Article Sidebar

Submitted
Jun 11, 2025
Published
Jun 11, 2025
Download
PDF
Statistic
Read Counter : 21 Download : 9

Main Article Content

Abstract

Progressive heterotopic ossification [HO] of soft connective tissues, such as muscles, tendons, and ligaments, is a hallmark of fibrodysplasia ossificans progressiva [FOP], popularly known as "Stone Man Syndrome," an incredibly rare autosomal dominant genetic condition. A gain-of-function mutation in the activin A receptor type 1 [ACVR1] gene, most frequently R206H, induces constitutive activation of the bone morphogenetic protein [BMP] signaling pathway, even in the absence of ligands, leading to this crippling illness. Congenital abnormalities of the great toes are the usual early childhood manifestation of FOP, frequently occurring before flare-ups that result in progressive immobility and disability. Clinical presentation, radiologic imaging, and confirming genetic tests are all necessary for the diagnosis. The condition is often misdiagnosed due to its rarity and complexity, which delays necessary early care. No curative therapy currently exists; management focuses on minimizing trauma, avoiding intramuscular procedures, and controlling flare-ups with corticosteroids. Surgical intervention is limited to select cases and must be approached with caution due to risk of further ossification. Ongoing research into ACVR1 inhibition and BMP pathway modulation holds promise for disease-modifying treatments. This review aims to consolidate current understanding of FOP’s genetic basis, clinical presentation, diagnostic approach, and evolving management strategies to improve outcomes in this challenging and life-limiting disorder.

Keywords

Fibrodysplasia ossificans progressiva activin A receptor type 1 bone morphogenetic protein corticosteroids heterotopic ossification

Article Details

How to Cite
Shaik Parveen, Gutha. Sisira Pushpa, Banothu. Anusha, & Goggela. Rajini. (2025). Stone Man Syndrome: Unraveling The Layers of A Rare Genetic Disorder. International Journal of Research in Pharmacology & Pharmacotherapeutics, 14(2), 423-432. Retrieved from https://ijrpp.com/ijrpp/article/view/677
Download Citation
Endnote/Zotero/Mendeley (RIS)
BibTeX

