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The Skeleton pp 349-359 | Cite as

Genetics of Achondroplasia and Hypochondroplasia

  • Giedre Grigelioniene
Chapter

Abstract

Achondroplasia and hypochondroplasia are relatively common skeletal dysplasias characterized by disproportionate short stature, rhizomelic shortening of the limbs, and increased head circumference. Short stature and body disproportion are usually severe and uniform in achondroplasia, whereas phenotype in hypochondroplasia varies from severe achondroplasia-like forms to mild shortness and body disproportion. Mild forms of hypochondroplasia are on clinical grounds difficult to differentiate from idiopathic short stature or normal height at the shorter end of the height spectrum.

Keywords

Growth Plate Short Stature Standard Deviation Score Tyrosine Kinase Domain Skeletal Dysplasia 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Hecht, J. T., Thompson, N. M., Weir, T., Patchell, L., and Horton, W. A. (1991) Cognitive and motor skills in achondroplastic infants: neurologic and respiratory correlates. Am. J. Med. Genet. 41, 208–211.CrossRefPubMedGoogle Scholar
  2. 2.
    Langer, L. O., Jr., Baumann, P. A., and Gorlin, R. J. (1967) Achondroplasia. Am. J. Roentgenol. Radium Ther. Nucl. Med. 100, 12–26.CrossRefPubMedGoogle Scholar
  3. 3.
    Scott, C. I. Jr. (1976) Achondroplastic and hypochondroplastic dwarfism. Clin. Orthop. Jan./Feb., 18–30.Google Scholar
  4. 4.
    Horton, W. A., Rotter, J. I., Kaitila, I., et al. (1977) Growth curves in achondroplasia. Birth Defects Orig. Artic. Ser. 13, 101–107.PubMedGoogle Scholar
  5. 5.
    Hall, B. D. and Spranger, J. (1979) Hypochondroplasia: clinical and radiological aspects in 39 cases. Radiology 133, 95–100.PubMedGoogle Scholar
  6. 6.
    Grigelioniene, G., Eklof, O., Laurencikas, E., Ollars, B., Hertel, N. T., Dumanski, J. P., and Hagenas, L. (2000) Asn540Lys mutation in fibroblast growth factor receptor 3 and phenotype in hypochondroplasia. Acta Paediatr. 89, 1072–1076.CrossRefPubMedGoogle Scholar
  7. 7.
    Brook, C. G. and de Vries, B. B. (1998) Skeletal dysplasias. Arch. Dis. Child. 79, 285–289.CrossRefPubMedGoogle Scholar
  8. 8.
    Appan, S., Laurent, S., Chapman, M., Hindmarsh, P. C., and Brook, C. G. (1990) Growth and growth hormone therapy in hypochondroplasia. Acta Paediatr. Scand. 79, 796–803.CrossRefPubMedGoogle Scholar
  9. 9.
    Bridges, N. A., Hindmarsh, P. C., and Brook, C. G. (1991) Growth of children with hypochondroplasia treated with growth hormone for up to three years. Harm. Res. 36, 56–60.CrossRefGoogle Scholar
  10. 10.
    Orioli, I. M., Castilla, E. E., and Barbosa-Neto, J. G. (1986) The birth prevalence rates for the skeletal dysplasias. J. Med. Genet. 23, 328–332.CrossRefPubMedGoogle Scholar
  11. 11.
    Martinez-Frias, M. L., Cereijo, A., Bermejo, E., Lopez, M., Sanchez, M., and Gonzalo, C. (1991) Epidemiological aspects of Mendelian syndromes in a Spanish population sample: I. Autosomal dominant malformation syndromes. Am. J. Med. Genet. 38, 622–625.CrossRefPubMedGoogle Scholar
  12. 12.
    Bellus, G. A., Hefferon, T. W., Ortiz de Luna, R. I., Hecht, J. T., Horton, W. A., Machado, M., et al. (1995) Achondronlasia is defined by recurrent G380R mutations of FGFR3. Am. J. Hum. Genet. 56, 368–373.PubMedGoogle Scholar
  13. 13.
    Stoll, C., Roth, M. P., and Bigel, P. (1982) A reexamination on parental age effect on the occurrence of new mutations for achondroplasia. Prog. Clin. Biol. Res. 104, 419–426.PubMedGoogle Scholar
  14. 14.
