Fibrodysplasia Ossificans Progressiva (FOP) is an extremely rare and debilitating genetic disorder characterized by the progressive replacement of soft tissues, such as muscles, tendons, and ligaments, with bone. In this condition an individual can become progressively immobile as their joints and muscles turn into bone, effectively immobilizing them.
FOP is caused by a mutation in the ACVR1 gene, which encodes a receptor for bone morphogenetic proteins (BMPs). This mutation results in the overactivity of the BMP signaling pathway, leading to the inappropriate formation of bone tissue in soft tissues.
Epidemiology
FOP is considered one of the rarest genetic disorders in the world. Its estimated incidence is approximately 1 in 2 million individuals. This rarity makes it challenging for healthcare professionals to encounter and diagnose cases of FOP.
The key feature of FOP is congenital malformations of the great toes, which are often present from birth. This characteristic can help in the early identification of affected individuals.
FOP affects individuals of all genders and ethnic backgrounds equally. There is no known gender or ethnic predilection for the condition.
Anatomy
Pathophysiology
The underlying cause of FOP is a mutation in the ACVR1 gene, which is located on chromosome 2. This mutation results in the overactivation of the BMP signaling pathway.
Generally, BMP signaling is tightly regulated to ensure that bone formation occurs only in specific locations, such as during skeletal development or bone repair after injury.
In FOP, the mutated ACVR1 gene leads to a receptor that is overly sensitive to BMP signaling. This excessive activation of the BMP pathway disrupts the normal tissue repair process.
FOP is the progressive formation of bone tissue in soft tissues, including muscles, tendons, ligaments, and connective tissues. This abnormal bone formation occurs in response to inflammation, tissue injury or surgery, which would not normally result in ossification.
Etiology
In individuals with FOP, a specific mutation occurs in the ACVR1 gene. This mutation results in the production of a hyperactive ACVR1 receptor that is overly sensitive to BMP signaling.
The mutated ACVR1 receptor, when activated by BMPs or other factors, sends signals that inappropriately stimulate the formation of bone tissue within soft tissues. This leads to the pathological process of heterotopic ossification, where bone forms in locations where it should not, such as in muscles, tendons, ligaments, and connective tissues.
FOP is typically inherited in an autosomal dominant manner which means an affected individual has a 50% chance of passing the mutated ACVR1 gene to each of their offspring.
Genetics
Prognostic Factors
The age at which FOP is diagnosed can influence the prognosis. Individuals diagnosed at a younger age may have a longer disease course ahead of them, potentially leading to more extensive heterotopic ossification and disability over time.
Early and appropriate medical management, including the management of acute ossification, can help mitigate the severity of FOP symptoms and potentially improve the long-term prognosis.
Efforts to preserve joint function and mobility through physical therapy and assistive devices can improve an individual’s ability to perform daily activities and maintain a better quality of life.
Clinical History
Fibrodysplasia Ossificans Progressiva (FOP) is diagnosed in childhood, with most affected individuals showing signs and symptoms of the condition during the first few years of life.
The congenital malformations of the great toes, which are often shorter and bent, these are a characteristic feature of FOP and can be present at birth. These toe malformations are often one of the earliest signs that lead to a diagnosis of FOP.
Physical Examination
Malformation of Toe: Congenital malformations of the great toes is the identification of FOP. These malformations can include shortened, bent, or abnormally shaped great toes.
Joint Mobility: Assessing joint mobility and range of motion is essential, as FOP leads to progressive limitations in joint movement. Restricted mobility, contractures, or stiffness in the joints, especially in the hips, knees, neck, shoulders, elbows, and spine, are characteristic findings in FOP.
Neurological Examination: Depending on the location and extent of ossification, a neurological examination may be conducted to assess for any neurological deficits, such as weakness, numbness, or altered reflexes.
Assessment of Skin and Soft Tissues: Skin changes, such as nodules or fibrous tissue, may be present overlying affected areas. The skin may also show signs of past flare-ups or surgical interventions.
Scars and Surgical History: Inquire about any history of surgical interventions, especially related to the removal of heterotopic bone, as this may influence the current clinical presentation.
Age group
Associated comorbidity
Individuals with FOP often experience chronic and severe pain due to the formation of bone within soft tissues, which can compress nerves and lead to discomfort. Pain management is a crucial aspect of FOP care.
Progressive ossification of joints and soft tissues can lead to restricted joint mobility and contractures, making it challenging for individuals with FOP to move and perform daily activities.
Abnormal bone formation in the jaw can lead to dental problems, including difficulties with chewing and oral hygiene. Regular dental care and adaptations may be required.
Difficulty with swallowing due to ossification in the throat and neck can lead to nutritional challenges.
Associated activity
Acuity of presentation
The progressive nature of FOP becomes more apparent over time. Individuals may develop progressive stiffness in joints and experience limitations in joint mobility.
