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. 1999 Mar;36(3):177–182.

Cleidocranial dysplasia: clinical and molecular genetics

S Mundlos 1
PMCID: PMC1734317  PMID: 10204840

Abstract

Cleidocranial dysplasia (CCD) (MIM 119600) is an autosomal dominant skeletal dysplasia characterised by abnormal clavicles, patent sutures and fontanelles, supernumerary teeth, short stature, and a variety of other skeletal changes. The disease gene has been mapped to chromosome 6p21 within a region containing CBFA1, a member of the runt family of transcription factors. Mutations in the CBFA1 gene that presumably lead to synthesis of an inactive gene product were identified in patients with CCD. The function of CBFA1 during skeletal development was further elucidated by the generation of mutated mice in which the Cbfa1 gene locus was targeted. Loss of one Cbfa1 allele (+/-) leads to a phenotype very similar to human CCD, featuring hypoplasia of the clavicles and patent fontanelles. Loss of both alleles (-/-) leads to a complete absence of bone owing to a lack of osteoblast differentiation. These studies show that haploinsufficiency of CBFA1 causes the CCD phenotype. CBFA1 controls differentiation of precursor cells into osteoblasts and is thus essential for membranous as well as endochondral bone formation.


Keywords: cleidocranial dysplasia; CBFA1

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Selected References

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  1. Becker A., Lustmann J., Shteyer A. Cleidocranial dysplasia: Part 1--General principles of the orthodontic and surgical treatment modality. Am J Orthod Dentofacial Orthop. 1997 Jan;111(1):28–33. doi: 10.1016/s0889-5406(97)70298-1. [DOI] [PubMed] [Google Scholar]
  2. Becker A., Shteyer A., Bimstein E., Lustmann J. Cleidocranial dysplasia: Part 2--Treatment protocol for the orthodontic and surgical modality. Am J Orthod Dentofacial Orthop. 1997 Feb;111(2):173–183. doi: 10.1016/s0889-5406(97)70213-0. [DOI] [PubMed] [Google Scholar]
  3. Brais B., Bouchard J. P., Xie Y. G., Rochefort D. L., Chrétien N., Tomé F. M., Lafrenière R. G., Rommens J. M., Uyama E., Nohira O. Short GCG expansions in the PABP2 gene cause oculopharyngeal muscular dystrophy. Nat Genet. 1998 Feb;18(2):164–167. doi: 10.1038/ng0298-164. [DOI] [PubMed] [Google Scholar]
  4. Brueton L. A., Reeve A., Ellis R., Husband P., Thompson E. M., Kingston H. M. Apparent cleidocranial dysplasia associated with abnormalities of 8q22 in three individuals. Am J Med Genet. 1992 Jun 1;43(3):612–618. doi: 10.1002/ajmg.1320430322. [DOI] [PubMed] [Google Scholar]
  5. COLE W. R., LEVIN S. Cleidocranial dysostosis. Br J Radiol. 1951 Oct;24(286):549–555. doi: 10.1259/0007-1285-24-286-549. [DOI] [PubMed] [Google Scholar]
  6. Chitayat D., Hodgkinson K. A., Azouz E. M. Intrafamilial variability in cleidocranial dysplasia: a three generation family. Am J Med Genet. 1992 Feb 1;42(3):298–303. doi: 10.1002/ajmg.1320420307. [DOI] [PubMed] [Google Scholar]
  7. Ducy P., Zhang R., Geoffroy V., Ridall A. L., Karsenty G. Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell. 1997 May 30;89(5):747–754. doi: 10.1016/s0092-8674(00)80257-3. [DOI] [PubMed] [Google Scholar]
  8. Feldman G. J., Robin N. H., Brueton L. A., Robertson E., Thompson E. M., Siegel-Bartelt J., Gasser D. L., Bailey L. C., Zackai E. H., Muenke M. A gene for cleidocranial dysplasia maps to the short arm of chromosome 6. Am J Hum Genet. 1995 Apr;56(4):938–943. [PMC free article] [PubMed] [Google Scholar]
  9. Francke U., Weber F., Sparkes R. S., Mattson P. D., Mann J. Duplication 11 (q21 to 23 leads to qter) syndrome. Birth Defects Orig Artic Ser. 1977;13(3B):167–186. [PubMed] [Google Scholar]
  10. Gelb B. D., Cooper E., Shevell M., Desnick R. J. Genetic mapping of the cleidocranial dysplasia (CCD) locus on chromosome band 6p21 to include a microdeletion. Am J Med Genet. 1995 Aug 28;58(2):200–205. doi: 10.1002/ajmg.1320580222. [DOI] [PubMed] [Google Scholar]
