Intersections of Fibrodysplasia Ossificans Progressiva and Traumatic Heterotopic Ossification.

Heterotopic ossification (HO) is a debilitating pathology where ectopic bone develops in areas of soft tissue. HO can develop as a consequence of traumatic insult or as a result of dysregulated osteogenic signaling, as in the case of the orphan disease fibrodysplasia ossificans progressiva (FOP). Traumatic HO (tHO) formation is mediated by the complex interplay of signaling between progenitor, inflammatory, and nerve cells, among others, making it a challenging process to understand. Research into the pathogenesis of genetically mediated HO (gHO) in FOP has established a pathway involving uninhibited activin-like kinase 2 receptor (ALK2) signaling that leads to downstream osteogenesis. Current methods of diagnosis and treatment lag behind pre-mature HO detection and progressive HO accumulation, resulting in irreversible decreases in range of motion and chronic pain for patients. As such, it is necessary to draw on advancements made in the study of tHO and gHO to better diagnose, comprehend, prevent, and treat both.

Contemporary perspectives on heterotopic ossification.

Heterotopic ossification (HO) is the formation of ectopic bone that is primarily genetically driven (fibrodysplasia ossificans progressiva [FOP]) or acquired in the setting of trauma (tHO). HO has undergone intense investigation, especially over the last 50 years, as awareness has increased around improving clinical technologies and incidence, such as with ongoing wartime conflicts. Current treatments for tHO and FOP remain prophylactic and include NSAIDs and glucocorticoids, respectively, whereas other proposed therapeutic modalities exhibit prohibitive risk profiles. Contemporary studies have elucidated mechanisms behind tHO and FOP and have described new distinct niches independent of inflammation that regulate ectopic bone formation. These investigations have propagated a paradigm shift in the approach to treatment and management of a historically difficult surgical problem, with ongoing clinical trials and promising new targets.

Long-term dental outcomes in patients with fibrodysplasia ossificans progressiva: a report of three cases of tooth extraction.

Fibrodysplasia ossificans progressiva (FOP) is an extremely rare autosomal dominant disorder characterized by congenital skeletal malformation and progressive heterotopic ossification. In the oral and maxillofacial region, deformity of the temporomandibular joint is a common feature of FOP, as well as restricted mouth opening derived from heterotopic ossification in the masticatory muscles. Since surgical procedures are generally not recommended because of the risk of flare-ups and increased heterotopic ossification, reports of tooth extractions and their outcomes in patients with FOP are limited. The present article reports the long-term oral outcomes of three Japanese patients with FOP, in whom the teeth were deliberately extracted to avoid the risk of oral inflammation causing further heterotopic ossification. The extractions were conducted under local or general anesthesia, and healing of sockets was nonproblematic with the formation of new bone. Undesirable events, including progression of heterotopic ossification in the oral and maxillofacial region and further restriction of mouth opening, were not apparent. The extractions also alleviated the existing inflammation, contributing to maintaining their oral hygiene. These cases suggest that deliberate planning and judicious surgery could induce favorable healing after tooth extractions in patients with FOP, leading to long-term stability of their oral health status.

Gene Therapy for Fibrodysplasia Ossificans Progressiva: Feasibility and Obstacles.

Fibrodysplasia ossificans progressiva (FOP) is a rare and devastating genetic disease, in which soft connective tissue is converted into heterotopic bone through an endochondral ossification process. Patients succumb early as they gradually become trapped in a second skeleton of heterotopic bone. Although the underlying genetic defect is long known, the inherent complexity of the disease has hindered the discovery of effective preventions and treatments. New developments in the gene therapy field have motivated its consideration as an attractive therapeutic option for FOP. However, the immune system's role in FOP activation and the as-yet unknown primary causative cell, are crucial issues which must be taken into account in the therapy design. While gene therapy offers a potential therapeutic solution, more knowledge about FOP is needed to enable its optimal and safe application.

Dental management of a 26-year-old female with fibrodysplasia ossificans progressiva: A case report.

