Jump to content

User:GhostRiver/fop

From Wikipedia, the free encyclopedia

Presentation

[edit]

A trademark symptom of fibrodysplasia ossificans progressiva (FOP) is a bilateral congenital malformation of the hallux valgus and great toe.[1] While the exact nature of this malformation varies from a simple deviation of the toe's curvature to a complete absence of the digit,[2] some malformation has been observed in more than 95% of observed FOP patients.[3] Most commonly, the patient suffers from a shortened first metatarsal and proximal phalange, the appearance of which is often exaggerated by the altered angles at which those bones are set. With age, these shortened bones fuse together. While shortening of these bones manifests bilaterally, the degree of shortening is often asymmetrical.[4] About half of patients also suffer from a congenital deformation of the thumbs.[2][3]

Heterotopic ossification can begin anywhere from birth to 25 years of age, but the average age of onset is five. By seven years of age, most patients experience some restricted movement due to ossification, and by 15 years of age, many possess drastically limited arm mobility.[5]

Causes

[edit]

Fibrodysplasia ossificans progressiva is a genetic disorder caused by a spontaneous mutation of the activin A receptor, type I (ACVR1) gene.[6] In every documented case of fibrodysplasia ossificans progressiva, whether familially or spontaneously manifesting, has involved a recurrent single nucleotide substitution on codon 206 of the ACVR1 gene, making it one of the most specific disease-causing mutations in the human genome.[7]

Like many disorders caused by genetic mutations, increased paternal age shows a positive correlation with FOP diagnosis.[8]

Because FOP is carried on an autosomal dominant allele, it is theoretically possible for the disease to pass from parent to child. In practice, however, the low reproductive fitness and shortened lifespan associated with the disease limits the number of cases that arise from genetic transmission.[9] As of 2005, fewer than ten families have been identified as having inherited FOP, and the inheritance within those families has almost exclusively been limited to two generations.[10] In one case where FOP was transmitted through three generations, both the proband and her father had been asymptomatic for the condition until adulthood, when they underwent surgery or experienced trauma.[11]

Mechanism

[edit]

Pathogenesis and pathophysiology

Diagnosis

[edit]

Characteristic biopsy findings and differential diagnosis

The rarity of fibrodysplasia ossificans progressiva affects diagnostic patterns, as physicians may be unaware of the disease and subsequently misdiagnose their patients. One study estimated that approximately 87% of individuals with FOP were initially given an incorrect diagnosis, with one-third misdiagnosed with cancer. This misdiagnosis in turn led to unnecessary invasive surgical procedures or therapeutic treatments.[12] The isolation of one recurrent genetic mutation in FOP has made it easier for doctors to ascertain the correct diagnosis through genetic testing of patients with the associated congenital toe malformation, even before heterotopic ossification begins.[7]

Screening

[edit]

Management

[edit]

The rare nature of fibrodysplasia ossificans progressiva and the variability of phenotypic presentation make it difficult for researchers to conduct controlled studies on best management practices. Additionally, no naturally presenting animal models of FOP exist for researchers to conduct trials. As a result, most recommended treatments are derived from anecdotal data or imperfect clinical studies.[13]

The 2006 discovery of the gene mutation responsible for the disease, however, has presented some potential treatment options,[14] the focus of which is targeted inhibition of the activated ACVR1 receptor.[15] A 2016 study found that palovarotene, a retinoic acid receptor gamma agonist, inhibited heterotopic ossification in mice while preserving joint, limb, and body motion, making it an attractive drug candidate to treat FOP.[16] The drawbacks of palovarotene treatment are that it would require chronic administration, but that daily administration results in skeletal toxicity.[17]

  • Activin A antibodies
  • Rapamycin
  • Imatinib

Prognosis

[edit]

Fibrodysplasia ossificans progressiva results in a considerably shortened lifespan. The degree of this shortening, however, varies widely among patients. The most common cause of death in FOP patients is cardiorespiratory failure, often caused by thoracic insufficiency syndrome.[18]

