Fibrodysplasia ossificans progressiva

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Fibrodysplasia ossificans progressiva
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Fibrodysplasia ossificans progressiva (FOP), sometimes referred to as Stone Man Syndrome, is an extremely rare disease of the connective tissue. A mutation of the body's repair mechanism causes fibrous tissue (including muscle, tendon, and ligament) to be ossified when damaged. In many cases, injuries can cause joints to become permanently frozen in place. Surgical removal of the extra bone growths has been shown to cause the body to "repair" the affected area with more bone.[1]


Children born with FOP have deformed big toes, possibly missing a joint or simply presenting with a notable lump at the minor joint. The first "flare-up" that leads to the formation of FOP bones usually occurs before the age of 10. FOP is a genetic disease. The bone growth progresses from the top downward, just as bones grow in fetuses. A child with FOP will typically develop bones starting at the neck, then on the shoulders, arms, chest area and finally on the feet. Specifically, FOP involvement is typically seen first in the dorsal, axial, cranial and proximal regions of the body. Later the disease progresses in the ventral, appendicular, caudal and distal regions of the body.[2] However it does not necessarily occur in this order due to injury-caused flare-ups. Often, the tumor-like lumps that characterize the disease appear suddenly.

The gene that causes ossification is normally deactivated after a fetus' bones are formed in the womb, but in patients with FOP, the gene keeps working. Aberrant bone formation in patients with FOP occurs when injured connective tissue or muscle cells at the sites of injury or growth incorrectly express an enzyme for bone repair during apoptosis (self-regulated cell death), resulting in lymphocytes containing excess bone morphogenetic protein 4 (BMP4) provided during the immune system response. The bone that results occurs independently of the normal skeleton, forming its own discrete skeletal elements. These elements, however, can fuse with normal skeletal bone.[3] Interestingly, the diaphragm, tongue, and extra-ocular muscles are spared in this process, as well as cardiac and smooth muscle.[2] Since the incorrect enzyme remains unresolved within the immune response, the body continues providing the incorrect BMP4-containing lymphocytes. BMP4 is a product that contributes to the development of the skeleton in the normal embryo.[4]

Because the disease is so rare, the symptoms are often misdiagnosed as cancer or fibrosis. This leads doctors to order biopsies, which can actually exacerbate the growth of these lumps.


Since the 1800s, there have been references in medicine describing people who apparently "turned to stone"; some of these cases may be attributable to FOP.

The best known FOP case is that of Harry Eastlack (1933–1973). His condition began to develop at the age of ten, and by the time of his death from pneumonia in November 1973, six days before his 40th birthday, his body had completely ossified, leaving him able to move only his lips.

Shortly before Eastlack's death, he made it known that he wanted to donate his body to science, in the hope that in death, he would be able to help find a cure for this little-understood and particularly cruel disease. Pursuant to his wishes, his preserved skeleton is now kept at the Mütter Museum in Philadelphia, and has proven to be an invaluable source of information in the study of FOP. There have approximately been 700 confirmed cases across the globe from an estimated 2500.[5]


There is no known cure for FOP. Attempts to surgically remove the bone result in more robust bone growth.[6] While under anesthesia, patients with FOP may face problems, which include difficulties with intubation, restrictive pulmonary disease, and changes in the electrical conduction system of the heart.[7] Activities that increase the risk of falling should be avoided, as injuries from falling can provoke the growth of bone.[8]

In 1999, scientists discovered that squalamine in sharks[9] might be useful in treating those suffering from FOP.[10] Squalamine is antiangiogenic and can prevent the growth of blood vessels in cartilaginous tissue, thus preventing creation of bone in sharks. A trial of squalamine started in 2002[11] but terminated about 2007. (Note that squalene is a different compound, also found in sharks, that has no such properties.)

