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What is Fibrodysplasia Ossificans Progressiva (FOP)?

FOP (previously known as myositis ossificans) is an ultra rare and severely disabling myopathy characterized by heterotopic ossification (HO), the abnormal growth of bone in muscles, tendons and soft tissue.

Over time, people with FOP lose mobility as sheets, ribbons and plates of extra bone form, locking joints and leading to cumulative loss of function and disability.

FOP is a progressive, chronic disease with most affected people confined to a wheelchair by the third decade of their life. People with FOP have an estimated median lifespan of 40 years, with death often resulting from the inability of the thorax to support normal respiration (thoracic insufficiency syndrome).

The disease is sometimes referred to as “stone man syndrome” because affected individuals are slowly imprisoned by a second skeleton. This image is used by kind permission of the College of Physicians of Philadelphia

This image is used by kind permission of the College of Physicians of Philadelphia

What Are the Signs and Symptoms of FOP?

Almost all people with FOP have a hallmark, bilateral toe malformation, in which the big toes are shortened and bent inwards resembling a bunion (hallux valgus).

Painful and recurrent episodes of soft tissue swelling called flare-ups often precede heterotopic bone formation. These flare-ups typically begin early in life and may occur spontaneously or after trauma, muscular stretching, overexertion and fatigue, intramuscular immunizations, mandibular blocks (nerve block injection) for dental work, or flu-like infections. Flare-ups may involve a combination of swelling (from mild to severe, or “tumor-like”), redness, warmth, pain and weakness or limited use of muscles/joints.

Bone formation in the jaw area can cause difficulty with speech and eating, potentially leading to severe malnutrition. Additionally, bone formation around the rib cage restricts expansion of the lungs and diaphragm and can cause respiratory compromise (condition in which the lungs cannot take in sufficient oxygen or expel sufficient carbon dioxide).

Other features associated with FOP include:

  • Curvature of a digit (clinodactyly)
  • Shortened thumbs (brachydactyly)
  • Short broad femoral necks (part of the thigh bone)
  • Osteochondromas (benign bone tumor) – commonly of the proximal or upper part of the tibia (large bone in lower front portion of leg)
  • Dental anomalies
  • A small percentage of people with FOP have very severe or very mild toe/thumb malformations, neurological manifestations, eye conditions, or sparse hair

Read more about early signs and symptoms of FOP in infancy and early childhood.

Clinical Features of FOP

Some images are courtesy of www.fopsverige.se

Why is Early Diagnosis Important?

Misdiagnosis or delays in diagnosis may have serious consequences for people living with FOP. Common diagnostic and medical procedures, such as biopsies, intramuscular injections and surgery can provoke flare-ups that exacerbate new bone formation. Common misdiagnoses include aggressive juvenile fibromatosis (a benign soft tissue tumor), lymphedema (swelling caused by excess fluid in tissues) and soft tissue sarcoma (malignant tumor).

87

percent of people with FOP reported they were initially misdiagnosed 

50

percent of these individuals underwent interventions that triggered bone formation and caused permanent loss of mobility 

4.1

is the average number of years from initial symptoms to a proper diagnosis of FOP

6

physicians is the average number consulted prior to a proper diagnosis of FOP

What Causes FOP?

Individuals with FOP have a mutation in the ACVR1 gene that encodes for the ACVR1/ALK2 receptor. This receptor is part of the bone morphogenetic protein, or BMP, signaling pathway and is critical in the regulation of cartilage and bone development and growth.

The mutation leads to increased activity of the ACVR1/ALK2 receptor and resulting excessive BMP signaling. Recent research has demonstrated that the mutated ACVR1/ALK2 receptor becomes overactive in the presence of activin-A, a protein (ligand) that helps to regulate cell behavior. Regardless of the mechanism of activation, protein messengers downstream of the ACVR1/ALK2 receptor called Smads have to undergo phosphorylation (are activated by the addition of phosphorus) and form complexes that deliver the excessive BMP signaling to the cell’s nucleus.

