Clinical Rheumatology

, Volume 25, Issue 4, pp 591–595 | Cite as

Intrafamilial phenotypic diversity in multiple epiphyseal dysplasia associated with a COL9A2 mutation (EDM2)

  • Mitsuhiko Takahashi
  • Yoshito Matsui
  • Tomohiro Goto
  • Gen Nishimura
  • Shiro Ikegawa
  • Hirofumi Ohashi
  • Natsuo Yasui
Case Report

Abstract

We describe a Japanese family with an autosomal dominant multiple epiphyseal dysplasia (MED EDM2) showing significant phenotypic diversity among the five affected members. Genomic analysis for COL9A2 identified an Ex3-1A>G heterozygous mutation, which has been proved to result in skipping of exon 3. The proband was a 9-year-old boy, who presented with ulnar club hands due to severe epiphyseal dysplasia in the distal ulnae. Radiological examination showed multiple epiphyseal dysplasias, predominantly involving the knee and the wrist. The hip appeared almost normal. The malalignment of the wrist was successfully treated with a limb lengthening procedure. The phenotype of the asymptomatic 12-year-old brother was similar to, but milder than, that of the proband. The asymptomatic 39-year-old mother, the 35-year-old uncle, and the 65-year-old grandmother with bilateral painful knees showed radiographically mild and severe osteoarthritis of the knee, respectively, and none of them had wrist deformity.

Keywords

COL9A2 EDM2 Multiple epiphyseal dysplasia Osteoarthritis Phenotype Ulnar club hands 

