosed with fibrodysplasia ossificans progressiva to avoid exposure to diagnostic biopsy and invasive dental procedures.
PubMed: 37799735
DOI: 10.5624/isd.20230069 -
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