References

  1. 1. Bridges AJ, Hsu KC, Singh A, Churchill R, Miles J. Fibrodysplasia [Myositis] ossificans progressiva. Seminars in Arthritis and Rheumatism. 1994;24[3]:155–164. doi: 10.1016/0049-0172[94]90071-X.
  2. 2. Calvert GT, Shore EM. Human leukocyte antigen B27 allele is not correlated with fibrodysplasia ossificans progressiva. Clin Orthop Relat Res. 1998;[346]:66–70.
  3. 3. "Medical Definition of fibrodysplasia ossificans progressiva". www.merriam-webster.com. Retrieved 8 May 2022. Pinkowski, Jen [1 March 2019]. "Here's what happens when your body tissues turn to bone". National Geographic. Archived from the original on 3 March 2019.
  4. 4. Kim JT, Yoon YH, Baek WK, Han JY, Chu YC, Kim HJ. Myositis ossificans of the chest wall simulating malignant neoplasm. Ann of Thorac Surg. 2000;70[5]:1718–1720.
  5. 5. Orhan K, Uyanik LO, Erkmen E, Kilinc Y. Unusually severe limitation of the jaw attributable to fibrodysplasia ossificans progressiva: a case report with cone-beam computed tomography findings. Oral Surg Oral Med Oral Pathol Oral Radiol. 2012;113[3]:404–409.
  6. 6. Lucotte G, Bathelier C, Mercier G, Gerard N, Lenoir G, Semonin O, et al. Localization of the gene for fibrodysplasia ossificans progressiva [FOP] to chromosome 17q21-22. Genet Couns. 2000;11[4]:329–334.
  7. 7. Xu MQ, Shore EM, Kaplan FS. Reported noggin mutations are PCR errors. Am J Med Genet. 2002;109[2]:161–163. doi: 10.1002/ajmg.10288. Stark William H, Krechel Susan W, Eggers Jr GWN. Anesthesia in ‘stone man’: Myositis ossif icans progressiva. J Clin Anes. 1990;2[5]:332–335.
  8. 8. Thickman D, Bonakdar-pour A, Clancy M, Van Orden J, Steel H. Fibrodysplasia ossificans progressiva. AJR Am J Roentgenol. 1982;139[5]:935–941.
  9. 9. Kaplan FS, Shore EM, Glaser DL. The medical management of fibrodysplasia ossificans current treatment consideration. Clin Proc intl clin consort FOP. 2005;1:1–71.
  10. 10. McCullough, Marie [28 February 2019]. "New Mutter Museum exhibit grants final wish for woman who turned to bone". The Philadelphia Inquirer. Retrieved 28 February 2019.
  11. 11. "Mütter Museum Reveals New Exhibit: Philadelphia Woman's Skeleton With Rare Bone Disease". Mütter Museum. 5 March 2019. Archived from the original on 28 August 2021. Retrieved 7 March 2020
  12. 12. Genetics Home Reference, U.S. National Library of Medicine, August 2007.Accessed February 18, 2014.
  13. 13. Martelli A, Santos AR Jr [2014] Cellular and morphological aspects of fibrodysplasia ossificans progressive . Lessons of formation, repair, and bone bioengineering. Organogenesis [Review] 10: 303-311.
  14. 14. Kasper, DL, Fauci AS, Longo DL, et al. [2005] eds. Harrison’s Principles of Internal Medicine. 16thed. McGraw-Hill Companies. New York NY 2286.
  15. 15. Martelli, Anderson; Santos, Arnaldo Rodrigues [3 July 2014]. "Cellular and morphological aspects of fibrodysplasia ossificans progressiva: Lessons of formation, repair, and bone bioengineering". Organogenesis. 10 [3]: 303–311.
  16. 16. Maiti D, Shilpa NM. " Stone Man Syndrome: A Rare and Debilitating Genetic Disorder with a Misguided Immune Response.
  17. 17. Allen RS, Tajer B, Shore EM, Mullins MC. Fibrodysplasia ossificans progressiva mutant ACVR1 signals by multiple modalities in the developing zebrafish. Elife. 2020 Sep 8;9:e53761.
  18. 18. José Antonio Valer, Cristina Sánchez-de-Diego, Carolina Pimenta-Lopes, Jose Luis Rosa and Francesc Ventura. ACVR1 Function in Health and Disease. Cells 2019;8:1366-92. doi:10.3390/cells8111366
  19. 19. Kohei Miyazono, Tomomasa Shimanuki. Bone Morphogenetic Protein Receptors and Actions. Principles of Bone Biology 2008; 3:1177-97
  20. 20. Kristi Wharton, Rik Derynck. TGFβ family signaling: novel insights in development and disease. Development 2009;136:3691-7.doi:10.1242/dev.040584
  21. 21. Guiqian Chen, Chuxia Deng, Yi-Ping Li. TGF-β and BMP Signaling in Osteoblast Differentiation and Bone Formation. International Journal of Biological Sciences 2012; 8[2]:272- 88. doi: 10.7150/ijbs.2929
  22. 22. Asadi S, Aranian MR. The Role of Genetics Mutations in Genes ACVR1, BMPR1A, BMPR1B, BMPR2, BMP4 in Stone Man Syndrome. J Hematol Hemother 5: 008.
  23. 23. Kaplan FS, Xu M, Glaser DL, et al. Early diagnosis of fibrodysplasia ossificans progressiva. Pediatrics. 2008;121[5]:e1295- 300.
  24. 24. Shore EM, Kaplan FS. Role of altered signal transduction in heterotopic ossification and fibrodysplasia ossificans progressiva. Curr Osteoporos Rep. 2011;9[2]:83-8