References

  1. 1.
    Spranger JW, Brill PW, Poznanski AK (2002) Multiple epiphyseal dysplasia. In: Spranger JW, Brill PW, Poznanski AK (eds) Bone dysplasias: an atlas of genetic disorders of skeletal development. Oxford University Press, New York, pp 141–146Google Scholar
  2. 2.
    Briggs MD, Chapman KL (2002) Pseudoachondroplasia and multiple epiphyseal dysplasia: mutation review, molecular interactions, and genotype to phenotype correlations. Human Mutat 19:465–478PubMedCrossRefGoogle Scholar
  3. 3.
    Jakkula E, Makitie O, Czarny-Ratacjzak M, Jackson GC, Damignani R, Susic M, Briggs MD, Cole WG, Ala-Kokko L (2005) Mutations in the known genes are not the major cause of MED; distinctive phenotypic entities among patients with no identified mutations. Eur J Hum Genet 13:292–301PubMedCrossRefGoogle Scholar
  4. 4.
    Eyre DR, Pietka T, Weis MA, Wu JJ (2004) Covalent cross-linking of the NC1 domain of collagen type IX to collagen type II in cartilage. J Biol Chem 279:2568–2574PubMedCrossRefGoogle Scholar
  5. 5.
    Chapman KL, Briggs MD, Mortier GR (2003) Review: clinical variability and genetic heterogeneity in multiple epiphyseal dysplasia. Pediatr Pathol Mol Med 22:53–75PubMedCrossRefGoogle Scholar
  6. 6.
    Muragaki Y, Mariman EC, van Beersum SE, Perala M, van Mourik JB, Warman ML, Olsen BR, Hamel BC (1996) A mutation in the gene encoding the alpha 2 chain of the fibril-associated collagen IX, COL9A2, causes multiple epiphyseal dysplasia (EDM2). Nat Genet 12:103–105PubMedCrossRefGoogle Scholar
  7. 7.
    Bonnemann CG, Cox GF, Shapiro F, Wu JJ, Feener CA, Thompson TG, Anthony DC, Eyre DR, Darras BT, Kunkel LM (2000) A mutation in the alpha 3 chain of type IX collagen causes autosomal dominant multiple epiphyseal dysplasia with mild myopathy. Proc Natl Acad Sci U S A 97:1212–1217PubMedCrossRefGoogle Scholar
  8. 8.
    Czarny-Ratajczak M, Lohiniva J, Rogala P, Kozlowski K, Perala M, Carter L, Spector TD, Kolodziej L, Seppanen U, Glazar R, Krolewski J, Latos-Bielenska A, Ala-Kokko L (2001) A mutation in COL9A1 causes multiple epiphyseal dysplasia: further evidence for locus heterogeneity. Am J Hum Genet 69:969–980PubMedCrossRefGoogle Scholar
  9. 9.
    Fiedler J, Stove J, Heber F, Brenner RE (2002) Clinical phenotype and molecular diagnosis of multiple epiphyseal dysplasia with relative hip sparing during childhood (EDM2). Am J Med Genet 112:144–153PubMedCrossRefGoogle Scholar
  10. 10.
    Holden P, Canty EG, Mortier GR, Zabel B, Spranger J, Carr A, Grant ME, Loughlin JA, Briggs MD (1999) Identification of novel pro-alpha2(IX) collagen gene mutations in two families with distinctive oligo-epiphyseal forms of multiple epiphyseal dysplasia. Am J Hum Genet 65:31–38PubMedCrossRefGoogle Scholar
  11. 11.
    Lohiniva J, Paassilta P, Seppanen U, Vierimaa O, Kivirikko S, Ala-Kokko L (2000) Splicing mutations in the COL3 domain of collagen IX cause multiple epiphyseal dysplasia. Am J Med Genet 90:216–222PubMedCrossRefGoogle Scholar
  12. 12.
    Nakashima E, Ikegawa S, Ohashi H, Kimizuka M, Nishimura G (2005) Double-layered patella in multiple epiphyseal dysplasia is not exclusive to DTDST mutation. Am J Med Genet A 133:106–107Google Scholar
  13. 13.
    Nakashima E, Kitoh H, Maeda K, Haga N, Kosaki R, Mabuchi A, Nishimura G, Ohashi H, Ikegawa S (2005) Novel COL9A3 mutation in a family with multiple epiphyseal dysplasia. Am J Med Genet A 132:181–184Google Scholar
  14. 14.
    Paassilta P, Lohiniva J, Annunen S, Bonaventure J, Le Merrer M, Pai L, Ala-Kokko L (1999) COL9A3: a third locus for multiple epiphyseal dysplasia. Am J Hum Genet 64:1036–1044PubMedCrossRefGoogle Scholar
  15. 15.
    Spayde EC, Joshi AP, Wilcox WR, Briggs M, Cohn DH, Olsen BR (2000) Exon skipping mutation in the COL9A2 gene in a family with multiple epiphyseal dysplasia. Matrix Biol 19:121–128PubMedCrossRefGoogle Scholar
  16. 16.
    Paassilta P, Lohiniva J, Goring HH, Perala M, Raina SS, Karppinen J, Hakala M, Palm T, Kroger H, Kaitila I, Vanharanta H, Ott J, Ala-Kokko L (2001) Identification of a novel common genetic risk factor for lumbar disk disease. JAMA 285:1843–1849PubMedCrossRefGoogle Scholar
  17. 17.
    Kapyla J, Jaalinoja J, Tulla M, Ylostalo J, Nissinen L, Viitasalo T, Vehvilainen P, Marjomaki V, Nykvist P, Saamanen AM, Farndale RW, Birk DE, Ala-Kokko L, Heino J (2004) The fibril-associated collagen IX provides a novel mechanism for cell adhesion to cartilaginous matrix. J Biol Chem 279:51677–51687PubMedCrossRefGoogle Scholar
  18. 18.
    Yasui N, Sato M, Ochi T, Kimura T, Kawahata H, Kitamura Y, Nomura S (1997) Three modes of ossification during distraction osteogenesis in the rat. J Bone Jt Surg Br 79:824–830CrossRefGoogle Scholar
  19. 19.
    Nakata K, Ono K, Miyazaki J, Olsen BR, Muragaki Y, Adachi E, Yamamura K, Kimura T (1993) Osteoarthritis associated with mild chondrodysplasia in transgenic mice expressing alpha 1(IX) collagen chains with a central deletion. Proc Natl Acad Sci U S A 90:2870–2874PubMedCrossRefGoogle Scholar
  20. 20.
    Sharma L (2001) Local factors in osteoarthritis. Curr Opin Rheumatol 13:441–446PubMedCrossRefGoogle Scholar

Copyright information

© Clinical Rheumatology 2006

Authors and Affiliations

  • Mitsuhiko Takahashi
    • 1
  • Yoshito Matsui
    • 1
  • Tomohiro Goto
    • 1
  • Gen Nishimura
    • 2
  • Shiro Ikegawa
    • 3
  • Hirofumi Ohashi
    • 4
  • Natsuo Yasui
    • 1
  1. 1.Department of Orthopaedics, Institute of Health Biosciences the University of Tokushima Graduate SchoolTokushimaJapan
  2. 2.Department of RadiologyTokyo Metropolitan Kiyose Children's Hospital TokyoJapan
  3. 3.Laboratory for Bone and Joint DiseasesSNP Research Center, RIKENTokyoJapan
  4. 4.Division of Medical GeneticsSaitama Children's Medical CenterIwatsukiJapan

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