The acute exacerbation of symptoms, known as “flare-ups,” can occur at any age and are often triggered by trauma, injury, or inflammation. These flare-ups lead to rapid and painful ossification within soft tissues and are a defining feature of FOP.
While some features of FOP may be evident from birth or early childhood, the condition generally progresses gradually over the years. New bone formation accumulates, further limiting mobility and causing increased disability.
Differential Diagnoses
Myositis Ossificans: Myositis ossificans is characterized by the formation of heterotopic bone within muscle tissue, often in response to trauma or injury.
Tumor-Induced Ossification: Some tumors can calcify or ossify, leading to the formation of hard masses within soft tissues. These tumors may need to be differentiated from FOP, especially when evaluating soft tissue masses.
Connective Tissue Disorders: Some connective tissue disorders, such as Marfan syndrome or Ehlers-Danlos syndrome, can present with joint laxity or musculoskeletal abnormalities, which may resemble aspects of FOP.
Trauma-Induced Heterotopic Ossification: Heterotopic ossification can occur in response to various factors, including surgery, burns, or trauma. Trauma-induced ossification can resemble FOP, but it lacks the genetic mutation characteristic of FOP.
Laboratory Studies
Imaging Studies
Procedures
Histologic Findings
Staging
Treatment Paradigm
Genetic Counseling: Early diagnosis is important for individuals with FOP to receive appropriate medical care and genetic counseling. Genetic testing can confirm the presence of the ACVR1 gene mutation responsible for FOP.
Pain Management: Individuals with FOP often experience chronic and severe pain due to the formation of bone within soft tissues. Pain management strategies may include nonsteroidal anti-inflammatory drugs (NSAIDs) or opioids.
Occupational Therapy: Physical therapy can help individuals with FOP maintain joint mobility, flexibility, and muscle strength. Occupational therapy may focus on adaptive strategies for daily activities to enhance independence and improve the quality of life.
Assistive Devices: Orthopedic devices, braces, and assistive devices can be beneficial in supporting joint function and mobility. These devices are often customized to meet the individual’s specific needs.
Flare-Up Management: Flare-ups in FOP, triggered by trauma or inflammation, can lead to rapid bone formation. Prompt recognition and management of flare-ups are critical to minimize the extent of ossification.
Avoid the Trauma: Preventing injuries and trauma is essential, as these can trigger flare-ups and exacerbate FOP. Individuals with FOP and their caregivers should be educated about the importance of avoiding activities and situations that could lead to injury.
Follow the safety measures: Identify and eliminate items or situations that may pose a risk of injury or trauma, such as sharp objects or furniture with hard edges.
Use soft or padded surfaces, such as cushions or mats, in areas where individuals with FOP spend time to reduce the risk of injury from falls or accidental bumps.
Accessible Living Spaces: Consider making structural changes or home modifications to enhance accessibility, such as ramps, widened doorways, or stairlifts. These changes can help individuals with mobility limitations navigate their living spaces more easily.
Assistive Devices and Mobility: Provide wheelchairs, walkers, or other mobility devices as needed to support independent mobility while minimizing the risk of falls or joint strain.
Use of Orthopedic devices: Custom orthopedic braces and supports can help stabilize joints and reduce pain and discomfort.
Good Sleep Environment: Use a comfortable mattress and appropriate pillows to ensure restful sleep and minimize pressure sores. Elevating the head of the bed slightly may help reduce the risk of aspiration and breathing difficulties.
Adaptive Clothing and Dressing: Choose clothing with features such as easy-open closures, stretchy fabrics, or adaptive designs to simplify dressing and reduce joint strain.
Use of Retinoic Acid Receptor Gamma Agonists
A gain-of-function mutation in the bone morphogenetic protein (BMP) type I receptor ALK2 (ACVR1) is the primary cause of unusual bone production, including heterotrophic ossification, in individuals with fibrodysplasia ossificans progressiva.
Palovarotene: Although it is an investigational drug; it lowers the BMP/ALK2 downstream signalling cascade by binding to RAR and preventing SMAD1/5/8 from becoming phosphorylated. This inhibits chondrogenesis and osteocyte differentiation that are dependent on ALK2/SMAD, which affects the development of endochondral bone.
It is Indicated for the decrease of new heterotopic ossification volume in adults and paediatric patients with fibrodysplasia ossificans progressiva (FOP) aged ≥8 years for females and ≥10 years for males.
Use of NSAIDs in the Flare-Up Management
A gain-of-function mutation in the bone morphogenetic protein (BMP) type I receptor ALK2 (ACVR1) is the primary cause of unusual bone production, including heterotrophic ossification, in individuals with fibrodysplasia ossificans progressiva.
