A genetic mouse model mimicking MET related human osteofibrous dysplasia is characterized by delays in fracture repair and defective osteogenesis.

Osteofibrous dysplasia (OFD) is a rare, benign, fibro-osseous lesion that occurs most commonly in the tibia of children. Tibial involvement leads to bowing and predisposes to the development of a fracture which exhibit significantly delayed healing processes, leading to prolonged morbidity. We previously identified gain-of-function mutations in the MET gene as a cause for OFD. In our present study, we test the hypothesis that gain-of-function MET mutations impair bone repair due to reduced osteoblast differentiation. A heterozygous Met exon 15 skipping (MetΔ15-HET) mouse was created to imitate the human OFD mutation. The mutation results in aberrant and dysregulation of MET-related signaling determined by RNA-seq in the murine osteoblasts extracted from the wide-type and genetic mice. Although no gross skeletal defects were identified in the mice, fracture repair was delayed in MetΔ15-HET mice, with decreased bone formation observed 2-week postfracture. Our data are consistent with a novel role for MET-mediated signaling regulating osteogenesis.

A Mathematical Model for Fibrous Dysplasia: The Role of the Flow of Mutant Cells.

Fibrous dysplasia (FD) is a mosaic non-inheritable genetic disorder of the skeleton in which normal bone is replaced by structurally unsound fibro-osseous tissue. There is no curative treatment for FD, partly because its pathophysiology is not yet fully known. We present a simple mathematical model of the disease incorporating its basic known biology, to gain insight on the dynamics of the involved bone-cell populations, and shed light on its pathophysiology. We develop an analytical study of the model and study its basic properties. The existence and stability of steady states are studied, an analysis of sensitivity on the model parameters is done, and different numerical simulations provide findings in agreement with the analytical results. We discuss the model dynamics match with known facts on the disease, and how some open questions could be addressed using the model.

Cystic degeneration of the fibrous dysplasia presenting with loss of vision.

Cystic degeneration of the fibrous dysplasia is a very rare clinical condition and may present with loss of vision when it involved the skull base. A 12-year-old female child presented with an enlargement of the skull. She was diagnosed as large skull base and skull vault tumor. She underwent partial removal of the tumor, and custom-made titanium implant was inserted. The diagnosis was fibrous dysplasia. Two years after the initial diagnosis, she presented with total loss of vision at her right eye. Radiological imaging confirmed the cystic degeneration within the tumor. She re-operated and the cyst fluid was evacuated in association with the removal of cyst wall. The diagnosis was the cystic degeneration of the fibrous dysplasia. Her vision was improved a few days after the surgery. Fibrous dysplasia of the skull base should be closely followed-up in order to prevent severe visual complications.

Fibrous dysplasia of the head and neck in Southern Finland: a retrospective study on clinical characteristics, diagnostics, and treatment.

PURPOSE: Fibrous dysplasia (FD) is a rare genetic disease with benign bone tumors. FD can affect one (monostotic FD) or multiple bones (polyostotic FD), with craniofacial lesions being common. Because of its rarity, there are only few clinical reports on FD in the head and neck region and its clinical characteristics remain incompletely defined. This study aimed to determine patient demographics, symptoms, diagnostics, and given treatment in patients with FD of the head and neck in a Finnish population. METHODS: A retrospective review on all patients diagnosed with or treated for FD of the head and neck at the Helsinki University Hospital during 2005-2020. RESULTS: In total 74 patients were identified; 54% were male and the mean age 45 years. Overall 95% had monostotic FD. Mandibula and maxilla were the most common anatomic sites. Majority of patients had symptoms, most commonly pain and lesion growth, and 49% had extra-skeletal symptoms. For all, diagnosis was primarily based on imaging findings, biopsies were obtained from 41%. Altogether 54 patients (73%) were managed by observation only, 20 patients (27%) received treatment; ten bisphosphonates, six surgery and four both. CONCLUSION: Although highly variable in its clinical manifestations, head and neck FD lesions are often symptomatic and impose risk for extra-skeletal complications. Treatment is often conservative but should be individually tailored. Future studies are encouraged to better define the disease characteristics and hopefully offer new treatment possibilities.

The Role of Surveillance in Predicting Fracture in Pediatric Patients With Incidentally Discovered Nonossifying Fibromas and Fibrous Cortical Defects: Is It Worth It?