PURPOSE: The purpose of the report is to present a rare case of clinical management of a 26-year-old patient with fibrodysplasia ossificans progressiva (FOP), and discuss treatment options and possible outcomes. SUMMARY: FOP is a rare autosomal dominant genetic disorder of the connective tissue that affects one in two million people. It is characterized by multiple areas of progressive heterotopic endochondral ossifications. The symptoms typically begin with painful soft tissue swellings in the patient's first decade, which frequently occur after minor trauma, but may also happen spontaneously. The soft tissue swellings eventually form hard bony masses that cause joint limitations, growth defects, skeletal deformities, and chronic pain. The results are severely limiting to the activities of daily living and overall quality of life with the average life expectancy being 40 years of age. Medical and dental treatment, including the use of general anesthesia, may be complicated by increased risk of ossification of the soft tissues in the airway and lungs. The following case report focuses on a 26-year-old Caucasian female, with FOP. The patient presented to the Erie County Medical Center Dental clinic in Spring 2019 with generalized dental pain. She reported a history of multiple dental infections over many years which were periodically treated with antibiotics. A thorough intraoral exam and radiographs were not able to be completed upon initial presentation due to severe trismus and mobility limitations. The patient was a wheelchair user, verbal, and maintained a completely liquid diet by mouth. The patient also had a medical history significant for dysphagia and aspiration. After a substantial pre-operative optimization process, the patient was brought to the operating room for full mouth dental extractions. At the 2-week follow-up from surgery the patient showed excellent healing. CONCLUSION: While there are greater potential risks with placing a patient with FOP patient under general anesthesia, proper management of dental disease can relieve the patient from recurrent infections and discomfort.

Myositis ossificans of the thigh causing external compression of the superficial femoral artery and vein: A case report.

RATIONALE: Myositis ossificans (MO) is a benign condition characterized by heterotopic bone formation in the skeletal muscle of extremities. Marked variation can occur in the incidence and location of the bone formed as well as resulting complications. Femoral vessel obstruction caused by MO is an extremely rare but disabling complication. Arterial occlusion may aggravate ischemic conditions, resulting in necrosis in the lower extremity. PATIENT CONCERNS: We report a 41-year-old female with progressive pain and swelling of the right thigh region for 1 year. DIAGNOSES: We diagnosed it as obstruction of the superficial femoral artery and vein caused by external compression of the MO between the sartorius and vastus medialis of the thigh. INTERVENTIONS AND OUTCOMES: Adherent tissues and mass were excised with care without damaging the femoral artery or the vein. However, normal morphology did not recover due to loss of elasticity of femoral vessels. Therefore, after resection of the narrowed region of the femoral artery, a femoral-to-femoral graft interposition using the greater saphenous vein was performed. At 12 months after the surgery, vessel reconstruction computed tomography images confirmed normal continuous flow of the femoral artery. LESSONS: Vascular compression and peripheral inflammatory response due to MO can cause loss of normal vascular morphology. Surgical excision of the mass and the involved femoral artery segment followed by femoral arterial reconstruction should be considered for lesions that do not spontaneously regress to prevent functional impairment and secondary complications in extremities.

Radiotherapy in Fibrodysplasia Ossificans Progressiva: A Case Report and Systematic Review of the Literature.

