Successful preimplantation genetic testing for fibrodysplasia ossificans progressiva: a case report.

PURPOSE OF THE STUDY: Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant condition that leads to significant disability and morbidity, characterised by the formation of heterotopic hard tissues within connective tissues. The condition has an incidence of approximately one per two million people worldwide. There is no known single effective treatment available for FOP. We report the world's first case of a healthy infant born following in vitro fertilisation (IVF) and preimplantation genetic testing for monogenic disorder (PGT-M) using Karyomapping for FOP. CASE PRESENTATION: A 30-year-old Caucasian female with FOP presented with her partner seeking IVF with PGT-M to achieve a healthy pregnancy with an embryo unaffected by FOP. METHODS: The couple underwent IVF and PGT-M using Karyomapping as the testing method. A multi-disciplinary team approach was utilised in planning this case, considering the additional risks of oocyte retrieval, pregnancy and childbirth in women with FOP. MAIN FINDINGS: The oocyte retrieval was covered with a 5-day course of prednisolone to reduce the risk of a localised inflammatory reaction, which could result in subsequent heterotopic ossification. This was subsequently weaned down with reducing doses every two days. The patient underwent uncomplicated oocyte retrieval, yielding 12 mature oocytes. Following intracytoplasmic sperm injection (ICSI), ten zygotes having two pro-nuclei were cultured, and six underwent trophoectoderm biopsy and vitrification 5-6 days after retrieval. PGT-M via Karyomapping revealed four out of six (66.7%) of blastocysts were not carriers of the maternal high-risk FOP allele. In total, the patient had three separate embryo transfers. Pregnancy was achieved following the third frozen embryo transfer, which went to 37 weeks' gestation, and delivered by Caesarean section. The baby was born in excellent condition and is unaffected by FOP. CONCLUSION: IVF/ICSI and PGT-M using Karyomapping was successfully implemented to identify embryos carrying the high-risk FOP allele resulting in a healthy livebirth.

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.

Pay Attention to the Osteochondromas in Fibrodysplasia Ossificans Progressiva.

BACKGROUND: Fibrodysplasia ossificans progressiva (FOP) is an extremely rare disease characterized by malformation of the bilateral great toes and progressive heterotopic ossification. The clinical features of FOP occur due to dysfunction of the bone morphogenetic protein (BMP) signaling pathway induced by the mutant activin A type I receptor/activin-like kinase-2 (ACVR1/ALK2) which contributes to the clinical features in FOP. Dysregulation of the BMP signaling pathway causes the development of osteochondroma. Poor awareness of the association between FOP and osteochondromas always results in misdiagnosis and unnecessary invasive operation. CASE PRESENTATION: In this study, we present a case of classical FOP involving osteochondroma. An 18-year-old male adolescent, born with deformity of bilateral big toes, complained multiple masses on his back for 1 year. The mass initially emerged with a tough texture and did not cause pain. It was misdiagnosed as an osteochondroma. After two surgeries, the masses became hard and spread around the entire back region. Meanwhile, extensive heterotopic ossification was observed around the back, neck, hip, knee, ribs, and mandible during follow-up. Osteochondromas were observed around the bilateral knees. No abnormalities were observed in the laboratory blood test results. Whole exome sequencing revealed missense mutation of ACVR1/ALK2 (c.617G > A; p.R206H) in the patient and confirmed the diagnosis of FOP. CONCLUSION: In summary, classical FOP always behaves as a bilateral deformity of the big toes, as well as progressive ectopic ossification and osteochondromas in the distal femur and proximal tibia. An understanding of the association between osteochondromas and FOP aids in diagnosis and avoids unnecessary invasive management in patients.

Disease aggravation following surgery in a rare patient suspected to Fibrodysplasia (Myositis) ossificans progressiva: a case report.

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.

[Recommendations for the healthcare of patients with FOP]. / Empfehlungen zur Versorgung von Patient:innen mit FOP.

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.

Patient-specific PEEK implant for treatment of temporal myositis ossificans (five years follow-up): A case report.

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.

A rare femoral heterotopic bone formation in a 14th-19th century female skeleton from Constância (Portugal).

