Case Of Fibrodysplasia Ossificans Progressiva Research Articles

Reduced GS Domain Serine/Threonine Requirements of Fibrodysplasia Ossificans Progressiva Mutant Type I BMP Receptor ACVR1 in the Zebrafish.

Fibrodysplasia ossificans progressiva (FOP) is a rare human genetic condition characterized by altered skeletal development and extraskeletal bone formation. All cases of FOP are caused by mutations in the type I bone morphogenetic protein (BMP) receptor gene ACVR1 that result in overactivation of the BMP signaling pathway. Activation of the wild-type ACVR1 kinase requires assembly of a tetrameric type I and II BMP receptor complex followed by phosphorylation of the ACVR1 GS domain by type II BMP receptors. Previous studies showed that the FOP-mutant ACVR1-R206H required type II BMP receptors and presumptive glycine/serine-rich (GS) domain phosphorylation for overactive signaling. Structural modeling of the ACVR1-R206H mutant kinase domain supports the idea that FOP mutations alter the conformation of the GS domain, but it is unclear how this leads to overactive signaling. Here we show, using a developing zebrafish embryo BMP signaling assay, that the FOP-mutant receptors ACVR1-R206H and -G328R have reduced requirements for GS domain phosphorylatable sites to signal compared to wild-type ACVR1. Further, ligand-independent and ligand-dependent signaling through the FOP-mutant ACVR1 receptors have distinct GS domain phosphorylatable site requirements. ACVR1-G328R showed increased GS domain serine/threonine requirements for ligand-independent signaling compared to ACVR1-R206H, whereas it exhibited reduced serine/threonine requirements for ligand-dependent signaling. Remarkably, while ACVR1-R206H does not require the type I BMP receptor partner, Bmpr1, to signal, a ligand-dependent GS domain mutant of ACVR1-R206H could signal independently of Bmpr1 only when Bmp7 ligand was overexpressed. Of note, unlike human ACVR1-R206H, the zebrafish paralog Acvr1l-R203H does not show increased signaling activity. However, in domain-swapping studies, the human kinase domain, but not the human GS domain, was sufficient to confer overactive signaling to the Acvr1l-R203H receptor. Together these results reflect the importance of GS domain activation and kinase domain functions in regulating ACVR1 signaling and identify mechanisms of reduced regulatory constraints conferred by FOP mutations. © 2023 American Society for Bone and Mineral Research (ASBMR).

A rare case of deformity: Fibrodysplasia ossificans progressiva

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder and the most debilitating condition of heterotopic ossification in humans. Misdiagnosis is common and they suffer from complications of incorrect diagnosis and subsequent inappropriate treatment hence, to create awareness, we are reporting a genetically confirmed case of FOP. A 10-year-old boy, born to a non-consanguineously married couple, presented with progressive stiffness of the neck, back, and limbs with restriction of movements. Examination showed two firm non-tender immobile swellings over the back with scoliosis towards the left side. A bilateral hallux valgus deformity with restricted movements of the great toe was noted. Outside treated as mixed connective tissue disorder without any improvement. The X-ray showed calcifications in the swellings. Genetic testing showed the pathogenic variant in the activin A receptor type 1 gene. The FOP should be considered in children presenting with progressive stiffness, deformity of the feet, and ectopic ossifications to avoid misdiagnosis and inappropriate treatment.

