Overview: Fibrodysplasia Ossificans Progressiva

Fibrodysplasia ossificans progressiva (FOP) is a disorder in which muscle tissue and connective tissue such as tendons and ligaments are gradually replaced by bone (ossified), forming bone outside the skeleton (extra-skeletal or heterotopic bone) that constrains movement. This process generally becomes noticeable in early childhood, starting with the neck and shoulders and proceeding down the body and into the limbs.



Read Also:

Everything About Herniated Disc and Back Pain

Risk Factors, Causes, Diagnosis, Treatment And Prevention Of Sciatica

Extra-skeletal bone formation causes progressive loss of mobility as the joints become affected. Inability to fully open the mouth may cause difficulty in speaking and eating. Over time, people with this disorder may experience malnutrition due to their eating problems. They may also have breathing difficulties as a result of extra bone formation around the rib cage that restricts expansion of the lungs.

Any trauma to the muscles of an individual with fibrodysplasia ossificans progressiva, such as a fall or invasive medical procedures, may trigger episodes of muscle swelling and inflammation (myositis) followed by more rapid ossification in the injured area. Flare-ups may also be caused by viral illnesses such as influenza.

People with fibrodysplasia ossificans progressiva are generally born with malformed big toes. This abnormality of the big toes is a characteristic feature that helps to distinguish this disorder from other bone and muscle problems. Affected individuals may also have short thumbs and other skeletal abnormalities.


Frequency

Fibrodysplasia ossificans progressiva is a very rare disorder, believed to occur in approximately 1 in 2 million people worldwide. Several hundred cases have been reported.


Genetic Changes

Mutations in the ACVR1 gene cause fibrodysplasia ossificans progressiva.

The ACVR1 gene provides instructions for producing a member of a protein family called bone morphogenetic protein (BMP) type I receptors. The ACVR1 protein is found in many tissues of the body including skeletal muscle and cartilage. It helps to control the growth and development of the bones and muscles, including the gradual replacement of cartilage by bone (ossification) that occurs in normal skeletal maturation from birth to young adulthood.

Researchers believe that a mutation in the ACVR1 gene may change the shape of the receptor under certain conditions and disrupt mechanisms that control the receptor's activity. As a result, the receptor may be constantly turned on (constitutive activation). Constitutive activation of the receptor causes overgrowth of bone and cartilage and fusion of joints, resulting in the signs and symptoms of fibrodysplasia ossificans progressiva.
Inheritance Pattern

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

Most cases of fibrodysplasia ossificans progressiva result from new mutations in the gene. These cases occur in people with no history of the disorder in their family. In a small number of cases, an affected person has inherited the mutation from one affected parent.


Diagnosis & Management

Laboratory Studies

The clinical presentation (especially the additional presence of a hallus valgus deformity) is suggestive of fibrodysplasia ossificans progressiva (FOP). Routine biochemical study results of mineral metabolism are usually within the reference range. In fibrodysplasia ossificans progressiva, increased alkaline phosphatase levels are characteristic for children (physiologic growth of the bones).



Imaging Studies

Changes associated with fibrodysplasia ossificans progressiva include abnormal formation of the great toe, abnormally shaped long bones with exostoses, and developmental fusion of cervical vertebrae.


The most characteristic features are areas of bony masses penetrating into muscles (mainly the paraspinal region).


CT scanning is the best method for detection of early fibrodysplasia ossificans progressiva lesions. Bone scintigraphy shows an increased uptake of radiolabeled diphosphonate before ossification can be demonstrated by radiographic examination.


CT evaluation may demonstrate heterotopic ossification of the pterygoid muscles, a likely cause jaw restriction and retrognathia in older patients. [26]



Procedures

A biopsy is generally not indicated in fibrodysplasia ossificans progressiva because of the frequent development of the lesions in the traumatization area.



Histologic Findings

Histologic examination shows a pronounced proliferation of fibroblasts within the muscles in several areas, leading to destruction of muscle fibers. Predominate mononuclear cell infiltrates are present within the muscles and in the subcutaneous connective tissue, with extensive proliferation of connective tissue fibroblasts replacing damaged muscle fibers, plus areas of newly formed bone tissue. In the center of fibrous material, bone or cartilage tissue may be detected. The well-developed osseous lesions show a typical picture of mature bone with Haversian systems. The muscle fibers usually secondarily degenerate. Smooth muscles are not involved. Note the image below.




Proliferation of fibroblasts within the muscle with partial replacement of the muscle fibers.

Medical Care

Fibrodysplasia ossificans progressiva (FOP) should be diagnosed during the neonatal period. [27] Early treatment of fibrodysplasia ossificans progressiva helps avoid the factors of aggravation, slow the progression of the disease, and provide the children with improved quality of life. No effective medical therapy is known for fibrodysplasia ossificans progressiva; bisphosphonates and corticosteroids are only beneficial during the flares. Gene therapy may hold promise in fibrodysplasia ossificans progressiva treatment.

Systemic steroids are sometimes used for acute flare-ups. Iontophoresis with steroids or acetic acid may improve diminished range of motion.

The discovery of the FOP gene reveals a highly conserved target in the transforming growth factor-beta/bone morphogenetic protein signaling pathway and compels therapeutic approaches for the development of small-molecule signal transduction inhibitors for activinlike kinase-2. [28] Effective therapies for fibrodysplasia ossificans progressiva may be based on blocking activinlike kinase-2 or blocking of activin receptor IA/activin–like kinase 2 signaling. [29]



Surgical Care

Patients with fibrodysplasia ossificans, a rare disorder, may require oral surgical and anesthetic procedures to control oral pain. The importance of a minimally invasive surgical technique and appropriate anesthetic management has been stressed. [30]


The experience using general anesthesia has been favorable, with awake nasal fiberoptic intubation evaluated as desirable for airway management. [31]

Source 1
Source 2