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Fibrodysplasia ossificans progressiva

Stone man syndrome, FOP

Overview

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.

Fibrodysplasia ossificans progressiva is an ultra rare disorder and is believed to occur in approximately 1 in 2 million people worldwide, with only several hundred cases having been reported. 

Symptoms - Fibrodysplasia ossificans progressiva

For unknown reasons, children born with FOP have deformed big toes, possibly missing a joint or simply presenting with a notable lump at the minor joint. The first "flare-up" that leads to the formation of FOP bones usually occurs before the age of 10. The bone growth progresses from the top downward, just as bones grow in fetuses. A child with FOP will typically develop bones starting at the neck, then on the shoulders, arms, chest area and finally on the feet.

Specifically, FOP involvement is typically seen first in the dorsal, axial, cranial and proximal regions of the body. Later the disease progresses in the ventral, appendicular, caudal and distal regions of the body. However, it does not necessarily occur in this order due to injury-caused flare-ups. Often, the tumor-like lumps that characterize the disease appear suddenly. This condition causes loss of mobility to affected joints, including inability to fully open the mouth limiting speech and eating. Extra bone formation around the rib cage restricts the expansion of lungs and diaphragm causing breathing complications.

Since the disease is so rare, the symptoms are often misdiagnosed as cancer or fibrosis. This leads physicians to order biopsies, which can actually exacerbate the growth of these lumps. However, those born with FOP tend to have malformed toes or thumbs which help distinguish this disorder from other skeletal problems.

Causes - Fibrodysplasia ossificans progressiva

FOP is caused by an autosomal dominant allele on chromosome 2q23-24.The allele has variable expressivity, but complete penetrance. Most cases are caused by spontaneous mutation in the gametes; most people with FOP cannot or choose not to have children. A similar but less catastrophic disease is fibrous dysplasia, which is caused by a post-zygotic mutation.

A mutation in the gene ACVR1 (also known as activin-like kinase 2 [ALK-2]) is responsible for the disease. ACVR1 encodes activin receptor type-1, a BMP type-1 receptor. The mutation causes substitution of codon 206 from arginine to histidine in the ACVR1 protein.This substitution causes abnormal activation of ACVR1, leading to the transformation of connective tissue and muscle tissue into a secondary skeleton. This causes endothelial cells to transform to mesenchymal stem cells and then to bone.

Genetics

FOP or Stone Man Syndrome is an autosomal dominant disorder that affects individuals who are heterozygous with a homozygous recessive partner, therefore their children will have 50% chance of being affected. Two affected individuals can produce unaffected children. The phenotypes of those who are homozygous dominant have more severe effects compared to those with heterozygous phenotype.

The gene that causes ossification is normally deactivated after a fetus's bones are formed in the womb, but in patients with FOP, the gene keeps working. Aberrant bone formation in patients with FOP occurs when injured connective tissue or muscle cells at the sites of injury or growth incorrectly express an enzyme for bone repair during apoptosis (self-regulated cell death), resulting in lymphocytes containing excess bone morphogenetic protein 4 (BMP4) provided during the immune system response. The bone that results occurs independently of the normal skeleton, forming its own discrete skeletal elements. These elements, however, can fuse with normal skeletal bone. Interestingly, the diaphragm, tongue, and extra-ocular muscles are spared in this process, as well as cardiac and smooth muscle. Since the incorrect enzyme remains unresolved within the immune response, the body continues providing the incorrect BMP4-containing lymphocytes. BMP4 is a product that contributes to the development of the skeleton in the normal embryo.

DNA sequencing electropherograms of a typical FOP patient can differ when being compared to two other patients. The cause of this mutation is in the ACVR1 gene. This gene provides instruction for a protein known as morphogenetic protein (BMP). This protein is responsible for growth and development of bone and muscles. Scientists and researchers theorize that a mutation in the ACVR1 changes the shape of the receptor and disrupts certain mechanisms that control the receptor's activity. There is a certain molecule, otherwise known as ligands, that binds at the site to cause this reaction to activate with which it forms a complex. Due to the mutation, however, the bind site is modified and no longer stops the reaction. The end result is an overgrowth of bone and cartilage and fusion of Joints.

This type of genetic disorder is so rare that only 1 in 2 million people worldwide acquire it. As it is such a rare disorder, only a few are reported at all. Most of the cases of FOP were results of a new gene mutation: these people had no history of this particular disorder in their family. There are some cases which have shown people inheriting the mutation from one affected parent.

Prevention - Fibrodysplasia ossificans progressiva

There is no proven way to prevent FOP, but there are some ways prevent flare-ups and reduce the risk of complications:

  • Good oral hygiene
  • Avoid wearing tight clothing, hard buttons or buckles, tight elastics, straps, or body braces , tight shoes or shoe laces, or any item that puts prolonged pressure on the body. Such items may increase the risk of experiencing a flare-up.
  • Avoid unnecessary intramuscular injections
  • Minimize the risk of traumatic injuries
  • Assisted mobility devices for some people to help them walk

Diagnosis - Fibrodysplasia ossificans progressiva

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.

