An Overview of Fibrodysplasia Ossificans Progressiva

Learn more about this rare disorder in which bone replaces tissue

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Fibrodysplasia Ossificans Progressiva (FOP) is a very rare inherited condition in which the connective tissues of the body including muscles, tendons, and ligaments, are gradually replaced by bone (in a process called ossification). The condition is present at birth but symptoms may not become apparent until early childhood. Ossification may occur randomly or after an injury.

Fibrodysplasis ossificans progressiva symptoms
Illustration by JR Bee, Verywell 

Symptoms

While a person is born with FOP, signs and symptoms of ossification may not become noticeable until a child gets a little older and has started to grow.

In newborns, the first sign of FOP is often a congenital abnormality of the toes. Shortly after birth, medical professionals or parents may notice the infant's big toes are shorter than the other toes. This malformation is seen in all people with FOP and is an important clue for making the diagnosis. A newborn may also have swelling around her eyes and scalp. In some cases this swelling may begin while the fetus is still in utero, though the condition is typically not diagnosed until after birth. Around 50 percent of people with the condition also have similar congenital malformations in the thumbs—other malformations have been observed as well, such as in the spine.

Most people with FOP will experience the condition's major symptoms for the first time (sometimes referred to as a "flare up") by the age of 10.

While the overall rate of the condition's progression is unknown, ossification tends to follow a particular pattern, starting in the neck and working its way down to the shoulders, torso, limbs, and feet.

However, since bone formation can be affected by injury (such as breaking an arm) or viral illness (such as influenza), the disease may not strictly follow this progression.

The primary symptoms of FOP depend on which parts of the body have become ossified. Tender lumps under the skin (subcutaneous nodules) are common with the condition. Sometimes, a mild fever will precede the formation of these nodules. Most people with FOP will have general symptoms of pain, stiffness, and a progressive lack of mobility as more bone formation occurs.

Depending on which parts of the body become ossified, more specific symptoms can include:

  • trouble eating that may lead to nutritional deficiencies or malnutrition.
  • difficulty speaking.
  • dental problems.
  • difficulty breathing.
  • respiratory infections.
  • hearing impairment.
  • hair loss (alopecia).
  • anemia.
  • nerve compression or entrapment.
  • right-sided congestive heart failure.
  • a curvature of the spine (scoliosis and kyphosis).
  • sensory abnormalities.
  • mild intellectual disability.
  • neurological symptoms.

People with FOP may have periods in their lives where they don't experience new bone growth. At other times, it may seem to happen randomly and in the absence of any obvious injury or illness. When ossification occurs in an unusual part of the body (where bone is not typically found) it can lead to fractures.

Over time, the formation of new bone and tissue swelling that accompanies this condition can severely affect how well a person is able to move.

In most cases, fibrodysplasia ossificans progressiva eventually leads to complete immobilization. Many people with the condition will become bedridden by the age of 30.

Causes

Most people who are born with FOP have the condition as a result of a random genetic mutation. While it is a genetic condition, however, it doesn't usually run in families.

A person only needs one affected gene to have FOP. Most cases happen because of a random mutation—a person rarely develops the condition because they inherited an abnormal gene from one of their parents. In genetics, this is known as an autosomal dominant disorder.

The gene mutation responsible for the condition was identified by researchers at the University of Pennsylvania—they identified a receptor on chromosome 2 called Activin Receptor Type IA (ACVR1). ACVR1 is present in the gene that encodes bone morphogenic proteins (BMP) which help form and repair the skeleton, starting when an embryo is still forming. Researchers believe the mutation in the gene prevents these receptors from being turned off, which allows uncontrolled bone to form in parts of the body where it normally would not appear throughout a person's life.

Diagnosis

Fibrodysplasia Ossificans Progressiva is very rare. Only a few thousand people are suspected to have the condition and there are only about 800 known patients of this condition in the world—285 of them are in the United States. FOP doesn't appear to be more common in infants of a particular race, and the condition is found about as often in boys as girls.

Diagnosing fibrodysplasia ossificans progressiva can be difficult. It's not unusual for the condition to initially be misdiagnosed as a form of cancer or a condition called Aggressive Juvenile Fibromatosis.