Palovarotene: Although it is an investigational drug; it lowers the BMP/ALK2 downstream signalling cascade by binding to RAR and preventing SMAD1/5/8 from becoming phosphorylated. This inhibits chondrogenesis and osteocyte differentiation that are dependent on ALK2/SMAD, which affects the development of endochondral bone.
It is Indicated for the decrease of new heterotopic ossification volume in adults and paediatric patients with fibrodysplasia ossificans progressiva (FOP) aged ≥8 years for females and ≥10 years for males.
Use of NSAIDs in the Flare-Up Management
NSAIDs, such as ibuprofen, maybe indicated to reduce inflammation and relieve pain during flare-ups or for chronic pain management.
In FOP, the formation of heterotopic bone during flare-ups can cause significant inflammation and pain.
Ibuprofen: It is a nonsteroidal anti-inflammatory drug (NSAID), has been considered as a treatment option for the management of flare-ups in Fibrodysplasia Ossificans Progressiva (FOP) to help reduce pain and inflammation.
Gene therapy: Treatment for fibrodysplasia ossificans progressiva may be possible with gene therapy. A potential treatment target for fibrodysplasia ossificans progressiva is inflammation-related mediators.
The identification of the FOP gene exposes a highly conserved target in the activin-like kinase-2 signalling pathway of the transforming growth factor-beta/bone morphogenetic protein signalling cascade and necessitates therapeutic strategies for its development.
Dental and Oral Procedures: Dental care is essential for individuals with FOP, as ossification in the jaw can lead to dental problems. Routine dental check-ups, cleanings, and dental procedures may be necessary.
Oral surgical and anaesthetic procedures: It may be necessary for people with the rare disorder fibrodysplasia ossificans progressiva (FOP) to manage oral pain. It has been emphasised the significance of using a minimally invasive surgical method and proper anaesthetic care.
Diagnosis phase: The first phase involves obtaining an accurate diagnosis of FOP, which often occurs during childhood due to the characteristic congenital toe malformations. Early diagnosis is essential to initiate appropriate medical care and interventions.
Symptom Management and Pain Relief Phase: After diagnosis, the focus is on managing symptoms and providing pain relief. Physical therapy and assistive devices are introduced to maintain joint mobility, muscle strength, and function, which helps improve the individual’s quality of life.
Prevent and Avoid the Trauma: Individuals with FOP and their caregivers are educated about the importance of avoiding injuries and trauma, as these can trigger flare-ups and exacerbate the condition.
Regular Follow-Up and Monitoring: Ongoing medical follow-up and monitoring are crucial to track the progression of FOP, manage symptoms, and adapt the treatment plan as needed.
Psychosocial Support and Mental Health Care: Emotional and psychological support, including counselling and support groups, is essential for individuals and families to cope with the psychosocial challenges of living with FOP. Mental health care addresses issues such as depression, anxiety, and social isolation.
Life and Palliative Care Phase: In advanced stages of FOP, palliative care and end-of-life care may be necessary to ensure comfort and dignity for the individual and their family.
Genetic Counselling Phase: This is very important for individuals with FOP and their families to understand the genetic inheritance pattern and make informed family planning decisions.
Take a dose of 5 mg orally daily Dosing Considerations
Get a negative pregnancy test as soon as possible before starting therapy and then every few weeks after that
For 8 to 13 years old:
For 10 to 19.9 kg body weight, take a dose of 2.5 mg orally every day
For 30 to 59.9 kg body weight, take a dose of 4 mg orally every day
For ≥60 kg body weight, take a dose of 5 mg orally every day
For ≥14 years old:
Take a dose of 5 mg orally every day Dosing Considerations
Get a negative pregnancy test as soon as possible before starting therapy and then every few weeks after that
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References
Fibrodysplasia Ossificans Progressiva: Causes, Symptoms, Treatment, Outlook (clevelandclinic.org)
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Home » CAD » Fibrodysplasia Ossificans Progressiva
Fibrodysplasia Ossificans Progressiva
Updated :
October 9, 2023
Fibrodysplasia Ossificans Progressiva (FOP) is an extremely rare and debilitating genetic disorder characterized by the progressive replacement of soft tissues, such as muscles, tendons, and ligaments, with bone. In this condition an individual can become progressively immobile as their joints and muscles turn into bone, effectively immobilizing them.
FOP is caused by a mutation in the ACVR1 gene, which encodes a receptor for bone morphogenetic proteins (BMPs). This mutation results in the overactivity of the BMP signaling pathway, leading to the inappropriate formation of bone tissue in soft tissues.
FOP is considered one of the rarest genetic disorders in the world. Its estimated incidence is approximately 1 in 2 million individuals. This rarity makes it challenging for healthcare professionals to encounter and diagnose cases of FOP.
The key feature of FOP is congenital malformations of the great toes, which are often present from birth. This characteristic can help in the early identification of affected individuals.
FOP affects individuals of all genders and ethnic backgrounds equally. There is no known gender or ethnic predilection for the condition.
