When I was a child I remembered being somewhat disturbed by the medusa in the film Clash of the Titans, who could turn someone into a stone statue by simply making eye contact. Years later I heard of a genetic disease that had a similar effect, where extra bone grows inside connective tissue such as muscles, tendons (which connect muscle to bone), ligaments (which connect bones to other bones across a joint), fascia (a thin layer that surrounds the muscle) and aponeurosus (connective tissues that join large muscle groups together). This process effectively stiffens a person's joints permanently, locking them into place. In some instances the condition has reduced a person's total mobility to that of a statue.
Affecting only one in every two million people (approximately 3,300 individuals worldwide, though only around 700 cases have been reported), this incredibly rare and devastating disease is known as fibrodysplasia ossificans progressiva (FOP) (which translates into “soft connective tissue that progressively turns into bone”). It is the only known condition which transforms one organ (in this case soft tissue) into something else (bone).
Early Symptoms of FOP
Children of a FOP patient have a 50 percent chance of inheriting the condition themselves. The condition is a congenital disease (meaning that it starts before birth), with the first noticeable symptom being a malformed big toe that may appear short, curved inward or bent. Congenital malformation of the thumbs also appears in around 50 percent of cases. Stiffness in the spine also often precedes heterotopic ossification (extra bone growth inside of the body by outside of the normal skeleton).
Individuals with FOP are born with a malformation of the joints that connect the ribs to the vertebrae in the spine, causing restrictions in the chest area that may result in making FOP sufferers rely more on the diaphragm muscle for respiration.
Children with FOP also tend to be unable to crawl and tend to drag themselves across the floor instead. This is due to the facet joints (small stabilizing joints that are in constant motion with the spine) in the back of the neck being malformed or fused, therefore limiting movement.
What Happens to FOP Patients
Throughout their life FOP sufferers experience flare-ups, which can begin as early as their first year of life and initially take the appearance of soft lumps or tumors on the neck, back and shoulders. This often results in the formation of new bone in these parts of the body. A single flare-up can last up to 8 weeks and during this time FOP sufferers are likely to experience redness, inflammation, stiffness, tissue swelling and discomfort in the affected areas as well as a low-grade fever and varying degrees of pain. Heterotopic ossification begins and becomes noticeable within the first two decades of life, with most people becoming aware of their condition by the age of 10.
While there is no certainty as to what causes flare-ups, researchers have found that it can be provoked by trauma to parts of the body caused by intramuscular injections, surgery, dental procedures, influenza-like viral illnesses and bumps and bruises from falling over.
Extra bone growth usually follows a pattern, progressing from head to toe and from back areas to regions at the front. FOP affects the neck, spine, chest, shoulders, elbows, wrists, hips, knees, ankles, jaw, and many other areas in between, while sparing the heart, diaphragm, tongue and extra-ocular muscles.
The ability to walk (ambulation), is often lost in one's 20s and 30s due to ankylosis (stiffening) in the hip. As the heterotopic ossification continues and people find themselves unable to move body parts, many FOP patients have to decide whether they want to spend the rest of their life standing up or sitting down and will require lifelong assistance in carrying out daily activities.
Hearing loss exists in around 50 percent of cases and progressive immobility and ossification in 100 percent, resulting in reduced fitness. Heterotopic ossification can also result in bones crowding the muscles around the lungs and the heart, limiting chest expansion and interfering with breathing, creating a greater likelihood of succumbing to cardiorespiratory complications from thoracic insufficiency syndrome, which affects more than 95 percent of FOP patients.
History of FOP
FOP was first reported in 1692, when French physician Guy Patin told a colleague about a meeting he had with a patient, whom he describes as becoming “hard as wood all over”. The condition wasn't put on the medical agenda until 1936 by London physician and ophthamologist (a specialist focusing on eye physiology and diseases), John Freke, who wrote about a 14-year-old boy who had swellings all over his back and neck that “arose from every rib and joined together in all parts of his back”, resembling “a bony pair of bodice”.
One of the most famous FOP patients was Henry Eastlack Jr. who died of pneumonia in 1973 at the age of 40 and whose entire body had become fused into one contiguous block due to extra bone growth. Eastlack decided that when he died his body should be donated to science, and it is now on display at the Mutter Museum of the College of Physicians in Philadelphia. Eastlack's body is used as a point of reference and research by FOP scientists.
Misdiagnosis
Due to its rarity, FOP is often misdiagnosed as a medical condition. A 2005 study that interviewed 138 FOP patients from around the world (around 51 percent of known FOP patients at the time who were members of the International FOP Association), found that:
- 87 percent of cases were misdiagnosed
- only 8 percent of the 184 medical text books examined contained adequate descriptions of FOP, including the caution that trauma (such as surgery, intramuscular injections etc.) can accelerate the process of renegade bone growth
- Only 10 percent of doctors had heard of FOP
- the most common misdiagnoses were cancer and fibramotosis, including aggressive fibramotosis and desmoid tumors (32 percent)
- the average number of years it took for patients to receive a correct diagnosis was 4.1 years
- the number of physicians consulted before a correct diagnosis ranged from 1-51 physicians, with the median number being 6
- 67 percent of patients underwent unnecessary and invasive procedures, such as biopsies
- 68 percent received inappropriate therapies, including physiotherapy (28 percent), chemotherapy (10 percent) or radiotherapy (5 percent), with multiple surgical procedures (2-6 procedures) taking place in around 8 percent of cases
- 49 percent reported permanent mobility loss as a result of invasive medical procedures that triggered a flare-up, leading to extra bone growth
- 53 percent of patients received accurate information when FOP was diagnosed correctly. However 17 percent of patients were given no information and 30 percent were given inaccurate details, with doctors usually telling the patient that they would die soon or the condition will eventually “burn out”
An example of misdiagnosis can be seen in the case of Ashley Kurpiel, whose story was broadcast on the T.V. program Mystery Diagnosis. When her mother noticed that her big toes were malformed and smaller than her other toes, the paediatrician reassured her that it was not serious. When a lump appeared on her back she was misdiagnosed with aggressive infantile fibramatosis that had spread to her right arm and shoulder (which were subsequently amputated by surgeons). It wasn't until significantly later when the condition spread to her left arm, preventing her from raising it without causing pain, that she was then diagnosed with FOP.
