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European Journal of Pediatrics

, Volume 169, Issue 11, pp 1417–1421 | Cite as

Fibrodysplasia ossificans progressiva (FOP): watch the great toes!

  • Mutlu Kartal-KaessEmail author
  • Eileen M. Shore
  • Meiqi Xu
  • Ludwig Schwering
  • Markus Uhl
  • Rudolf Korinthenberg
  • Charlotte Niemeyer
  • Frederick S. Kaplan
  • Melchior Lauten
Short Report

Abstract

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder and the most disabling condition of heterotopic (extraskeletal) ossification in humans. Extraskeletal bone formation associated with inflammation preceding the osseous conversion usually begins in the first decade, predominantly in the head, neck, and shoulders. All patients have malformed great toes. Most patients have a spontaneous mutation of the ACVR1 gene. We report a 17-year-old girl with malformed great toes who had her first episode of heterotopic ossification and impaired mobility of the left hip at the age of 13 years. No inflammatory fibroproliferative masses preceded the onset of heterotopic ossification. Radiographic studies demonstrated myositis ossificans, but failure to associate the great toe malformation with heterotopic ossification led to a failure to diagnose FOP. She underwent repeated and unnecessary operative procedures to remove a recurrent lesion. FOP was finally suspected when the great toe malformation was correlated with the trauma-induced heterotopic ossification. Genetic analysis confirmed the presence of the classic FOP mutation (ACVR1 c.617G>A; R206H). This case highlights the importance of examining the great toes in anyone with heterotopic ossification. The association of malformations of the great toe with heterotopic ossification in all cases of classic FOP will lead to prompt clinical diagnosis and the prevention of iatrogenic harm.

Keywords

Fibrodysplasia ossificans progressiva (FOP) Heterotopic ossification ACVR1 ALK2 

Notes

Conflicts of interest

None.