  11. Goodman R. M., Tadmor R., Zaritsky A., Becker S. A. Evidence for an autosomal recessive form of cleidocranial dysostosis. Clin Genet. 1975 Jul;8(1):20–29. doi: 10.1111/j.1399-0004.1975.tb01950.x. [DOI] [PubMed] [Google Scholar]
  12. Hall B. D. Syndromes and situations associated with congenital clavicular hypoplasia or agenesis. Prog Clin Biol Res. 1982;104:279–288. [PubMed] [Google Scholar]
  13. Hitchin A. D. Cementum and other root abnormalities of permanent teeth in cleidocranial dysostosis. Br Dent J. 1975 Oct 21;139(8):313–318. doi: 10.1038/sj.bdj.4803603. [DOI] [PubMed] [Google Scholar]
  14. Huang L. F., Fukai N., Selby P. B., Olsen B. R., Mundlos S. Mouse clavicular development: analysis of wild-type and cleidocranial dysplasia mutant mice. Dev Dyn. 1997 Sep;210(1):33–40. doi: 10.1002/(SICI)1097-0177(199709)210:1<33::AID-AJA4>3.0.CO;2-2. [DOI] [PubMed] [Google Scholar]
  15. International nomenclature of constitutional diseases of bone. Revision--May, 1977. J Pediatr. 1978 Oct;93(4):614–616. doi: 10.1016/s0022-3476(78)80897-x. [DOI] [PubMed] [Google Scholar]
  16. JACKSON W. P. U. Osteo-dental dysplasia (cleido-cranial dysostosis); the "Arnold head". Acta Med Scand. 1951;139(4):292–307. [PubMed] [Google Scholar]
  17. Jarvis J. L., Keats T. E. Cleidocranial dysostosis. A review of 40 new cases. Am J Roentgenol Radium Ther Nucl Med. 1974 May;121(1):5–16. doi: 10.2214/ajr.121.1.5. [DOI] [PubMed] [Google Scholar]
  18. Jensen B. L., Kreiborg S. Craniofacial abnormalities in 52 school-age and adult patients with cleidocranial dysplasia. J Craniofac Genet Dev Biol. 1993 Apr-Jun;13(2):98–108. [PubMed] [Google Scholar]
  19. Jensen B. L., Kreiborg S. Craniofacial growth in cleidocranial dysplasia--a roentgencephalometric study. J Craniofac Genet Dev Biol. 1995 Jan-Mar;15(1):35–43. [PubMed] [Google Scholar]
  20. Jensen B. L., Kreiborg S. Dental treatment strategies in cleidocranial dysplasia. Br Dent J. 1992 Mar 21;172(6):243–247. doi: 10.1038/sj.bdj.4807836. [DOI] [PubMed] [Google Scholar]
  21. Jensen B. L., Kreiborg S. Development of the dentition in cleidocranial dysplasia. J Oral Pathol Med. 1990 Feb;19(2):89–93. doi: 10.1111/j.1600-0714.1990.tb00803.x. [DOI] [PubMed] [Google Scholar]
  22. Jensen B. L. Somatic development in cleidocranial dysplasia. Am J Med Genet. 1990 Jan;35(1):69–74. doi: 10.1002/ajmg.1320350113. [DOI] [PubMed] [Google Scholar]
  23. Kempfle B. Dysostosis cleidocranialis familiaris. Dtsch Zahnarztl Z. 1965 Dec 1;20(12):1364–1369. [PubMed] [Google Scholar]
  24. Komori T., Yagi H., Nomura S., Yamaguchi A., Sasaki K., Deguchi K., Shimizu Y., Bronson R. T., Gao Y. H., Inada M. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell. 1997 May 30;89(5):755–764. doi: 10.1016/s0092-8674(00)80258-5. [DOI] [PubMed] [Google Scholar]
  25. LEVIN E. J., SONNENSCHEIN H. Cleidocranial dysostosis. N Y State J Med. 1963 May 15;63:1562–1566. [PubMed] [Google Scholar]
  26. Lee B., Thirunavukkarasu K., Zhou L., Pastore L., Baldini A., Hecht J., Geoffroy V., Ducy P., Karsenty G. Missense mutations abolishing DNA binding of the osteoblast-specific transcription factor OSF2/CBFA1 in cleidocranial dysplasia. Nat Genet. 1997 Jul;16(3):307–310. doi: 10.1038/ng0797-307. [DOI] [PubMed] [Google Scholar]
  27. Lukinmaa P. L., Jensen B. L., Thesleff I., Andreasen J. O., Kreiborg S. Histological observations of teeth and peridental tissues in cleidocranial dysplasia imply increased activity of odontogenic epithelium and abnormal bone remodeling. J Craniofac Genet Dev Biol. 1995 Oct-Dec;15(4):212–221. [PubMed] [Google Scholar]
