Figure - available from: Rheumatology International
This content is subject to copyright. Terms and conditions apply.
Source publication
Fibrodysplasia ossificans progressiva (FOP), is a rare autosomal dominant connective tissue disease with a prevalence of 1 in 2 million. It is characterized by congenital foot deformities and multiple heterotopic ossifications in fibrous tissue. It usually starts with painful soft tissue swellings occurring with attacks at the ages of three or four...
Similar publications
Background:
Rare diseases (RDs) affect less than 5/10,000 people in Europe and fewer than 200,000 individuals in the United States. In rheumatology, RDs are heterogeneous and lack systemic classification. Clinical courses involve a variety of diverse symptoms, and patients may be misdiagnosed and not receive appropriate treatment. The objective of...
Citations
... Understanding the mechanism of the FOP is vital to its management despite the lack of effective treatments available nowadays. [47][48][49] High-dose corticosteroids are limited to relieve the early inflammatory flare-ups that occur spontaneously or after trauma (especially the ossification in the coronal process) in brief time, considering the difficulty in evaluating the onset of adverse events. 3,4,50 Nonsteroidal anti-inflammatory such as indomethacin are used to suppress the inflammation in flare-ups. ...
... 3,4,50 Nonsteroidal anti-inflammatory such as indomethacin are used to suppress the inflammation in flare-ups. 47,51,52 In this patient, the indomethacin was effective in controlling the newly developed mass and relieving the symptoms. After discontinuing indomethacin, the patient complained of a new mass in the submaxilla and a more serious joint movement disorder. ...
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.
... [4] At present, there is no cure for FOP; thus, the aim has been limited to preventing further ossification and to providing patients with care and rehabilitation. [4,6] ...
... The soft-tissue injuries can also occur due to biopsies, surgical procedures, intramuscular injections, or local anesthetics and these are also one of the leading causes of the development of flareups. [4,6] It has been noted that in most cases, the pattern of ossification initially involves the neck followed by the thoracic and lumbar spine with involvement of the limbs seen in later stages resulting in a fixed, immobile, and disabling condition. [8] The patients due to their inability to move or bend are thus rendered dependent and become wheelchairbound or bedridden in the second decade of their life due to bony ankylosis of all the major axial and appendicular joints. ...
... [8] FOP is a very rare disease and chances of misdiagnosis are very high due to the similarity with patterns of various diseases such as arthritis, rheumatic diseases, and soft-tissue sarcomas, leading to improper management of the cases. [6,9] FOP is generally diagnosed on clinical grounds based on the presence of its hallmark features of congenital anomalies of the great toes, along with progressive heterotopic ossification. Biopsies and other invasive diagnostic approaches are not recommended as they may worsen the disease process. ...
Fibrodysplasia ossificans progressiva (FOP) is a rare debilitating inherited disorder which is characterized by great toe malformation and progressive heterotopic ossification of connective tissue in which tendons and ligaments are gradually replaced by bone. The extraskeletal heterotopic bone limits the patient’s mobility. The average age of onset is the first 2 decades of life with the current prevalence rate of 1 in 2 million cases worldwide. Thorough clinical examination, characteristic radiological findings, and genetic analysis pave a way in making an early diagnosis for better care and management of the patient with FOP.
... If surgery is inevitable, short-term use of corticosteroids is recommended to inhibit ossification in the surgical site. 11,12 Kardelen Gencer-Atalay in 2019 reported a case of 18 years old female with FOP and with 5 years follow up. He reported that short-term use of corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs) is recommended for acute attacks and bisphosphonates for chronic disease. ...
... Significant walking improvement (hip and trunk movement) was observed after 10 sessions of radiation therapy. 11 In 2019 a literature review was done, case reports and clinical trial published between 2009 and 2018 were included. ...
... The frequency and severity of Flare-ups decreased significantly during treatment. 11 Two patients with FOP who received Rapamycin were reported by Kaplan et al. Although Rapamycin is reported to be successful in animal models, but in both cases it in no way affected disease progression. ...