The activated Smads regulate gene expression so that the progenitor (stem) cells that are recruited in the affected muscle or soft tissue are directed to become cartilage. The formed cartilage is then invaded by blood vessels and ultimately, the muscle or soft tissue is destroyed and replaced by heterotopic bone.

Approximately 95 percent of FOP cases are thought to be caused by sporadic (de novo) mutations in the ACVR1 gene, while the remaining 5 percent are thought to be inherited in an autosomal dominant manner. The most common ACVR1 gene mutation, R206H, is present in 97 percent of people with FOP.

How Prevalent is FOP?

FOP is ultra rare with an approximate prevalence of 1.3 individual for every million lives. About 850 people have a known diagnosis of FOP. Of these, over 500 are members of the International Fibrodysplasia Ossificans Progressiva Association (IFOPA), a well-organized patient advocacy group.

How is FOP Treated?

There are currently no approved treatments for FOP. Steroids and NSAIDs can be used, but only to manage swelling  and pain  associated with flare-ups. Surgery to remove extra bone results in explosive abnormal bone growth, further limiting mobility.   Guidelines for symptomatic flare-up management can be found at the IFOPA website (www.ifopa.org).

References:

International Fibrodysplasia Ossificans Progressiva Association. FOP Fact Sheet.  Accessed June 10, 2015 via http://www.ifopa.org/fop-fact-sheet.html

National Institutes for Health. Fibrodysplasia Ossificans Progressiva. Accessed June 10, 2015 via http://ghr.nlm.nih.gov/condition/fibrodysplasia-ossificans-progressiva

Kaplan et. al. Early Mortality and Cardiorespiratory Failure in Patients with Fibrodysplasia Ossificans Progressiva. J Bone Joint Surg Am. 2010 Mar; 92(3): 686–691.

Mahboubi S. et. al. Fibrodysplasia ossificans progressiva. Pediatr Radiol. 2001 May;31(5):307-14.

Kaplan et. al. Early Mortality and Cardiorespiratory Failure in Patients with Fibrodysplasia Ossificans Progressiva. J Bone Joint Surg Am. 2010 Mar; 92(3): 686–691.

Kaplan et. al. Early diagnosis of fibrodysplasia ossificans progressiva. Pediatrics. 2008 May;121(5):e1295-300. doi: 10.1542/peds.2007-1980.

Zhang et. al. The phenotype and genotype of fibrodysplasia ossificans progressiva in China: A report of 72 cases. Bone. 2013 (57). 386–391

Pignolo et. al. Fibrodysplasia Ossificans Progressiva: Clinical and Genetic Aspects. Orphanet J Rare Dis. 2011; 6: 80.

Kaplan et. al. Fibrodysplasia ossificans progressiva: mechanisms and models of skeletal metamorphosis. Dis Model Mech. 2012 Nov; 5(6): 756–762.

Kaplan et. al. Early Diagnosis of Fibrodysplasia Ossificans Progressiva. Pediatrics. 2008 May; 121(5): e1295–e1300.

Brantus JF et. al. Effects of intravenous etidronate and oral corticosteroids in fibrodysplasia ossificans progressiva. Clin Orthop Relat Res. 1998 Jan;(346):117-20.

Kitterman et. al. Neurological symptoms in individuals with fibrodysplasia ossificans progressive. J Neurol. 2012 Dec; 259(12): 2636–2643.

International Fibrodysplasia Ossificans Progressiva Association. FOP FAQ. Accessed on June 10, 2015 via http://www.ifopa.org/what-is-fop/faq.html

Kaplan et. al. Early diagnosis of fibrodysplasia ossificans progressiva. Pediatrics. 2008 May;121(5):e1295-300. doi: 10.1542/peds.2007-1980.

Hatsell et. al. ACVR1R206H receptor mutation causes fibrodysplasia ossificans progressive by imparting responsiveness to activin A. Science Translational Medicine. 2015 Sept; 303(7): 303ra137.