The underlying cause of FOP is a mutation in the ACVR1 gene, which is located on chromosome 2. This mutation results in the overactivation of the BMP signaling pathway.
Generally, BMP signaling is tightly regulated to ensure that bone formation occurs only in specific locations, such as during skeletal development or bone repair after injury.
In FOP, the mutated ACVR1 gene leads to a receptor that is overly sensitive to BMP signaling. This excessive activation of the BMP pathway disrupts the normal tissue repair process.
FOP is the progressive formation of bone tissue in soft tissues, including muscles, tendons, ligaments, and connective tissues. This abnormal bone formation occurs in response to inflammation, tissue injury or surgery, which would not normally result in ossification.
In individuals with FOP, a specific mutation occurs in the ACVR1 gene. This mutation results in the production of a hyperactive ACVR1 receptor that is overly sensitive to BMP signaling.
The mutated ACVR1 receptor, when activated by BMPs or other factors, sends signals that inappropriately stimulate the formation of bone tissue within soft tissues. This leads to the pathological process of heterotopic ossification, where bone forms in locations where it should not, such as in muscles, tendons, ligaments, and connective tissues.
FOP is typically inherited in an autosomal dominant manner which means an affected individual has a 50% chance of passing the mutated ACVR1 gene to each of their offspring.
The age at which FOP is diagnosed can influence the prognosis. Individuals diagnosed at a younger age may have a longer disease course ahead of them, potentially leading to more extensive heterotopic ossification and disability over time.
Early and appropriate medical management, including the management of acute ossification, can help mitigate the severity of FOP symptoms and potentially improve the long-term prognosis.
Efforts to preserve joint function and mobility through physical therapy and assistive devices can improve an individual’s ability to perform daily activities and maintain a better quality of life.
Fibrodysplasia Ossificans Progressiva (FOP) is diagnosed in childhood, with most affected individuals showing signs and symptoms of the condition during the first few years of life.
The congenital malformations of the great toes, which are often shorter and bent, these are a characteristic feature of FOP and can be present at birth. These toe malformations are often one of the earliest signs that lead to a diagnosis of FOP.
Malformation of Toe: Congenital malformations of the great toes is the identification of FOP. These malformations can include shortened, bent, or abnormally shaped great toes.
Joint Mobility: Assessing joint mobility and range of motion is essential, as FOP leads to progressive limitations in joint movement. Restricted mobility, contractures, or stiffness in the joints, especially in the hips, knees, neck, shoulders, elbows, and spine, are characteristic findings in FOP.
Neurological Examination: Depending on the location and extent of ossification, a neurological examination may be conducted to assess for any neurological deficits, such as weakness, numbness, or altered reflexes.
Assessment of Skin and Soft Tissues: Skin changes, such as nodules or fibrous tissue, may be present overlying affected areas. The skin may also show signs of past flare-ups or surgical interventions.
Scars and Surgical History: Inquire about any history of surgical interventions, especially related to the removal of heterotopic bone, as this may influence the current clinical presentation.
Individuals with FOP often experience chronic and severe pain due to the formation of bone within soft tissues, which can compress nerves and lead to discomfort. Pain management is a crucial aspect of FOP care.
Progressive ossification of joints and soft tissues can lead to restricted joint mobility and contractures, making it challenging for individuals with FOP to move and perform daily activities.
Abnormal bone formation in the jaw can lead to dental problems, including difficulties with chewing and oral hygiene. Regular dental care and adaptations may be required.
Difficulty with swallowing due to ossification in the throat and neck can lead to nutritional challenges.
The progressive nature of FOP becomes more apparent over time. Individuals may develop progressive stiffness in joints and experience limitations in joint mobility.
The acute exacerbation of symptoms, known as “flare-ups,” can occur at any age and are often triggered by trauma, injury, or inflammation. These flare-ups lead to rapid and painful ossification within soft tissues and are a defining feature of FOP.
While some features of FOP may be evident from birth or early childhood, the condition generally progresses gradually over the years. New bone formation accumulates, further limiting mobility and causing increased disability.
Myositis Ossificans: Myositis ossificans is characterized by the formation of heterotopic bone within muscle tissue, often in response to trauma or injury.
Tumor-Induced Ossification: Some tumors can calcify or ossify, leading to the formation of hard masses within soft tissues. These tumors may need to be differentiated from FOP, especially when evaluating soft tissue masses.
Connective Tissue Disorders: Some connective tissue disorders, such as Marfan syndrome or Ehlers-Danlos syndrome, can present with joint laxity or musculoskeletal abnormalities, which may resemble aspects of FOP.
Trauma-Induced Heterotopic Ossification: Heterotopic ossification can occur in response to various factors, including surgery, burns, or trauma. Trauma-induced ossification can resemble FOP, but it lacks the genetic mutation characteristic of FOP.
