Pediatric Radiology

, Volume 42, Issue 1, pp 15–23 | Cite as

The importance of conventional radiography in the mutational analysis of skeletal dysplasias (the TRPV4 mutational family)

  • Stefan F. NemecEmail author
  • Daniel H. Cohn
  • Deborah Krakow
  • Vincent A. Funari
  • David L. Rimoin
  • Ralph S. Lachman


The spondylo and spondylometaphyseal dysplasias (SMDs) are characterized by vertebral changes and metaphyseal abnormalities of the tubular bones, which produce a phenotypic spectrum of disorders from the mild autosomal-dominant brachyolmia to SMD Kozlowski to autosomal-dominant metatropic dysplasia. Investigations have recently drawn on the similar radiographic features of those conditions to define a new family of skeletal dysplasias caused by mutations in the transient receptor potential cation channel vanilloid 4 (TRPV4). This review demonstrates the significance of radiography in the discovery of a new bone dysplasia family due to mutations in a single gene.


Skeletal dysplasias Spondylometaphyseal dysplasias TRPV4 Radiography 



The authors wish to thank Ms. Mary McAllister (John Hopkins University, Baltimore, MD) for her assistance in editing the manuscript. This work has been supported by a grant from the National Institutes of Health (5P01 HD022657-25).


  1. 1.
    Krakow D, Rimoin DL (2010) The skeletal dysplasias. Genet Med 12:327–341PubMedGoogle Scholar
  2. 2.
    Warman ML, Cormier-Daire V, Hall C et al (2011) Nosology and classification of genetic skeletal disorders: 2010 revision. Am J Med Genet A 155A:943–968PubMedGoogle Scholar
  3. 3.
    Lachman RS, Tiller GE, Graham JM Jr et al (1992) Collagen, genes and the skeletal dysplasias on the edge of a new era: a review and update. Eur J Radiol 14:1–10PubMedCrossRefGoogle Scholar
  4. 4.
    Spranger J, Winterpacht A, Zabel B (1993) The type II collagenopathies: a spectrum of chondrodysplasias. Eur J Pediatr 153:56–65Google Scholar
  5. 5.
    Superti-Furga A, Hästbacka J, Rossi A (1996) A family of chondrodysplasias caused by mutations in the diastrophic dysplasia sulfate transporter gene and associated with impaired sulfation of proteoglycans. Ann N Y Acad Sci 785:195–201PubMedCrossRefGoogle Scholar
  6. 6.
    Krakow D, Robertson SP, King LM et al (2004) Mutations in the gene encoding filamin B disrupt vertebral segmentation, joint formation and skeletogenesis. Nat Genet 36:405–410PubMedCrossRefGoogle Scholar
  7. 7.
    Rock MJ, Prenen J, Funari VA et al (2008) Gain-of-function mutations in TRPV4 cause autosomal dominant brachyolmia. Nat Genet 40:999–1003PubMedCrossRefGoogle Scholar
  8. 8.
    Krakow D, Vriens J, Camacho N et al (2008) Mutations in the gene encoding the calcium-permeable ion channel TRPV4 produce spondylometaphyseal dysplasia, Kozlowski type and metatropic dysplasia. Am J Hum Genet 84:307–315CrossRefGoogle Scholar
  9. 9.
    Dai J, Kim OH, Cho TJ et al (2010) Novel and recurrent TRPV4 mutations and their association with distinct phenotypes within the TRPV4 dysplasia family. J Med Genet 47:704–709PubMedCrossRefGoogle Scholar
  10. 10.
    Dai J, Cho TJ, Unger S et al (2010) TRPV4-pathy, a novel channelopathy affecting diverse systems. J Hum Genet 55:400–402PubMedCrossRefGoogle Scholar
  11. 11.
    Mourão PA, Toledo SP, Nader HB et al (1973) Excretion of chondroitin sulfate C with low sulfate content by patients with generalized platyspondyly (brachyolmia). Biochem Med 7:415–423CrossRefGoogle Scholar
  12. 12.
    Shohat M, Lachman R, Gruber HE et al (1989) Brachyolmia: radiographic and genetic evidence of heterogeneity. Am J Med Genet 33:209–219PubMedCrossRefGoogle Scholar
  13. 13.