BACKGROUND: Nonossifying fibroma (NOF) and fibrous cortical defect (FCDs), the most common benign pediatric bone lesions, are usually incidental x-ray findings. Surveillance of characteristic lesions has been recommended to monitor for enlargement and assess fracture risk. However, no accepted fracture risk prediction guidelines exist, so indications for prophylactic surgery are unclear. The study's purposes were to (1) characterize the timing of NOF/FCD-associated fractures, (2) quantify the resources devoted to surveillance, and (3) evaluate the potential for surveillance to prevent pathologic fracture. METHODS: A single institution retrospective review was conducted to identify pediatric patients (below 18 y old) with clinical-radiographic documentation of an NOF or FCD diagnosis from 2012 to 2020. Patients who presented with fracture were tallied but excluded from the surveillance analysis. Patients without at least one follow-up visit were also excluded. Lesional radiographic features were characterized on initial imaging. The number of visits and imaging studies devoted to surveillance were tabulated. The number of fractures and prophylactic surgeries were recorded to quantify the potential of surveillance to prevent pathologic fractures. RESULTS: The study population presenting without fracture consisted of 301 patients with 364 lesions with a mean follow-up of 20 months. By contrast, over the same period, 38 patients presented with NOF/FCD associated pathologic fractures. Surveillance included 1037 additional imaging tests over 1311 follow-up visits, or on average, 3.4 imaging studies and 4.4 visits per patient. During surveillance, only 2 (0.55%) lesions fractured. Another 10/364 (2.8%) patients underwent curettage and grafting, suggesting that-at best-the potential for preventing pathologic fracture by surveillance, assuming all 10 patients who underwent surgery would have subsequently fractured along with the 2 documented fractures, is 3.3% of lesions (12/364). CONCLUSIONS: The small number of fractures and surgeries during the follow-up period probably does not justify additional resources for surveillance beyond the initial visit, except in symptomatic patients with large lesions. However, subsequent visits may play a role in educating patients and their families regarding the natural history of these lesions. LEVEL OF EVIDENCE: Prognostic Level II-retrospective study.

Vitamin D Attenuates Fibrotic Properties of Fibrous Dysplasia-Derived Cells for the Transit towards Osteocytic Phenotype.

Fibrous dysplasia (FD) poses a therapeutic challenge due to the dysregulated extracellular matrix (ECM) accumulation within affected bone tissues. In this study, we investigate the therapeutic potential of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in managing FD by examining its effects on FD-derived cells in vitro. Our findings demonstrate that 1,25(OH)2D3 treatment attenuates the pro-fibrotic phenotype of FD-derived cells by suppressing the expression of key pro-fibrotic markers and inhibiting cell proliferation and migration. Moreover, 1,25(OH)2D3 enhances mineralization by attenuating pre-osteoblastic cellular hyperactivity and promoting maturation towards an osteocytic phenotype. These results offer valuable insights into potential treatments for FD, highlighting the role of 1,25(OH)2D3 in modulating the pathological properties of FD-derived cells.

Fibrocartilaginous Dysplasia of the Proximal Femur in Two Pediatric Patients, Including a Pathologic Fracture in a Patient With McCune-Albright Syndrome.

Fibrocartilaginous dysplasia (FCD) is a variant of fibrous dysplasia that often involves the proximal femur in young adults. It has a similar appearance on imaging as other entities but has stippled calcifications within the lesion. The differential diagnosis often includes benign and malignant tumors such as fibrous dysplasia, chondroblastoma, enchondroma, and chondrosarcoma. Histology is required for diagnosis and treatment is typically surgical due to the potential for pain, pathologic fracture, and deformity. We report the clinical presentation, imaging findings, and management of two pediatric patients with fibrocartilaginous dysplasia of the proximal femur to (1) highlight that recognition that fibrous dysplasia may contain cartilage upon frozen section will avoid overly aggressive therapy, and (2) FCD can occur in the McCune-Albright syndrome.

[Osteosarcoma Secondary to Polyostotoic Fibrous Dysplasia of the Ribs].