Fibrodysplasia ossificans progressiva (FOP) is an autosomal dominant disease, characterized by the formation of heterotopic ossification (HO) in muscles, ligaments, and tendons. Flare-ups, an inflammatory process that often precedes the formation of HO, can occur spontaneously, but trauma is also a common trigger. It is not known whether radiotherapy, especially in higher doses, might cause sufficient trauma or inflammation to trigger a flare-up and subsequent HO in FOP patients. We report the case of a patient undergoing radiotherapy for the treatment of a 1-cm-wide basal cell carcinoma (BCC) of the lower lip. In addition, we present a systematic review of the available literature. Our patient received 54 Gy in 18 fractions with orthovoltage therapy, resulting in a clinical complete response of the tumor. Six months after treatment, there were no signs of HO either clinically or on [18F]NaF PET/CT. The systematic review identified 11 publications describing either radiation treatment in FOP or radiation therapy as a cause of HO in non-FOP patients. Six case reports described the use of radiation in FOP patients for various reasons, including one with a high-dose treatment of a lip BCC using superficial X-ray therapy. The remaining five studies described the use of low-dose radiotherapy to prevent or treat either an FOP flare-up or HO formation. None of these cases showed worsening of disease that could be attributed to the use of radiation therapy. Radiation induced HO in non-FOP patients was rare and occurred in five studies. The largest of these studies suggested that HO was induced after treatment with high doses, resulting in more widespread evidence of tissue damage, potentially being the end result of this damage. In conclusion, available reports suggest no contraindication to radiotherapy in FOP patients; although the number of cases was small, systematic toxicity reports often were not available, and none of the reports described high-dose, high-energy radiation treatment at locations such as muscle and joint regions.

A Case of Soft Tissue Ossifications: A Case Report.

CASE: A patient who had previously been diagnosed with fibrodysplasia ossificans progressiva was seen for hip pain and progressive soft tissue ossifications. Through a careful clinical examination, by which a subtype of brachydactyly was noted, the Albright hereditary osteodystrophy phenotype was recognized, and a new diagnosis of pseudopseudohypoparathyroidism was established. This paucisymptomatic condition often remains unidentified; however, its transmission can lead to more potentially serious diseases. CONCLUSIONS: A careful diagnostic process, including physical examination, is essential. Even if advanced tests exist, small clinical findings can lead to the proper conclusion. In our case, a finger pointed us in the right direction.

Nontraumatic Myositis Ossificans as an Uncommon Cause of Scoliosis: Case Report and Review of the Literature.

BACKGROUND: A 5-year-old pediatric patient developed scoliosis associated with nontraumatic myositis ossificans in the lumbar region. Although there have been reports in literature of syndromes leading to widespread muscle ossifications resulting in shoulder deformities owing to impaired movement in the facet joints, to the best of our knowledge there has been no report of scoliosis associated with myositis ossificans. CASE DESCRIPTION: The case presented is of a 5-year-old girl who developed scoliosis associated with nontraumatic myositis ossificans in the lumbar region. On the thoracolumbar radiograph, a hyperintense lesion was seen at the right-side L2-L3 level and scoliosis with a Cobb angle of 16.2° to the right side. The decision for surgery was made with the consideration of the existing scoliosis and that the complaints were associated with paravertebral calcified lesions adjacent to the facet joints. After surgery, the scoliosis improved. CONCLUSIONS: Nontraumatic, paravertebral myositis ossificans at an early age is a very rare pathology. Therefore, it must be recognized that spine deformities such as scoliosis and kyphosis can develop in neglected cases of paravertebral myositis ossificans. In addition, there is a high risk of confusion with malignant pathologies, such as osteosarcoma, in this area. Removal of the mass eliminates both the pain of myositis ossificans and prevents the development of scoliosis.

NF-κB/MAPK activation underlies ACVR1-mediated inflammation in human heterotopic ossification.

BACKGROUND: Inflammation helps regulate normal growth and tissue repair. Although bone morphogenetic proteins (BMPs) and inflammation are known contributors to abnormal bone formation, how these pathways interact in ossification remains unclear. METHODS: We examined this potential link in patients with fibrodysplasia ossificans progressiva (FOP), a genetic condition of progressive heterotopic ossification caused by activating mutations in the Activin A type I receptor (ACVR1/ALK2). FOP patients show exquisite sensitivity to trauma, suggesting that BMP pathway activation may alter immune responses. We studied primary blood, monocyte, and macrophage samples from control and FOP subjects using multiplex cytokine, gene expression, and protein analyses; examined CD14+ primary monocyte and macrophage responses to TLR ligands; and assayed BMP, TGF-ß activated kinase 1 (TAK1), and NF-κB pathways. RESULTS: FOP subjects at baseline without clinically evident heterotopic ossification showed increased serum IL-3, IL-7, IL-8, and IL-10. CD14+ primary monocytes treated with the TLR4 activator LPS showed increased CCL5, CCR7, and CXCL10; abnormal cytokine/chemokine secretion; and prolonged activation of the NF-κB pathway. FOP macrophages derived from primary monocytes also showed abnormal cytokine/chemokine secretion, increased TGF-ß production, and p38MAPK activation. Surprisingly, SMAD phosphorylation was not significantly changed in the FOP monocytes/macrophages. CONCLUSIONS: Abnormal ACVR1 activity causes a proinflammatory state via increased NF-κB and p38MAPK activity. Similar changes may contribute to other types of heterotopic ossification, such as in scleroderma and dermatomyositis; after trauma; or with recombinant BMP-induced bone fusion. Our findings suggest that chronic antiinflammatory treatment may be useful for heterotopic ossification.