    Gardner J, Beighton P (1994) Brachyolmia: an autosomal dominant form. Am J Med Genet 49:308–312PubMedCrossRefGoogle Scholar
  14. 14.
    Kozlowski K, Maroteaux P, Spranger JW (1967) La dysostose spondylometaphysaire. Presse Med 75:2769Google Scholar
  15. 15.
    Lachman RS (2007) Spondylometaphyseal dysplasia, Kozlowski type (SMD Kozlowski). In: Taybi & Lachman’s Radiology of syndromes, metabolic disorders and skeletal dysplasias, 5th edn. Mosby, Elsevier, Philadelphia, pp 1080–1085Google Scholar
  16. 16.
    Maroteaux P, Spranger J, Wiedemann HR (1966) Metatrophic dwarfism. Arch Kinderheilkd 173:211–226PubMedGoogle Scholar
  17. 17.
    Geneviève D, Le Merrer M, Feingold J et al (2008) Revisiting metatropic dysplasia: presentation of a series of 19 novel patients and review of the literature. Am J Med Genet A 146:992–996Google Scholar
  18. 18.
    Lachman RS (2007) Brachyolmia. In: Taybi & Lachman’s Radiology of syndromes, metabolic disorders and skeletal dysplasias, 5th edn. Mosby, Elsevier, Philadelphia, pp 891–892Google Scholar
  19. 19.
    Camacho N, Krakow D, Johnykutty S et al (2010) Dominant TRPV4 mutations in nonlethal and lethal metatropic dysplasia. Am J Med Genet A 152:1169–1177Google Scholar
  20. 20.
    Lachman RS (2007) Metatropic dysplasia. In: Taybi & Lachman’s Radiology of syndromes, metabolic disorders and skeletal dysplasias, 5th edn. Mosby, Elsevier, Philadelphia, pp 1000–1001Google Scholar
  21. 21.
    Murray LW, Bautista J, James PL et al (1989) Type II collagen defects in the chondrodysplasias. I. Spondyloepiphyseal dysplasias. Am J Hum Genet 45:5–15PubMedGoogle Scholar
  22. 22.
    Hästbacka J, Superti-Furga A, Wilcox WR et al (1996) Atelosteogenesis type II is caused by mutations in the diastrophic dysplasia sulfate-transporter gene (DTDST): evidence for a phenotypic series involving three chondrodysplasias. Am J Hum Genet 58:255–262PubMedGoogle Scholar
  23. 23.
    Farrington-Rock C, Firestein MH, Bicknell LS et al (2006) Mutations in two regions of FLNB result in atelosteogenesis I and III. Hum Mutat 27:705–710PubMedCrossRefGoogle Scholar
  24. 24.
    Cohn DH (1996) Mutations affecting multiple functional domains of FGFR3 cause different skeletal dysplasias: a personal retrospective in honor of John Wasmuth. Ann N Y Acad Sci 785:160–163PubMedCrossRefGoogle Scholar
  25. 25.
    Savarirayan R, White SM, Goodman FR et al (2003) Broad phenotypic spectrum caused by an identical heterozygous CDMP-1 mutation in three unrelated families. Am J Med Genet A 117:136–142Google Scholar
  26. 26.
    Guilak F, Leddy HA, Liedtke W (2010) Transient receptor potential vanilloid 4: The sixth sense of the musculoskeletal system? Ann N Y Acad Sci 1192:404–409PubMedCrossRefGoogle Scholar
  27. 27.
    Masuyama R, Vriens J, Voets T et al (2008) TRPV4-mediated calcium influx regulates terminal differentiation of osteoclasts. Cell Metab 8:257–265PubMedCrossRefGoogle Scholar
  28. 28.
    Nishimura G, Dai J, Lausch E et al (2010) Spondylo-epiphyseal dysplasia, Maroteaux type (pseudo-Morquio syndrome type 2), and parastremmatic dysplasia are caused by TRPV4 mutations. Am J Med Genet A 152:1443–1449Google Scholar
  29. 29.
    Auer-Grumbach M, Olschewski A, Papić L et al (2010) Alterations in the ankyrin domain of TRPV4 cause congenital distal SMA, scapuloperoneal SMA and HMSN2C. Nat Genet 42:160–164PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Stefan F. Nemec
    • 1
    Email author
  • Daniel H. Cohn
    • 1
  • Deborah Krakow
    • 1
  • Vincent A. Funari
    • 1
  • David L. Rimoin
    • 1
  • Ralph S. Lachman
    • 1
  1. 1.International Skeletal Dysplasia RegistryMedical Genetics Institute, Cedars Sinai Medical CenterLos AngelesUSA

Personalised recommendations