  28. Miyoshi H., Shimizu K., Kozu T., Maseki N., Kaneko Y., Ohki M. t(8;21) breakpoints on chromosome 21 in acute myeloid leukemia are clustered within a limited region of a single gene, AML1. Proc Natl Acad Sci U S A. 1991 Dec 1;88(23):10431–10434. doi: 10.1073/pnas.88.23.10431. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Mundlos S., Huang L. F., Selby P., Olsen B. R. Cleidocranial dysplasia in mice. Ann N Y Acad Sci. 1996 Jun 8;785:301–302. doi: 10.1111/j.1749-6632.1996.tb56290.x. [DOI] [PubMed] [Google Scholar]
  30. Mundlos S., Mulliken J. B., Abramson D. L., Warman M. L., Knoll J. H., Olsen B. R. Genetic mapping of cleidocranial dysplasia and evidence of a microdeletion in one family. Hum Mol Genet. 1995 Jan;4(1):71–75. doi: 10.1093/hmg/4.1.71. [DOI] [PubMed] [Google Scholar]
  31. Mundlos S., Olsen B. R. Heritable diseases of the skeleton. Part I: Molecular insights into skeletal development-transcription factors and signaling pathways. FASEB J. 1997 Feb;11(2):125–132. doi: 10.1096/fasebj.11.2.9039954. [DOI] [PubMed] [Google Scholar]
  32. Mundlos S., Olsen B. R. Heritable diseases of the skeleton. Part II: Molecular insights into skeletal development-matrix components and their homeostasis. FASEB J. 1997 Mar;11(4):227–233. [PubMed] [Google Scholar]
  33. Mundlos S., Otto F., Mundlos C., Mulliken J. B., Aylsworth A. S., Albright S., Lindhout D., Cole W. G., Henn W., Knoll J. H. Mutations involving the transcription factor CBFA1 cause cleidocranial dysplasia. Cell. 1997 May 30;89(5):773–779. doi: 10.1016/s0092-8674(00)80260-3. [DOI] [PubMed] [Google Scholar]
  34. Muragaki Y., Mundlos S., Upton J., Olsen B. R. Altered growth and branching patterns in synpolydactyly caused by mutations in HOXD13. Science. 1996 Apr 26;272(5261):548–551. doi: 10.1126/science.272.5261.548. [DOI] [PubMed] [Google Scholar]
  35. Nakai H., Yamamoto Y., Kuroki Y. Partial trisomy of 11 and 22 due to familial translocation t(11;22)(q23;q11), inherited in three generations. Hum Genet. 1979 Oct 2;51(3):349–355. doi: 10.1007/BF00283408. [DOI] [PubMed] [Google Scholar]
  36. Nienhaus H., Mau U., Zang K. D., Henn W. Pericentric inversion of chromosome 6 in a patient with cleidocranial dysplasia. Am J Med Genet. 1993 Jul 1;46(6):630–631. doi: 10.1002/ajmg.1320460605. [DOI] [PubMed] [Google Scholar]
  37. Okuda T., van Deursen J., Hiebert S. W., Grosveld G., Downing J. R. AML1, the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver hematopoiesis. Cell. 1996 Jan 26;84(2):321–330. doi: 10.1016/s0092-8674(00)80986-1. [DOI] [PubMed] [Google Scholar]
  38. Otto F., Thornell A. P., Crompton T., Denzel A., Gilmour K. C., Rosewell I. R., Stamp G. W., Beddington R. S., Mundlos S., Olsen B. R. Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell. 1997 May 30;89(5):765–771. doi: 10.1016/s0092-8674(00)80259-7. [DOI] [PubMed] [Google Scholar]
  39. Palmer C. G., Bader P., Slovak M. L., Comings D. E., Pettenati M. J. Partial deletion of chromosome 6p: delineation of the syndrome. Am J Med Genet. 1991 May 1;39(2):155–160. doi: 10.1002/ajmg.1320390208. [DOI] [PubMed] [Google Scholar]
  40. Ramesar R. S., Greenberg J., Martin R., Goliath R., Bardien S., Mundlos S., Beighton P. Mapping of the gene for cleidocranial dysplasia in the historical Cape Town (Arnold) kindred and evidence for locus homogeneity. J Med Genet. 1996 Jun;33(6):511–514. doi: 10.1136/jmg.33.6.511. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Schinzel A. Trisomy 20pter = to q11 in a malformed boy from a t(13;20)(p11;q11) translocation-carrier mother. Hum Genet. 1980 Feb;53(2):169–172. doi: 10.1007/BF00273490. [DOI] [PubMed] [Google Scholar]
  42. Schuch P., Fleischer-Peters A. Zur Klinik der Dysostosis cleidocranialis. Z Kinderheilkd. 1967;98(2):107–132. [PubMed] [Google Scholar]
  43. Sillence D. O., Ritchie H. E., Selby P. B. Animal model: skeletal anomalies in mice with cleidocranial dysplasia. Am J Med Genet. 1987 May;27(1):75–85. doi: 10.1002/ajmg.1320270109. [DOI] [PubMed] [Google Scholar]

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