Explore the rare genetic disorder called fibrodysplasia ossificans progressiva (FOP) and its symptoms, causes, and management on Meri Sehat.

Fibrodysplasia Ossificans Progressiva (FOP)

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ZAKA CLINIC GULBERG LAHORE

Saad Ullah Siddiqui

Overview

Fibrodysplasia ossificans progressiva (FOP) is an extremely rare genetic disorder characterized by bone formation outside the skeleton (heterotopic ossification). Muscles and connective tissue, such as the ligaments and tendons, are replaced by bone<a href="#accordion">[1]</a>. 
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The genetic condition is extremely rare, affecting approximately 1 in 1 million people globally. As per research, the French have the highest prevalence rate of FOP, with a whopping 1.36 per million being affected by this disease. 
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Fibrodysplasia ossificans progressiva (FOP) causes the body&#39;s skeletal muscles and soft connective tissues to metamorphose, or turn into bone. Thus, locking joints in place and making it difficult to move them. Ultimately, resulting in a second &ldquo;skeleton&rdquo; being formed. 
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The median lifespan of people affected by FOP is 56 years.

While the first case of fibrodysplasia ossificans progressiva (FOP) may have been described by Guy Patin in 1692, it wasn&rsquo;t until 1740 that the first detailed description of the disease came forward, courtesy of Dr. John Freke. 
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One case in particular that proved to be key in helping scientists understand this disease was of Harry Eastlack, from Philadelphia, who died at the age of 39 due to pneumonia. At the time of death, his entire body had completely ossified, except his lips. Today his skeleton is preserved and on display in The Mutter Museum of the College of Physicians in Philadelphia. Normal skeletons need to be glued together or fixed by wires so they can stand as one piece, which is not the case for his skeleton. It stands as a single piece. This is because sheets of bones that had ossified, connected his spine and shoulders, as well as other parts, such as limbs and spine, and pelvis and thighs.&nbsp; 
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Harry was born with the characteristic malformed greater toe, but no other abnormalities. Symptoms began at the age of 5 when he was hit by a car and fractured his leg. Thereafter, progressive heterotopic bone formation began in his lower limb and then soon spread to other parts of his body. However, his diagnosis was relatively late as doctors ignored the chances of FOP due to its uncommon nature. As a result, Harry underwent 11 operations along with several other biopsies. These delays resulted in the progression of the disease. 
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Now it has been discovered that attempts to remove this heterotopic bone generally result in explosions of new bone development. Moreover, minor soft tissue damage, muscle straining, over-exertion and weariness, intramuscular vaccines, injections for dental procedures, falls, and influenza-like diseases can all cause flare-ups<a href="#accordion">[1][2][3][4][5][6]</a>. 
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Signs and Symptoms

A malformation of the big toe at birth is a characteristic symptom of fibrodysplasia ossificans progressiva (FOP). Both the toes are shortened and turned inward towards each other. This bending of the toe is termed hallux valgus. The shortening of the great toe is due to a deformed distal first metatarsal and a missing or altered first phalanx. 
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Half the affected individuals may also have a congenitally abnormal thumb. Patients may also present with a missing or abnormal interphalangeal joint. Other toe and finger anomalies may include unusually small fingers and toes (microdactyly), and/or persistent fixation of the fifth finger in a bent posture (clinodactyly). Additional congenital signs may involve proximal medial tibial osteochondromas, distortion of the cervical segment of the spinal cord, and a femur with an unusually short, wide neck.&nbsp; 
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During early childhood, the following symptoms may develop:

<ul>
	<li>Painful fibrous nodules over the shoulders, back, and neck, usually following a trauma</li>
	<li>The tumor-like growths&nbsp; soon turn into bone (heterotopic ossification)</li>
	<li>Difficulty eating and talking due to involvement of jaw muscles</li>
	<li>Body stiffness&nbsp;</li>
	<li>Loss of mobility causing difficulty in walking, sitting, etc</li>
	<li>Chronic swelling in various areas of the body</li>
	<li>Spinal deformities, such as kyphosis and scoliosis</li>
	<li>Increased fractures</li>
	<li>Increased sensitivity to respiratory infections 
	&nbsp;</li>
</ul>

Although it&#39;s not always the case, a virus or injury will frequently trigger&nbsp;a flare-up. Flare-ups commonly last six to eight weeks and occur throughout life, spreading to the rest of the body. They might result in aches, swelling, joint stiffness, general discomfort, and a low-grade fever.

