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Osteologie 2018; 27(04): 215-221
DOI: 10.1055/s-0038-1676925
Seltene Knochenerkrankungen – Rare bone diseases
Georg Thieme Verlag KG Stuttgart · New York

Fibrodysplasia Ossificans Progressiva – FOP

Fibrodysplasia Ossificans Progressiva – FOP
L. Seefried
1   Klinische Studieneinheit, Orthopädische Klinik König-Ludwig-Haus, Universität Würzburg
,
R. Morhart
2   Abtlg. für Kinder- und Jugendmedizin am Klinikum Garmisch- Partenkirchen
,
O. Semler
3   Klinik für Kinder- und Jugendmedizin, Uniklinik Köln
› Author Affiliations
Further Information

Publication History

received: 23 October 2018

accepted: 06 November 2018

Publication Date:
10 January 2019 (online)

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Zusammenfassung

Bei der Fibrodysplasia ossificans progressiva (FOP) besteht aufgrund einer aktivierenden Mutation im Gen für den Activin A Rezeptor Typ 1 (ACVR1 / ALK2), eine Prädisposition zu heterotoper Knochenbildung in Weichgeweben, insbesondere der Muskulatur. Die Prävalenz der Erkrankung wird in einer Größenordnung von 1 pro 1–2 Mio. angegeben. Klinisch kommt es intrauterin zu Fehlbildungen, z. B. zu einem bds. Hallux valgus, der bei der überwiegenden Mehrheit der Patienten bereits bei Geburt besteht. Postnatal kommt es meist in den ersten Lebensjahren beginnend im Schulter-/ Nackenbereich episodenartig bereits nach kleineren Verletzungen zu schmerzhaften Weichteilreaktionen, sogenannten flareups die nachfolgend im Sinne einer enchondralen Ossifikation verknöchern. Die Akkumulation dieser irreversiblen Verknöcherungen im Weichgewebe bedingt eine zunehmende Einschränkung der Beweglichkeit bis hin zur kompletten Einsteifung des Körpers. Letztlich kommt es durch die fortschreitende Rigidität des Thorax zu einer respiratorischen Insuffizienz und kardialer Dekompensation.

Therapeutisch steht im Vordergrund die Vermeidung von Traumata als Auslöser für die Entstehung extraossären Knochengewebes, insbesondere auch der Verzicht auf unnötige iatrogene Schädigungen durch Operationen, Biopsien und intramuskuläre Injektionen. Supportiv sind eine adäquate Hilfsmittelversorgung, psychologische Unterstützung und eine analgetische Versorgung erforderlich. Im Falle eines Traumas werden kurzfristig hochdosiert Glucocorticoide empfohlen, um das Risiko und Ausmaß der flare-ups und nachfolgender Verknöcherungen zu reduzieren. Ergänzend können NSAR hilfreich sein. Derzeit werden unterschiedliche neue Therapieansätze entwickelt. Am weitesten fortgeschritten ist dabei der Retinolsäure Rezeptor Gamma (RARg) Agonist Palovarotene, der durch Interferenz mit der ALK2 vermittelten Signalkaskade einen zentralen Punkt im Pathomechanismus der Erkrankung adressiert.

Summary

Fibrodysplasia ossificans progressiva (FOP) is caused by an activating mutation in the Activin- Rezeptor 1 (ACVR1 / ALK2) Gene on Chromosome 2q23–24. Associated increased activity of the receptor predisposes to the development of heterotopic ossifications in the connective tissue, particularly in the muscles. The prevalence of the disorder is estimated to range between 1 in 1–2 Mio persons. At the time of birth, the only hallmark of the disease is a characteristic malformation of the great toe. During childhood, affected patients episodically develop painful soft tissue reactions, so-called flare-ups, marked by inflammation and swelling upon minor trauma. Subsequently these lesions form bone structures within the soft tissues by means of endochondral ossification. Typically, first lesions occur in the proximal, cranial, dorsal regions of the body, i. e. around the shoulder and the neck. Ossifications are irreversible and accumulate over time in the soft tissues, thereby progressively limiting patients’ mobility. Increasing limitations of chest expansion eventually compromise respiratory capacity, promote the risk for pneumonia and right-sided heart failure.

Therapeutic approaches focus on preventing additional trauma and interventions that might trigger additional heterotopic ossification, including avoidance of iatrogenic interventions like operations, biopsies and intramuscular injections. Supportive care comprises psychologic counseling, provision with appropriate technical tools as well as analgesic treatment, preferentially using NSAIDs. In case of a trauma, short term treatment with high doses of glucocorticoids is recommended in order to reduce the risk and extension of flare-ups and subsequent ossifications. Currently various novel therapeutic approaches are being evaluated. Among these, the retinoic acid receptor gamma (RARg) agonist Palovarotene is most advance in development. By binding to RARg, Palovarotene directly targets and interferes with the ALK2 induced signaling cascade considered a central aspect of the pathomechanism of the disease.