P065 A case of fibrodysplasia ossificans progressiva in Kenya

Abstract Background Fibrodysplasia Ossificans Progressiva (FOP) is an extremely rare and disabling disorder affecting 1 in 2 million individuals worldwide. It is caused by mutations in bone morphogenetic protein which leads to extra-skeletal ossification of soft tissues in a characteristic cranio-caudal pattern. Hallux valgus, episodic flares and progressive functional disability are characteristic features. The cause of death is often cardio-respiratory failure following thoracic insufficiency. The objective of our case study is to describe a rare but interesting case of fibrodysplasia ossificans progressiva (FOP) in an African setting. Methods This was a retrospective case review Results Two-year-old boy presented with painful firm masses of bony consistency over the axilla, neck, occiput and the forehead for seven months. He developed progressive inability to lift the arms, flex his neck and had a characteristic stiff posture while walking. The masses had a waxing and waning nature lasting about 4–5 days but with no complete resolution. He was previously treated with antibiotics for lymphadenitis which was diagnosed by biopsy of the neck mass at a different health facility. On examinationhe had bony masses on the posterior aspect of the neck tender on palpation and attached to the underlying subcutaneous tissue. Similar masses were found on his anterior and posterior chest wall measuring 1 cm by 1 cm anteriorly and larger masses- measuring 5 cm by 5 cm posteriorly. He had bilateral hallux valgus and both elbows held in fixed flexion. His fingers had varying degrees of fixed flexion. The lower limbs were unaffected. Laboratory evaluation within normal ranges. extensive dystrophic soft tissue calcification around both elbows outlining the joint capsules. dystrophic soft tissue calcification in the bilateral axillae extensive “sheet like” soft tissue dystrophic calcifications overlying the posterior elements of the vertebral column separate from the vertebrae. Histology showed muscle replacement by hyaline cartilage and bone with intervening fibromyxoid stroma. Discussion & Conclusions This case is meant to raise awareness of this rare disease across Africa. The misdiagnosis of FOP approaches 90% of cases worldwide. Definitive genetic testing of FOP is now available and can now confirm a diagnosis before the appearance of heterotopic ossifications. Clinical suspicion of FOP early in life on the basis of malformed great toes can lead to early clinical diagnosis. Current management focuses on early diagnosis, avoidance of trauma and optimization of function. A short course of oral steroids is beneficial in prevention of flares.

Heterotopic ossification on the volar surface of the distal radius in a child with fibrodysplasia ossificans progressiva: challenges in surgical excision of a rare condition

Fibrodysplasia ossificans progressiva (FOP) is one of the genetic and developmental forms of heterotopic ossification. We report a case of FOP on the volar surface of the distal radius, located close to the median nerve and radial artery with neurologic symptoms secondary to median nerve entrapment. The patient underwent surgical excision of the heterotopic lesion followed by radiation therapy. He had no signs of recurrence with more than 1 year of follow-up. Careful microsurgical dissection of the heterotopic mass must be performed to prevent the formation of new painful lesions and iatrogenic neurovascular injury. In this syndrome, the possibility of nerve entrapment due to the heterotopic lesion should be considered as the cause of neuropathic pain. Early genetic testing for confirmation of the suspected diagnosis can avoid having to do an unnecessary biopsy.

The Developmental Phenotype of the Great Toe in Fibrodysplasia Ossificans Progressiva.

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder in which extensive heterotopic ossification (HO) begins to form during early childhood and progresses throughout life. Although HO does not occur during embryonic development, children who carry the ACVR1R206H mutation that causes most cases of FOP characteristically exhibit malformation of their great toes at birth, indicating that the mutation acts during embryonic development to alter skeletal formation. Despite the high prevalence of the great toe malformation in the FOP population, it has received relatively little attention due to its clinically benign nature. In this study, we examined radiographs from a cohort of 41 FOP patients ranging from 2 months to 48 years of age to provide a detailed analysis of the developmental features, progression, and variability of the great toe malformation of FOP, which include absent skeletal structures, malformed epiphyses, ectopic ossification centers, malformed first metatarsals and phalangeal fusion.

Fibrodysplasia ossificans progressiva mutant ACVR1 signals by multiple modalities in the developing zebrafish.

Fibrodysplasia ossificans progressiva (FOP) is a rare human genetic disorder characterized by altered skeletal development and extraskeletal ossification. All cases of FOP are caused by activating mutations in the type I BMP/TGFβ cell surface receptor ACVR1, which over-activates signaling through phospho-Smad1/5 (pSmad1/5). To investigate the mechanism by which FOP-ACVR1 enhances pSmad1/5 activation, we used zebrafish embryonic dorsoventral (DV) patterning as an assay for BMP signaling. We determined that the FOP mutants ACVR1-R206H and -G328R do not require their ligand binding domain to over-activate BMP signaling in DV patterning. However, intact ACVR1-R206H has the ability to respond to both Bmp7 and Activin A ligands. Additionally, BMPR1, a type I BMP receptor normally required for BMP-mediated patterning of the embryo, is dispensable for both ligand-independent signaling pathway activation and ligand-responsive signaling hyperactivation by ACVR1-R206H. These results demonstrate that FOP-ACVR1 is not constrained by the same receptor/ligand partner requirements as WT-ACVR1.

