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Successful preimplantation genetic testing for fibrodysplasia ossificans progressiva: a case report.Journal of Medical Case Reports Apr 2024Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant condition that leads to significant disability and morbidity, characterised by the formation of...
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.
Topics: Humans; Female; Myositis Ossificans; Preimplantation Diagnosis; Adult; Pregnancy; Fertilization in Vitro; Genetic Testing; Oocyte Retrieval; Infant, Newborn; Prednisolone; Karyotyping
PubMed: 38664849
DOI: 10.1186/s13256-024-04504-4 -
Brain & NeuroRehabilitation Mar 2024Myositis ossificans is uncommon in patients with nontraumatic brain injuries. This report presents a challenging case in which myositis ossificans was diagnosed and...
Myositis ossificans is uncommon in patients with nontraumatic brain injuries. This report presents a challenging case in which myositis ossificans was diagnosed and treated by medical management in a patient who was unable to complain of any symptoms due to akinetic mutism that occurred after nontraumatic subarachnoid hemorrhage. The patient had intermittent high-grade fever, and laboratory tests showed elevated C-reactive protein and D-dimer levels without clinical signs of infection two months after subarachnoid hemorrhage. Lower-extremity venography using computed tomography was performed to rule out deep venous thrombosis. There was no thrombus, but right vastus medialis muscle showed inflammatory change with faint multilayered curvilinear hyperdense rims. The administration of indomethacin helped prevent abnormal bone formation. For the early detection of myositis ossificans, careful observation of clinical presentation and a high index of clinical suspicion is necessary in brain-injured patients. Further, elevated serum inflammatory markers accompanied by elevated alkaline phosphatase can be a critical clue. Early computed tomography helps identify early 'string sign' prior to characteristic ossification. Our report highlights that the myositis ossificans is remediable by early detection and appropriate nonsurgical management.
PubMed: 38585031
DOI: 10.12786/bn.2024.17.e9 -
Turkish Journal of Physical Medicine... Mar 2024Functional leg length discrepancy results from soft tissue tightness or weakness across any joint in the lower extremity or spine. Herein, we present a 23-year-old...
Functional leg length discrepancy results from soft tissue tightness or weakness across any joint in the lower extremity or spine. Herein, we present a 23-year-old female patient with leg length discrepancy due to a nontraumatic myositis ossificans (MO). Interpretation of the imaging findings is quite decisive in diagnosing soft tissue pathologies. It is particularly valid for MO to differentiate from other malignant or infectious lesions. There is no consensus on the treatment of nontraumatic MO. Although there are studies stating the contrary, surgical interventions should be considered as second option for patients who failed with nonsurgical treatments such as physical therapy.
PubMed: 38549818
DOI: 10.5606/tftrd.2023.11593 -
Biomolecules Mar 2024Inflammation is a major driver of heterotopic ossification (HO), a condition of abnormal bone growth in a site that is not normally mineralized. (Review)
Review
BACKGROUND
Inflammation is a major driver of heterotopic ossification (HO), a condition of abnormal bone growth in a site that is not normally mineralized.
PURPOSE OF REVIEW
This review will examine recent findings on the roles of inflammation and the immune system in fibrodysplasia ossificans progressiva (FOP). FOP is a genetic condition of aggressive and progressive HO formation. We also examine how inflammation may be a valuable target for the treatment of HO. Rationale/Recent findings: Multiple lines of evidence indicate a key role for the immune system in driving FOP pathogenesis. Critical cell types include macrophages, mast cells, and adaptive immune cells, working through hypoxia signaling pathways, stem cell differentiation signaling pathways, vascular regulatory pathways, and inflammatory cytokines. In addition, recent clinical reports suggest a potential role for immune modulators in the management of FOP.
FUTURE PERSPECTIVES
The central role of inflammatory mediators in HO suggests that the immune system may be a common target for blocking HO in both FOP and non-genetic forms of HO. Future research focusing on the identification of novel inflammatory targets will help support the testing of potential therapies for FOP and other related conditions.
Topics: Humans; Myositis Ossificans; Ossification, Heterotopic; Cell Differentiation; Signal Transduction; Inflammation
PubMed: 38540775
DOI: 10.3390/biom14030357 -
Biomolecules Mar 2024Heterotopic 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... (Review)
Review
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.
Topics: Humans; Myositis Ossificans; Ossification, Heterotopic; Osteogenesis; Bone and Bones
PubMed: 38540768
DOI: 10.3390/biom14030349 -
Biomolecules Mar 2024Fibrodysplasia ossificans progressiva (FOP) is a rare congenital disorder characterized by abnormal bone formation due to ACVR1 gene mutations. The identification of the...
