Sections

Sections Fibrodysplasia Ossificans Progressiva
Overview
Presentation
DDx
Workup
Treatment
Medication
Media Gallery
References

Presentation

History

In most cases, fibrodysplasia ossificans progressiva (FOP) starts in early infancy with episodes of soft tissue swelling; however, reports exist of in utero involvement. It may be first evident in an infant as recurrent diffuse soft-tissue scalp and periorbital swelling.^[19]

Ectopic bone formation is usually first evident in early childhood in children aged 2-6 years. The main target is the axial musculature, but eventually ectopic bone formation occurs in the ligaments, the fascia, the aponeuroses, the tendons, and the joint capsules. Involvement often demonstrates a proximal-to-distal predilection. Approximately half of the flare-ups seem to be spontaneous, while the other half appear to be trauma related.^[20]

Most patients become bedridden by time they are in their 30s.

Chronic neurological symptoms are common in these patients.^[21]These findings include neuropathic pain, especially in females (15%). Many had other sensory abnormalities.

Physical Examination

Fibrodysplasia ossificans progressiva (FOP) lesions are characterized by painful, tender, rubbery, soft-tissue indurations, usually precipitated by a trauma. Lesions mainly develop in the paraspinal muscles of the back and in the limb girdles. Some of the tumors undergo ossification, which can also affect the tendons, the ligaments, and the fascia. Widespread arthropathy throughout the axial and appendicular skeleton may be evident.^[22]

Characteristics of diagnostic value are a hallus valgus deformity (present at birth), torticollis (due to involvement of the sternocleidomastoid muscle), joint immobilization (due to periarticular ossificans), and a thorax deformity (both lateral and anteroposterior).

Fibrodysplasia ossificans progressiva limited to the maxillofacial region has been described.^[23]It may produce a fusion between the mandibular ramus and the zygomatic complex and trismus.

All proximal tibial osteochondromas are a common phenotypic feature.^{[24, 25]}Mobility is restricted because of ankylosis of the spine and the rib cage.

Fibrodysplasia ossificans progressiva is sometimes associated with alopecia and deafness.^[26]

Aslan et al reported ankylosis of the jaw and van der Meij et al reported restricted mandibular movement, both associated with fibrodysplasia ossificans progressiva.^{[27, 28]}

Note the images below.

Widespread tumors and indurations mainly in the scapular area, found on radiographic examination to consist of heterotopic bone formation.

View Media Gallery

Typical hallus valgus deformity.