Sarcomatous transformation of fibrous dysplasia is extremely rare. We present the case of a 54-yearold man with multiple rib masses, multiple enlarged lymph nodes throughout the body, and multiple osteolytic lesions on computed tomography( CT). A positron emission tomography( PET) scan showed abnormal enhancement in each. A needle biopsy of the right supraclavicular fossa lymph node revealed sarcoidosis. Considering the possibility of malignancy associated with sarcoidosis, a rib tumor resection and mediastinal lymph node biopsy were performed to confirm the diagnosis of the rib lesion. The pathology results showed that the rib mass was a low-grade central osteosarcoma and the mediastinal lymph node was sarcoidosis. The distribution of the lesions was consistent with osteosarcoma secondary to multiple fibrous bone dysplasia. As the osteosarcoma was low grade, the patient was followed up. Three years after surgery, there was no increase in residual disease.

[A Case of Breast Cancer Complicated by Fibrous Dysplasia That Was Difficult to Differentiate from Bone Metastasis].

A 58-year-old woman with HER2-negative hormone-sensitive postmenopausal breast cancer underwent preoperative bone scintigraphy and CT to search for distant metastasis. Bone metastasis was suspected in the spinous process of the seventh cervical vertebra. MRI revealed a mass that was hypointense on T1- and T2-weighted images and hyperintense on diffusion- weighted images, with intense contrast enhancement, indicating bone metastasis at cT1N0M1, Stage Ⅳ(M: OSS). The patient underwent partial mastectomy and sentinel lymph node biopsy. The postoperative diagnosis was pT2N0cM1, Stage Ⅳ, with the status of bone metastasis being key to staging. PET-CT showed uptake in the spinous process of the seventh cervical vertebra but no other metastatic findings. However, solitary bone metastasis to the cervical spinous process is atypical. CT-guided needle biopsy confirmed benign fibrous dysplasia, and the final diagnosis was breast cancer at pT2N0M0, Stage ⅡA. Fibrous dysplasia is characterized by impaired osteogenesis leading to fibroplasia and commonly occurs in the skull, jaw bones, ribs, and limbs. Solitary fibrous dysplasia in the cervical spinous process is rare. The lesion was asymptomatic and pathologically benign, requiring no treatment. The patient underwent postoperative radiation therapy for the conserved breast and is followed up with endocrine therapy.

Patient-Derived Organoids Recapitulate Pathological Intrinsic and Phenotypic Features of Fibrous Dysplasia.

Fibrous dysplasia (FD) is a rare bone disorder characterized by the replacement of normal bone with benign fibro-osseous tissue. Developments in our understanding of the pathophysiology and treatment options are impeded by the lack of suitable research models. In this study, we developed an in vitro organotypic model capable of recapitulating key intrinsic and phenotypic properties of FD. Initially, transcriptomic profiling of individual cells isolated from patient lesional tissues unveiled intralesional molecular and cellular heterogeneity. Leveraging these insights, we established patient-derived organoids (PDOs) using primary cells obtained from patient FD lesions. Evaluation of PDOs demonstrated preservation of fibrosis-associated constituent cell types and transcriptional signatures observed in FD lesions. Additionally, PDOs retained distinct constellations of genomic and metabolic alterations characteristic of FD. Histological evaluation further corroborated the fidelity of PDOs in recapitulating important phenotypic features of FD that underscore their pathophysiological relevance. Our findings represent meaningful progress in the field, as they open up the possibility for in vitro modeling of rare bone lesions in a three-dimensional context and may signify the first step towards creating a personalized platform for research and therapeutic studies.

Diagnostic journey for individuals with fibrous dysplasia / McCune albright syndrome (FD/MAS).

BACKGROUND: Reducing delayed diagnosis is a significant healthcare priority for individuals with rare diseases. Fibrous Dysplasia/ McCune Albright Syndrome (FD/MAS) is a rare bone disease caused by somatic activation mutations of NASA. FD/MAS has a broad clinical phenotype reflecting variable involvement of bone, endocrine and other tissues, distribution and severity. The variable phenotype is likely to prolong the diagnostic journey for patients further. AIM: To describe the time from symptom onset to final diagnosis in individuals living with FDMAS. METHODS: We used the UK-based RUDY research database ( www.rudystudy.org ), where patients self-report their diagnosis of FD/MAS. Participants are invited to complete the diagnostic journey based on the EPIRARE criteria. RESULTS: 51 individuals diagnosed with FD/MAS were included in this analysis. Among them, 70% were female, and the median age was 51.0 years (IQR 34.5-57.5]. 12 (35%) individuals reported McCune Albright Syndrome, 11 (21.6%) craniofacial and 11(21.6%) for each of poly- and mono-ostotic FD and 6 (11.8%) did not know their type of FD/MAS. Pain was the commonest first symptom (58.8%), and 47.1% received another diagnosis before the diagnosis of FD/MAS. The median time to final diagnosis from the first symptom was two years with a wide IQR (1,18) and range (0-59 years). Only 12 (23.5%) of individuals were diagnosed within 12 months of their first symptoms. The type of FD/MAS was not associated with the reported time to diagnosis. Significant independent predictors of longer time to final diagnosis included older current age, younger age at first symptom and diagnosis after 2010. CONCLUSION: Individuals with FDMAS have a variable time to diagnosis that can span decades. This study highlights the need for further research on how to improve diagnostic pathways within Orthopaedic and Ear, Nose and Throat (ENT)/Maxillofacial services. Our data provides a baseline to assess the impact of novel NHS diagnostic networks on reducing the diagnostic odyssey.