OBJECTIVE: This paper aims to: (1) document a rare femoral heterotopic ossification (HO), and (2) discuss its aetiology and impact on the individual's locomotion and daily living activities. MATERIALS: Adult female skeleton (SG.14-SK.7) from the village of Constância (Portugal), and dated from the 14th-19th centuries CE. METHODS: The biological profile and the macroscopic analysis of the bone changes were assessed using standardized methods. RESULTS: The macroscopic analysis revealed a large bony mass (8 cm length) located immediately inferior to the small trochanter of the right femur. The lesion exhibited a compact, tubular appearance located at the site of attachment of the pectineus muscle. No signs of bone fracture were observed. CONCLUSIONS: The morphology of the SG.14-SK.7 femoral lesion is compatible with a probable case of myositis ossificans traumatica (MOT), secondary to acute trauma of the pectineus muscle. The underlying trauma episode, such as random accidental and/or occupation-related injury, is unknown. However, it is highly possible that this self-limiting condition significantly impaired the individual's daily life and mobility. SIGNIFICANCE: Evidence of severe acute muscle trauma is a rare finding compared with HO secondary to bone trauma and other minor muscle injuries. Moreover, no cases of MOT affecting the pectineus muscle have been reported in the paleopathological literature to date. LIMITATIONS: Although unlikely, a case of neurogenic or burn-related HO cannot be completely disregarded. It was not possible to undertake radiography as part of this study. SUGGESTIONS FOR FURTHER RESEARCH: The use of imaging techniques to complement the paleopathological description is advised.

The Fibrodysplasia Ossificans Progressiva Physical Function Questionnaire (FOP-PFQ): A patient-reported, disease-specific measure.

OBJECTIVES: To assess the reliability and validity of age-specific versions of the Fibrodysplasia Ossificans Progressiva Physical Function Questionnaire (FOP-PFQ), developed to measure the impact of FOP on physical function and activities of daily living. METHODS: FOP-PFQ development included a literature review, two iterative phases of qualitative work involving individuals with FOP, and clinical expert review. The analysis used pooled FOP-PFQ data from an FOP natural history study (NCT02322255), a patient registry (NCT02745158), and phase II trials (NCT02190747; NCT02279095; NCT02979769). Item-level and factor analysis informed item retention and determined factor structure. Reliability was evaluated using Cronbach's alpha and intraclass correlation coefficients. Convergent validity was assessed by comparing scores with age, the Cumulative Analogue Joint Involvement Scale (CAJIS), the Patient-Reported Outcomes Measurement Information System Global Health Scale (PROMIS), and heterotopic ossification (HO) volume. Known-groups validity assessment used age, CAJIS, and HO volume. RESULTS: Factor analysis confirmed a two-factor solution: Mobility and Upper Extremity. Results reflected high internal consistency and were supportive of test-retest reliability; correlation coefficients >0.90 demonstrated FOP-PFQ scores were stable over a one- to three-week period. The majority of scores were moderately (r = 0.30-0.50) to highly (r ≥ 0.50) correlated with CAJIS and HO volume, supporting convergent validity. With the exception of some age-based and functional groups, FOP-PFQ scores were significantly worse in groups with more severe disease, demonstrating known-groups validity. CONCLUSION: The FOP-PFQ was demonstrated to be a reliable, valid measure that may be responsive to change in individuals with FOP, although some results were inconclusive for pediatric versions.

Myositis Ossificans with Aneurysmal Bone Cystic Changes at the Thoracic Paraspinal Region: A Case Report.

Myositis ossificans (MO) is a benign heterotopic bone formation in muscle or soft tissue. It is a self-limiting disease that is usually initiated by trauma and often occurs in the extremities of the body. Here we report a rare case of traumatic myositis ossificans caused by unusual trauma (extracorporeal shock wave therapy) at thoracic paraspinal muscles. After a needle biopsy, the lesion increased in size, and the patient's symptoms worsened. Malignant soft tissue tumors such as osteosarcoma should be differentiated, so excision of the mass was performed. The final diagnosis was MO with aneurysmal bone cystic change. This case is a very rare form of MO that showed an unusual cause, location, clinical course, and pathologic result on follow-up. This can be an instructive case for radiologists as it is a common disease entity with unusual manifestations.

Current challenges and opportunities in the care of patients with fibrodysplasia ossificans progressiva (FOP): an international, multi-stakeholder perspective.