View Media Gallery

Differential Diagnoses

Pignolo RJ, Baujat G, Brown MA, De Cunto C, DiRocco M, Hsiao EC, et al. Natural history of fibrodysplasia ossificans progressiva: cross-sectional analysis of annotated baseline phenotypes. Orphanet J Rare Dis. 2019 May 3. 14 (1):98. [QxMD MEDLINE Link].
Pignolo RJ, Baujat G, Brown MA, De Cunto C, Di Rocco M, Hsiao EC, et al. Correction to: Natural history of fibrodysplasia ossificans progressiva: cross-sectional analysis of annotated baseline phenotypes. Orphanet J Rare Dis. 2019 May 23. 14 (1):113. [QxMD MEDLINE Link].
Kaplan FS, Zasloff MA, Kitterman JA, Shore EM, Hong CC, Rocke DM. Early mortality and cardiorespiratory failure in patients with fibrodysplasia ossificans progressiva. J Bone Joint Surg Am. 2010 Mar. 92(3):686-91. [QxMD MEDLINE Link]. [Full Text].
Muthu V, Khaire NS, Varma S. Fibrodysplasia ossificans progressiva-primum non nocere. Clin Rheumatol. 2014 Apr. 33(4):591-2. [QxMD MEDLINE Link].
Feldman G, Li M, Martin S, et al. Fibrodysplasia ossificans progressiva, a heritable disorder of severe heterotopic ossification, maps to human chromosome 4q27-31. Am J Hum Genet. 2000 Jan. 66(1):128-35. [QxMD MEDLINE Link].
de la Pena LS, Billings PC, Fiori JL, Ahn J, Kaplan FS, Shore EM. Fibrodysplasia ossificans progressiva (FOP), a disorder of ectopic osteogenesis, misregulates cell surface expression and trafficking of BMPRIA. J Bone Miner Res. 2005 Jul. 20(7):1168-76. [QxMD MEDLINE Link].
Shore EM, Glaser DL, Gannon FH. Osteogenic induction in hereditary disorders of heterotopic ossification. Clin Orthop Relat Res. 2000 May. 303-16. [QxMD MEDLINE Link].
Shore EM, Xu M, Feldman GJ, et al. A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat Genet. 2006 May. 38(5):525-7. [QxMD MEDLINE Link].
Fontaine K, Semonin O, Legarde JP, Lenoir G, Lucotte G. A new mutation of the noggin gene in a French Fibrodysplasia ossificans progressiva (FOP) family. Genet Couns. 2005. 16(2):149-54. [QxMD MEDLINE Link].
Nakajima M, Haga N, Takikawa K, Manabe N, Nishimura G, Ikegawa S. The ACVR1 617G>A mutation is also recurrent in three Japanese patients with fibrodysplasia ossificans progressiva. J Hum Genet. 2007. 52(5):473-5. [QxMD MEDLINE Link].
Furuya H, Ikezoe K, Wang L, et al. A unique case of fibrodysplasia ossificans progressiva with an ACVR1 mutation, G356D, other than the common mutation (R206H). Am J Med Genet A. 2008 Feb 15. 146A(4):459-63. [QxMD MEDLINE Link].
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 Mar. 30(3):379-90. [QxMD MEDLINE Link].
Petrie KA, Lee WH, Bullock AN, et al. Novel mutations in ACVR1 result in atypical features in two fibrodysplasia ossificans progressiva patients. PLoS One. 2009. 4(3):e5005. [QxMD MEDLINE Link]. [Full Text].
Nakahara Y, Katagiri T, Ogata N, Haga N. ACVR1 (587T>C) mutation in a variant form of fibrodysplasia ossificans progressiva: second report. Am J Med Genet A. 2014 Jan. 164A(1):220-4. [QxMD MEDLINE Link].
Song GA, Kim HJ, Woo KM, Baek JH, Kim GS, Choi JY, et al. Molecular consequences of the ACVR1 R206H mutation of fibrodysplasia ossificans progressiva. J Biol Chem. 2010 May 12. [QxMD MEDLINE Link].
Herrera-Esparza R, Pacheco-Tovar D, Bollain-Y-Goytia JJ, Torres Del Muro F, Ramírez-Sandoval R, Pacheco-Tovar MG, et al. An Activin Receptor IA/Activin-Like Kinase-2 (R206H) Mutation in Fibrodysplasia Ossificans Progressiva. Case Rep Genet. 2013. 2013:260371. [QxMD MEDLINE Link]. [Full Text].
Baujat G, Choquet R, Bouée S, Jeanbat V, Courouve L, Ruel A, 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 Jun 30. 12 (1):123. [QxMD MEDLINE Link].
Haga N, Nakashima Y, Kitoh H, Kamizono J, Katagiri T, Saijo H, et al. Fibrodysplasia Ossificans Progressiva: Review and Research Activities in Japan. Pediatr Int. 2019 Nov 27. [QxMD MEDLINE Link].
Lin FY, Lin CH, Shu G, Chen CK. Fibrodysplasia ossificans progressiva: initial presentation with a preosseous lesion of the scalp and its MRI appearance. Skeletal Radiol. 2016 Jul. 45 (7):991-6. [QxMD MEDLINE Link].
Pignolo RJ, Bedford-Gay C, Liljesthröm M, Durbin-Johnson BP, Shore EM, Rocke DM, et al. The Natural History of Flare-Ups in Fibrodysplasia Ossificans Progressiva (FOP): A Comprehensive Global Assessment. J Bone Miner Res. 2016 Mar. 31 (3):650-6. [QxMD MEDLINE Link].
Kitterman JA, Strober JB, Kan L, Rocke DM, Cali A, Peeper J, et al. Neurological symptoms in individuals with fibrodysplasia ossificans progressiva. J Neurol. 2012 Dec. 259(12):2636-43. [QxMD MEDLINE Link]. [Full Text].
Towler OW, Shore EM, Kaplan FS. Skeletal malformations and developmental arthropathy in individuals who have fibrodysplasia ossificans progressiva. Bone. 2020 Jan. 130:115116. [QxMD MEDLINE Link].
Kriegbaum RK, Hillerup S. Fibrodysplasia ossificans progressiva (FOP): Report of a case with extra-articular ankylosis of the mandible. J Craniomaxillofac Surg. 2013 Mar 16. [QxMD MEDLINE Link].
Deirmengian GK, Hebela NM, O'Connell M, Glaser DL, Shore EM, Kaplan FS. Proximal tibial osteochondromas in patients with fibrodysplasia ossificans progressiva. J Bone Joint Surg Am. 2008 Feb. 90(2):366-74. [QxMD MEDLINE Link].
Chichareon V, Arpornmaeklong P, Donsakul N. Fibrodysplasia ossificans progressiva and associated osteochondroma of the coronoid process in a child. Plast Reconstr Surg. 1999 Apr. 103(4):1238-43. [QxMD MEDLINE Link].
Levy CE, Lash AT, Janoff HB, Kaplan FS. Conductive hearing loss in individuals with fibrodysplasia ossificans progressiva. Am J Audiol. 1999 Jun. 8(1):29-33. [QxMD MEDLINE Link].