Imaging of Fibro-osseous Lesions and Other Bone Conditions of the Jaws.

This review directs the focus on the imaging features of various fibro-osseous lesions and other bone lesions that can be of similar presentation. Broad diagnosis of "fibrous osseous lesion" may culminate in improper treatment and management. Radiographic discriminating factors between these entities are highlighted and summarized to improve the diagnostic process when encountering these lesions.

A pathogenic role for brain-derived neurotrophic factor (BDNF) in fibrous dysplasia of bone.

Brain derived neurotrophic factor (BDNF) is a neurotrophin, expressed in the central nervous system and in peripheral tissues, that is regulated by the Gsα/cAMP pathway. In bone, it regulates osteogenesis and stimulates RANKL secretion and osteoclast formation in osteolytic tumors such as Multiple Myeloma. Fibrous dysplasia (FD) of bone is a rare genetic disease of the skeleton caused by gain-of-function mutations of the Gsα gene in which RANKL-dependent enhanced bone resorption is a major cause of bone fragility and clinical morbidity. We observed that BDNF transcripts are expressed in human FD lesions. Specifically, immunolocalization studies performed on biopsies obtained from FD patients revealed the expression of BDNF in osteoblasts and, to a lower extent, in the spindle-shaped cells within the fibrous tissue. Therefore, we hypothesized that BDNF can play a role in the pathogenesis of FD by stimulating RANKL secretion and bone resorption. To test this hypothesis, we used the EF1α-GsαR201C mouse model of the human disease (FD mice). Western blot analysis revealed a higher expression of BDNF in bone segments of FD mice compared to WT mice and the immunolabeling pattern within mouse FD lesions was similar to that observed in human FD. Treatment of FD mice with a monoclonal antibody against BDNF reduced the fibrous tissue along with the number of osteoclasts and osteoblasts within femoral lesions. These results reveal BDNF as a new player in the pathogenesis of FD and a potential molecular mechanism by which osteoclastogenesis may be nourished within FD bone lesions. They also suggest that BDNF inhibition may be a new approach to reduce abnormal bone remodeling in FD.

Comparison of 18 F-FAPI and 18 F-FDG PET/CT in a Patient With Fibrous Dysplasia.

ABSTRACT: A 16-year-old woman presented with an acute headache on the left side. A head CT scan revealed bone destruction in the skull. Subsequent 18 F-FDG and 18 F-FAPI PET/CT scans were performed within a week. The 18 F-FDG PET/CT indicated mild uptake in the regions of bone destruction, whereas the 18 F-FAPI PET/CT displayed significant tracer accumulation. The patient was ultimately diagnosed with fibrous dysplasia.

RANKL inhibition reduces lesional cellularity and Gαs variant expression and enables osteogenic maturation in fibrous dysplasia.

Fibrous dysplasia (FD) is a rare, disabling skeletal disease for which there are no established treatments. Growing evidence supports inhibiting the osteoclastogenic factor receptor activator of nuclear kappa-B ligand (RANKL) as a potential treatment strategy. In this study, we investigated the mechanisms underlying RANKL inhibition in FD tissue and its likely indirect effects on osteoprogenitors by evaluating human FD tissue pre- and post-treatment in a phase 2 clinical trial of denosumab (NCT03571191) and in murine in vivo and ex vivo preclinical models. Histological analysis of human and mouse tissue demonstrated increased osteogenic maturation, reduced cellularity, and reduced expression of the pathogenic Gαs variant in FD lesions after RANKL inhibition. RNA sequencing of human and mouse tissue supported these findings. The interaction between osteoclasts and mutant osteoprogenitors was further assessed in an ex vivo lesion model, which indicated that the proliferation of abnormal FD osteoprogenitors was dependent on osteoclasts. The results from this study demonstrated that, in addition to its expected antiosteoclastic effect, denosumab reduces FD lesion activity by decreasing FD cell proliferation and increasing osteogenic maturation, leading to increased bone formation within lesions. These findings highlight the unappreciated role of cellular crosstalk between osteoclasts and preosteoblasts/osteoblasts as a driver of FD pathology and demonstrate a novel mechanism of action of denosumab in the treatment of bone disease.TRIAL REGISTRATION: ClinicalTrials.gov NCT03571191.