A Case of Fibrodysplasia Ossificans Progressiva Complicated by Influenza Pneumonia Treated with Long-Term Intensive Care

A Case of Fibrodysplasia Ossificans Progressiva Complicated by Influenza Pneumonia Treated with Long-Term Intensive Care

A RARE VARIANT OF THE HEREDITARY FORM OF MYOSITIS OSSIFICANS IN CLINICAL PRACTICE OF ONCOLOGIST

Myositis ossificans is a rare disorder, characterized by heterotopic bone formation in muscles or soft tissues which is often mistaken for neoplasia. The reasons for ossification in these tissues may be different. In most cases there is a previous trauma, but etiology may be inheritable. Heritable myositis ossificans also called Fibrodysplasia Ossificans Progressiva (FOP) is associated with mutations in the ACVR1 gene and congenital abnormalities, of which malformations of the great toes is constant as well as wide femur neck. We report a case of FOP in the 9-year-old girl admitted to the clinic with swelling of the scapula and neck with a supposed diagnosis of mesenchymoma. The identified a rare germline mutation in the ACVR1 gene was the decisive factor in confirming the diagnosis of the initial manifestation of FOP, before features of ossification can be were visible during histological examination. The case is of interest because of the rarity of the pathology and the difficulty of diagnosing the early manifestation of POF before the formation of the morphological picture and the need for a multidisciplinary approach in the management of these patients

Rare painful pediatric deformity; when surgery does harm: Case report and review of the literature

Fibrodysplasia ossificans progressiva (FOP) is a connective tissue disease that is extremely rare. Fibrous tissue in muscles, tendons, and ligaments get ossified spontaneously or damaged by a mutation of the body's repair mechanism. In this report, we present a case of FOP, which is considered one of the rarest diseases that can cause scoliosis and new bone formation around the spine and almost everywhere in the body. A 14-year-old female presented with scoliosis and limitation in spine and upper limb movements. The condition started at the age of 9 years with a painful mass in the right side of the upper back. At that time, the parents asked for medical help; a general surgeon advised and performed an excisional biopsy of the mass. Subsequently, the mass reappeared and continued to grow, covering nearly the entire back. Radiological investigations revealed a well-formed bony band extending from the right shoulder to the iliac bone posteriorly with bony formations in the left shoulder, back, medial aspects of the arms, axilla, and buttocks. FOP is an extremely challenging disorder with difficulties in both diagnosis and management, and large malformed toes with well-formed ossification anywhere in the body should raise the suspicion of the diagnosis. Any surgical intervention, including biopsy, will harm the patient and should be avoided.

Drosophila models of FOP provide mechanistic insight.

Fibrodysplasia ossificans progressiva (FOP) is a rare bone disease characterized by episodic events of heterotopic ossification (HO). All cases of FOP have been attributed to mutations in the ACVR1 gene that render the encoded BMP type I ALK2 receptor hypersensitive, resulting in the activation of BMP signaling, at inappropriate times in inappropriate locations. The episodic or sporadic nature of HO associated with FOP rests with the occurrence of specific 'triggers' that push the hypersensitive ALK2-FOP receptor into full signaling mode. Identification of these triggers and their mechanism of action is critical for preventing HO and its devastating consequences in FOP patients. Models of FOP, generated in Drosophila, are shown to activate the highly conserved BMP signaling pathway in both Drosophila cell culture and in developing tissues in vivo. The most common FOP mutation, R206H, in ALK2 and its synonymous mutation, K262H, in the orthologous Drosophila receptor Sax, abolish the ability of wild type receptors to inhibit BMP ligand-induced signaling and lead to ubiquitous pathway activation in both cases but with important differences. When expressed in Drosophila, human ALK2R206H exhibits constitutive signaling. SaxK262H on the other hand can elicit excessive signaling similar to that observed for ALK2R206H in mammalian systems in vivo. For example, hyperactive signaling mediated by SaxK262H is triggered by an increase in ligand or in type II receptors. Interestingly, while the constitutive nature of ALK2R2026H in Drosophila requires activation by the type II receptor, it does not require its ligand binding domain. The differences exhibited by the two Drosophila FOP models enable a valuable comparative analysis poised to reveal critical regulatory mechanisms governing signaling output from these mutated receptors. Modifier screens using these Drosophila FOP models will be extremely valuable in identifying genes or compounds that reduce or prevent the hyperactive BMP signaling that initiates HO associated with FOP.

