Stone Man Syndrome: Turning into a living statue
For most people, falling is a minor injury which is only slightly painful and certainly not a cause for alarm, but this isn’t the case for everyone. Individuals with fibrodysplasia ossificans progressiva (FOP), better known as Stone Man Syndrome, live their lives in fear of minor injuries, which trigger the progression of their condition. FOP is a rare disease which affects one in two million people; it slowly turns connective tissue such as tendons, muscles, and ligaments into bone.1 Stone Man Syndrome currently has no treatment, and although there is research into finding a treatment for the disease, the disease’s rarity and patient fragility make it difficult to study. Despite these obstacles scientists are making progress, finding creative ways to create a treatment for this peculiar disease.
The human skeleton provides the framework for the body, permits movement, and protects internal organs. Normally bones develop in the fetal stage and continue to grow into adolescence stopping upon reaching adulthood. Bone growth occurs at the growth plate at both ends of a bone, the bone grows as cartilage cells are ossified, turning them into bone.2 Upon reaching adulthood there is no more growth of cartilage, and bone completely replaces the remaining cartilage. The problem with FOP is that bone growth does not stop upon reaching adulthood, and continues to grow abnormally, creating a second skeleton; this process is known as heterotopic ossification (HO).1 This second skeleton grows over connective tissue, and once formed it is permanent.
The cause of FOP was discovered in 2006, following a 15-year search to find the gene responsible for the disease. A point mutation in the ACVR1 gene is associated with the development of FOP.1 The normal function of the ACVR1 gene is to provide instructions for producing bone morphogenetic protein (BMP) type 1 receptors. This protein is located in both skeletal muscle and cartilage helping to control the growth and development of bones including ossification.3 The mutation found in FOP patients changes the shape of the BMP1 receptor, causing it to have increased signalling even in the absence of a ligand.1 The effect of this becomes worsened upon injury of soft tissues, such as ligaments and muscles, as there is increased release of BMP1 receptors which leads to the growth of bone cells at the site of the injury.3
FOP has a major impact on patients’ lives. FOP causes difficulty of movement, joint stiffness, and can lead to difficulties with eating and breathing. Most patients with FOP are bedridden by age 20 and have a life expectancy of 40 years.4 Patients with FOP must adjust their lifestyle so as to not quicken the progression of their condition by being careful to avoid injury, which means not playing contact sports and avoiding falls. As the disease continues to progress, patients eventually become unable to perform simple tasks of daily life such as cooking or bathing.4 Life also becomes increasingly expensive for patients with FOP, costs for caregivers, and tools to help individuals maintain their independence despite their limited mobility.
Despite the effects of this disease patients such as 18-year-old Seanie Nammock from London do their best to stay positive. Nammock was diagnosed with FOP at the age of 12 when her mother noticed an abnormally large hump on her back after a fall. The inflamed area was being replaced with bone causing excruciating pain for Nammock, which caused her doctor to make the diagnosis. Nammock’s neck and backbone have since fused together preventing her from lifting her arms beyond her waist.4 Nammock can no longer play tag rugby or visit the gymnasium as she used to do. Despite her diagnosis, Nammock does her best to live her life as any normal teen girl would; she spends time with friends, cooks, shops and has her friends help her with hair and makeup.
As previously mentioned, research on FOP is very difficult to conduct; presently there are only 800 people in the world with the disease that researchers are aware of making it challenging to conduct proper clinical trials. Currently, the main treatments for patients with FOP are high-dose corticoids taken within 24 hours of a flare-up to reduce inflammation and tissue swelling.5 Other drugs such as muscle relaxants, and other drugs which reduce inflammation may be recommended for use by a physician, but these treatments do nothing to stop the progression of the disease, they only help manage the symptoms.5 Another method which has been proven ineffective and is no longer used is surgery to remove excess bone, which only ends up causing an increase in ossification due to its intrusive nature.1 The best chance for prevention of FOP lies in drug development which is currently being explored by scientists.