Fibrodysplasia Ossificans Progressiva: A Case Report.

Fibrodysplasia ossificans progressiva is a genetic disorder of the connective tissue differentiation characterized by congenital malformation of the big toes and progressive heterotopic ossification in the extra skeletal tissues like tendons, ligaments, fascia and skeletal muscles leading to permanent disability. The prevalence is one in two million people. During childhood, it may be asymptomatic but in later life, progressive stiffness of major joints renders movement of the individual impossible. Currently, there is no effective treatment for this debilitating disease. Here, we present a case of 27 year old male with clinical and radiological features of fibrodysplasia ossificans progressiva.

Severe trismus and contraindicated exodontia in a patient with fibrodysplasia ossificans progressiva: case report.

Fibrodysplasia ossificans progressiva is a rare genetic disease of connective tissue in which muscles, ligaments, and tendons ossify either spontaneously or after trauma. Patients can develop physical disabilities and restriction of respiratory function. A patient attended a maxillofacial surgery outpatient clinic with severe trismus and mouth opening limited to 2mm. The risks of intervention were many from both anaesthetic and surgical perspectives, which prevented the extraction of carious teeth. The patient was referred to a special care dentistry team who provided endodontic stabilisation without local anaesthesia. In the case of severe infection, surgical intervention would be challenging to justify.

Fibrodysplasia ossificans progressiva: a current review of imaging findings.

OBJECTIVE: Fibrodysplasia ossificans progressiva is a rare genetic disorder characterized by congenital skeletal deformities and soft tissue masses that progress to heterotopic ossification. Deformities of the great toes are distinctive, and heterotopic ossification in the soft tissues follows an expected anatomic and temporal pattern. In addition to heterotopic ossification, osteochondromata, middle ear ossification, demyelination, lymphedema, and venous thrombosis are characteristic. Awareness of this constellation of findings is important to early diagnosis and surveillance. CONCLUSIONS: Recognition of the imaging manifestations of fibrodysplasia ossificans progressiva is imperative to early diagnosis in order to appropriately direct patient care and preclude unnecessary biopsies or surgical procedures.

Unresolving trismus following third molar surgery: Report of a case of fibrodysplasia ossificans progressiva with review of literature.

BACKGROUND: Trismus is a problem commonly encountered by the dental practitioner. It has a number of potential causes, and its treatment will depend on the cause. However, there are very few reports of trismus due to fibrodysplasia ossificans progressiva (FOP) following third molar surgery. CLINICAL PRESENTATION: FOP is a rare human genetic disorder with characteristic clinical features like progressive formation of extraskeletal bone or heterotopic ossification and congenital malformation of the great toes. CLINICAL SIGNIFICANCE: It is troublesome to the maxillofacial surgeon, that minimal manipulation and minor surgery can induce bone formation in soft tissues of the head and neck region, particularly the masticatory muscles and the temporomandibular joint. This paper presents a case of severe trismus following third molar extraction, intractable by routine treatment methods, which was later diagnosed as FOP.

Fibroplasia Ossificans Progressiva: A Case Report of a Rare Disease Entity.