  25. 25. Delai PLR, Kantanie S, Santili C, et al. Fibrodysplasia ossificans progressiva: a hereditary illness of multidisciplinary interest. Rev Bras Ortop. 2004;39[4]:205-13.
  26. 26. Mahboubi S, Glaser DL, Shore EM, Kaplan FS. Fibrodysplasia ossificans progressiva. Pediatr Radiol. 2001;31[5]:307-14.
  27. 27. Kaplan FS, Xu M, Seemann P, et al. Classic and atypical fibrodysplasia ossificans progressiva [FOP] phenotypes are caused by mutations in the bone morphogenetic protein [BMP] type I receptor ACVR1. Hum Mutat. 2009;30[3]:379-90.
  28. 28. Baujat G, Choquet R, Bouée S, et al. Prevalence of fibrodysplasia ossificans progressiva [FOP] in France: an estimate based on a record linkage of two national databases. Orphanet J Rare Dis. 2017;12[1]:123.
  29. 29. Kaplan FS, Shore EM. Perspective: progressive osseous heteroplasia. J Bone Miner Res. 2000;15[11]:2084-94.
  30. 30. Pignolo RJ, Durbin-Johnson BP, Rocke DM, Kaplan FS. Joint-specific risk of impaired function in fibrodysplasia ossificans progressiva [FOP]. Bone. 2020;140:115549.
  31. 31. Wang H, Lindborg C, Lounev V, et al. Cellular Hypoxia Promotes Heterotopic Ossification by Amplifying BMP Signaling. J Bone Miner Res. 2016;31[9]:1652-65.
  32. 32. Kaplan FS, Murray JE, Sylvester JE, et al. The ethical imperative to treat rare disorders: principles and guidelines for managing fibrodysplasia ossificans progressiva. Bone. 2018;109:282-4
  33. 33. Pignolo RJ, Shore EM, Kaplan FS. Fibrodysplasia ossificans progressiva: diagnosis and management. Curr Osteoporos Rep. 2013;11[2]:179-86.
  34. 34. Kaplan FS, Al Mukaddam M, Baujat G, et al. The medical management of fibrodysplasia ossificans progressiva: current treatment considerations. Proc Intl Clin Council FOP. 2019;1:1-111.
  35. 35. Kaplan FS, Pignolo RJ, Al Mukaddam M. Bone morphogenetic protein signaling inhibition for the treatment of fibrodysplasia ossificans progressiva. Curr Osteoporos Rep. 2016;14[5]:169-75.
  36. 36. Wentworth KL, Masharani U, Hsiao EC. Therapeutic advances for blocking heterotopic ossification in fibrodysplasia ossificans progressiva. Br J Clin Pharmacol. 2019;85[6]:1180-7.
  37. 37. Kaplan FS, Al Mukaddam M, Shore EM. Therapeutic approaches to fibrodysplasia ossificans progressiva. Bone. 2018;109:247-55.
  38. 38. Chakkalakal SA, Uchibe K, Convente MR, et al. Palovarotene inhibits heterotopic ossification and maintains limb mobility and growth in mice with the human ACVR1R206H fibrodysplasia ossificans progressiva [FOP] mutation. J Bone Miner Res. 2016;31[9]:1666-75.
  39. 39. Haviv R, Moshe V, De Benedetti F, et al. A novel therapeutic approach for fibrodysplasia ossificans progressiva using IL1β receptor antagonist. J Bone Miner Res. 2019;34[9]:1657-66.
  40. 40. Kaplan FS, Al Mukaddam M, Pignolo RJ. Acute and chronic care considerations for patients with fibrodysplasia ossificans progressiva. Curr Osteoporos Rep. 2020;18[5]:531-40.
  41. 41. Connor JM, Evans DA. Genetic aspects of fibrodysplasia ossificans progressiva. J Med Genet. 1982;19[1]:35-9.
  42. 42. Pignolo RJ, Bedford-Gay C, Liljesthröm M, et al. The natural history of flare-ups in fibrodysplasia ossificans progressiva: a comprehensive global assessment. J Bone Miner Res. 2016;31[3]:650-6.
  43. 43. Kaplan FS, Zasloff MA, Kitterman JA, et al. Early mortality and cardiorespiratory failure in patients with fibrodysplasia ossificans progressiva. J Bone Joint Surg Am. 2010;92[3]:686-91.
  44. 44. Hsiao EC, Di Rocco M, Cali A, et al. Special considerations for clinical trials in fibrodysplasia ossificans progressiva [FOP]. Br J Clin Pharmacol. 2019;85[6]:1199-207.
  45. 45. Pignolo RJ, Shore EM, Kaplan FS. Fibrodysplasia ossificans progressiva: clinical and genetic aspects. Orphanet J Rare Dis. 2011;6:80.
  46. 46. Kaplan FS, Al Mukaddam M, Pignolo RJ. Emergency care of patients with fibrodysplasia ossificans progressiva. Muscle Nerve. 2019;59[4]:397-403.
  47. 47. Kaplan FS, Al Mukaddam M, Pignolo RJ. A cumulative analogue joint involvement scale [CAJIS] for fibrodysplasia ossificans progressiva [FOP]. Bone. 2017;101:123-8.
  48. 48. Mantick N, Bachman E, Baujat G, et al. The FOP connection registry: Design of an international patient-sponsored registry for fibrodysplasia ossificans progressiva. Bone. 2018;109:285-90.
  49. 49. Shore EM, Kaplan FS. Insights from a rare genetic disorder of extra-skeletal bone formation, fibrodysplasia ossificans progressiva [FOP]. Bone. 2008;43[3]:427-33.