As of November 2010, there are no registered clinical trials for FOP.[12]


FOP is caused by an autosomal dominant allele on chromosome 2q23-24. The allele has variable expressivity, but complete penetrance. Most cases are caused by spontaneous mutation in the gametes; most people with FOP cannot have children. A study has determined that it affects approximately 1 in every 2 million people ("1.8 (SE ± 1.04) × 10-6 mutations per gene per generation").[13] A similar but less catastrophic disease is fibrous dysplasia, which is caused by a post-zygotic mutation.

A mutation in the gene ACVR1 (= ALK2) is responsible for the disease.[14] ACVR1 encodes activin receptor type-1, a BMP type-1 receptor. The mutation causes the ACVR1 protein to have the amino acid histidine substituted for the amino acid arginine at position 206.[15] This causes endothelial cells to transform to mesenchymal stem cells and then to bone.[16]


  • International FOP Association
  • Cohen MM, Howell RE (1999). "Etiology of fibrous dysplasia and McCune-Albright syndrome". International journal of oral and maxillofacial surgery. 28 (5): 366–371. doi:10.1034/j.1399-0020.1999.285280512.x. PMID 10535539.
  • Henderson, Mark (April 24, 2006). "Rare 'stone man' gene that changes muscle into bone -News-World-US & Americas-TimesOnline". The Times. London. Retrieved 2007-06-02.


  1. ^ "ABC News: When Body Turns to Bone". Retrieved 2007-06-02.
  2. ^ a b Fibrodysplasia ossificans progressiva. Frederick S. Kaplan, MD, Martine Le Merrer, MD, PhD, Professor of Genetics, David L. Glaser, MD, Robert J. Pignolo, MD, PhD, Robert Goldsby, MD, Joseph A. Kitterman, MD, Jay Groppe, PhD, and Eileen M. Shore, PhD
  3. ^ Insights from a Rare Genetic Disorder of Extra-Skeletal Bone Formation, Fibrodysplasia Ossificans Progressiva (FOP). Eileen M. Shore and Frederick S. Kaplan
  4. ^ Kierszenbaum, Abraham (2002). Histology and cell biology. New York: Mosby. ISBN 978-0-323-01639-1.
  5. ^
  6. ^ American Academy of Orthopaedic Surgeons (May 2006). "Fibrodysplasia Ossificans Progressiva (FOP)". Retrieved 2011-10-07.
  7. ^ Newton, M.C. "Fibrodysplasia Ossificans Progressiva". British Journal of Anaesthesia. Retrieved October 25, 2011. Unknown parameter |coauthors= ignored (|author= suggested) (help)
  8. ^ The New York Times, "Finally, With Genetic Discovery, Hope for Escape From a Prison of Bone", May 9, 2006
  9. ^ BioInfoBank Library. "Squalamine: an aminosterol antibiotic from the shark". Retrieved 2010-07-19.
  10. ^ BBC News, "Shark therapy for bizarre bone disease," March 24, 1999
  11. ^ "Article: Squalamine Trial For The Treatment Of Fibrodysplasia Ossificans... | AccessMyLibrary - Promoting library advocacy". AccessMyLibrary. 2002-02-08. Retrieved 2010-07-19.
  12. ^
  13. ^ Connor JM, Evans DA (1982). "Genetic aspects of fibrodysplasia ossificans progressiva". J. Med. Genet. 19 (1): 35–39. doi:10.1136/jmg.19.1.35. PMC 1048816. PMID 7069743.
  14. ^ Shore EM; Xu M; Feldman GJ; et al. (2006). "A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva". Nat. Genet. 38 (5): 525–527. doi:10.1038/ng1783. PMID 16642017. Unknown parameter |author-separator= ignored (help)
  15. ^ News Release of FOP's Cause
  16. ^ Dinther; et al. (2010). "ALK2 R206H mutation linked to fibrodysplasia ossificans progressiva confers constitutive activity to the BMP type I receptor and sensitizes mesenchymal cells to BMP-induced osteoblast differentiation and bone formation". Journal of Bone and Mineral Research: 091211115834058–35. doi:10.1359/jbmr.091110.

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