Aslan G, Celik F, Gorgu M. Unusual ankylosis of the jaw due to fibrodysplasia ossificans progressiva. Ann Plast Surg. 1999 Nov. 43(5):576-8. [QxMD MEDLINE Link].
van der Meij EH, Becking AG, van der Waal I. Fibrodysplasia ossificans progressiva. An unusual cause of restricted mandibular movement. Oral Dis. 2006 Mar. 12(2):204-7. [QxMD MEDLINE Link].
Jeziorska M, Dabska M, Buraczewski J. [Myositis ossificans (clinico-pathological entity often diagnosed erroneously as malignant tumor)]. Nowotwory. 1980 Apr-Jun. 30(2):183-94. [QxMD MEDLINE Link].
Pignolo RJ, McCarrick-Walmsley R, Wang H, et al. Plasma-Soluble Biomarkers for Fibrodysplasia Ossificans Progressiva (FOP) Reflect Acute and Chronic Inflammatory States. J Bone Miner Res. 2022 Mar. 37 (3):475-483. [QxMD MEDLINE Link].
Zaghloul KA, Heuer GG, Guttenberg MD, Shore EM, Kaplan FS, Storm PB. Lumbar puncture and surgical intervention in a child with undiagnosed fibrodysplasia ossificans progressiva. J Neurosurg Pediatr. 2008 Jan. 1(1):91-4. [QxMD MEDLINE Link].
Chuang TL, Ho KW, Wang YF. A Bizarre Bone Scan of Fibrodysplasia Ossificans Progressiva. Clin Nucl Med. 2018 Jun. 43 (6):433-435. [QxMD MEDLINE Link].
Carvalho DR, Farage L, Martins BJ, Speck-Martins CE. Craniofacial findings in fibrodysplasia ossificans progressiva: computerized tomography evaluation. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2011 Apr. 111(4):499-502. [QxMD MEDLINE Link].
Hoy SM. Palovarotene: First Approval. Drugs. 2022 Apr. 82 (6):711-716. [QxMD MEDLINE Link].
Hsiao EC, Di Rocco M, Cali A, Zasloff M, Al Mukaddam M, Pignolo RJ, et al. Special considerations for clinical trials in fibrodysplasia ossificans progressiva (FOP). Br J Clin Pharmacol. 2019 Jun. 85 (6):1199-1207. [QxMD MEDLINE Link].
Peng K, Cheung K, Lee A, Sieberg C, Borsook D, Upadhyay J. Longitudinal Evaluation of Pain, Flare-Up, and Emotional Health in Fibrodysplasia Ossificans Progressiva: Analyses of the International FOP Registry. JBMR Plus. 2019 Aug. 3 (8):e10181. [QxMD MEDLINE Link].
Dzukou T, Barbier C, Spyckerelle C, Labarriere F, Vittu G, Kremp O. [Fibrodysplasia ossificans progressiva in children. The interest of early diagnosis and treatment]. Presse Med. 2005 Mar 12. 34(5):373-7. [QxMD MEDLINE Link].
Pignolo RJ, Hsiao EC, Al Mukaddam M, Baujat G, Berglund SK, Brown MA, et al. Reduction of New Heterotopic Ossification (HO) in the Open-Label, Phase 3 MOVE Trial of Palovarotene for Fibrodysplasia Ossificans Progressiva (FOP). J Bone Miner Res. 2023 Mar. 38 (3):381-394. [QxMD MEDLINE Link]. [Full Text].
Matsuo K, Chavez RD, Barruet E, Hsiao EC. Inflammation in Fibrodysplasia Ossificans Progressiva and Other Forms of Heterotopic Ossification. Curr Osteoporos Rep. 2019 Dec. 17 (6):387-394. [QxMD MEDLINE Link].
Kaplan FS, Glaser DL, Pignolo RJ, Shore EM. A new era for fibrodysplasia ossificans progressiva: a druggable target for the second skeleton. Expert Opin Biol Ther. 2007 May. 7(5):705-12. [QxMD MEDLINE Link].
Kaplan FS, Le Merrer M, Glaser DL, et al. Fibrodysplasia ossificans progressiva. Best Pract Res Clin Rheumatol. 2008 Mar. 22(1):191-205. [QxMD MEDLINE Link]. [Full Text].
Palhares DB, Nascimento DR, Palhares MG, Lopes S, de L, Cristhina P, et al. Propranolol and ascorbic acid in control of fibrodysplasia ossificans progressiva flare-ups due to accidental falls. Intractable Rare Dis Res. 2019 Feb. 8 (1):24-28. [QxMD MEDLINE Link].
Clinical Trials Committee of the International Clinical Council on FOP (ICC). A message from the ICC on FOPCon. International Fibrodysplasia Ossificans Progressiva Association. Available at https://www.ifopa.org/icc_on_fopcon_therapy. May 24, 2019; Accessed: September 13, 2019.
Kaplan FS, Al Mukaddam M, Baujat G, et al. Emergency medical information and treatment guidelines for medical professionals. International Fibrodysplasia Ossificans Progressiva Association. Available at https://www.ifopa.org/for_medical_professionals. June 2019; Accessed: September 13, 2019.
Wadenya R, Fulcher M, Grunwald T, Nussbaum B, Grunwald Z. A description of two surgical and anesthetic management techniques used for a patient with fibrodysplasia ossificans progressiva. Spec Care Dentist. 2010 May. 30(3):106-9. [QxMD MEDLINE Link].
Kilmartin E, Grunwald Z, Kaplan FS, Nussbaum BL. General anesthesia for dental procedures in patients with fibrodysplasia ossificans progressiva: a review of 42 cases in 30 patients. Anesth Analg. 2014 Feb. 118(2):298-301. [QxMD MEDLINE Link].
Wentworth KL, Masharani U, Hsiao EC. Therapeutic advances for blocking heterotopic ossification in fibrodysplasia ossificans progressiva. Br J Clin Pharmacol. 2019 Jun. 85 (6):1180-1187. [QxMD MEDLINE Link].
Shaikh U, Khan A, Kumari P, Ishfaq A, Ekhator C, Yousuf P, et al. Novel Therapeutic Targets for Fibrodysplasia Ossificans Progressiva: Emerging Strategies and Future Directions. Cureus. 2023 Jul. 15 (7):e42614. [QxMD MEDLINE Link]. [Full Text].
Cappato S, Giacopelli F, Ravazzolo R, Bocciardi R. The Horizon of a Therapy for Rare Genetic Diseases: A "Druggable" Future for Fibrodysplasia Ossificans Progressiva. Int J Mol Sci. 2018 Mar 26. 19 (4):[QxMD MEDLINE Link].
Altschuler EL. Consideration of Rituximab for fibrodysplasia ossificans progressiva. Med Hypotheses. 2004. 63(3):407-8. [QxMD MEDLINE Link].
Alexander KA, Tseng HW, Fleming W, Jose B, Salga M, Kulina I, et al. Inhibition of JAK1/2 Tyrosine Kinases Reduces Neurogenic Heterotopic Ossification After Spinal Cord Injury. Front Immunol. 2019. 10:377. [QxMD MEDLINE Link].