A case of fibrodysplasia ossificans progressiva with sternocleidomastoid muscle calcification

Fibrodysplasia ossificans progressiva (FOP) is a rare and disabling genetic condition characterized by congenital skeletal malformations and progressive heterotopic ossification in humans with no ethnic, racial, gender, or geographic predilection. Diagnosis of this condition can be made clinically in the presence of radiographic evidence of heterotopic ossification along with symmetrical malformations of the great toes. The course of the disease is unpredictable and often progresses in the early childhood and patients become immobile and confined to a wheelchair by their twenties. Survival beyond the third decade is uncommon. We hereby report a case of FOP in a 7½-year-old girl.

Role of radiotherapy in management of Fibrodysplasia ossificans progressiva

Fibrodysplasia ossificans progressiva (FOP) is an extremely rare genetic disorder with widespread extra-skeletal bone formation. This disease usually begins with typical ossification pattern in early childhood, causing increasing disability and making patients totally disabled by the age of 30 years. Ectopic ossification can be triggered by any trauma as small as intramuscular injections, with no effective cure. Radiotherapy can be helpful in impeding ossification, although this treatment is not yet supported by strict evidence. Here in, we present a clinically diagnosed case of Fibrodysplasia Ossificans Progressiva managed with radiotherapy for symptomatic relief. This case indicates that radiotherapy can be useful in these patients.

A rare case of Fibrodysplasia ossificans progressive

Fibrodysplasia ossificans progressiva (FOP), a rare and disabling genetic condition characterized by congenital malformations of the great toes and progressive heterotopic endochondral ossification (HEO) which is the most catastrophic of HEO disorders in humans. We hereby report a case of FOP in a 3 year old female child with multiple HEO and genetically confirmed missense variation of exon 6 of the ACVR1 gene.

Genetic disorders with heterotopic ossificans.

Fibrodysplasia ossificans progressiva (FOP) and progressive ossific heteroplasia (POH) are rare genetic disorders characterized by heterotopic bone formation leading to progressive loss of mobility and function. We report three cases of these rare disorders (two cases of FOP and one case of POH), which were clinically diagnosed and underwent genetic analysis. The aim of this report is to highlight the clinical features and the differences between these two conditions. We would also like to emphasize on the morbidity that can arise from unnecessary invasive investigations for diagnostic purposes.

開口障害を伴った進行性骨化性線維異形成症の1例

Fibrodysplasia ossificans progressiva (FOP) is a rare hereditary disease characterized by heterotopic ossification of skeletal muscles, tendons, and ligaments. In the oral and maxillofacial region, FOP leads to eating disorders caused by a limited range of mouth opening. At a late stage, respiratory function is impaired by limited movement of the thorax. We reported a rare case of FOP with trismus and discuss the related literature. A 28-year-old woman was referred to our hospital because of trismus in December 2011. She had heterotopic ossification in the left scapula and was given a diagnosis of FOP at the age of 17 years. Extraoral examination showed temporary pain extending from the left temporomandibular joint to the buccal region when she opened the mouth. A maximal mouth opening of 3 mm was confirmed. Intraoral examination showed an inflammatory reaction at the gingiva of the maxillary left third molar. Magnetic resonance imaging showed high intensity of the left lateral pterygoid muscle. Nonsteroidal anti-inflammatory drugs and injectable bisphosphonates were administered, followed by mouth opening training. Her maximal mouth opening markedly improved to 22 mm 1 year after initial presentation, without any recrudescence.