Fibrodysplasia ossificans progressiva is a connective tissue disorder in which connective tissues (ligaments, tendons) are gradually ossified and replaced by bone, there is extra skeletal bone formation. Any trauma can aggravate ossification in soft tissue. This condition usually is noticed at childhood. There is restriction of movements in major joints. We report a case of 2 years old boy with fibrodysplasia ossificans progressiva, who was brought by his parents to our OPD with history of swelling on back, scapular region and forehead for last 4 months. Parents also reported limitations of movements in spine and bilateral shoulders. Radiographs shows heterotrophic ossification in paraspinal muscles of dorsolumbar spine, and latissimus dorsi and trapezius muscle. Clinical and radiological evidence was of Fibrodysplasia ossificans progressiva. Treatment strategy is mainly based on prevention of trauma or injury, educating parents about the disease and medical management for acute painful episodes.
... Other therapies such as art therapy, music therapy, dance and theater are tools in creative processes with the aim of improving deficiencies by favoring well-being. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] Conclusion Even though it is rare, the disease has some striking characteristics that favor early diagnosis. The help of genetics is crucial to characterize FOP and assertively determine adequate prevention, therapy and rehabilitation. ...
Introduction: Fibrodysplasia Ossificans Progressiva causes gradual limitation of joint range of motion by heterotopic osteogenesis in various connective tissue structures. It is a rare autosomal dominant disease and is correlated with the presence of congenital malformation of the bilateral hallux valgus, presence of ossification that appears spontaneously or precipitated by trauma. Method: The search for the respective titles for FOP and Rehabilitation via a bibliographic review in the Pubmed database, the titles and abstracts were discriminated when they did not bring in their content the treatment of this disease. Results and Discussion: The 9-year-old patient comes with complaints of pain in the joints of the shoulders, elbows, cervical and thoracic spine. Slow walking, structural deformities in the axial axis of the cervico-thoracic spine, decreased shoulder abduction up to 15°, limited elbow flexion and extension. The FOP treatment strategy is a comprehensive program of activities to prevent the myriad possibilities of trauma, from avoiding unnecessary surgical procedures, injections and even biopsies. Dry needling or acupuncture techniques are always contraindicated. Hydrotherapy turns out to be another useful tool in the process of preventing and relieving injuries, contributing to physical conditioning in a safe environment with low impact and cardiopulmonary performance. From the clinical observations, there will be indication of orthoses, auxiliary means for locomotion or adapted wheelchairs. Devices with voice command facilitate some daily activities, encouraging music therapy, dance or theater also favors the well-being of these patients. Conclusion: The disease has some striking characteristics that favor early diagnosis. Injury prevention, medical management of acute painful flare-ups, and rehabilitation are pillars of treatment. There is still no curative treatment, however, the determination of a therapeutic plan prevents future trauma and can guarantee an adequate prognosis even though it is difficult and full of functional limitations for patients.
... Fibrodysplasia Ossificans Progressiva is rare congenital disorder which occurs most commonly as result of new mutation [1][2][3][4][5]. It is inherited as autosomal dominant disease [1,2,6,7].This disease is manifested by extra skeletal bone formation in axial musculature, which start developing in first decade of life, apart from this bilateral hallux valgus deformity is present since birth. This disease occurs due to mutation in the FOP gene located on chromosome 4. ...
... The common mode of death being respiratory compromise [8]. This disease is most often misdiagnosed resulting in iatrogenic insult to the patient [6]. ...
... Bisphosphonates may be used to treat patients with metastatic bone disease to prevent or delay skeletal consequences such as pathologic fracture, radiation to the bone, and malignancy-related hypercalcemia [11][12][13][14][15] ...