FOP does not cause an overgrowth of bone to the tongue, diaphragm, cardiac muscle, smooth muscle, or extraocular muscles<a href="#accordion">[11]</a>. 
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Causes

Fibrodysplasia ossificans progressiva is an autosomal dominant disorder and occurs as a result of a mutation of the ACVR1 gene. Only one copy of the altered gene is required to cause the disorder and this copy can be inherited from either of the two parents. Thus, the chances of an affected individual passing the abnormal gene to an offspring are 50%. However, in most cases, FOP occurs sporadically. 
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The ACVR1 gene is responsible for making bone morphogenic protein (BMP) type 1 receptor which is involved in the growth and development of bones and muscles. The receptors also play a role in ossification, which is the replacement of cartilage by bone. Gene mutation affects the activity of the receptor, causing an overgrowth of bone and cartilage<a href="#accordion">[1]</a>. 
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Currently, there are no screening tests for fibrodysplasia ossificans progressiva. 
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Diagnosis

In most situations, a patient&#39;s typical big toe deformity, together with quickly altering swellings on the head, neck, or back, may be used to accurately diagnose fibrodysplasia ossificans progressiva (FOP). 
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Other than a clinical evaluation, genetic testing for the ACVR1 gene may also be used to confirm the diagnosis. Doctors may also conduct the following tests: 
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<ul>
	<li>Laboratory Studies - In children, raised alkaline phosphatase levels are indicative of FOP.</li>
	<li>Imaging Studies - The most effective way to detect early FOP lesions is by CT scanning. Even before ossification is seen by radiographic examination, bone scintigraphy can be used to reveal a greater absorption of radiolabeled diphosphonate in places where lesions are beginning to form. In elderly individuals, heterotopic ossification of the pterygoid muscles may be shown on a CT scan, which is a possible cause of retrognathia and jaw constriction. Other imaging tests that help in examining new bone growth include X-rays.</li>
	<li>Procedures - Biopsy is generally not recommended in FOP, due to the chances of the disease aggravating and the frequency of flare-ups increasing. 
	&nbsp;</li>
</ul>

It is believed that 80 percent or more of FOP cases are misdiagnosed due to a lack of awareness of the condition. FOP sufferers and their families throughout the world have experienced agony and suffering as a result of these diagnostic mistakes. For instance, incorrect diagnosis has resulted in needless intrusive treatments, like biopsies (which can cause a flare-up), and long-term side effects from medical interventions, such as loss of mobility<a href="#accordion">[8][9][10]</a>. 
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Treatment

While there is no cure for FOP, treatment options are available for managing symptoms. Steroids are often used for relieving pain and inflammation associated with flare-ups. Moreover, nonsteroidal anti-inflammatory drugs, cyclo-oxygenase-2 inhibitors, leukotriene inhibitors, and mast cell stabilizers have also been used to treat chronic pain and recurrent flare-ups, but no therapy has yet been proven to be effective in changing the course of the disease&#39;s natural history. Although persistent immunosuppression is not generally advised due to the possibility of significant morbidity in the presence of severe restrictive chest wall disease, a recent report suggested that it may have some use. 
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Occupational therapy is also beneficial for patients with FOP. Braces, special shoes, and devices that help the patient walk are often used. 
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<h5>Future Treatment Possibilities Of Fibrodysplasia Ossificans Progressiva</h5>

Blocking Activity Of The Mutant FOP Receptor - STIs, or signal transduction inhibitors, have the potential to become strong therapeutics. Dorsomorphin, a small-molecule STI, was recently found by researchers. This molecule can inhibit all type I BMP receptors, preventing the overgrowth of bone. Importantly, this small-molecule STI completely inhibits all BMP-specific signaling in cells that have the overexpressed FOP gene, thus its use in the treatment of FOP presents as a breakthrough discovery.&nbsp; 
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Inhibiting The Inflammatory And Neuro-inflammatory Triggers Of FOP Flare-Ups - In FOP, sensory neurons control the innate immune system and enhance the production of heterotopic bone. This transformation is facilitated by substance P, a powerful neuro-inflammatory protein with 11 amino acids that functions as a bridge between the innate immune system and the sensory branch of the nervous system to trigger and increase heterotopic ossification. Recent studies focus on inhibiting the release of such inflammatory proteins to prevent flare-ups. 
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Inhibiting The Mutant FOP Allele - Using connective tissue progenitor cells from FOP patients, Kaplan et al. created inhibitory RNA (RNAi) duplexes that could precisely suppress the mutant copy of the ACVR1/ALK2 gene. The increased BMP signaling in FOP cells was reduced by this RNAi strategy to levels seen in control cells. However, the proof-of-concept study is yet to be tested on animals or humans<a href="#accordion">[10]</a>. 
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The tumor-like swellings can appear anywhere on the body. As the tissues are replaced by bone, the patient may lose the ability to move the body part. Thus, making it&nbsp; more difficult to: 
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<ul>
	<li>Breath as your lungs cannot fully expand</li>
	<li>Eat</li>
	<li>Keep balance</li>
	<li>Walk or sit</li>
	<li>Speak</li>
</ul>

