Fibrodysplasia ossificans progressiva (FOP)

What is fibrodysplasia ossificans progressive (FOP)?

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder that causes muscles, tendons, and other soft tissues to turn permanently into bone. Extra bone forms across joints making movement difficult and sometimes impossible. This process of ossification continues throughout a patient's life. FOP affects many areas of the body including, but not limited to, the neck, spine, chest, shoulders, elbows, wrists, hips, knees, ankles and jaw.

FOP is a progressive disease, which means it typically gets worse as the patient ages. The rate of new bone formation differs for each person, and the disease's progression is generally unpredictable.

FOP is known to affect about 2,500 people globally, across all ethnicities, ages, genders, and races. Because FOP is such a rare disease, experts believe that 80 percent or more of the cases are misdiagnosed and the number of people with FOP may actually be much higher.

Experts in both pediatric and adult endocrinology, genetics, orthopedics, orthopedic surgery and rheumatology at UCSF Benioff Children's Hospitals are among the few in the country who readily diagnose and treat FOP. In addition, researchers at UCSF are studying how the disease progresses and working to identify new therapies.  

Causes of FOP

Fibrodysplasia ossificans progressiva is caused by a gene mutation in the ACVR1/ALK2 gene that can either be inherited or occur spontaneously. FOP is an autosomal dominant condition, which means that a person only needs to get the mutation for FOP from one parent to inherit the disease. In most cases, however, FOP develops as a new mutation—an accident of nature. A person with FOP, however, has a 50% chance of passing it on to their child. 

Symptoms of FOP

A telltale sign of fibrodysplasia ossificans progressiva is a malformation of a newborn's big toes. Sometimes these are described as "baby bunions" or the toes are shortened where the first joint in the toe is malformed.  This malformation, which is apparent at birth, consists of a short big toe with an abnormal turning of the toe called a valgus deviation.

During early childhood, patients with FOP can form painful fibrous nodules, or significant soft tissue or tumor-like swellings called "flare-ups," usually over the neck, back, and shoulders. These nodules often develop after a child experiences some sort of trauma to the body, such as a bump or fall. Episodes can also occur without any warning or without an obvious traumatic event.  In many cases, the nodules transform into bone during a process known as heterotopic ossification.  This new bone can cause deformities in the body and can cause loss of motion.

Some patients may also have a low-grade fever during a flare-up. The episodes can last as long as six to eight weeks. The disease typically starts along the trunk and neck, and then progresses to the limbs as the child gets older. 

Although a person is born with FOP, extra bone may not appear at birth. They may go months or years without experiencing a flare-up or bone formation.

Diagnosis of FOP

In most cases, an accurate diagnosis of fibrodysplasia ossificans progressiva can be made based on a patient's characteristic malformation of the big toe, in addition to rapidly changing swellings on the head, neck or back.  Genetic testing for mutations in the ACVR1 gene can help clarify if a patient has FOP or another bone formation disease.

When a patient is suspected of having FOP, it is important to stop intramuscular injections (including vaccinations) and not do any elective surgical procedures, as these events can trigger more bone formation. 

Errors in diagnosing FOP have caused pain and suffering for FOP patients and their families worldwide. Misdiagnosis has led to unnecessary invasive procedures, such as biopsies, as well as permanent complications from medical interventions, including loss of mobility. Three of the most common misdiagnoses for FOP are cancer, aggressive juvenile fibromatosis (also called desmoid tumors) and progressive osseous heteroplasia, another rare disease characterized by the abnormal growth of bone.

Treatment of FOP

Until recently, there was no effective treatment for fibrodysplasia ossificans progressiva. However, in 2023, the FDA approved the first drug shown to control the growth of new bone, palovarotene (Sohonos). Its development was based, in part, on clinical research studies done at UCSF. The drug offers new promise for improving quality of life for FOP patients.

Other therapies focus on alleviating the pain and inflammation experienced during flare-ups. They include high dose corticosteroids, as well as other pain and anti-inflammation medications. Other medications such as more powerful anti-inflammatory medications are currently being studied as potential therapies for FOP.

Surgery is not an option for removing the excess bones because surgery often results in more bone formation. Elective surgeries should not be performed in patients with FOP.

Patients also may have opportunities to participate in clinical trials of promising treatments for fibrodysplasia ossificans progressiva. Learn more about the process and potential benefits of enrolling your child in a clinical trial.