BACKGROUND: Fibrodysplasia ossificans progressiva (FOP), also known as Myositis ossificans progressiva or Munchmeyer's disease, is an extremely rare and disabling genetic condition of congenital skeletal malformations and progressive heterotopic ossification (HO). The disease is characterized by congenital skeletal anomalies and progressive ectopic bone formation in connective tissues such as ligaments, muscles and tendons. The disease has an incidence of about 1 in 2 million population. CASE DETAILS: We report a case of a 2-year and 8-month old male child with an initial diagnosis of soft tissue sarcoma based on fine needle aspiration (FNAC) of neck swelling. CONCLUSION: Fibroplasia ossificans progressive (FOP) characteristically manifests with bilateral malformation of the great toe and progressive heterotopic ossification (HO). Clinicians and radiologists should be aware of these to prevent permanent disability.

Prevalence and risk factors for kidney stones in fibrodysplasia ossificans progressiva.

The worldwide prevalence and risk factors for kidney stones in patients with fibrodysplasia ossificans progressiva (FOP) are unknown. We conducted a survey of 383 patient-members of the International Fibrodysplasia Ossificans Progressiva Association, comprising the entire global membership of the international FOP community. Two hundred seven patients from 31 nations and 6 continents (54%) responded. Nineteen of 207 respondents had kidney stones, revealing a worldwide prevalence of 9.2%. In a confirmatory follow-up study of subjects participating in a longitudinal FOP natural history study, 9 of 114 individuals reported a history of kidney stones (7.9%). In both study populations patients with kidney stones were found to be more functionally impaired compared to those without nephrolithiasis. The prevalence of kidney stones in the adult FOP population of the Unites States was 15.8% (9/57 individuals) compared to a sex- and age-weighted prevalence of 4.5% (p=4×10-5) in the general population. Although geographical variation exists, patients with FOP have an approximately three-fold greater prevalence of kidney stones than the general population. This unusually high prevalence may be due to high bone turnover from chronic immobilization, or to unknown mechanistic effects of the activating FOP mutation in activin A receptor, type I/activin-like kinase-2 (ACVR1/ALK2), increasing the disease burden and morbidity in this already disabling condition.

[Characteristics of the joint involvement in fibrodysplasia ossificans progressiva and follow up].

Objective: To summarize the clinical data of 15 patients with fibrodysplasia ossificans progressiva (FOP), follow up and analyze the characteristics of the joint involvement in FOP. Method: From May 2005 to December 2016, fifteen FOP cases had been diagnosed in the Children's Hospital Capital Institute of Pediatrics. All medical records and follow-up data were collected and a retrospective analysis was made on the joint involvement in FOP. Pearson correlation analysis was used for data, P<0.05 for the difference was statistically significant. Result: There were 8 males and 7 females in 15 cases. The age of onset was 2(1-6)years. The age at diagnosis was 6 (4-9) years. All cases had hallux valgus deformity and bone mass formation. Twelve cases had joints involvement on enrollment into this study: 8 cervical vertebra, 7 shoulder joint, 5 hip joint, 4 elbow joint, 3 wrist joint, 2 temporomandibular joint, 2 lumbar vertebra. The age of diagnosis and duration of disease were positively correlated with the number of the involved joints (r=0.523, 0.628; P=0.045, 0.012); mild changes were found in joint imaging. Thirteen cases received telephone follow-up, the average duration of follow-up was 6(3-7)years, no change in 11 cases, disease progress in 2 cases. Conclusion: Joint involvement is a common complication of FOP, especially the cervical vertebra.Multiple joints involvement, dominant functional impairment, and mild imaging changes are the characteristics of joint lesions caused by FOP.The number of involved joints gradually increases with increase of age of the patients and the prolonged course of the disease.

A fatal case of metastatic squamous cell carcinoma in a patient with myositis ossificans traumatica.

Myositis ossificans traumatica is a rare disease associated with chronic wounds and fistulae. Chronic ulcers, fistulae and wounds can transform into squamous cell carcinoma, the so-called Marjolin's ulcer. We describe a rapid, progressive and fulminant course of a metastatic squamous cell carcinoma arising from a chronic wound in a patient with myositis ossificans traumatica.