 
Some people also experience a curving of their spine, either from the top to the bottom or from side to side. Moreover, as the range of motion gets restricted, people become more at risk of catching infections. Heart failure (cardiac muscles are unable to pump adequately), malnutrition, pneumonia, alopecia, and deafness are some of the complications of the disease<a href="#accordion">[11]</a>. 
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Although FOP is a genetic disorder, certain factors can increase the risk of flare-ups. These include:

<ul>
	<li>Trauma or injury</li>
	<li>Viral infections</li>
	<li>Dental procedures</li>
	<li>Surgery 
	&nbsp;</li>
</ul>

Physicians suggest the following for individuals with a family history of FOP:

<ol>
	<li>Chromosomal testing of baby or embryo, via amniocentesis</li>
	<li>Frequent check-ups</li>
	<li>Keeping a look out for joint stiffness or nodule formation</li>
	<li>Avoid activities that present the risk of injury</li>
	<li>Avoid intramuscular injections</li>
	<li>Avoid undergoing general anesthesia&nbsp; 
	&nbsp;</li>
</ol>
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Key Points

<ul>
	<li>Fibrodysplasia ossificans progressiva (FOP) is an extremely rare genetic connective tissue disorder characterized by the aberrant formation of bone in parts of the body where the bone is not ordinarily present (heterotopic ossification), such as the ligaments, tendons, and skeletal muscles.</li>
	<li>FOP patients typically present with malformed oversized toes at birth, this may or may not be accompanied by other skeletal deformities.</li>
	<li>The disease is autosomal dominant and occurs as a result of a mutation of the ACVR1 gene. This means that the chances of an affected individual passing the abnormal gene to an offspring is 50%</li>
	<li>Body stiffness and restricted movement are observed in all individuals, and it may impact jaw muscles as well, limiting the patient&rsquo;s ability to eat or speak.</li>
	<li>Some people also experience curvature in their spine, either from the top to the bottom or from side to side.</li>
	<li>It is believed that 80 percent or more of cases of FOP are misdiagnosed by doctors due to a lack of awareness of the condition among them.</li>
	<li>Currently, no cure has been found for FOP, however, treatment options focus on managing symptoms. Steroids and NSAIDs are often administered to help control flare-ups.</li>
	<li>Although the disease is not curable at the moment, early diagnosis and treatment options can increase lifespan as well as control symptoms. 
	&nbsp;</li>
</ul>
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[1] Fibrodysplasia Ossificans Progressiva. NORD (National Organization for Rare Disorders).

[2]  Pignolo RJ, Wang H, Kaplan FS. Fibrodysplasia Ossificans Progressiva (FOP): A segmental progeroid syndrome. Frontiers.

[3] Fibrodysplasia Ossificans Progressiva: Medlineplus Genetics. MedlinePlus.

[4] Pignolo, R.J., Hsiao, E.C., Baujat, G. et al. Prevalence of fibrodysplasia ossificans progressiva (FOP) in the United States: estimate from three treatment centers and a patient organization. Orphanet J Rare Dis 16, 350 (2021)

[5] Kamal AF, Novriansyah R, Rahyussalim, Prabowo Y, Siregar NC. Fibrodysplasia Ossificans Progressiva: Difficulty in Diagnosis and Management A case report and literature review. J Orthop Case Rep. 2015;5(1):26-30. doi:10.13107/jocr.2250-0685.248

[6] Kaplan FS. The skeleton in the closet. Gene. 2013;528(1):7-11. doi:10.1016/j.gene.2013.06.022

[7] Pignolo, R.J., Shore, E.M. & Kaplan, F.S. Fibrodysplasia Ossificans Progressiva: Clinical and Genetic Aspects. Orphanet J Rare Dis 6, 80 (2011).

[8] Fibrodysplasia Ossificans Progressiva. ucsfbenioffchildrens.org.

[9] Robert A Schwartz MD. Fibrodysplasia Ossificans Progressiva workup. Laboratory Studies, Imaging Studies, Procedures

[10]  Pignolo RJ, Shore EM, Kaplan FS. Fibrodysplasia ossificans progressiva: diagnosis, management, and therapeutic horizons. Pediatr Endocrinol Rev. 2013;10 Suppl 2(0 2):437-448.