    Wilkin, D. J., Szabo, J. K., Cameron, R., Henderson, S., Bellus, G. A., Mack, M. L., et al. (1998) Mutations in fibroblast growth-factor receptor 3 in sporadic cases of achondroplasia occur exclusively on the paternally derived chromosome. Am. J. Hum. Genet. 63, 711–716.CrossRefPubMedGoogle Scholar
  15. 15.
    Bowen, P. (1974) Achondroplasia in two sisters with normal parents. Birth Defects Orig. Artic. Ser. 10, 31–36.PubMedGoogle Scholar
  16. 16.
    Henderson, S., Sillence, D., Loughlin, J., Bennetts, B., and Sykes, B. (2000) Germline and somatic mosaicism in achondroplasia. J. Med. Genet. 37, 956–958.CrossRefPubMedGoogle Scholar
  17. 17.
    McKusick, V. A., Kelly, T. E., and Dorst, J. P. (1973) Observations suggesting allelism of the achondroplasia and hynnchondronlasia genes. I. Med. Genet. 10. 11–16.CrossRefGoogle Scholar
  18. 18.
    Shiang, R., Thompson, L. M., Zhu, Y. Z., Church, D. M., Fielder, T. J., Bocian, M., et al. (1994) Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell 78, 335–342.CrossRefPubMedGoogle Scholar
  19. 19.
    Bellus, G. A., McIntosh, I., Smith, E. A., Aylsworth, A. S., Kaitila, I., Horton, W. A., et al. (1995) A recurrent mutation in the tyrosine kinase domain of fibroblast growth factor receptor 3 causes hypochondroplasia. Nat. Genet. 10, 357–359.CrossRefPubMedGoogle Scholar
  20. 20.
    Prinos, P., Costa, T., Sommer, A., Kilpatrick, M. W., and Tsipouras, P. (1995) A common FGFR3 gene mutation in hypochondroplasia. Hum. Mol. Genet. 4, 2097–2101.CrossRefPubMedGoogle Scholar
  21. 21.
    Bonaventure, J., Rousseau, F., Legeai-Mallet, L., Le Merrer, M., Munnich, A., and Maroteaux, P. (1996) Common mutations in the fibroblast growth factor receptor 3 (FGFR 3) gene account for achondroplasia, hypochondroplasia, and thanatophoric dwarfism. Am. J. Med. Genet. 63,148–154.CrossRefPubMedGoogle Scholar
  22. 22.
    Rousseau, F., Bonaventure, J., Legeai-Mallet, L., Schmidt, H., Weissenbach, J., Maroteaux, P., et al. (1996) Clinical and genetic heterogeneity of hypochondroplasia. J. Med. Genet. 33,749–752.CrossRefPubMedGoogle Scholar
  23. 23.
    Prinster, C., Carrera, P., Del Maschio, M., Weber, G., Maghnie, M., Vigone, M. C., et al. (1998) Comparison of clinical-radiological and molecular findings in hypochondroplasia. Am. J. Med. Genet. 75, 109–112.CrossRefPubMedGoogle Scholar
  24. 24.
    Ramaswami, U., Rumsby, G., Hindmarsh, P. C., and Brook, C. G. (1998) Genotype and phenotype in hypochondroplasia. J. Pediatr. 133, 99–102.CrossRefPubMedGoogle Scholar
  25. 25.
    Tsai, F. J., Wu, J. Y., Tsai, C. H., and Chang, J. G. (1999) Identification of a common N540K mutation in 8/18 Taiwanese hypochondroplasia patients: further evidence for genetic heterogeneity. Clin. Genet. 55. 279–250.CrossRefPubMedGoogle Scholar
  26. 26.
    Stoilov, I., Kilpatrick, M. W., Tsipouras, P., and Costa, T. (1995) Possible genetic heterogeneity in hypochondroplasia. J. Med. Genet. 32, 492–493.CrossRefPubMedGoogle Scholar
  27. 27.
    Prinster, C., Del Maschio, M., Beluffi, G., Maghnie, M., Weber, G., Del Maschio, A., et al. (2001) Diagnosis of hypochondroplasia: the role of radiological interpretation. Italian Study Group for Hypochondroplasia. Pediatr. Radiol. 31, 203–208.CrossRefPubMedGoogle Scholar
  28. 28.
    Angle, B., Hersh, J. H., and Christensen, K. M. (1998) Molecularly proven hypochondroplasia with cloverleaf skull deformity: a novel association. Clin. Genet. 54, 417–420.CrossRefPubMedGoogle Scholar
  29. 29.