Epidemiology

[edit]

The rare nature of FOP, as well as a potential lack of awareness within certain geographic communities, makes it difficult to ascertain how prevalent the disease is in the worldwide population. An early study indicated that FOP had a prevalence rate of 0.61 per one million individuals,[19] but more recent analyses have estimated that the rate is closer to 0.88 per one million,[20] or 1.36 per one million.[21] While even these rates are believed to be lower than the actual worldwide prevalence due to undiagnosed cases, estimations of FOP's prevalence have become more accurate as care facilities for the disease have become centralized and registries have been created to list patients.[20] The prevalence of FOP is consistent across gender, and it has been observed in equal rates across all racial and ethnic groups.[22]

Within national populations, FOP tends to be more prevalent in more populous regions, where geographical clustering would be expected.[19] [23] Despite this, the prevalence of FOP varies dramatically across regions, ranging from 0.65 per million in North America, 0.47 per million in Western Europe, and 0.27 per million in Latin America to 0.05 per million in Africa and 0.04 per million in Asia and Oceania. It has been theorized that, like many rare diseases, FOP is underdiagnosed in geographic regions where there is less awareness of the disorder, as well as less regional and global infrastructure in place to connect patients to larger databases and registries.[24] To assist with this latter issue, the International FOP Association created in 2018 the FOP Connection Registry, a voluntary database to capture disease and demographic information from both patients and physicians.[25]

History

[edit]

The first known description of fibrodysplasia ossificans progressiva arises from a letter that the French physician Guy Patin wrote to his colleague dated August 27, 1648, in which he describes a young woman who "turned to wood".[26] A more detailed description of the disorder was published in 1740 by the English surgeon John Freke, who wrote to the Royal Society about a 14-year-old boy who was suffering from"many large swellings on his back which began about three years since", and which "make, as it were, a fixed bony pair of bodice".[27][28]

Society and culture

[edit]

Social perceptions, cultural history, stigma, economics, religious aspects, awareness, legal issues, notable cases

Two skeletons of patients with fibrodysplasia ossificans progressiva are on display at the Mütter Museum of the College of Physicians of Philadelphia. Harry Raymond Eastlack asked that his body be donated to science shortly before his death in 1973.[29] The display of his skeleton allowed researchers at the Center for Research In FOP and Related Disorders in Philadelphia to examine the remains, and in 1995 and 2000, the museum lent Eastlack's skeleton to the International FOP Association for their annual symposium.[30] In 2019, the skeleton of Carol Orzel joined Eastlack at the Mütter Museum. A Philadelphia native, Orzol was inspired to donate her body to science after seeing Eastlack's skeleton on display at the 1995 symposium.[31]

Research directions

[edit]