Media Gallery

Widespread tumors and indurations mainly in the scapular area, found on radiographic examination to consist of heterotopic bone formation.
Typical hallus valgus deformity.
Proliferation of fibroblasts within the muscle with partial replacement of the muscle fibers.

of 3

Author

Robert A Schwartz, MD, MPH Professor and Head of Dermatology, Professor of Pathology, Professor of Pediatrics, Professor of Medicine, Rutgers New Jersey Medical School

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, New York Academy of Medicine, Royal College of Physicians of Edinburgh, Sigma Xi, The Scientific Research Honor Society

Disclosure: Nothing to disclose.

Coauthor(s)

Slawomir Majewski, MD Professor and Director, Department of Dermatology and Venereology, Warsaw School of Medicine, Poland

Disclosure: Nothing to disclose.

Specialty Editor Board

David F Butler, MD Former Section Chief of Dermatology, Central Texas Veterans Healthcare System; Professor of Dermatology, Texas A&M University College of Medicine; Founding Chair, Department of Dermatology, Scott and White Clinic

David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, Association of Military Dermatologists, Phi Beta Kappa, Texas Dermatological Society

Disclosure: Nothing to disclose.

Jeffrey J Miller, MD Associate Professor of Dermatology, Pennsylvania State University College of Medicine; Staff Dermatologist, Pennsylvania State Milton S Hershey Medical Center

Jeffrey J Miller, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, Society for Investigative Dermatology, Association of Professors of Dermatology, North American Hair Research Society

Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Additional Contributors

Jean Paul Ortonne, MD Chair, Department of Dermatology, Professor, Hospital L'Archet, Nice University, France

Jean Paul Ortonne, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Sebastian S Majewski †

Disclosure: Nothing to disclose.

Stefania Jablonska, MD † Former Chairman, Professor Emeritus, Department of Dermatology, Warsaw School of Medicine, Poland

Disclosure: Nothing to disclose.

Sections Fibrodysplasia Ossificans Progressiva
Overview
Presentation
DDx
Workup
Treatment
Medication
Media Gallery
References

Fibrodysplasia Ossificans Progressiva Clinical Presentation

History

Physical Examination

References

Tables

Contributor Information and Disclosures

What would you like to print?