BACKGROUND: Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare, disabling genetic disorder characterized by congenital malformations of the great toes and progressive heterotopic ossification of soft and connective tissues. Assiduous attention to the unmet needs of this patient community is crucial to prevent potential iatrogenic harm and optimize care for individuals with FOP. OBJECTIVE: To gather international expert opinion and real-world experience on the key challenges for individuals with FOP and their families, highlight critical gaps in care, communication, and research, and provide recommendations for improvement. METHODS: An international group of expert clinicians, patients and patient advocates, caregivers and representatives from the international FOP community participated in a virtual, half-day meeting on 22 March 2021 to discuss the key unmet needs of individuals with FOP. RESULTS: Individuals with FOP often face the frustration of long diagnostic journeys, the burden of self-advocacy and the navigation of novel care pathways. Globally, patients with FOP are also confronted with inequities in access to diagnosis and specialist care, and consequently, unequal access to registries, clinical trials, and essential support from patient associations. Organizations such as the International FOP Association, the International Clinical Council on FOP, and national FOP organizations work to provide information, facilitate access to expert clinical guidance, nurture patient empowerment, fund FOP research and/or foster meaningful collaborations with the research community. The non-profit Tin Soldiers Global FOP Patient Search program aims to identify and provide a pathway to diagnosis and care for individuals with FOP, particularly in underserved communities. Such global initiatives and the increasingly widespread use of telemedicine and digital platforms offer opportunities to improve vital access to care and research. CONCLUSIONS: This multi-stakeholder perspective highlights some of the unmet needs of individuals with FOP and their families. Regional and international organizations play an important role in improving the quality of life of those they reach in the global FOP community. However, globally, fundamental issues remain around raising awareness of FOP among healthcare professionals, identifying individuals with FOP, reducing time to diagnosis, and ensuring access to best practice in care, support, and clinical research. Medical writing support was industry-sponsored.

"I Can't Take off My Shirt or Do My Own Hair"-A Qualitative Investigation of the Symptoms and Impact Experience of Children and Adolescents with Fibrodysplasia Ossificans Progressiva (FOP).

INTRODUCTION: Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare, severely disabling, autosomal dominant, congenital disease characterized by progressive multi-focal heterotopic ossification (HO) of skeletal muscle, ligaments, tendons, and fascia. Past FOP studies have focused on the clinical aspects of the disease; therefore, there is a paucity of qualitative research on the patient experience. Our objective was to better understand the experience of children and adolescents living with FOP from their and their parents' perspectives. METHODS: We conducted a qualitative research study comprising in-depth, open-ended interviews with children and adolescents with FOP and their parents. Semi-structured interviews were conducted via phone call or Microsoft Teams with parent-child dyads (n = 11), adolescents (n = 6), and two clinicians. Children/adolescents and their parents were asked open-ended questions to elicit their daily experience of FOP. RESULTS: Concepts were organized into two major themes: symptoms of FOP and the impact of FOP on daily life. Symptoms of FOP reported by children/adolescents, parents, and clinicians were pain, swelling, redness, and stiffness. Functional impacts of flares and FOP in general included accommodations, mobility, activities of daily living, daily activities, and social activities. Impacts were attributed to the difficulties children and adolescents faced living with a disease that prohibited common activities. CONCLUSIONS: This research documented the experience of children and adolescents with FOP and its effects on their daily lives. It provides a conceptual model for further exploration of the symptoms and impacts important to children and adolescents with FOP and their parents. Children and adolescents and their parents offered novel insights into life with the disease that have not previously been discussed in published literature. Future studies should build upon our conceptual model to create a holistic view of the patient experience of FOP, to inform clinical practice, and the assessment of the patient experience in clinical trials for the disease.

[Progressive myositis ossificans: Case report]. / Miositis osificante progresiva: reporte de un caso.

Background: Myositis ossificans progressiva (MOP) is a low prevalence hereditary connective tissue disease (1:2,000,000 habitants). It is characterized by heterotopic ossification with an uncertain behavior that has been exceptionally related to neoplasms. The objective was to know the coexistence of MOP with neoplasms of mesodermal origin, so that they can be considered in the diagnosis of other patients, as well as formulate hypotheses to clarify their association. Clinical case: 27-year-old female with right gluteal and ischitiobial muscle pain that increased with exercise, without remission with analgesics until limiting the mobility of both extremities. A bone series was requested where areas of heterogeneous radiolucency were evidenced in the region of, both, thighs and pelvis in an irregular manner, similar to bone density, which was compatible with the ultrasound and tomographic findings; we concluded that they were images of myositis ossificans of the hip. The patient reported gastric symptoms and an endoscopy was requested, which histopathologically reported diffuse gastric carcinoma with signet ring cells; cabinet images showed an ovarian tumor. Conclusion: MOP is a low prevalence disease, which is why its knowledge and suspicion are essential for the diagnosis. We found little literature that involves the three entities; therefore, their pathophysiology and understanding is limited. Regarding MOP, at this moment there is no curative treatment; however, an accurate diagnosis allows to start rehabilitation in a timely manner with an improvement in the quality of life.

