Fibrodysplasia Ossificans Progressiva

Fibrodysplasia ossificans progressiva is an extremely rare genetic condition where muscle tissue and connective tissues like tendons and ligaments gradually turn into bone outside the skeleton, progressively limiting movement and causing severe disability throughout a person’s life.

FOP, Myositis ossificans progressiva, Progressive myositis ossificans, Progressive ossifying myositis, Münchmeyer disease, Stone man disease

Table of contents

• What is Fibrodysplasia Ossificans Progressiva?
• How Common is the Condition?
• What Causes FOP?
• How is FOP Inherited?
• Signs and Symptoms
• How FOP Affects the Body
• Diagnosis
• Historical Background

What is Fibrodysplasia Ossificans Progressiva?

Fibrodysplasia ossificans progressiva is a disorder in which muscle tissue and connective tissue such as tendons and ligaments are gradually replaced by bone, forming bone outside the skeleton that limits movement.^[1] This new bone formation is called heterotopic ossification, which means bone grows in places where it shouldn’t normally exist.^[5]

The bone that forms in people with FOP is not just hardened calcium deposits. It is identical to normal bone tissue, but it grows in improper locations throughout the body.^[3] This process eventually creates a second skeleton that progressively restricts a person’s ability to move. FOP is the only known medical condition in which tissue of one organ system changes into that of another.^[3]

The condition affects many areas of the body including the neck, spine, chest, shoulders, elbows, wrists, hips, knees, ankles, and jaw.^[5] This process generally becomes noticeable in early childhood, starting with the neck and shoulders and proceeding down the body and into the limbs.^[1] FOP is a progressive disease, which means it typically gets worse as the patient ages, though the rate of new bone formation differs for each person and the disease’s progression is generally unpredictable.^[5]

• Skeletal muscle
• Tendons
• Ligaments
• Neck
• Shoulders
• Spine
• Chest
• Elbows
• Wrists
• Hips
• Knees
• Ankles
• Jaw
• Rib cage
• Big toes

How Common is the Condition?

Fibrodysplasia ossificans progressiva is a very rare condition. It is believed to occur in approximately 1 in 1 million to 1 in 2 million people worldwide.^[1][2] FOP is known to affect about 2,500 people globally, across all ethnicities, ages, genders, and races.^[5] Several hundred cases have been reported, though experts believe that 80 percent or more of cases are misdiagnosed, and the number of people with FOP may actually be much higher.^[1][5]

Fibrodysplasia ossificans progressiva can affect anyone because it’s most often the result of a new genetic mutation that wasn’t inherited from a parent.^[2] Genetic mutations are unpredictable and occur during fertilization due to an error when cells divide and replicate.^[2]

What Causes FOP?

Variants, also known as mutations, in the ACVR1 gene cause fibrodysplasia ossificans progressiva.^[1] This gene provides instructions for making a member of a protein family called bone morphogenetic protein (BMP) type I receptors.^[1] The ACVR1 protein is found in many tissues of the body including skeletal muscle and cartilage, and it helps to control the growth and development of the bones and muscles.^[1]

Studies show that variants in the ACVR1 gene disrupt mechanisms that control the receptor’s activity. As a result, the receptor is turned on when it normally should not be.^[1] Too much receptor activity causes overgrowth of bone and cartilage, resulting in the signs and symptoms of fibrodysplasia ossificans progressiva.^[1] The bone morphogenetic proteins lead to the formation of heterotopic bone in the soft tissues.^[4]

How is FOP Inherited?

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.^[1] 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.^[5]

Most cases of fibrodysplasia ossificans progressiva result from new variants in the gene. These cases occur in people with no history of the disorder in their family.^[1] In most cases, FOP develops as a new mutation—an accident of nature.^[5] In a small number of cases, an affected person has inherited the variant from one affected parent.^[1] A person with FOP has a 50% chance of passing it on to their child.^[5]

Signs and Symptoms

A telltale sign of fibrodysplasia ossificans progressiva is a malformation of a newborn’s big toes.^[5] 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.^[1] Sometimes these are described as “baby bunions” or the toes are shortened where the first joint in the toe is malformed.^[5] This malformation, which is apparent at birth, consists of a short big toe with an abnormal turning of the toe called a valgus deviation.^[5] Affected individuals may also have short thumbs and other skeletal abnormalities.^[1]

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.^[5] 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.^[5] 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 called myositis followed by more rapid ossification in the injured area.^[1] Flare-ups may also be caused by viral illnesses such as influenza.^[1] Some patients may also have a low-grade fever during a flare-up.^[5]

In many cases, the nodules transform into bone during a process known as heterotopic ossification.^[5] This new bone can cause deformities in the body and can cause loss of motion.^[5]

How FOP Affects the Body

Extra-skeletal bone formation causes progressive loss of mobility as the joints become affected.^[1] People diagnosed with fibrodysplasia ossificans progressiva have a restricted range of motion due to their muscles and connective tissue gradually turning into bone.^[2] Extra bone forms across joints making movement difficult and sometimes impossible.^[5] The condition ultimately immobilizes sufferers as new bone replaces musculature and fuses with the existing skeleton.^[3]

Inability to fully open the mouth may cause difficulty in speaking and eating.^[1] Children may experience difficulty eating, which can lead to malnutrition, and speaking because irregular bone growth causes the mouth to not open completely.^[2] Over time, people with this disorder may experience malnutrition due to their eating problems.^[1]

They may also have breathing difficulties as a result of extra bone formation around the rib cage that restricts expansion of the lungs.^[1] Extra bone growth around the rib cage can restrict how lungs expand and cause breathing difficulties.^[2] The median age of survival is roughly around 40 years.^[4] Death occurs in such cases primarily due to thoracic insufficiency syndrome and related complications.^[4]

Any type of trauma to the body can cause a flare-up of the condition. This could be after surgery, a fall or an illness like the flu. These trigger swelling and inflammation of the muscles that lasts for days to months around the affected area.^[2] Surgical removal of ossified bone causes the body to “repair” the affected area with additional bone.^[3]

Diagnosis

The diagnosis of FOP is clinical, based on skeletal malformations including malformed great toes, soft tissue swelling, and progressive heterotopic ossification, but requires genetic confirmation through testing for an ACVR1 gene mutation.^[13] PCR is the main diagnostic modality for the analysis of genetic mutation in FOP.^[4]

Making a diagnosis of fibrodysplasia ossificans progressiva was difficult for a long time as there were no reliable biomarkers for such cases that could be evaluated in urine or peripheral blood.^[4] If FOP is suspected, all elective procedures such as surgeries, biopsies, and immunizations should be deferred until a definitive diagnosis is made.^[13]

Historical Background

Early cases of fibrodysplasia ossificans progressiva emerged in the 17th and 18th centuries where physicians first documented their findings.^[2] Dr. Guy Patin first described FOP, which he said caused men to become as “stone”, in 1692.^[3]

The condition received the name “myositis ossificans progressiva,” which means “muscle turns progressively to bone,” in the early 1900s.^[2] FOP was originally called myositis ossificans progressiva and was thought to affect only muscle.^[3]

After extensive genetic research by Dr. Victor McKusick of Johns Hopkins University School of Medicine, the condition’s name changed to fibrodysplasia ossificans progressiva to better reflect how both soft tissue and muscle turn to bone.^[2] Dr. Victor A. McKusick gave the disease its modern name in 1970, when he discovered it does not only affect muscle.^[3]

In 2006, a research team at the University of Pennsylvania School of Medicine identified the specific genetic mutation that causes the condition.^[2]