References

[edit]
  1. ^ Towler, O. Will; Shore, Eileen M.; Xu, Meiqi; Bamford, Abbey; Anderson, Ilse; Pignolo, Robert J.; Kaplan, Frederick S. (1 July 2017). "The congenital great toe malformation of fibrodysplasia ossificans progressiva? - A close call". European Journal of Medical Genetics. 60 (7): 399–402. doi:10.1016/j.ejmg.2017.04.013. ISSN 1769-7212. PMID 28473268. Retrieved April 2, 2022.
  2. ^ a b Hüning, Irina; Gillessen-Kaesbach, Gabriele (2014). "Fibrodysplasia Ossificans Progressiva: Clinical Course, Genetic Mutations and Genotype-Phenotype Correlation". Molecular Syndromology. 5 (5): 201–211. doi:10.1159/000365770. ISSN 1661-8769. PMID 25337067. Retrieved April 2, 2022.
  3. ^ a b Kaplan, Frederick S.; Glaser, David L.; Shore, Eileen M.; Deirmengian, Gregory K.; Gupta, Rishi; Delai, Patricia; Morhart, Rolf; Smith, Roger; Le Merrer, Martine; Rogers, John G.; Connor, J. Michael; Kitterman, Joseph A. (1 September 2005). "The phenotype of fibrodysplasia ossificans progressiva". Clinical Reviews in Bone and Mineral Metabolism. 3 (3): 183–188. doi:10.1385/BMM:3:3-4:183. ISSN 1559-0119. Retrieved March 30, 2022.
  4. ^ Harrison, Richard J.; Pitcher, J. David; Mizel, Mark S.; Temple, H. Thomas; Scully, Sean P. (November 2005). "The Radiographic Morphology of Foot Deformities in Patients with Fibrodysplasia Ossificans Progressiva". Foot & Ankle International. 26 (11): 937–941. doi:10.1177/107110070502601107. ISSN 1071-1007. PMID 16309607. Retrieved April 2, 2022.
  5. ^ Cohen, R. B.; Hahn, G. V.; Tabas, J. A.; Peeper, J.; Levitz, C. L.; Sando, A.; Sando, N.; Zasloff, M.; Kaplan, F. S. (February 1993). "The natural history of heterotopic ossification in patients who have fibrodysplasia ossificans progressiva. A study of forty-four patients". The Journal of Bone & Joint Surgery. 75 (2): 215–219. doi:10.2106/00004623-199302000-00008. ISSN 0021-9355. PMID 8423182. Retrieved March 30, 2022.
  6. ^ Shore, Eileen M; Xu, Meiqi; Feldman, George J; Fenstermacher, David A; Cho, Tae-Joon; Choi, In Ho; Connor, J Michael; Delai, Patricia; Glaser, David L; LeMerrer, Martine; Morhart, Rolf; Rogers, John G; Smith, Roger; Triffitt, James T; Urtizberea, J Andoni; Zasloff, Michael; Brown, Matthew A; Kaplan, Frederick S (1 May 2006). "A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva". Nature Genetics. 38 (5): 525–527. doi:10.1038/ng1783. Retrieved March 3, 2022.
  7. ^ a b Kaplan, Frederick S.; Xu, Meiqi; Glaser, David L.; Collins, Felicity; Connor, Michael; Kitterman, Joseph; Sillence, David; Zackai, Elaine; Ravitsky, Vardit; Zasloff, Michael; Ganguly, Arupa; Shore, Eileen M. (1 May 2008). "Early Diagnosis of Fibrodysplasia Ossificans Progressiva". Pediatrics. 121 (5): e1295–e1300. doi:10.1542/peds.2007-1980. Retrieved 20 February 2022.
  8. ^ Rogers, J. G.; Chase, G. A. (1 April 1979). "Paternal age effect in fibrodysplasia ossificans progressiva". Journal of Medical Genetics. 16 (2): 147–148. doi:10.1136/jmg.16.2.147. ISSN 0022-2593. PMID 287808. Retrieved April 2, 2022.
  9. ^ Kaplan, Frederick S.; McCluskey, William; Hahn, Gregory; Tabas, Jeffrey A.; Muenke, Maximilian; Zasloff, Michael A. (August 1993). "Genetic transmission of fibrodysplasia ossificans progressiva. Report of a family". The Journal of Bone & Joint Surgery. 75 (8): 1214–1220. doi:10.2106/00004623-199308000-00011. PMID 8354680. Retrieved March 3, 2022.