Schlüsselwörter

Fibrodysplasia ossificans progressiva - Myositis ossificans progressiva - Heterotope Ossifikationen - kongenitaler Hallux valgus - Flare-up

Keywords

Fibrodysplasia ossificans progressiva - myositis ossificans progressiva - heterotopic ossifications - kongenital hallux valgus - flare-up
 

  • Literatur

  • 1 Kaplan FS. The skeleton in the closet. Gene 2013; 528 (01) 7-11.
    CrossrefPubMedGoogle Scholar
  • 2 Münchmeyer E. Über Myositis ossificans progressiva. Zeitschrit für rationelle Medizin 1868: 34 Band.
    Google Scholar
  • 3 Baujat G, Choquet R, Bouee 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; 12 (01) 123.
    CrossrefPubMedGoogle Scholar
  • 4 Huning I, Gillessen-Kaesbach G. Fibrodysplasia ossificans progressiva: clinical course, genetic mutations and genotype-phenotype correlation. Molecular syndromology 2014; 05 (05) 201-211.
    CrossrefPubMedGoogle Scholar
  • 5 Shore EM, Xu M, Feldman GJ, Fenstermacher DA, Cho TJ, Choi IH. et al. A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat Genet 2006; 38 (05) 525-527.
    CrossrefPubMedGoogle Scholar
  • 6 Le V, Anderson E, Akiyama T, Wharton KA. Drosophila models of FOP provide mechanistic insight. Bone 2018; 109: 192-200.
    CrossrefPubMedGoogle Scholar
  • 7 Hino K, Ikeya M, Horigome K, Matsumoto Y, Ebise H, Nishio M. et al. Neofunction of ACVR1 in fibrodysplasia ossificans progressiva. Proc Natl Acad Sci U S A 2015; 112 (50) 15438-15443.
    CrossrefPubMedGoogle Scholar
  • 8 Shore EM, Kaplan FS. Inherited human diseases of heterotopic bone formation. Nat Rev Rheumatol 2010; 06 (09) 518-527.
    CrossrefPubMedGoogle Scholar
  • 9 Cohen RB, Hahn GV, Tabas JA, Peeper J, Levitz CL, Sando A. et al. The natural history of heterotopic ossification in patients who have fibrodysplasia ossificans progressiva. A study of forty-four patients. J Bone Joint Surg Am 1993; 75 (02) 215-219.
    PubMedGoogle Scholar
  • 10 Schaffer AA, Kaplan FS, Tracy MR, O’Brien ML, Dormans JP, Shore EM. et al. Developmental anomalies of the cervical spine in patients with fibrodysplasia ossificans progressiva are distinctly different from those in patients with Klippel-Feil syndrome: clues from the BMP signaling pathway. Spine (Phila Pa 1976) 2005; 30 (12) 1379-1385.
    CrossrefPubMedGoogle Scholar
  • 11 Pignolo RJ, Shore EM, Kaplan FS. Fibrodysplasia ossificans progressiva: clinical and genetic aspects. Orphanet J Rare Dis 2011; 06: 80.
    CrossrefPubMedGoogle Scholar
  • 12 Kussmaul WG, Esmail AN, Sagar Y, Ross J, Gregory S, Kaplan FS. Pulmonary and cardiac function in advanced fibrodysplasia ossificans progressiva. Clin Orthop Relat Res 1998; 346: 104-109.
    Google Scholar
  • 13 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; 92 (03) 686-691.
    CrossrefPubMedGoogle Scholar
  • 14 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; 90 (02) 366-374.
    CrossrefPubMedGoogle Scholar
  • 15 Morales-Piga A, Bachiller-Corral J, Gonzalez-Herranz P, Medrano-SanIldelfonso M, Olmedo-Garzon J, Sanchez-Duffhues G. Osteochondromas in fibrodysplasia ossificans progressiva: a widespread trait with a streaking but overlooked appearance when arising at femoral bone end. Rheumatology international 2015; 35 (10) 1759-1767.
    CrossrefPubMedGoogle Scholar
  • 16 Levy CE, Lash AT, Janoff HB, Kaplan FS. Conductive hearing loss in individuals with fibrodysplasia ossificans progressiva. Am J Audiol 1999; 08 (01) 29-33.
    CrossrefPubMedGoogle Scholar
  • 17 Kaplan FS, Xu M, Seemann P, Connor JM, Glaser DL, Carroll L. 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 (03) 379-390.
    CrossrefPubMedGoogle Scholar
  • 18 Cali IL, Rossano L. Fibrodysplasia ossificans progressiva: The patient voice. Bone 2018; 109: 291-294.
    CrossrefPubMedGoogle Scholar
  • 19 Kaplan FS, Le Merrer M, Glaser DL, Pignolo RJ, Goldsby RE, Kitterman JA. et al. Fibrodysplasia ossificans progressiva. Best Pract Res Clin Rheumatol 2008; 22 (01) 191-205.
    CrossrefPubMedGoogle Scholar
  • 20 Kitterman JA, Strober JB, Kan L, Rocke DM, Cali A, Peeper J. et al. Neurological symptoms in individuals with fibrodysplasia ossificans progressiva. Journal of neurology 2012; 259 (12) 2636-2643.