Introducción: la miositis osificante progresiva (MOP) es una enfermedad hereditaria del tejido conectivo de baja prevalencia (1:2,000,000 habitantes). Se caracteriza por osificación heterotópica con un comportamiento incierto que excepcionalmente se ha relacionado con neoplasias. Se buscó conocer la coexistencia de la MOP con neoplasias de origen mesodérmico, para que sean consideradas en el diagnóstico de otros pacientes, así como formular hipótesis para esclarecer su asociación. Caso clínico: mujer de 27 años con dolor de músculo isquitiobial y glúteo derecho que incrementaba con el ejercicio, sin remisión con analgésicos hasta limitar la movilidad de ambas extremidades. Se solicitó una serie ósea donde se evidenciaron zonas de radiolucidez heterogénea en la región de ambos muslos y pelvis de manera irregular, semejante a densidad ósea, que fue compatible con los hallazgos ecográficos y tomográficos; se concluyó que eran imágenes relacionadas con miositis osificante de cadera. La paciente refirió sintomatología gástrica y se solicitó una endoscopía que histopatológicamente reportó carcinoma gástrico difuso con células en anillo de sello; las imágenes de gabinete mostraron tumoración ovárica. Conclusión: la MOP es una patología de baja prevalencia, por lo que su conocimiento y sospecha son fundamentales para el diagnóstico. Hay poca literatura que involucre a las tres entidades; por ende, su fisiopatología y comprensión es limitada. En cuanto a la MOP, aún no hay un tratamiento curativo; sin embargo, el diagnóstico certero permite iniciar rehabilitación de manera oportuna con mejoría de la calidad de vida.

Social and clinical impact of COVID-19 on patients with fibrodysplasia ossificans progressiva.

BACKGROUND: COVID-19, caused by the SARS-CoV-2 virus, is a severe inflammatory condition. Patients with pre-existing conditions including diabetes, hypertension, and cardiovascular disease are at particularly high risk of complications. Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare and debilitating genetic disorder that is characterized by a pro-inflammatory state, which leads to progressive heterotopic ossification and complications after trauma, including intramuscular vaccinations. To better understand the impact of COVID-19 on patients with FOP, we first examined the social impact of the pandemic using data from the FOP Registry managed by the International FOP Association. We also identified patients with FOP who were exposed to or contracted the SARS-CoV-2 virus, or who received a COVID-19 vaccine, to investigate if patients with FOP were at increased risks of complications from SARS-CoV2 exposure or vaccination. RESULTS: Data from 326 individuals in 69 countries in the International FOP Association FOP Connection Registry were examined using patient-reported outcomes measurement information system (PROMIS) global health scale scores. Twenty-six (28.9%) participants aged ≥ 15 years old rated their satisfaction with their social activities and relationships as poor in 2020, which was an increase from 18 (18.9%) in 2019, prior to the SARS-CoV-2 outbreak. Similar trends were noted for physical and mental health in the pediatric population. Frequency of physician visits was not changed, but a larger portion of patients reported missing dental visits in 2020 compared with 2019 (31.5% vs. 41.7%). A second cohort with 32 subjects was tracked after SARS-CoV-2 exposure or vaccination. Ten subjects were positively diagnosed with COVID-19, 15 received a COVID-19 vaccine, and seven had high-risk SARS-CoV-2 exposure but either did not have a confirmed clinical diagnosis or tested negative. Subjects who tested positive for the virus showed no major complications or increased FOP disease activity, though our sample size is very limited. Among the 15 subjects who received a COVID-19 vaccine, using the International Clinical Council on FOP guidelines for prophylaxis with ibuprofen or acetaminophen, only one person experienced flare-like activity at the injection site. CONCLUSIONS: Patients with FOP showed a significant decrease in social activities that was reflective of the isolation and mobility changes in this debilitated population. In our limited cohort, the majority of the patients with FOP who tested positive for COVID-19 showed no major complications. Also, although limited in sample size, the majority of patients who received a COVID-19 vaccination and followed guidelines from the FOP International Clinical Council tolerated vaccination well. Only one person experiencing flare activity following their injection. Thus, the risks and benefits of COVID-19 vaccination needs to be discussed carefully so as to support informed decisions.

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.

An ACVR1R375P pathogenic variant in two families with mild fibrodysplasia ossificans progressiva.

Genetic variants are vital in informing clinical phenotypes, aiding physical diagnosis, guiding genetic counseling, understanding the molecular basis of disease, and potentially stimulating drug development. Here we describe two families with an ultrarare ACVR1 gain-of-function pathogenic variant (codon 375, Arginine > Proline; ACVR1R375P ) responsible for a mild nonclassic fibrodysplasia ossificans progressiva (FOP) phenotype. Both families include people with the ultrarare ACVR1R375P variant who exhibit features of FOP while other individuals currently do not express any clinical signs of FOP. Thus, the mild ACVR1R375P variant greatly expands the scope and understanding of this rare disorder.