Fibrodysplasia ossificans progressive is a debilitating autosomal dominant disease characterized by postnatal progressive heterotopic which tissue that connects things together ossification and congenital deformities of the big toes. Fibrodysplasia ossificans progressiva affects about one out of every two million newborns born world wide. Almost ninetypercent of people with fibrodysplasia ossificans progressiva are misdiagnosed and treated wrongly, resulting in ineffective treatments. Approximately 700 cases have been identified so far around the world. Clinical examinations, radiographic evaluations, and ACVR1 gene mutation testing are all considered confirmatory approaches for early illness diagnosis. Case Presentation: We're reporting on the case of a 45-year-old man who was admittedt in our facility. He had clinical and radiological evidence of fibrodysplasia ossificans progressing, as well as multiple painful lumps on his back due to hard masses and rigidity of his shoulders, neck, and left hip.His left hip ossification was surgically removed, but he experienced an increased ossification reaction and early impairment as a result. Conclusion: Fibrodysplasia ossificans progressive is an uncommon and severe illness that, if misdiagnosed, can result in inappropriate surgical intervention and early paralysis with disastrous consequences. We need to educate clinicians and patients' families concerning the disease, as well as its symptoms for early detection and how to prevent flare-ups, in order to improve quality of life.
... In FOP, HO of musculoskeletal tissue causes long-term, severe disability. However, alongside the physical limitations that many FOP patients undergo and which can begin during childhood stages of life [10,33,36], the core pathological elements of FOP such as HO induction and growth may lead to other downstream manifestations [34]. Pain in FOP, is most often associated with recurrent soft tissue swelling or flare-ups, which in many circumstances precedes new HO lesions or expansion of existing ones [36,37,46]. ...
Background
Pain is a highly prevalent symptom experienced by patients across numerous rare musculoskeletal conditions. Much remains unknown regarding the central, neurobiological processes associated with clinical pain in musculoskeletal disease states. Fibrodysplasia ossificans progressiva (FOP) is an inherited condition characterized by substantial physical disability and pain. FOP arises from mutations of the bone morphogenetic protein (BMP) receptor Activin A receptor type 1 (ACVR1) causing patients to undergo painful flare-ups as well as heterotopic ossification (HO) of skeletal muscles, tendons, ligaments, and fascia. To date, the neurobiological processes that underlie pain in FOP have rarely been investigated. We examined pain and central pain mechanism in FOP as a model primary musculoskeletal condition. Central nervous system (CNS) functional properties were investigated in FOP patients (N = 17) stratified into low (0–3; 0–10 Scale) and high (≥ 4) pain cohorts using functional near-infrared spectroscopy (fNIRS). Associations among clinical pain, mental health, and physical health were also quantified using responses derived from a battery of clinical questionnaires.
Results
Resting-state fNIRS revealed suppressed power of hemodynamic activity within the slow-5 frequency sub-band (0.01–0.027 Hz) in the prefrontal cortex in high pain FOP patients, where reduced power of slow-5, prefrontal cortex oscillations exhibited robust negative correlations with pain levels. Higher clinical pain intensities were also associated with higher magnitudes of depressive symptoms.
Conclusions
Our findings not only demonstrate a robust coupling among prefrontal cortex functionality and clinical pain in FOP but lays the groundwork for utilizing fNIRS to objectively monitor and central pain mechanisms in FOP and other musculoskeletal disorders.
... Early clinical observations and investigations revealed that flare-ups are a key source of pain in FOP patients (Gencer-Atalay et al., 2019;Gomez-Alonso, 2020;Peng et al., 2019). Flare-ups as well as severe pain may last for weeks or even months. ...
For patients diagnosed with a rare musculoskeletal or neuromuscular disease, pain may transition from acute to chronic; the latter yielding additional challenges for both patients and care providers. We assessed the present understanding of pain across a set of ten rare, noninfectious, noncancerous disorders; Osteogenesis Imperfecta, Ehlers-Danlos Syndrome, Achondroplasia, Fibrodysplasia Ossificans Progressiva, Fibrous Dysplasia/McCune-Albright Syndrome, Complex Regional Pain Syndrome, Duchenne Muscular Dystrophy, Infantile- and Late-Onset Pompe disease, Charcot-Marie-Tooth Disease, and Amyotrophic Lateral Sclerosis. Through the integration of natural history, cross-sectional, retrospective, clinical trials, & case studies we described pathologic and genetic factors, pain sources, phenotypes, and lastly, existing therapeutic approaches. We highlight that while rare diseases possess distinct core pathologic features, there are a number of shared pain phenotypes and mechanisms that may be prospectively examined and therapeutically targeted in a parallel manner. Finally, we describe clinical and research approaches that may facilitate more accurate diagnosis, monitoring, and treatment of pain as well as elucidation of the evolving nature of pain phenotypes in rare musculoskeletal or neuromuscular illnesses.