  10. ^ Cite error: The named reference genetics was invoked but never defined (see the help page).
  11. ^ Connor, J. M.; Skirton, H.; Lunt, P. W. (1 August 1993). "A three generation family with fibrodysplasia ossificans progressiva". Journal of Medical Genetics. 30 (8): 687–689. doi:10.1136/jmg.30.8.687. ISSN 0022-2593. PMID 8411056. Retrieved April 2, 2022.
  12. ^ Kitterman, Joseph A.; Kantanie, Sharon; Rocke, David M.; Kaplan, Frederick S. (November 1, 2005). "Iatrogenic Harm Caused by Diagnostic Errors in Fibrodysplasia Ossificans Progressiva". Pediatrics. 116 (5): e654–e661. doi:10.1542/peds.2005-0469. Retrieved February 20, 2022.
  13. ^ Glaser, David L.; Kaplan, Frederick S. (2005). "Treatment Considerations for the Management of Fibrodysplasia Ossificans Progressiva". Clinical Reviews in Bone and Mineral Metabolism. 3 (3–4): 243–250. doi:10.1385/BMM:3:3-4:243. Retrieved February 20, 2022.
  14. ^ McCullough, Marie (February 28, 2019). "Therapies in sight for FOP, a disease that turns muscle to bone". The Philadelphia Inquirer. Retrieved March 31, 2022.
  15. ^ Kitoh, Hiroshi (2 September 2020). "Clinical Aspects and Current Therapeutic Approaches for FOP". Biomedicines. 8 (9): 325. doi:10.3390/biomedicines8090325. Retrieved March 31, 2022.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  16. ^ Chakkalakal, Salin A.; Uchibe, Kenta; Convente, Michael R.; Zhang, Deyu; Economides, Aris N.; Kaplan, Frederick S.; Pacifici, Maurizio; Iwamoto, Masahiro; Shore, Eileen M. (September 2016). "Palovarotene Inhibits Heterotopic Ossification and Maintains Limb Mobility and Growth in Mice With the Human ACVR1 R206H Fibrodysplasia Ossificans Progressiva (FOP) Mutation". Journal of Bone and Mineral Research. 31 (9): 1666–1675. doi:10.1002/jbmr.2820. Retrieved March 31, 2022.
  17. ^ Lees-Shepard, John B.; Nicholas, Sarah-Anne E.; Stoessel, Sean J.; Devarakonda, Parvathi M.; Schneider, Michael J.; Yamamoto, Masakazu; Goldhamer, David J. (18 September 2018). "Palovarotene reduces heterotopic ossification in juvenile FOP mice but exhibits pronounced skeletal toxicity". eLife. 7: e40814. doi:10.7554/eLife.40814. ISSN 2050-084X. Retrieved March 31, 2022.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  18. ^ Kaplan, Frederick S.; Zasloff, Michael A.; Kitterman, Joseph A.; Shore, Eileen M.; Hong, Charles C.; Rocke, David M. (March 2010). "Early Mortality and Cardiorespiratory Failure in Patients with Fibrodysplasia Ossificans Progressiva:". The Journal of Bone and Joint Surgery-American Volume. 92 (3): 686–691. doi:10.2106/JBJS.I.00705. PMID 20194327. Retrieved February 18, 2022.
  19. ^ a b Connor, J. M.; Evans, D. A. (1 February 1982). "Genetic aspects of fibrodysplasia ossificans progressiva". Journal of Medical Genetics. 19 (1): 35–39. doi:10.1136/jmg.19.1.35. ISSN 0022-2593. PMID 7069743. Retrieved April 2, 2022.