Osteofibrous dysplasia: a narrative review.

Osteofibrous dysplasia (OFD) is a rare, benign, self-limited bone disorder with a relatively low incidence, accounting for approximately 0.2% of all primary bone tumors. It was frequently found intra-cortical of the mid-shaft of the tibia. OFD can also occur in other skeletal regions, including the fibula, ulna, radius, femur, humerus, ischium, rib, tarsus, metatarsals, vertebral, and capitate. OFD can present with asymptomatic, mass, pain, swelling, deformity, and even pathological fracture. OFD might be misdiagnosed as adamantinoma (AD) and because they are three subtypes origin from the same family of bone tumors and have similar imaging features. Moreover, pathology could provide evidence for an accurate diagnosis of OFD, but misdiagnosis may occur due to small sampling materials. To date, few studies have comprehensively introduced the epidemiology, clinical manifestations, pathogenesis, radiological features, pathology, and treatment for OFD. We herein discuss clinical signs, diagnosis methods, and treatment options of OFD to improve the understanding of OFD, which is helpful for accurate diagnosis and appropriate treatment.

Craniomaxillofacial Fibro-osseous Lesions in Children.

Craniofacial fibro-osseous lesions represent a diverse spectrum of pathologic conditions where fibrous tissue replaces healthy bone, resulting in the formation of irregular, woven bone. They are more commonly diagnosed in young people, with treatment strategies dependent on clinical behavior and skeletal maturity. This article discusses the examples of craniofacial fibro-osseous lesions, based on the latest classifications, along with their diagnostic criteria and management.

Transcriptomic Signature and Pro-Osteoclastic Secreted Factors of Abnormal Bone-Marrow Stromal Cells in Fibrous Dysplasia.

Fibrous dysplasia (FD) is a mosaic skeletal disorder caused by somatic activating variants of GNAS encoding for Gαs and leading to excessive cyclic adenosine monophosphate signaling in bone-marrow stromal cells (BMSCs). The effect of Gαs activation in the BMSC transcriptome and how it influences FD lesion microenvironment are unclear. We analyzed changes induced by Gαs activation in the BMSC transcriptome and secretome. RNAseq analysis of differential gene expression of cultured BMSCs from patients with FD and healthy volunteers, and from an inducible mouse model of FD, was performed, and the transcriptomic profiles of both models were combined to build a robust FD BMSC genetic signature. Pathways related to Gαs activation, cytokine signaling, and extracellular matrix deposition were identified. To assess the modulation of several key secreted factors in FD pathogenesis, cytokines and other factors were measured in culture media. Cytokines were also screened in a collection of plasma samples from patients with FD, and positive correlations of several cytokines to their disease burden score, as well as to one another and bone turnover markers, were found. These data support the pro-inflammatory, pro-osteoclastic behavior of FD BMSCs and point to several cytokines and other secreted factors as possible therapeutic targets and/or circulating biomarkers for FD.

Dilemma with implant placement in patients with florid cemento-osseous dysplasia: A literature review.

METHODOLOGY: An electronic search was done in PUBMED, SCOPUS, and a hand search was done in radiology, periodontology, and oral surgery journals. The search yielded 428 results, from which only 6 articles were selected for this literature review. Both prospective and retrospective studies were included. Clinical studies with information on the pre-implant condition of the site, detailed implant procedure, and follow-up after implant placement of more than 6 months were only considered for this review. RESULTS AND CONCLUSION: Limited clinical studies, shorter follow-up periods were the shortcomings of this review. However, it can be summarized that dental implants should not be placed at the site of FCOD, however can be placed at adjacent sites. Variations in implant type or the implant length had no bearing on the survival of implants at the sites of FCOD.