Fibrodysplasia ossificans progressiva (FOP) is a rare congenital disorder characterized by abnormal bone formation due to ACVR1 gene mutations. The identification of the molecular mechanisms underlying the ectopic bone formation and expansion in FOP is critical for the effective treatment or prevention of HO. Here we find that Hh signaling activation is required for the aberrant ectopic bone formation in FOP. We show that the expression of (), a Hh ligand, as well as downstream Hh signaling, was increased in ectopic bone lesions in ; mice. Pharmacological treatment with an Ihh-neutralizing monoclonal antibody dramatically reduced chondrogenesis and ectopic bone formation. Moreover, we find that the activation of Yap in the FOP mouse model and the genetic deletion of halted ectopic bone formation and decreased expression. Our mechanistic studies showed that Yap and Smad1 directly bind to the Ihh promoter and coordinate to induce chondrogenesis by promoting expression. Therefore, the Yap activation in FOP lesions promoted ectopic bone formation and expansion in both cell-autonomous and non-cell-autonomous manners. These results uncovered the crucial role of the Yap-Ihh axis in FOP pathogenesis, suggesting the inhibition of Ihh or Yap as a potential therapeutic strategy to prevent and reduce HO.
Topics: Mice; Animals; Hedgehog Proteins; Chondrogenesis; Osteogenesis; Ossification, Heterotopic; Myositis Ossificans; Mutation
PubMed: 38540766
DOI: 10.3390/biom14030347 -
Stem Cell Research & Therapy Mar 2024Fibrodysplasia 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...
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 (iMSC), which is a neutralizing receptobody, were constructed. Furthermore, patient-derived iMSCs and FOP mouse model (ACVR1, female) were used to confirm the inhibitory function of ACVR2B-Fc fusion protein secreted by iMSC 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.
Topics: Female; Humans; Mice; Animals; Myositis Ossificans; Ossification, Heterotopic; Bone Morphogenetic Proteins; Signal Transduction; Mice, Transgenic; Mutation; Activin Receptors, Type II
PubMed: 38500216
DOI: 10.1186/s13287-024-03691-7 -
Radiology Case Reports May 2024Myositis ossificans is delineated and distinguished by the generation and deposition of cartilaginous and osseous soft tissues. It generally occurs in the lower...
Myositis ossificans is delineated and distinguished by the generation and deposition of cartilaginous and osseous soft tissues. It generally occurs in the lower extremities and is caused by direct trauma. During the different developmental stages of maturation, the lesion has different radiological appearances that can be confused with sarcomas. Here, we present the case of a 38-year-old woman who presented to the outpatient clinic with a painful mass in the lateral chest wall that had rapidly expanded and increased in size. The patient had no history of trauma. Chest computed tomography revealed an intramuscular mass in the lateral chest wall; postcontrast images demonstrated heterogeneous enhancement and peripheral calcification. The patient was then referred to our center for subsequent assessment and examinations. Pathological examination findings confirmed the diagnosis of myositis ossificans. Surgical resection was performed after obtaining patient consent. The symptoms experienced by the patient were successfully relieved, and no evidence of recurrence was observed during the 2-year follow-up period. Knowledge of the atypical locations of myositis ossificans, calcification patterns at different stages, and radiopathological correlations can help accurately diagnose myositis ossificans and avoid unnecessary medical imaging and interventions.
PubMed: 38434781
DOI: 10.1016/j.radcr.2024.01.089 -
Frontiers in Pediatrics 2024The aim of this study was to assess the clinical and radiographic outcomes of cubitus varus treatments based on different fixation methods: Locking plate vs....
BACKGROUND
The aim of this study was to assess the clinical and radiographic outcomes of cubitus varus treatments based on different fixation methods: Locking plate vs. Kirschner-wires (K-wires) and cast fixation.
METHODS
This retrospective study of 28 patients was performed in lateral-wedge osteotomy for cubitus varus deformity in our hospital from July 2018 to July 2020. 14 patients in group A were treated by locking plate after lateral closing-wedge osteotomy, whereas other 14 patients were treated by K-wires in group B. We measured the bony union and carrying angle. The clinical and radiographic outcomes were assessed according to the Bellemore criteria.
RESULTS
No nonunion, neurovascular injury or myositis ossificans was noted at follow-up. In group A, 1 patient with lateral condylar prominence was found. In group B, 2 patients with pinning site infection were treated successfully with oral antibiotics and 2 patients needed revision surgery for residual varus. According to the Bellemore criteria, statistically significant difference was noted between the two groups . In the present study, no statistically significant difference was noted in the length of incision and operation time between the 2 groups >. However, the postoperative carrying angle was significantly different at final follow-up between the 2 groups .
CONCLUSIONS
Compared with K-wires and cast fixation, we recommend the wedge osteotomy with lateral locking plate to treat the cubitus varus deformity because locking plate could achieve better functional and cosmetic results and stabilize the distal humerus rigidly.
PubMed: 38405594
DOI: 10.3389/fped.2024.1344283 -
Biomolecules Feb 2024Heterotopic ossification (HO) is most dramatically manifested in the rare and severely debilitating disease, fibrodysplasia ossificans progressiva (FOP), in which...
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.
Topics: Female; Mice; Animals; Male; Myositis Ossificans; Ossification, Heterotopic; Osteogenesis; Mutation; Bone and Bones
PubMed: 38397414
DOI: 10.3390/biom14020177