Current treatment options are palliative, and symptom-modifying but do nothing to prevent the progression of the disease. What is needed is a drug which prevents FOP from ever occurring. Current research is being done to prevent the excessive signalling of the BMP1 receptor, and within the last year progress has been made. Many studies have found that blocking BMP1 activity through inhibitors is the most effective way of decreasing the progression of FOP.6-8 One study by Hatsell et al. in 2015 has determined that activin A, a protein which normally functions to inhibit the BMP receptor, stimulates the mutated receptor in FOP patients.9 Additionally, when the antibody to activin A was present in mouse studies no ossification occurred.9 This discovery is a big step forward as it provides a target for future drug development. By focusing on how to apply this discovery to human patients’ scientists can work to create a cure for FOP.
A different study by Chakkalakal et al. in 2016 has produced promising results, it emphasized the inhibition of secondary messenger systems in the BMP pathway, stopping the formation of cartilage which would ultimately turn into bone.10 The drug Palovarotene prevented the formation of cartilage in mice studies, which stops it from being ossified and turning into bone.10 Palovarotene is currently being tested in Phase 2 clinical studies to determine an appropriate dosage of the drug in treating FOP.11 This development is a major step forward for patients with FOP because it provides a potential treatment for a disease that for so long has been considered untreatable.
The ultimate goal of FOP research is to provide a cure so affected individuals can regain their independence and enjoy a higher quality life. As clinical trials progress and additional research is conducted, scientists will continue to advance towards this goal.
1. Kaplan F, Merrer M, Glaser D et al. Fibrodysplasia ossificans progressiva. Best Practice & Research Clinical Rheumatology. 2008;22(1):191-205. doi:10.1016/j.berh.2007.11.007.
2. Kini UNandesh B. Physiology Of Bone Formation, Remodeling, And Metabolism. 1st ed. Bangalore: St. Johns Medical College and Hospital; 2012.
3. Fibrodysplasia ossificans progressiva. Genetics Home Reference. 2016. Available at: https://ghr.nlm.nih.gov/condition/fibrodysplasia-ossificans-progressiva#genes.
4. Stone Man Syndrome. STONE MAN SYNDROME. 2016. Available at: http://www.stonemansyndrome.com/.
5. Glaser DKaplan F. Treatment Considerations for the Management of Fibrodysplasia Ossificans Progressiva. Clinical Reviews in Bone and Mineral Metabolism. 2005;3(3-4):243-250. doi:10.1385/bmm:3:3-4:243.
6. Fujimoto M, Ohte S, Osawa K et al. Mutant Activin-Like Kinase 2 in Fibrodysplasia Ossificans Progressiva are Activated via T203 by BMP Type II Receptors. Molecular Endocrinology. 2015;29(1):140-152. doi:10.1210/me.2014-1301.
7. Micha D, Voermans E, Eekhoff M et al. Inhibition of TGFβ signaling decreases osteogenic differentiation of fibrodysplasia ossificans progressiva fibroblasts in a novel in vitro model of the disease. Bone. 2016;84:169-180. doi:10.1016/j.bone.2016.01.004.
8. Kaplan F, Glaser D, Pignolo R, Shore E. A new era for fibrodysplasia ossificans progressiva: a druggable target for the second skeleton. Expert Opinion on Biological Therapy. 2007;7(5):705-712. doi:10.1517/14712518.104.22.1685.
9. Hatsell S, Idone V, Wolken D et al. ACVR1R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A. Science Translational Medicine. 2015;7(303):303ra137-303ra137. doi:10.1126/scitranslmed.aac4358.
10. Chakkalakal S, Uchibe K, Convente M et al. Palovarotene Inhibits Heterotopic Ossification and Maintains Limb Mobility and Growth in Mice With the HumanACVR1R206HFibrodysplasia Ossificans Progressiva (FOP) Mutation. Journal of Bone and Mineral Research. 2016;31(9):1666-1675. doi:10.1002/jbmr.2820.
11. An Open-Label Extension Study of Palovarotene to Treat Preosseous Flare-ups in FOP Subjects - Full Text View - ClinicalTrials.gov. Clinicaltrialsgov. 2016. Available at: https://clinicaltrials.gov/ct2/show/NCT02279095?cond=%22fibrodysplasia+ossificans+progressiva%22+OR+%22Myositis+Ossificans%22&rank=4.
Cite This Article:
Smith E., Zheng K., Chan G., Ho J. Stone Man Syndrome: Turning into a living statue. Illustrated by P. Taarea. Rare Disease Review. January 2017. DOI:10.13140/RG.2.2.26455.68000.