Mortality of FOP Sufferers
Examining the death of 60 FOP patients over a 33-year period, a 2010 study estimated that the median life expectancy for a person with FOP was 40 years, although the ages ranged from 3 to 77 years old. The study found that the most common causes of death in FOP patients are:
- cardiorespiratory failure from thoracic insufficiency syndrome, where due to extra bone growth in the chest area normal respiration or lung growth can not be supported. This affected 54 percent of the 60 deceased, with a median age of 42 years.
- pneumonia, which affected 15 percent of the 60 deceased (who had a median age of 40 years)
- head injuries from falling over, which happened to 11 percent of the deceased - this group had a median age of 41 years, but ranged from 32 to 46 years.
The FOP Gene
In 2006 Dr. Fredrick Kaplan from Pennsylvania University, led a study that determined the cause for FOP was a mutation in the activin A receptor, type I (ACVR1) gene, also known as 'activin receptor-like kinase 2' (ALK2), which is a member of a protein family called 'bone morphogenetic protein (BMP) type I receptors'.
Everyone has two copies of the ACVR1/ALK2 gene in every cell of their body, which helps the growth and development of bones and muscles. In FOP patients one ACVR1/ALK2 copy is damaged, resulting in over-activity of the ACVR1 genes and leading to renegade bone formation and fusion of joints.
FOP Treatment
Unfortunately as there is no cure for FOP, it progressively gets worse and never better. Surgery to remove new bone growth, has been ineffective, as it usually provokes explosive new born formation in that part of the body. A large variety of medications have been tried without much success, including:
- adrenocorticotropic hormone (ACTH)
- oral etidronate
- non-steroidal anti-inflammatory agents
- steroids
- ethylene
- diamine tetraacetic acid (EDTA)
- interferon
- thalidomide
- squalamine
- prednisone.
In October 2011, scientists at the Research for FOP and Related Disorders at the University of Pennsylvania made a promising discovery. Using a small sequence of ribonucleic acid (RNA), a macromolecule similar to DNA, scientists were able to block the damaged copy of the ACVR1/ALK2 gene, while leaving the healthy copy untouched. The procedure returned ACVR1/ALK2 cellular activity to normal.
Scientists used progenitor stem cells from discarded baby teeth of FOP patients, which contained the exact combination of damaged and normal ACVR1/ALK2 genes in all classically affected FOP patients worldwide. However the scientists have not yet discovered an efficient and safe method of delivering the RNA molecules to cells in the human body.
“We still have a long way to go”, the researchers acknowledged “but we've taken the first big step”.
Bibliography:
- International Fibrodysplasia Ossificans Progressiva Association website, http://www.ifopa.org/
- Kantanie S, Delai P.L.R, Kaplan F.S & Shore. E.M (eds). 'What is FOP? Fibrodysplasia ossificans progressiva: A Guidebook for Families'. Florida, USA; International FOP Association, 2009.
- Kaplan F.S, Glaser D.L, Pignolo R.J & Shore E.M. (eds), 'Clinical Reviews on Bone and Mineral Metabolism'. New York, USA; Humana Press Inc. Vol.3, Nos.3-4, 2005.
- Kaplan, F.S, Kaplan, J & Shore E.M. Genetic Technology Restores Normal BMP Signalling and Suppresses Bone Differentiation in a Human Stem Cell Model of FOP: Proof of Principle for the Treatment of FOP. Accessed on 2/1/2012.
- Kaplan F.S, Zasloff M.A, Kitterman J.A, Shore E.M, Hong C.C, MD & Rocke, D.M, “Early Mortality and Cardiorespiratory Failure in Patients with Fibrodysplasia Ossificans Progressiva”, The Journal of Bone and Joint Surgery, 2010 March Vol 92. No.3
- Kitterman J.A, Kantanie S, Rocke D.M and Kaplan F.S. “Latrogenic Harm Caused by Diagnostic Errors in Fibrodysplasia Ossificans Progressiva”, Paediatrics, Volume 116, No.5 November 2005.
- Mystery Diagnosis: 'The Girl Who Couldn't Move', T.V Series Broadcast on 2/3/2009.
- Moore E., Xu M, Feldman, G.J., Fenstermacher D.A., The FOP International Research Consortium, Brown M.A., Kaplan F.S.,“A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva”, Nature Genetics, Volume 38, Number 5, May 2006.
- U.S Department of Health and Human Services, “ACVR1”, Accessed on 2/1/2012.
Paul Campobasso - I live in Melbourne, Australia and recently graduated from university completing a Bachelor of Arts with Honours in Politics and a ...