    Wuechner, C., Nordqvist, A. C., Winterpacht, A., Zabel, B., and Schalling, M. (1996) Developmental expression of splicing variants of fibroblast growth factor receptor 3 (FGFR3) in mouse. Int. J. Dev. Biol. 40. 1185–1188.PubMedGoogle Scholar
  30. 30.
    Peters, K., Ornitz, D., Werner, S., and Williams, L. (1993) Unique expression pattern of the FGF receptor 3 gene during mouse organogenesis. Dev. Biol. 155, 423–430.CrossRefPubMedGoogle Scholar
  31. 31.
    Delezoide, A. L., Benoist-Lasselin, C., Legeai-Mallet, L., Le Merrer, M., Munnich, A., Vekemans, M., et al. (1998) Spatio-temporal expression of FGFR 1,2 and 3 genes during human embryo fetal ossification. Mech. Dev. 77. 19–30.CrossRefPubMedGoogle Scholar
  32. 32.
    Ornitz, D. (2000) Fibroblast Growth Factors, Chondrogenesis, and Related Clinical Disorders, in Skeletal Growth Factors (Canalis, E., ed.). Lippincott Williams and Wilkins, Philadelphia, pp. 197–209.Google Scholar
  33. 33.
    Weksler, N. B., Lunstrum, G. P., Reid, E. S., and Horton, W. A. (1999) Differential effects of fibroblast growth factor (FGF) 9 and FGF2 on proliferation, differentiation and terminal differentiation of chondrocytic cells in vitro. Biocherm. J. 342, 677–682.CrossRefGoogle Scholar
  34. 34.
    Tavormina, P. L., Shiang, R., Thompson, L. M., Zhu, Y. Z., Wilkin, D. J., Lachman, R. S., et al. (1995) Thanatophoric dysplasia (types I and II) caused by distinct mutations in fibroblast growth factor receptor 3. Nat. Genet. 9. 321–328.CrossRefPubMedGoogle Scholar
  35. 35.
    Burke, D., Wilkes, D., Blundell, T. L., and Malcolm, S. (1998) Fibroblast growth factor receptors: lessons from the genes. Trends Biochem. Sci. 23. 59–62.CrossRefPubMedGoogle Scholar
  36. 36.
    Bellus, G. A., Bamshad, M. J., Przylepa, K. A., Dorst, J., Lee, R. R., Hurko, O., et al. (1999) Severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN): phenotypic analysis of a new skeletal dysplasia caused by a Lys650Met mutation in fibroblast growth factor receptor 3. Am. J. Med. Genet. 85, 53–65.CrossRefPubMedGoogle Scholar
  37. 37.
    Vajo, Z., Francomano, C. A., and Wilkin, D. J. (2000) The molecular and genetic basis of fibroblast growth factor receptor 3 disorders: the achondroplasia family of skeletal dysplasias, Muenke craniosynostosis, and Crouzon syndrome with acanthosis nigricans. Endocr. Rev. 21. 23–39.CrossRefPubMedGoogle Scholar
  38. 38.
    Colvin, J. S., Bohne, B. A., Harding, G. W., McEwen, D. G., and Ornitz, D. M. (1996) Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3. Nat. Genet. 12, 390–397.CrossRefPubMedGoogle Scholar
  39. 39.
    Deng, C., Wynshaw-Boris, A., Zhou, F., Kuo, A., and Leder, P. (1996) Fibroblast growth factor receptor 3 is a negative regulator of bone growth. Cell 84, 911–921.CrossRefPubMedGoogle Scholar
  40. 40.
    Webster, M. K. and Donoghue, D. J. (1996) Constitutive activation of fibroblast growth factor receptor 3 by the transmembrane domain point mutation found in achondroplasia. EMBO J. 15, 520–527.PubMedGoogle Scholar
  41. 41.
    Naski, M. C., Wang, Q., Xu, J., and Ornitz, D. M. (1996) Graded activation of fibroblast growth factor receptor 3 by mutations causing achondroplasia and thanatophoric dysplasia. Nat. Genet. 13, 233–237.CrossRefPubMedGoogle Scholar
  42. 42.
    Raffioni, S., Zhu, Y. Z., Bradshaw, R. A., and Thompson, L. M. (1998) Effect of transmembrane and kinase domain mutations on fibroblast growth factor receptor 3 chimera signaling in PC12 cells. A model for the control of receptor tyrosine kinase activation. J. Biol. Chem. 273. 35250–35259CrossRefPubMedGoogle Scholar
  43. 43.