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.

A doctor may suspect a diagnosis of a genetic condition on the basis of a person’s physical characteristics and family history, or on the results of a screening test.

Genetic testing is one of several tools that doctors use to diagnose genetic conditions. The approaches to making a genetic diagnosis include:

  • A physical examination: Certain physical characteristics, such as distinctive facial features, can suggest the diagnosis of a genetic disorder. A geneticist will do a thorough physical examination that may include measurements such as the distance around the head (head circumference), the distance between the eyes, and the length of the arms and legs. Depending on the situation, specialized examinations such as nervous system (neurological) or eye (ophthalmologic) exams may be performed. The doctor may also use imaging studies including x-rays, computerized tomography (CT) scans, or magnetic resonance imaging (MRI) to see structures inside the body.

  • Personal medical history: Information about an individual’s health, often going back to birth, can provide clues to a genetic diagnosis. A personal medical history includes past health issues, hospitalizations and surgeries, allergies, medications, and the results of any medical or genetic testing that has already been done.

  • Family medical history: Because genetic conditions often run in families, information about the health of family members can be a critical tool for diagnosing these disorders. A doctor or genetic counselor will ask about health conditions in an individual’s parents, siblings, children, and possibly more distant relatives. This information can give clues about the diagnosis and inheritance pattern of a genetic condition in a family.

  • Laboratory tests, including genetic testing: Molecular, chromosomal, and biochemical genetic testing are used to diagnose genetic disorders. Other laboratory tests that measure the levels of certain substances in blood and urine can also help suggest a diagnosis.

Genetic testing is currently available for many genetic conditions. However, some conditions do not have a genetic test; either the genetic cause of the condition is unknown or a test has not yet been developed. In these cases, a combination of the approaches listed above may be used to make a diagnosis. Even when genetic testing is available, the tools listed above are used to narrow down the possibilities (known as a differential diagnosis) and choose the most appropriate genetic tests to pursue.

A diagnosis of a genetic disorder can be made anytime during life, from before birth to old age, depending on when the features of the condition appear and the availability of testing. Sometimes, having a diagnosis can guide treatment and management decisions. A genetic diagnosis can also suggest whether other family members may be affected by or at risk of a specific disorder. Even when no treatment is available for a particular condition, having a diagnosis can help people know what to expect and may help them identify useful support and advocacy resources.

Prognosis - Fibrodysplasia ossificans progressiva

The median lifespan is about 40 years of age. Most patients commonly die of complications of thoracic insufficiency syndrome by the end of the second decade of life

Treatment - Fibrodysplasia ossificans progressiva

There is no known cure for FOP. Attempts to surgically remove the bone result in more robust bone growth.While under anesthesia, patients with FOP may face problems, which include difficulties with intubation, restrictive pulmonary disease, and changes in the electrical conduction system of the heart. Activities that increase the risk of falling should be avoided, as injuries from falling can provoke the growth of bone.

In 1999, scientists discovered that squalamine in sharks might be useful in treating those suffering from FOP. Squalamine is antiangiogenic and can prevent the growth of blood vessels in cartilaginous tissue, thus preventing creation of bone in sharks. The Genaera Corporation announced a trial of squalamine in 2002 but terminated about 2007. (Note that squalene is a different compound, also found in sharks, that has no such properties.) Clinical trials of isotretinoin, etidronate with oral corticosteroids, and perhexiline maleate have failed to demonstrate effectiveness, though the variable course of the disease and small numbers of patients leave some room for uncertainty. In April 2013 the La Jolla Pharmaceutical Company was granted orphan drug status for testing of 4-(6-(4-(piperazin-1-yl)phenyl_pyrazolo[1,5-a]pyrimidin-3-yl)quinoline hydrochloride for treatment of FOP.

Researchers believe that specific kinase inhibitors can be developed that will block the aberrant ACVR1 activity, and are actively investigating dorsomorphin and K02288 as lead compounds with the intention of developing effective therapies. For example, the more potent dorsomorphin derivative LDN-193189 reduced ossification in a transgenic mouse model, in which the engineering of adult ACVR1 activity created an inflammation-dependent ossification sensitive to corticosteroid treatment.

Another major direction in research is the development of therapeutics based on allele-specific RNA interference to block the aberrant gene from directing production of ACVR1. However, effective treatment by this means may require a better knowledge of what cell types are responsible for the disease, so that inhibitory RNA can be produced from them in the long term.

Although this disorder is currently incurable, understanding and researching the cause of bone formation in FOP could aid in the treatment of other bone disorders, especially common ones such as fractures, hip replacement surgery, and other heterotopic ossifications that occur in trauma or burn victims.

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by Scott Harwood
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