... The condition was commonly known as myositis ossificans progressiva (MOP) until 1940 when the name Fibrodysplasia Ossificans Progressiva (FOP) was proposed by Bauer & Bode and adopted by McKusick in 1960 in recognition of the primary connective tissue involvement of tendons, ligaments, fascia and aponeuroses [9,10]. FOP is characterized by childhood onset heterotopic ossification following painful soft tissue swellings (flare-ups) precipitated by soft tissue injury, viral infections, minor trauma or fatigue [11]. These acute flare-ups may develop spontaneously but are usually preceded by traumatic soft tissue injuries. ...
... These acute flare-ups may develop spontaneously but are usually preceded by traumatic soft tissue injuries. Soft tissue trauma from biopsies, surgical procedures, intramuscular injections, or local anaesthetics (such as mandibular blocks) for dental procedures have been reported to cause iatrogenic harm resulting in acute soft tissue flare-ups [4,11]. The soft tissue swelling is followed by ossification and when multiple, causes growth defects, skeletal deformities and chronic pain [11]. ...
... Soft tissue trauma from biopsies, surgical procedures, intramuscular injections, or local anaesthetics (such as mandibular blocks) for dental procedures have been reported to cause iatrogenic harm resulting in acute soft tissue flare-ups [4,11]. The soft tissue swelling is followed by ossification and when multiple, causes growth defects, skeletal deformities and chronic pain [11]. Progressive episodes of HO lead to ankylosis of all major joints of the axial and appendicular skeleton, including the TMJ, leading to impaired mobility of the joints1. ...
We present two cases of Fibrodysplasia Ossificans Progressiva (FOP), a rare genetic disorder characterized by heterotopic ossification and malformation of the great toes. The heterotopic ossification is preceded by episodic soft tissue swellings (flare-ups) and results in restricted mobility of the joints. Its rarity, especially in the maxillofacial region, often results in misdiagnosis. Episodes of painful new bone results from any surgical attempt to excise the heterotopic bone. It is imperative for clinicians to be aware of this condition in order to make early diagnosis and to prevent iatrogenic harm to these patients through unnecessary diagnostic or surgical procedures. In addition, with this information, clinicians can take the necessary precautions in the prevention of oral disease and maintenance of meticulous oral hygiene.
... The effect of various pharmacological compounds on heterotopic ossification acting at different levels of the Smad signaling pathway has been studied. Findings so far about FOP´s pathophysiology are still insufficient and numerous targeted non-interventional and interventional treatments have been reported in the literature, but no consensus in the treatment has been provided yet [21][22][23][24]. ...
Heterotopic Ossification is a pathological process that is defined as extraskeletal bone formation in both muscle and soft tissue. The most severe condition of HO, a rare genetic form, is the Fibrodysplasia Ossificans Progressive (FOP). Some data suggest that nicotinamide therapy shows major clinical improvement in patients with FOP. This relational analytic study seeks to present the results of molecular findings of the effect of nicotinamide in the differentiation of C2C12 cell line to osteoblasts. To assess this objective, cells were cultured, immunochemistry histologic, and molecular assays were run to analyze the effect of nicotinamide in osteoblastic differentiation in different times of exposure to BMP2 and/or nicotinamide. Nicotinamide inhibits osteoblastogenesis in a dose-dependent way in vitro in the C2C12 cell line. It has an inhibitory effect on the phosphorylation of the Smad 1/5/8 complex without a significant difference in osteoblastogenesis classic gene expression. The rational use of nicotinamide could be of great clinical utility as a new preventive therapeutic tool in pathologies where bone formation occurs in extra-skeletal sites.
