Fibrodysplasia ossificans progressiva (FOP) is an exceptionally rare genetic disorder, representing humans\' most debilitating form of extraskeletal ossification. It is characterized by progressive postnatal heterotopic ossification of connective tissue and malformations of the big toes. In FOP, ectopic ossification usually begins in the upper paraspinal muscles and then spreads from axial to appendicular regions, cranial to caudal directions, and proximal to distal sites. The mean life expectancy for these patients is typically 40-50 years. Most patients need partial or complete assistance with walking by age 30, and common causes of death include thoracic insufficiency syndrome and pneumonia. We present the case of a patient with an advanced stage of FOP, highlighting its complex and progressive nature. The patient exhibits severe impairment of jaw mobility, swallowing difficulties, speech impediments, and hearing impairment. Additionally, severe kyphoscoliosis, heterotopic ossification of intercostal and paravertebral muscles, and ankylosis of the spine and all major joints of the upper and lower extremities, except the metacarpophalangeal and proximal interphalangeal joints, are evident. We discuss disease presentation, current management options, and rehabilitation challenges. To our knowledge, this is the first reported case of this rare disease from our country.

Myositis ossificans (MO) is characterized by benign heterotopic ossificans in soft tissues like muscles, which can be classified into nonhereditary MO and fibrodysplasia ossificans progressiva (FOP). Although MO has been studied for decades, no research reviewed and analyzed the features of publications in this field quantitatively and qualitatively. Using bibliometrics tools (bibliometrix R package, VOSviewer, and CiteSpace), we conducted a bibliometric analysis of 1280 articles regarding MO in the Web of Science Core Collection database from 1993 to 2022. The annual number of publications and related research areas in the MO field increased gradually in the past 20 years. The USA contributed the most percentage (42.58%) of articles. The University of Pennsylvania (UPenn) and the Journal Bone published the most articles among all institutions and journals. Kaplan FS and Shore EM from UPenn were the top two scholars who made the largest contributions to this field. Keyword analysis showed that research hotspots changed from traumatic MO and clinical management of MO to the genetic etiology, pathogenesis, and treatment of FOP. This study can provide new insights into the research trends of MO and helps researchers grasp and determine future study directions more easily.

OBJECTIVE: Fibrodysplasia ossificans progressiva (FOP) is one of the most catastrophic forms of genetic heterotopic ossification (HO). FOP is characterized by severe, progressive inflammatory flare-ups, that often lead to HO. The flare-ups are associated with increased inflammatory cytokine production, suggesting auto-inflammatory features driven by interleukin-1β (IL-1β). This study describes the short- and long-term responses of FOP patients to anti-IL-1 therapy.
METHODS: Previously, we reported that a patient with FOP treated with anti-IL-1 agents showed dramatically lower rates of flare-ups, improved flare-up symptoms, decreased use of glucocorticoids, and apparently decreased size of residual lesions. Plasma analyses also showed marked elevation in IL-1β levels during a FOP flare, further supporting a role of IL-1β in the pathogenesis of FOP flares. Here, we report results from long-term therapy with IL-1 inhibitors in that patient, and describe 3 additional patients, from two medical centers.
RESULTS: All 4 patients showed persistent improvement in flare activity during treatment with IL-1 inhibitors, with minimal formation of new HO sites. Two patients who stopped therapy experienced resurgence of flare activity that was re-suppressed upon re-initiation. These patients had IL-1β levels comparable to those in IL-1β-driven diseases. Child Health Assessment Questionnaires confirmed extensive subjective improvements in the pain and general health visual analogue scales.
CONCLUSIONS: This case series demonstrates significant benefits from IL-1 inhibitors for reducing flare activity and improving the general health of patients with FOP. These data provide strong support for additional studies to better understand the function of IL-1 inhibition, primarily in reducing formation new HO.
BACKGROUND: RH received support from the International FOP Association ACT grant; ECH received support from NIH/NIAMS R01AR073015 and the UCSF Robert Kroc Chair in Connective Tissue and Rheumatic Diseases III.

The formation of bone outside the normal skeleton, or heterotopic ossification (HO), occurs through genetic and acquired mechanisms. Fibrodysplasia ossificans progressiva (FOP), the most devastating genetic condition of HO, is due to mutations in the ACVR1/ALK2 gene and is relentlessly progressive. Acquired HO is mostly precipitated by injury or orthopedic surgical procedures but can also be associated with certain conditions related to aging. Cellular senescence is a hallmark of aging and thought to be a tumor-suppressive mechanism with characteristic features such as irreversible growth arrest, apoptosis resistance, and an inflammatory senescence-associated secretory phenotype (SASP). Here, we review possible roles for cellular senescence in HO and how targeting senescent cells may provide new therapeutic approaches to both FOP and acquired forms of HO.

暂无摘要。

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.