    Bellus, G. A., Spector, E. B., Speiser, P. W., Weaver, C. A., Garber, A. T., Bryke, C. R., et al. (2000) Distinct missense mutations of the FGFR3 1ys650 codon modulate receptor kinase activation and the severity of the skeletal dysplasia phenotype. Am. J. Hum. Genet. 67. 1411–1421.CrossRefPubMedGoogle Scholar
  44. 44.
    Chen, L., Adar, R., Yang, X., Monsonego, E. O., Li, C., Hauschka, P. V., et al. (1999) Gly369Cys mutation in mouse FGFR3 causes achondroplasia by affecting both chondrogenesis and osteogenesis. J. Clin. Invest. 104, 1517–1525.CrossRefPubMedGoogle Scholar
  45. 45.
    Monsonego-Ornan, E., Adar, R., Feferman, T., Segev, O., and Yayon, A. (2000) The transmembrane mutation G380R in fibroblast growth factor receptor 3 uncouples ligand-mediated receptor activation from downregulation. Mol. Cell. Biol. 20, 516–522.CrossRefPubMedGoogle Scholar
  46. 46.
    Delezoide, A. L., Lasselin-Benoist, C., Legeai-Mallet, L., Brice, P., Senee, V., Yayon, A., et al. (1997) Abnormal FGFR 3 expression in cartilage of thanatophoric dysplasia fetuses. Hum. Mol. Genet. 6, 1899–1906.CrossRefPubMedGoogle Scholar
  47. 47.
    Naski, M. C., Colvin, J. S., Coffin, J. D., and Ornitz, D. M. (1998) Repression of hedgehog signaling and BMP4 expression in growth plate cartilage by fibroblast growth factor receptor 3. Development 125, 4977–4988.PubMedGoogle Scholar
  48. 48.
    Li, C., Chen, L., Iwata, T., Kitagawa, M., Fu, X. Y., and Deng, C. X. (1999) A Lys644Glu substitution in fibroblast growth factor receptor 3 (FGFR3) causes dwarfism in mice by activation of STATs and ink4 cell cycle inhibitors. Hum. Mol. Genet. 8, 35–44.CrossRefPubMedGoogle Scholar
  49. 49.
    Wang, Y., Spatz, M. K., Kannan, K., Hayk, H., Avivi, A., Gorivodsky, M., et al. (1999) A mouse model for achondronlasia produced by targeting fibroblast growth factor receptor 3. Proc. Natl. Acad. Sci. USA 96, 4455–4460.CrossRefPubMedGoogle Scholar
  50. 50.
    Iwata, T., Chen, L., Li, C., Ovchinnikov, D. A., Behringer, R. R., Francomano, C. A., et al. (2000) A neonatal lethal mutation in FGFR3 uncouples proliferation and differentiation of growth plate chondrocytes in embryos. Hum. Mol. Genet. 9, 1603–1613.CrossRefPubMedGoogle Scholar
  51. 51.
    Segev, O., Chumakov, I., Nevo, Z., Givol, D., Madar-Shapiro, L., Sheinin, Y., et al. (2000) Restrained chondrocyte proliferation and maturation with abnormal growth plate vascularization and ossification in human FGFR-3(G380R) transgenic mice. Hum. Mol. Genet. 9, 249–258.CrossRefPubMedGoogle Scholar
  52. 52.
    Rimoin, D. L. (1975) The chondrodystrophies. Adv. Hum. Genet. 5, 1–118.CrossRefPubMedGoogle Scholar
  53. 53.
    Legeai-Mallet, L., Benoist-Lasselin, C., Delezoide, A. L., Munnich, A., and Bonaventure, J. (1998) Fibroblast growth factor receptor 3 mutations promote apoptosis but do not alter chondrocyte proliferation in thanatophoric dysplasia. J. Biol. Chem. 273, 13007–13014.CrossRefPubMedGoogle Scholar
  54. 54.
    Shimizu, A., Tada, K., Shukunami, C., Hiraki, Y., Kurokawa, T., Magane, N., and Kurokawa-Seo, M. (2001) A novel alternatively spliced fibroblast growth factor receptor 3 isoform lacking the acid box domain is expressed during chondrogenic differentiation of ATDC5 cells. J. Biol. Chem. 276, 11031–11040.CrossRefPubMedGoogle Scholar
  55. 55.