Activin Signaling Disruption in the Cochlea Does Not Influence Hearing in Adult Mice

Activin, a member of the TGF-F superfamily, was found to play an important role in the development, repair and apoptosis of different tissues and organs. Accordingly, activin signaling is involved in the development of the cochlea. Activin binds to its receptor ActRII, then dimerizes with ActRI and induces a signaling pathway resulting in gene expression. A study reported a case of fibrodysplasia ossificans progressiva with an unusual mutation in the ActRI gene leading to sensorineural hearing loss. This draws attention to the role of activin and its receptors in the developed cochlea. To date, only the expression of ActRII is known in the adult mammalian cochlea. In this study, we present for the first time the presence of activin A and ActRIB in the adult cochlea. Transgenic mice with postnatal dominant-negative ActRIB expression causing disruption of activin signaling in vivo were used for assessing cochlear morphology and hearing ability through the auditory brainstem response (ABR) threshold. Nonfunctioning ActRIB did not affect the ABR thresholds and did not alter the microscopic anatomy of the cochlea. We conclude, therefore, that activin signaling is not necessary for hearing in adult mice under physiological conditions but may be important during and after damaging events in the inner ear. i 2014 S. Karger AG, Basel

Fibrodysplasia ossificans progressiva: A case report

Fibrodysplasia ossificans progressiva (FOP) is a genetic disorder with unknown cause. Disease is characterized by heterotopic ossifications of connective tissue and congenital malformations of distal part of extremities. Most cases are sporadic and transmitted as autosomal dominant. As very few cases of FOP are being reported in Indian literature, we, therefore, report one such case here. Our case is a 20 years-old female patient who had bilateral short great toes with hallux valgus associated with heterotopic ossifications of connective tissue with restrictions of range of motion and disability of daily living activities. We have diagnosed it as FOP based on our physical examination and skeletal x-rays findings. DOI: http://dx.doi.org/10.3126/ajms.v5i4.9915 Asian Journal of Medical Sciences 2014 Vol.5(4); 113-115

Fibrodysplasia ossificans progressiva

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder principally affecting young children. It is a slowly progressive disease characterized by progressive fibroblastic proliferation leading to calcification and ossification. Early diagnosis can be challenging, yet important to avoid unnecessary invasive medical procedures which may play a role in disease progression. At a later stage of the disease, patients suffer from muscle stiffness, inability to move, contraction deformities and difficulties in respiration. Many patients die during early adult life due to respiratory failure or pneumonia. A case of FOP will be presented illustrating the clinicopathological features of this disorder.

Fibrodysplasia ossificans progressiva diagnosed as ankylosing spondylitis: A case report

Introduction: Fibrodysplasia (myositis) ossificans progressiva is a rare and very crippling form of disease characterized by great toe malformation and heterotopic bone formation. We herein report a case of fibrodysplasia ossificans progressiva in whom the onset of complaints was after 20 years of age which led physicians to confuse this case with ankylosing spondylitis.

FOP: still turning into stone

Fibrodysplasia ossificans progressiva (FOP) is a rare catastrophic genetic condition of extraskeletal (heterotopic) ossification. One in every two million people is affected worldwide, with no ethnic, racial, gender, or geographic predisposition. Most cases of FOP arise from a spontaneous missense mutation in the gene encoding bone morphogenic protein (BMP) type II receptor (ACVR1/ALK2). Affected individuals are normal at birth apart from malformed great toes. Onset of clinical symptoms is usually in the first decade of life, presenting with episodic emergence of painful rapidly appearing tumor-like soft tissue swellings (flare-ups). Heterotopic bone replaces the skeletal muscles, tendons, ligaments, and connective tissue at the site of the damage through a process of endochondral ossification, causing fixation of joints and permanent limitation of motion. Most affected individuals are confined to wheelchair in the third decade of life. Worldwide rate of misdiagnosis of FOP is very high; clinicians often fail to associate the two classic clinical features of FOP: rapidly developing soft tissue swellings and the abnormal great toes. The current case presents a previously undiagnosed 39-year-old FOP patient, sadly a victim of lack of clinical awareness of this rare condition. As a result of repetitive iatrogenic harm, he has tragically "turned into stone."