UNASSIGNED: Fibrodysplasia Ossificans Progressiva is an ultra-rare genetic disorder of progressive soft tissue ossification. Due to unawareness and poor clinical suspicion, the rate of misdiagnosis, delay in diagnosis, and unnecessary diagnostic procedures leading to permanent injury and lifelong disability is common. Here we report this rare genetic disorder in a six years old child who was initially misdiagnosed as multiple exostoses and operated on.
METHODS: A 6 year old child presented with swellings over the posterior neck and back for four years. The patient was misdiagnosed as a case of multiple exostoses and an excisional biopsy was done a year back. The swelling worsened after the excision; currently, she cannot move her neck from side to side, and flex and extend. Examination revealed multiple hard and slightly tender masses over the posterior neck, para scapular and thoracolumbar para spinal region. She also has hallux valgus deformity that had been present since birth. CT (computed tomography) scan confirmed extensive extra-skeletal soft tissue ossification.
UNASSIGNED: The progression of heterotopic ossification is characteristically anatomic and orderly, typically initially involving the body\'s dorsal, axial, cranial, and proximal regions and later in the ventral, appendicular, caudal, and distal regions. Skeletal muscles of the tongue, diaphragm, extra-ocular muscles, cardiac muscles, and smooth muscles are inexplicably spared.
CONCLUSIONS: Early diagnosis prevents potentially harmful diagnostic and therapeutic procedures. The characteristic big toes malformation is the most important and best key for the early suspicion of the diagnosis.

BACKGROUND: Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease caused by a gain-of-function mutation in ACVR1, which is a bone morphogenetic protein (BMP) type I receptor. Moreover, it causes progressive heterotopic ossification (HO) in connective tissues. Using FOP patient-derived induced pluripotent stem cells (FOP-iPSCs) and mouse models, we elucidated the underlying mechanisms of FOP pathogenesis and identified a candidate drug for FOP.
METHODS: In the current study, healthy mesenchymal stem/stromal cells derived from iPSCs (iMSCs) expressing ACVR2B-Fc (iMSCACVR2B-Fc), which is a neutralizing receptobody, were constructed. Furthermore, patient-derived iMSCs and FOP mouse model (ACVR1R206H, female) were used to confirm the inhibitory function of ACVR2B-Fc fusion protein secreted by iMSCACVR2B-Fc on BMP signaling pathways and HO development, respectively.
RESULTS: We found that secreted ACVR2B-Fc attenuated BMP signaling initiated by Activin-A and BMP-9 in both iMSCs and FOP-iMSCs in vitro. Transplantation of ACVR2B-Fc-expressing iMSCs reduced primary HO in a transgenic mouse model of FOP. Notably, a local injection of ACVR2B-Fc-expressing iMSCs and not an intraperitoneal injection improved the treadmill performance, suggesting compound effects of ACVR2B-Fc and iMSCs.
CONCLUSIONS: These results offer a new perspective for treating FOP through stem cell therapy.

BACKGROUND: Fibrodysplasia ossificans progressiva (FOP) is an extremely rare connective tissue disease characterized by subsequent ossification of skeletal muscles, tendons, ligaments, and other fibrous tissues. The ossification of these tissues progresses during childhood and leads to limb and trunk deformities. Since any surgery may trigger subsequent ossification, it is relatively contraindicated for patients with FOP. In this report, we describe our experience in performing tracheostomy in a pediatric patient with FOP who developed a restrictive respiratory disorder due to progressive deformity of the trunk.
METHODS: A 12-year-old boy, diagnosed with FOP at the age of one, was referred for a tracheotomy after requiring 2 months of oral intubation and mechanical ventilation due to severe deformity-induced dyspnea. After changing from oral intubation to nasal intubation, we carefully considered the indications and benefits of tracheostomy in patients with FOP. Eventually, tracheostomy was successfully performed using our surgical design: creating a skin incision at the level of the cricoid cartilage that can always be identified, creating inverted U-shaped incision on the anterior tracheal wall to make a flap, and suturing the entire circumference of the tracheotomy and skin. One month after the surgery, he regained normal breathing and pronunciation and returned to school. The patient showed no unfavorable postoperative outcomes over a 4-year follow-up period.
CONCLUSIONS: Tracheostomy in our pediatric case of FOP required careful perioperative management. However, it could effectively improve the patient\'s quality of life.

Heterotopic ossification (HO) is most dramatically manifested in the rare and severely debilitating disease, fibrodysplasia ossificans progressiva (FOP), in which heterotopic bone progressively accumulates in skeletal muscles and associated soft tissues. The great majority of FOP cases are caused by a single amino acid substitution in the type 1 bone morphogenetic protein (BMP) receptor ACVR1, a mutation that imparts responsiveness to activin A. Although it is well-established that biological sex is a critical variable in a range of physiological and disease processes, the impact of sex on HO in animal models of FOP has not been explored. We show that female FOP mice exhibit both significantly greater and more variable HO responses after muscle injury. Additionally, the incidence of spontaneous HO was significantly greater in female mice. This sex dimorphism is not dependent on gonadally derived sex hormones, and reciprocal cell transplantations indicate that apparent differences in osteogenic activity are intrinsic to the sex of the transplanted cells. By circumventing the absolute requirement for activin A using an agonist of mutant ACVR1, we show that the female-specific response to muscle injury or BMP2 implantation is dependent on activin A. These data identify sex as a critical variable in basic and pre-clinical studies of FOP.