  20. ^ a b Pignolo, Robert J.; Hsiao, Edward C.; Baujat, Genevieve; Lapidus, David; Sherman, Adam; Kaplan, Frederick S. (5 August 2021). "Prevalence of fibrodysplasia ossificans progressiva (FOP) in the United States: estimate from three treatment centers and a patient organization". Orphanet Journal of Rare Diseases. 16 (1): 350. doi:10.1186/s13023-021-01983-2. ISSN 1750-1172. PMID 34353327. Retrieved April 2, 2022.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  21. ^ Baujat, Geneviève; Choquet, Rémy; Bouée, Stéphane; Jeanbat, Viviane; Courouve, Laurène; Ruel, Amélie; Michot, Caroline; Le Quan Sang, Kim-Hanh; Lapidus, David; Messiaen, Claude; Landais, Paul; Cormier-Daire, Valérie (30 June 2017). "Prevalence of fibrodysplasia ossificans progressiva (FOP) in France: an estimate based on a record linkage of two national databases". Orphanet Journal of Rare Diseases. 12 (1): 123. doi:10.1186/s13023-017-0674-5. ISSN 1750-1172. PMID 28666455. Retrieved April 2, 2022.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  22. ^ Shore, Eileen M.; Feldman, George J.; Xu, Meiqi; Kaplan, Frederick S. (2005). "The Genetics of Fibrodysplasia Ossificans Progressiva". Clinical Reviews in Bone and Mineral Metabolism. 3 (3–4): 201–204. doi:10.1385/BMM:3:3-4:201. Retrieved February 26, 2022.
  23. ^ She, Dunmin; Zhang, Keqin (1 April 2018). "Fibrodysplasia ossificans progressiva in China". Bone. 109: 101–103. doi:10.1016/j.bone.2017.11.016. ISSN 8756-3282. PMID 29175272. Retrieved April 2, 2022.
  24. ^ Liljesthröm, Moira; Pignolo, Robert J.; Kaplan, Frederick S. (2020). "Epidemiology of the Global Fibrodysplasia Ossificans Progressiva (FOP) Community". Journal of Rare Diseases Research & Treatment. 5 (2): 31–36. doi:10.29245/2572-9411/2020/2.1196. Retrieved February 26, 2022.
  25. ^ Mantick, Neal; Bachman, Eric; Baujat, Genevieve; Brown, Matt; Collins, Oliver; De Cunto, Carmen; Delai, Patricia; Eekhoff, Marelise; zum Felde, Roger; Grogan, Donna Roy; Haga, Nobuhiko; Hsiao, Edward; Kantanie, Sharon; Kaplan, Frederick; Keen, Richard; Milosevic, Jelena; Morhart, Rolf; Pignolo, Robert; Qian, Xiaobing; di Rocco, Maja; Scott, Christiaan; Sherman, Adam; Wallace, Marin; Williams, Nicky; Zhang, Keqin; Bogard, Betsy (1 April 2018). "The FOP Connection Registry: Design of an international patient-sponsored registry for Fibrodysplasia Ossificans Progressiva". Bone. 109: 285–290. doi:10.1016/j.bone.2017.08.032. ISSN 8756-3282. PMID 28866367. Retrieved April 2, 2022.
  26. ^ Patin, Guy (1692). Lettres choisies de feu Mr. Guy Patin, Volume I (in French). Cologne: Pierre du Laurens. pp. 52–53. Retrieved February 20, 2022. Pour ce qui eft de cette observation que vous avez faite de cette femme qui est devenué dure comme du bois, c'est un exemple fort rare.
  27. ^ Kaplan, Frederick S. (2005). "Fibrodysplasia Ossificans Progressiva: A Historical Perspective". Clinical Reviews in Bone and Mineral Metabolism. 3: 179–181. doi:10.1385/BMM:3:3-4:179. Retrieved February 20, 2022.
  28. ^ Freke, John (December 31, 1740). "XXIV. A letter from Mr. John Freke, F. R. S. Surgeon to St. Bartholomew's Hospital to the Royal Society, relating a case of extraordinary exostoses on the back of boy". Philosophical Transactions of the Royal Society. 41 (456): 369–370. doi:10.1098/rstl.1739.0066. Retrieved February 20, 2022.
  29. ^ Zimmer, Carl (June 2013). "The Girl Who Turned to Bone". The Atlantic. Retrieved February 20, 2022.
  30. ^ Kaplan, Frederick S. (October 1, 2013). "The skeleton in the closet". Gene. 528 (1): 7–11. doi:10.1016/j.gene.2013.06.022. PMID 23810943. Retrieved February 20, 2022.
  31. ^ McCullough, Marie (February 28, 2019). "Mutter Musuem exhibit grants final wish for woman who turned to bone". The Philadelphia Inquirer. Retrieved February 20, 2022.