Genetic Counseling: Early diagnosis is important for individuals with FOP to receive appropriate medical care and genetic counseling. Genetic testing can confirm the presence of the ACVR1 gene mutation responsible for FOP.
Pain Management: Individuals with FOP often experience chronic and severe pain due to the formation of bone within soft tissues. Pain management strategies may include nonsteroidal anti-inflammatory drugs (NSAIDs) or opioids.
Occupational Therapy: Physical therapy can help individuals with FOP maintain joint mobility, flexibility, and muscle strength. Occupational therapy may focus on adaptive strategies for daily activities to enhance independence and improve the quality of life.
Assistive Devices: Orthopedic devices, braces, and assistive devices can be beneficial in supporting joint function and mobility. These devices are often customized to meet the individual’s specific needs.
Flare-Up Management: Flare-ups in FOP, triggered by trauma or inflammation, can lead to rapid bone formation. Prompt recognition and management of flare-ups are critical to minimize the extent of ossification.
Avoid the Trauma: Preventing injuries and trauma is essential, as these can trigger flare-ups and exacerbate FOP. Individuals with FOP and their caregivers should be educated about the importance of avoiding activities and situations that could lead to injury.
Dermatology, General
Follow the safety measures: Identify and eliminate items or situations that may pose a risk of injury or trauma, such as sharp objects or furniture with hard edges.
Use soft or padded surfaces, such as cushions or mats, in areas where individuals with FOP spend time to reduce the risk of injury from falls or accidental bumps.
Accessible Living Spaces: Consider making structural changes or home modifications to enhance accessibility, such as ramps, widened doorways, or stairlifts. These changes can help individuals with mobility limitations navigate their living spaces more easily.
Assistive Devices and Mobility: Provide wheelchairs, walkers, or other mobility devices as needed to support independent mobility while minimizing the risk of falls or joint strain.
Use of Orthopedic devices: Custom orthopedic braces and supports can help stabilize joints and reduce pain and discomfort.
Good Sleep Environment: Use a comfortable mattress and appropriate pillows to ensure restful sleep and minimize pressure sores. Elevating the head of the bed slightly may help reduce the risk of aspiration and breathing difficulties.
Adaptive Clothing and Dressing: Choose clothing with features such as easy-open closures, stretchy fabrics, or adaptive designs to simplify dressing and reduce joint strain.
Dermatology, General
A gain-of-function mutation in the bone morphogenetic protein (BMP) type I receptor ALK2 (ACVR1) is the primary cause of unusual bone production, including heterotrophic ossification, in individuals with fibrodysplasia ossificans progressiva.
Palovarotene: Although it is an investigational drug; it lowers the BMP/ALK2 downstream signalling cascade by binding to RAR and preventing SMAD1/5/8 from becoming phosphorylated. This inhibits chondrogenesis and osteocyte differentiation that are dependent on ALK2/SMAD, which affects the development of endochondral bone.
It is Indicated for the decrease of new heterotopic ossification volume in adults and paediatric patients with fibrodysplasia ossificans progressiva (FOP) aged ≥8 years for females and ≥10 years for males.
Dermatology, General
A gain-of-function mutation in the bone morphogenetic protein (BMP) type I receptor ALK2 (ACVR1) is the primary cause of unusual bone production, including heterotrophic ossification, in individuals with fibrodysplasia ossificans progressiva.
Palovarotene: Although it is an investigational drug; it lowers the BMP/ALK2 downstream signalling cascade by binding to RAR and preventing SMAD1/5/8 from becoming phosphorylated. This inhibits chondrogenesis and osteocyte differentiation that are dependent on ALK2/SMAD, which affects the development of endochondral bone.
It is Indicated for the decrease of new heterotopic ossification volume in adults and paediatric patients with fibrodysplasia ossificans progressiva (FOP) aged ≥8 years for females and ≥10 years for males.
Dermatology, General
NSAIDs, such as ibuprofen, maybe indicated to reduce inflammation and relieve pain during flare-ups or for chronic pain management.
In FOP, the formation of heterotopic bone during flare-ups can cause significant inflammation and pain.
Ibuprofen: It is a nonsteroidal anti-inflammatory drug (NSAID), has been considered as a treatment option for the management of flare-ups in Fibrodysplasia Ossificans Progressiva (FOP) to help reduce pain and inflammation.
Dermatology, General
Gene therapy: Treatment for fibrodysplasia ossificans progressiva may be possible with gene therapy. A potential treatment target for fibrodysplasia ossificans progressiva is inflammation-related mediators.
The identification of the FOP gene exposes a highly conserved target in the activin-like kinase-2 signalling pathway of the transforming growth factor-beta/bone morphogenetic protein signalling cascade and necessitates therapeutic strategies for its development.
Dental and Oral Procedures: Dental care is essential for individuals with FOP, as ossification in the jaw can lead to dental problems. Routine dental check-ups, cleanings, and dental procedures may be necessary.