    CrossrefPubMedGoogle Scholar
  • 21 Kaplan FS, Xu M, Glaser DL, Collins F, Connor M, Kitterman J. et al. Early diagnosis of fibrodysplasia ossificans progressiva. Pediatrics 2008; 121 (05) e1295-e1300.
    CrossrefPubMedGoogle Scholar
  • 22 Kaplan FS, Tabas JA, Gannon FH, Finkel G, Hahn GV, Zasloff MA. The histopathology of fibrodysplasia ossificans progressiva. An endochondral process. J Bone Joint Surg Am 1993; 75 (02) 220-230.
    PubMedGoogle Scholar
  • 23 Kitterman JA, Kantanie S, Rocke DM, Kaplan FS. Iatrogenic harm caused by diagnostic errors in fibrodysplasia ossificans progressiva. Pediatrics 2005; 116 (05) e654-e661.
    CrossrefPubMedGoogle Scholar
  • 24 Pignolo RJ, Shore EM, Kaplan FS. Fibrodysplasia ossificans progressiva: diagnosis, management, and therapeutic horizons. Pediatr Endocrinol Rev 2013; 10 (Suppl. 2): 437-448.
    PubMedGoogle Scholar
  • 25 Pignolo RJ, Bedford-Gay C, Liljesthrom 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; 31 (03) 650-656.
    CrossrefPubMedGoogle Scholar
  • 26 Faruqi T, Dhawan N, Bahl J, Gupta V, Vohra S, Tu K. et al. Molecular, phenotypic aspects and therapeutic horizons of rare genetic bone disorders. BioMed research international 2014; 2014: 670842.
    PubMedGoogle Scholar
  • 27 Kaplan FS, Pignolo RJ, Shore EM. From mysteries to medicines: drug development for fibrodysplasia ossificans progressive. Expert Opin Orphan Drugs 2013; 01 (08) 637-649.
    Google Scholar
  • 28 Mao L, Yano M, Kawao N, Tamura Y, Okada K, Kaji H. Role of matrix metalloproteinase-10 in the BMP-2 inducing osteoblastic differentiation. Endocr J 2013; 60 (12) 1309-1319.
    CrossrefPubMedGoogle Scholar
  • 29 Giacopelli F, Cappato S, Tonachini L, Mura M, Di Lascio S, Fornasari D. et al. Identification and characterization of regulatory elements in the promoter of ACVR1, the gene mutated in Fibrodysplasia Ossificans Progressiva. Orphanet J Rare Dis 2013; 08: 145.
    CrossrefPubMedGoogle Scholar
  • 30 Mura M, Cappato S, Giacopelli F, Ravazzolo R, Bocciardi R. The role of the 3’UTR region in the regulation of the ACVR1/Alk-2 gene expression. PLoS One 2012; 07 (12) e50958.
    CrossrefPubMedGoogle Scholar
  • 31 Chaikuad A, Alfano I, Kerr G, Sanvitale CE, Boergermann JH, Triffitt JT. et al. Structure of the bone morphogenetic protein receptor ALK2 and implications for fibrodysplasia ossificans progressiva. J Biol Chem 2012; 287 (44) 36990-36998.
    CrossrefPubMedGoogle Scholar
  • 32 Sinha S, Uchibe K, Usami Y, Pacifici M, Iwamoto M. Effectiveness and mode of action of a combination therapy for heterotopic ossification with a retinoid agonist and an anti-inflammatory agent. Bone 2016; 90: 59-68.
    CrossrefPubMedGoogle Scholar
  • 33 Kaplan F. Palovarotene Reduces New Heterotopic Ossification in Fibrodysplasia Ossificans Progressiva (FOP). JBMR. 2018 33. (Suppl. 1): MON-1066.
    PubMedGoogle Scholar
  • 34 Hatsell SJ, Idone V, Wolken DM, Huang L, Kim HJ, Wang L. et al. ACVR1R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A. Sci Transl Med 2015; 07 (303) 303ra137.
    CrossrefPubMedGoogle Scholar
  • 35 Alessi DMWolken, Idone V, Hatsell SJ, Yu PB, Economides AN. The obligatory role of Activin A in the formation of heterotopic bone in Fibrodysplasia Ossificans Progressiva. Bone 2018; 109: 210-217.
    CrossrefPubMedGoogle Scholar
  • 36 Upadhyay J, Xie L, Huang L, Das N, Stewart RC, Lyon MC. et al. The Expansion of Heterotopic Bone in Fibrodysplasia Ossificans Progressiva Is Activin A-Dependent. J Bone Miner Res 2017; 32 (12) 2489-2499.
    CrossrefPubMedGoogle Scholar
  • 37 Kaplan FS, Andolina JR, Adamson PC, Teachey DT, Finklestein JZ, Ebb DH. et al. Early clinical observations on the use of imatinib mesylate in FOP: A report of seven cases. Bone 2018; 109: 276-280.
    CrossrefPubMedGoogle Scholar
  • 38 Colmenares-Bonilla D, Gonzalez-Segoviano A. Bone Resection Osteotomy in Fibrodysplasia Ossificans Progressiva. Journal of orthopaedic case reports 2018; 08 (01) 39-43.
    Google Scholar