    Su, W. C., Kitagawa, M., Xue, N., Xie, B., Garofalo, S., Cho, J., et al. (1997) Activation of Stat 1 by mutant fibroblast growth-factor receptor in thanatophoric dysplasia type II dwarfism. Nature 386, 288–292.CrossRefPubMedGoogle Scholar
  56. 56.
    Bi, W., Deng, J. M., Zhang, Z., Behringer, R. R., and de Crombrugghe, B. (1999) Sox9 is required for cartilage tormation. Nat. Genet. 22, 85–89.CrossRefPubMedGoogle Scholar
  57. 57.
    Huang, W., Chung, U. I., Kronenberg, H. M., and de Crombrugghe, B. (2001) The chondrogenic transcription factor Sox9 is a target of signaling by the parathyroid hormone-related peptide in the growth plate of endochondral bones. Proc. Natl. Acad. Sci. USA 98, 160–165.CrossRefPubMedGoogle Scholar
  58. 58.
    Murakami, S., Kan, M., McKeehan, W. L., and de Crombrugghe, B. (2000) Up-regulation of the chondrogenic Sox9 gene by fibroblast growth factors is mediated by the mitogen-activated protein kinase pathway. Proc. Natl. Acad. Sci. USA 97, 1113–1118.CrossRefPubMedGoogle Scholar
  59. 59.
    Karp, S. J., Schipani, E., St-Jacques, B., Hunzelman, J., Kronenberg, H., and McMahon, A. P. (2000) Indian hedgehog coordinates endochondral bone growth and morphogenesis via parathyroid hormone related-protein-dependent and -independent pathways. Development 127, 543–548.PubMedGoogle Scholar
  60. 60.
    Henderson, J. E., Naski, M. C., Aarts, M. M., Wang, D., Cheng, L., Goltzman, D., and Ornitz, D. M. (2000) Expression of FGFR3 with the G380R achondroplasia mutation inhibits proliferation and maturation of CFK2 chondrocytic cells. J. Bone Miner. Res. 15, 155–165.CrossRefPubMedGoogle Scholar
  61. 61.
    Ikegawa, S., Fukushima, Y., Isomura, M., Takada, F., and Nakamura, Y. (1995) Mutations of the fibroblast growth factor receptor-3 gene in one familial and six sporadic cases of achondroplasia in Japanese patients. Hum. Genet. 96, 309–311.CrossRefPubMedGoogle Scholar
  62. 62.
    Superti-Furga, A., Eich, G., Bucher, H. U., Wisser, J., Giedion, A., Gitzelmann, R., et al. (1995) A glycine 375-tocysteine substitution in the transmembrane domain of the fibroblast growth factor receptor-3 in a newborn with achondronlasia. Eur. J. Pediatr. 154, 215–219.CrossRefPubMedGoogle Scholar
  63. 63.
    Winterpacht, A., Hilbert, K., Stelzer, C., Schweikardt, T., Decker, H., Segerer, H., et al. (2000) A novel mutation in FGFR-3 disrupts a putative N-glycosylation site and results in hypochondroplasia. Physiol. Genomics 2, 9–12.PubMedGoogle Scholar
  64. 64.
    Grigelioniene, G., Hagenas, L., Eklof, O., Neumeyer, L., Haereid, P. E., and Anvret, M. (1998) A novel missense mutation Ile538Val in the fibroblast growth factor receptor 3 in hypochondroplasia. Mutations in brief no. 122. Online. Hum. Mutat. 11. 333.CrossRefPubMedGoogle Scholar
  65. 65.
    Mortier, G., Nuytinck, L., Craen, M., Renard, J. P., Leroy, J. G., and de Paepe, A. (2000) Clinical and radiographic features of a family with hypochondroplasia owing to a novel Asn540Ser mutation in the fibroblast growth factor receptor gene J MM ed Genet. 37. 220–224.Google Scholar
  66. 66.
    Deutz-Terlouw, P. P., Losekoot, M., Aalfs, C. M., Hennekam, R. C., and Bakker, E. (1998) Asn540Thr substitution in the fibroblast growth factor receptor 3 tyrosine kinase domain causing hypochondroplasia. Hum. Mutat. Suppl 1, S62–S65.CrossRefPubMedGoogle Scholar

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  • Giedre Grigelioniene

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