Oral surgical and anaesthetic procedures: It may be necessary for people with the rare disorder fibrodysplasia ossificans progressiva (FOP) to manage oral pain. It has been emphasised the significance of using a minimally invasive surgical method and proper anaesthetic care.
Dermatology, General
Diagnosis phase: The first phase involves obtaining an accurate diagnosis of FOP, which often occurs during childhood due to the characteristic congenital toe malformations. Early diagnosis is essential to initiate appropriate medical care and interventions.
Symptom Management and Pain Relief Phase: After diagnosis, the focus is on managing symptoms and providing pain relief. Physical therapy and assistive devices are introduced to maintain joint mobility, muscle strength, and function, which helps improve the individual’s quality of life.
Prevent and Avoid the Trauma: Individuals with FOP and their caregivers are educated about the importance of avoiding injuries and trauma, as these can trigger flare-ups and exacerbate the condition.
Regular Follow-Up and Monitoring: Ongoing medical follow-up and monitoring are crucial to track the progression of FOP, manage symptoms, and adapt the treatment plan as needed.
Psychosocial Support and Mental Health Care: Emotional and psychological support, including counselling and support groups, is essential for individuals and families to cope with the psychosocial challenges of living with FOP. Mental health care addresses issues such as depression, anxiety, and social isolation.
Life and Palliative Care Phase: In advanced stages of FOP, palliative care and end-of-life care may be necessary to ensure comfort and dignity for the individual and their family.
Genetic Counselling Phase: This is very important for individuals with FOP and their families to understand the genetic inheritance pattern and make informed family planning decisions.
Fibrodysplasia Ossificans Progressiva: Causes, Symptoms, Treatment, Outlook (clevelandclinic.org)
Fibrodysplasia Ossificans Progressiva – Symptoms, Causes, Treatment | NORD (rarediseases.org)
medtigo
Fibrodysplasia Ossificans Progressiva
Updated :
October 9, 2023
Fibrodysplasia Ossificans Progressiva (FOP) is an extremely rare and debilitating genetic disorder characterized by the progressive replacement of soft tissues, such as muscles, tendons, and ligaments, with bone. In this condition an individual can become progressively immobile as their joints and muscles turn into bone, effectively immobilizing them.
FOP is caused by a mutation in the ACVR1 gene, which encodes a receptor for bone morphogenetic proteins (BMPs). This mutation results in the overactivity of the BMP signaling pathway, leading to the inappropriate formation of bone tissue in soft tissues.
FOP is considered one of the rarest genetic disorders in the world. Its estimated incidence is approximately 1 in 2 million individuals. This rarity makes it challenging for healthcare professionals to encounter and diagnose cases of FOP.
The key feature of FOP is congenital malformations of the great toes, which are often present from birth. This characteristic can help in the early identification of affected individuals.
FOP affects individuals of all genders and ethnic backgrounds equally. There is no known gender or ethnic predilection for the condition.
The underlying cause of FOP is a mutation in the ACVR1 gene, which is located on chromosome 2. This mutation results in the overactivation of the BMP signaling pathway.
Generally, BMP signaling is tightly regulated to ensure that bone formation occurs only in specific locations, such as during skeletal development or bone repair after injury.
In FOP, the mutated ACVR1 gene leads to a receptor that is overly sensitive to BMP signaling. This excessive activation of the BMP pathway disrupts the normal tissue repair process.
FOP is the progressive formation of bone tissue in soft tissues, including muscles, tendons, ligaments, and connective tissues. This abnormal bone formation occurs in response to inflammation, tissue injury or surgery, which would not normally result in ossification.
In individuals with FOP, a specific mutation occurs in the ACVR1 gene. This mutation results in the production of a hyperactive ACVR1 receptor that is overly sensitive to BMP signaling.
The mutated ACVR1 receptor, when activated by BMPs or other factors, sends signals that inappropriately stimulate the formation of bone tissue within soft tissues. This leads to the pathological process of heterotopic ossification, where bone forms in locations where it should not, such as in muscles, tendons, ligaments, and connective tissues.
FOP is typically inherited in an autosomal dominant manner which means an affected individual has a 50% chance of passing the mutated ACVR1 gene to each of their offspring.
The age at which FOP is diagnosed can influence the prognosis. Individuals diagnosed at a younger age may have a longer disease course ahead of them, potentially leading to more extensive heterotopic ossification and disability over time.
Early and appropriate medical management, including the management of acute ossification, can help mitigate the severity of FOP symptoms and potentially improve the long-term prognosis.
Efforts to preserve joint function and mobility through physical therapy and assistive devices can improve an individual’s ability to perform daily activities and maintain a better quality of life.
Fibrodysplasia Ossificans Progressiva (FOP) is diagnosed in childhood, with most affected individuals showing signs and symptoms of the condition during the first few years of life.