References

  1. 1.
    Anonymous (2010) The medical management of FOP: current treatment considerations. www.ifopa.org
  2. 2.
    Cohen RB, Hahn GV, Tabas JA et al (1993) The natural history of heterotopic ossification in patients who have fibrodysplasia ossificans progressiva. A study of forty-four patients. J Bone Joint Surg Am 75:215–219PubMedGoogle Scholar
  3. 3.
    Connor JM, Evans DA (1982) Fibrodysplasia ossificans progressiva. The clinical features and natural history of 34 patients. J Bone Joint Surg Br 64:76–83PubMedGoogle Scholar
  4. 4.
    Deirmengian GK, Hebela NM, O’Connell M et al (2008) Proximal tibial osteochondromas in patients with fibrodysplasia ossificans progressiva. J Bone Joint Surg Am 90:366–374CrossRefPubMedGoogle Scholar
  5. 5.
    Glaser DL, Kaplan FS (2005) Treatment considerations for the management of fibrodysplasia ossificans progressiva. Clin Rev Bone Mineral Metabol 3:243–250CrossRefGoogle Scholar
  6. 6.
    Glaser DL, Rocke DM, Kaplan FS (1998) Catastrophic falls in patients who have fibrodysplasia ossificans progressiva. Clin Orthop Relat Res 346:110–116CrossRefPubMedGoogle Scholar
  7. 7.
    Kaplan FS, Glaser DL, Pignolo RJ, Shore EM (2007) A new era for fibrodysplasia ossificans progressiva: a druggable target for the second skeleton. Expert Opin Biol Ther 7:705–712CrossRefPubMedGoogle Scholar
  8. 8.
    Kaplan FS, Glaser DL, Shore EM et al (2005) The phenotype of fibrodysplasia ossificans progressiva. Clin Rev Bone Mineral Metabol 3:183–188CrossRefGoogle Scholar
  9. 9.
    Kaplan FS, Glaser DL, Shore EM et al (2007) Hematopoietic stem-cell contribution to ectopic skeletogenesis. J Bone Joint Surg Am 89:347–357CrossRefPubMedGoogle Scholar
  10. 10.
    Kaplan FS, Groppe J, Pignolo RJ, Shore EM (2007) Morphogen receptor genes and metamorphogenes: skeleton keys to metamorphosis. Ann N Y Acad Sci 1116:113–133CrossRefPubMedGoogle Scholar
  11. 11.
    Kaplan FS, Le Merrer M, Glaser DL et al (2008) Fibrodysplasia ossificans progressiva. Best Pract Res Clin Rheumatol 22:191–205CrossRefPubMedGoogle Scholar
  12. 12.
    Kaplan FS, Shore EM (2008) Fibrodysplasia (myositis) ossificans progressiva. In: Rosen CS (ed) Primer on the metabolic bone diseases and disorders of mineral metabolism. The American Society for Bone and Mineral Research, Lippincott-Raven, Philadelphia, pp 442–444Google Scholar
  13. 13.
    Kaplan FS, Shore EM, Connor JM (2002) Fibrodysplasia ossificans progressiva. In: Royce PM, Steinmann B (eds) Connective tissue and its heritable disorders: molecular, genetic, and medical aspects, 2nd edn. Wiley-Liss, New York, pp 827–840Google Scholar
  14. 14.
    Kaplan FS, Tabas JA, Gannon FH et al (1993) The histopathology of fibrodysplasia ossificans progressiva. An endochondral process. J Bone Joint Surg Am 75:220–230PubMedGoogle Scholar
  15. 15.
    Kaplan FS, Xu M, Glaser DL et al (2008) Early diagnosis of fibrodysplasia ossificans progressiva. Pediatrics 121:e1295–e1300CrossRefPubMedGoogle Scholar
  16. 16.
    Kaplan FS, Xu M, Seemann P, Connor JM et al (2009) Classic and atypical fibrodysplasia ossificans progressiva (FOP) phenotypes are caused by mutations in the bone morphogenetic protein (BMP) type I receptor ACVR1. Hum Mutat 30:379–390CrossRefPubMedGoogle Scholar
  17. 17.
    Kitterman JA, Kantanie S, Rocke DM, Kaplan FS (2005) Iatrogenic harm caused by diagnostic errors in fibrodysplasia ossificans progressiva. Pediatrics 116:e654–e661CrossRefPubMedGoogle Scholar
  18. 18.
    Lanchoney TF, Cohen RB, Rocke DM et al (1995) Permanent heterotopic ossification at the injection site after diphtheria–tetanus–pertussis immunizations in children who have fibrodysplasia ossificans progressiva. J Pediatr 126:762–764CrossRefPubMedGoogle Scholar
  19. 19.
    McKusick VA (2010) Heritable disorders of connective tissue. Mosby, St Louis, MOGoogle Scholar
  20. 20.
    Rocke DM, Zasloff M, Peeper J et al (1994) Age- and joint-specific risk of initial heterotopic ossification in patients who have fibrodysplasia ossificans progressiva. Clin Orthop Relat Res 301:243–248PubMedGoogle Scholar
  21. 21.
    Scarlett RF, Rocke DM, Kantanie S et al (2004) Influenza-like viral illnesses and flare-ups of fibrodysplasia ossificans progressiva. Clin Orthop Relat Res 423:275–279CrossRefPubMedGoogle Scholar
  22. 22.
    Schaffer AA, Kaplan FS, Tracy MR et al (2005) 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) 30:1379–1385Google Scholar
  23. 23.
    Shen Q, Little SC, Xu M et al (2009) The fibrodysplasia ossificans progressiva R206H ACVR1 mutation activates BMP-independent chondrogenesis and zebrafish embryo ventralization. J Clin Invest 119:3462–3472PubMedGoogle Scholar
  24. 24.
    Shore EM, Feldman GJ, Xu M, Kaplan FS (2005) The genetics of fibrodysplasia ossificans progressiva. Clin Rev Bone Mineral Metabol 3:201–204CrossRefGoogle Scholar
  25. 25.
    Shore EM, Kaplan FS (2008) Insights from a rare genetic disorder of extra-skeletal bone formation, fibrodysplasia ossificans progressiva (FOP). Bone 43:427–433CrossRefPubMedGoogle Scholar
  26. 26.
    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 38:525–527CrossRefPubMedGoogle Scholar
  27. 27.
    Yu PB, Deng DY, Lai CS et al (2008) BMP type I receptor inhibition reduces heterotopic [corrected] ossification. Nat Med 14:1363–1369CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Mutlu Kartal-Kaess
    • 1
    • 6
    Email author
  • Eileen M. Shore
    • 2
  • Meiqi Xu
    • 2
  • Ludwig Schwering
    • 3
  • Markus Uhl
    • 4
  • Rudolf Korinthenberg
    • 1
  • Charlotte Niemeyer
    • 6
  • Frederick S. Kaplan
    • 5
  • Melchior Lauten
    • 7
  1. 1.Department of Pediatrics and Adolescent MedicineUniversity HospitalFreiburgGermany
  2. 2.Departments of Orthopaedic Surgery and GeneticsUniversity of Pennsylvania School of MedicinePhiladelphiaUSA
  3. 3.Departments of Orthopaedic Surgery and TraumatologyUniversity Hospital FreiburgFreiburgGermany
  4. 4.Department of RadiologySt. JosefskrankenhausFreiburgGermany
  5. 5.Departments of Orthopaedic Surgery and MedicineUniversity of Pennsylvania School of MedicinePhiladelphiaUSA
  6. 6.Department of Pediatric Hematology & OncologyUniversity HospitalFreiburgGermany
  7. 7.Department of Pediatric Hematology & OncologyUniversity Hospital Schleswig-Holstein, Campus LuebeckLuebeckGermany

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