Early in the course of FOP, if tissue is biopsied and examined under a microscope (histologic exam), it may share some similarities with aggressive juvenile fibromatosis. However, with the latter condition, the lesions do not progress to fully formed bone as they do in FOP. This can help a doctor make a distinction between the two.

One major diagnostic clue that would lead a doctor to suspect FOP as opposed to another condition is the presence of short, malformed big toes. If a tissue biopsy is unclear, a clinical exam of a child can help a doctor rule out aggressive juvenile fibromatosis. Children with the condition do not have the congenital malformation of toes or fingers, but a child with FOP nearly always does.

Another condition, Progressive Osseous Heteroplasia, can also be confused with fibrodysplasia ossificans progressiva. The key distinction when making the diagnosis is that bone growth in progressive osseous heteroplasia usually begins on the skin, not under it. These osseous plaques on the surface of the skin distinguish the condition from the tender nodules that occur in FOP.

Other tests a doctor may use if they suspect FOP include:

  • a thorough medical history and physical exam.
  • radiologic tests like computed tomography (CT) or bone scintigraphy (bone scan) to look for skeletal changes.
  • lab tests to measure alkaline phosphatase levels.
  • genetic testing to look for mutations.

If FOP is suspected, doctors will generally try to avoid any invasive tests, procedures, or biopsies because trauma usually results in more bone formation in someone with the condition.

While the condition doesn't typically run in families, parents who have a child diagnosed with FOP may find genetic counseling helpful.

Treatment

There is currently no cure for FOP. There is also no definitive or standard course of treatment. The treatments that do exist are not effective for every patient and therefore the primary goal is to treat symptoms and prevent bone growth when possible.

While treatment won't stop the progression of the condition, the medical decisions for managing pain and other symptoms associated with FOP will depend on the individual patient's needs. A doctor may recommend trying one or more of the following treatments to improve a patient's quality of life:

  • high-dose Prednisone or another corticosteroid during a flare-up.
  • drugs like Rituximab (typically used to treat rheumatoid arthritis).
  • iontophoresis, which uses an electric current to deliver medicine through the skin.
  • muscle relaxants or injections of a local anesthetic.
  • drugs called bisphosphonates that are used to help protect bone density.
  • non-steroidal anti-inflammatory drugs (NSAIDs).
  • medications to inhibit mast cells which may help reduce inflammation.

Ossification often occurs randomly and can not be completely prevented, but it also can happen in response to inflammation, injury, and illness.

Therefore, recommendations about activity, lifestyle, preventative care, and interventions may be made beginning in childhood.

These recommendations may include:

  • avoiding situations that could result in injury, like playing sports.
  • avoiding invasive medical procedures such as biopsies, dental work, and intramuscular immunizations.
  • prophylactic antibiotics to protect against illness or infection when appropriate.
  • infection prevention measures such as proper hand hygiene to guard against common viral illnesses (such as influenza) and other respiratory viruses as well as complications like pneumonia.
  • occupational and physical therapy.
  • mobility aids and other assistive devices such as walkers or wheelchairs.
  • other medical devices that can help assist with activities of daily living such as dressing and bathing.
  • medical devices or other safety interventions to help prevent falls, such as when rising from bed or showering.
  • assistance programs as needed as disability increases.
  • psychological and social support for patients and their families.
  • educational support, including special education and home-schooling.
  • genetic counseling for families may be useful.

Invasive procedures or surgeries to attempt to remove areas of abnormal bone growth are not advised, as the trauma of surgery almost invariably leads to the development of further ossification. If surgery is absolutely necessary, the most minimally-invasive technique possible should be used. Patients with FOP also may require special anesthesia considerations.

There have been several clinical trials in recent years with the goal of developing better treatment options for people with FOP.

A Word From Verywell

FOP is an extremely rare condition where a gene mutation causes the connective tissues of the body, including muscles, tendons, and ligaments, to become gradually replaced by bone (ossification). There is no cure for FOP and diagnosing it can be difficult. Treatment is mostly supportive and the progression of the condition is usually fairly unpredictable. Taking steps to avoid injury and other situations that would increase ossification may help reduce the number of "flares" a person has, but new bone may still form without any clear cause. FOP usually leads to complete immobility, and most people are bed-ridden by age 30. However, there are clinical trials underway that hopefully find better treatment options to improve the quality of life and the outcomes for patients with the condition.

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