The congenital malformations of the great toes, which are often shorter and bent, these are a characteristic feature of FOP and can be present at birth. These toe malformations are often one of the earliest signs that lead to a diagnosis of FOP.
Malformation of Toe: Congenital malformations of the great toes is the identification of FOP. These malformations can include shortened, bent, or abnormally shaped great toes.
Joint Mobility: Assessing joint mobility and range of motion is essential, as FOP leads to progressive limitations in joint movement. Restricted mobility, contractures, or stiffness in the joints, especially in the hips, knees, neck, shoulders, elbows, and spine, are characteristic findings in FOP.
Neurological Examination: Depending on the location and extent of ossification, a neurological examination may be conducted to assess for any neurological deficits, such as weakness, numbness, or altered reflexes.
Assessment of Skin and Soft Tissues: Skin changes, such as nodules or fibrous tissue, may be present overlying affected areas. The skin may also show signs of past flare-ups or surgical interventions.
Scars and Surgical History: Inquire about any history of surgical interventions, especially related to the removal of heterotopic bone, as this may influence the current clinical presentation.
Individuals with FOP often experience chronic and severe pain due to the formation of bone within soft tissues, which can compress nerves and lead to discomfort. Pain management is a crucial aspect of FOP care.
Progressive ossification of joints and soft tissues can lead to restricted joint mobility and contractures, making it challenging for individuals with FOP to move and perform daily activities.
Abnormal bone formation in the jaw can lead to dental problems, including difficulties with chewing and oral hygiene. Regular dental care and adaptations may be required.
Difficulty with swallowing due to ossification in the throat and neck can lead to nutritional challenges.
The progressive nature of FOP becomes more apparent over time. Individuals may develop progressive stiffness in joints and experience limitations in joint mobility.
The acute exacerbation of symptoms, known as “flare-ups,” can occur at any age and are often triggered by trauma, injury, or inflammation. These flare-ups lead to rapid and painful ossification within soft tissues and are a defining feature of FOP.
While some features of FOP may be evident from birth or early childhood, the condition generally progresses gradually over the years. New bone formation accumulates, further limiting mobility and causing increased disability.
Myositis Ossificans: Myositis ossificans is characterized by the formation of heterotopic bone within muscle tissue, often in response to trauma or injury.
Tumor-Induced Ossification: Some tumors can calcify or ossify, leading to the formation of hard masses within soft tissues. These tumors may need to be differentiated from FOP, especially when evaluating soft tissue masses.
Connective Tissue Disorders: Some connective tissue disorders, such as Marfan syndrome or Ehlers-Danlos syndrome, can present with joint laxity or musculoskeletal abnormalities, which may resemble aspects of FOP.
Trauma-Induced Heterotopic Ossification: Heterotopic ossification can occur in response to various factors, including surgery, burns, or trauma. Trauma-induced ossification can resemble FOP, but it lacks the genetic mutation characteristic of FOP.
Genetic Counseling: Early diagnosis is important for individuals with FOP to receive appropriate medical care and genetic counseling. Genetic testing can confirm the presence of the ACVR1 gene mutation responsible for FOP.
Pain Management: Individuals with FOP often experience chronic and severe pain due to the formation of bone within soft tissues. Pain management strategies may include nonsteroidal anti-inflammatory drugs (NSAIDs) or opioids.
Occupational Therapy: Physical therapy can help individuals with FOP maintain joint mobility, flexibility, and muscle strength. Occupational therapy may focus on adaptive strategies for daily activities to enhance independence and improve the quality of life.
Assistive Devices: Orthopedic devices, braces, and assistive devices can be beneficial in supporting joint function and mobility. These devices are often customized to meet the individual’s specific needs.
Flare-Up Management: Flare-ups in FOP, triggered by trauma or inflammation, can lead to rapid bone formation. Prompt recognition and management of flare-ups are critical to minimize the extent of ossification.
Avoid the Trauma: Preventing injuries and trauma is essential, as these can trigger flare-ups and exacerbate FOP. Individuals with FOP and their caregivers should be educated about the importance of avoiding activities and situations that could lead to injury.
Dermatology, General
Follow the safety measures: Identify and eliminate items or situations that may pose a risk of injury or trauma, such as sharp objects or furniture with hard edges.
Use soft or padded surfaces, such as cushions or mats, in areas where individuals with FOP spend time to reduce the risk of injury from falls or accidental bumps.
Accessible Living Spaces: Consider making structural changes or home modifications to enhance accessibility, such as ramps, widened doorways, or stairlifts. These changes can help individuals with mobility limitations navigate their living spaces more easily.
Assistive Devices and Mobility: Provide wheelchairs, walkers, or other mobility devices as needed to support independent mobility while minimizing the risk of falls or joint strain.
Use of Orthopedic devices: Custom orthopedic braces and supports can help stabilize joints and reduce pain and discomfort.
Good Sleep Environment: Use a comfortable mattress and appropriate pillows to ensure restful sleep and minimize pressure sores. Elevating the head of the bed slightly may help reduce the risk of aspiration and breathing difficulties.
Adaptive Clothing and Dressing: Choose clothing with features such as easy-open closures, stretchy fabrics, or adaptive designs to simplify dressing and reduce joint strain.
Dermatology, General
A gain-of-function mutation in the bone morphogenetic protein (BMP) type I receptor ALK2 (ACVR1) is the primary cause of unusual bone production, including heterotrophic ossification, in individuals with fibrodysplasia ossificans progressiva.
Palovarotene: Although it is an investigational drug; it lowers the BMP/ALK2 downstream signalling cascade by binding to RAR and preventing SMAD1/5/8 from becoming phosphorylated. This inhibits chondrogenesis and osteocyte differentiation that are dependent on ALK2/SMAD, which affects the development of endochondral bone.
It is Indicated for the decrease of new heterotopic ossification volume in adults and paediatric patients with fibrodysplasia ossificans progressiva (FOP) aged ≥8 years for females and ≥10 years for males.
Dermatology, General
A gain-of-function mutation in the bone morphogenetic protein (BMP) type I receptor ALK2 (ACVR1) is the primary cause of unusual bone production, including heterotrophic ossification, in individuals with fibrodysplasia ossificans progressiva.
Palovarotene: Although it is an investigational drug; it lowers the BMP/ALK2 downstream signalling cascade by binding to RAR and preventing SMAD1/5/8 from becoming phosphorylated. This inhibits chondrogenesis and osteocyte differentiation that are dependent on ALK2/SMAD, which affects the development of endochondral bone.
It is Indicated for the decrease of new heterotopic ossification volume in adults and paediatric patients with fibrodysplasia ossificans progressiva (FOP) aged ≥8 years for females and ≥10 years for males.
Dermatology, General
NSAIDs, such as ibuprofen, maybe indicated to reduce inflammation and relieve pain during flare-ups or for chronic pain management.
In FOP, the formation of heterotopic bone during flare-ups can cause significant inflammation and pain.
Ibuprofen: It is a nonsteroidal anti-inflammatory drug (NSAID), has been considered as a treatment option for the management of flare-ups in Fibrodysplasia Ossificans Progressiva (FOP) to help reduce pain and inflammation.
Dermatology, General
Gene therapy: Treatment for fibrodysplasia ossificans progressiva may be possible with gene therapy. A potential treatment target for fibrodysplasia ossificans progressiva is inflammation-related mediators.
The identification of the FOP gene exposes a highly conserved target in the activin-like kinase-2 signalling pathway of the transforming growth factor-beta/bone morphogenetic protein signalling cascade and necessitates therapeutic strategies for its development.
Dental and Oral Procedures: Dental care is essential for individuals with FOP, as ossification in the jaw can lead to dental problems. Routine dental check-ups, cleanings, and dental procedures may be necessary.
Oral surgical and anaesthetic procedures: It may be necessary for people with the rare disorder fibrodysplasia ossificans progressiva (FOP) to manage oral pain. It has been emphasised the significance of using a minimally invasive surgical method and proper anaesthetic care.
Dermatology, General
Diagnosis phase: The first phase involves obtaining an accurate diagnosis of FOP, which often occurs during childhood due to the characteristic congenital toe malformations. Early diagnosis is essential to initiate appropriate medical care and interventions.
Symptom Management and Pain Relief Phase: After diagnosis, the focus is on managing symptoms and providing pain relief. Physical therapy and assistive devices are introduced to maintain joint mobility, muscle strength, and function, which helps improve the individual’s quality of life.
Prevent and Avoid the Trauma: Individuals with FOP and their caregivers are educated about the importance of avoiding injuries and trauma, as these can trigger flare-ups and exacerbate the condition.
Regular Follow-Up and Monitoring: Ongoing medical follow-up and monitoring are crucial to track the progression of FOP, manage symptoms, and adapt the treatment plan as needed.
Psychosocial Support and Mental Health Care: Emotional and psychological support, including counselling and support groups, is essential for individuals and families to cope with the psychosocial challenges of living with FOP. Mental health care addresses issues such as depression, anxiety, and social isolation.
Life and Palliative Care Phase: In advanced stages of FOP, palliative care and end-of-life care may be necessary to ensure comfort and dignity for the individual and their family.
Genetic Counselling Phase: This is very important for individuals with FOP and their families to understand the genetic inheritance pattern and make informed family planning decisions.
Fibrodysplasia Ossificans Progressiva: Causes, Symptoms, Treatment, Outlook (clevelandclinic.org)
Fibrodysplasia Ossificans Progressiva – Symptoms, Causes, Treatment | NORD (rarediseases.org)
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