Orofacial Clefting

Abstract

Cleft lip and cleft palate are major birth defects that have a complex etiology involving both genetic and environmental factors. The integration of modern molecular and developmental genetic techniques with epidemiologic studies is beginning to unravel the complex molecular pathways driving normal craniofacial morphogenesis and how these are disturbed in orofacial clefting.

Keywords: cleft lip; cleft palate; complex disorder; positional cloning; candidate gene

Figure 1.

Development of the lip and palate in the mouse. (a) Facial development of an embryonic day 10.5 mouse (equivalent to approximately 4 weeks of development in a human embryo) as revealed by scanning electron microscopy. The development of the nasal pit has divided the lower aspect of the frontonasal prominence into paired medial and lateral nasal process. The maxillary and mandibular processes surround the developing mouth. (b) By embryonic day 12.5 in the mouse (equivalent to approximately 6 weeks of development in an human embryo), the upper lip has been formed by fusion of the medial nasal processes and the maxillary processes. (c) A frontal histologic section through an embryonic day 13.5 mouse head indicates that the paired palatal shelves initially grow vertically down the sides of the tongue. (d) By mouse embryonic day 14.5 (equivalent to approximately 8/9 weeks of development in a human embryo), the palatal shelves have elevated to a horizontal position above the tongue and have begun to fuse together. fnp: frontonasal prominence; mnp: medial nasal process; lnp: lateral nasal process; mx: maxillary process; mp: mandibular process; mand: mandible; p: developing secondary palate; t: tongue; mc: Meckel's cartilage.

Figure 2.

Clinical pictures of various types of orofacial cleft: (a) unilateral cleft lip in which only one side of the lip is affected; (b) bilateral cleft lip and palate in which both sides of the lip are affected; (c) isolated cleft of the secondary palate in which the lip is not involved.

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References

van den Boogaard MJ, Dorland M, Beemer FA and van Amstel HK (2000) MSX1 mutation is associated with orofacial clefting and tooth agenesis in humans. Nature Genetics 24: 342–343.

Braybrook C, Doudney K, Marcano ACB, et al. (2001) The T‐box transcription factor gene TBX22 is mutated in X‐linked cleft palate and ankyloglossia. Nature Genetics 29: 179–183.

Celli J, Duijf P, Hamel BC, et al. (1999) Heterozygous germline mutations in the p53 homolog p63 are the cause of EEC syndrome. Cell 99: 143–153.

Kondo S, Schutte BC, Richardson RJ, et al. (2002) Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes. Nature Genetics 32: 285–289.

Marazita ML, Field LL, Cooper ME, et al. (2002) Genome scan for loci involved in cleft lip with or without cleft palate, in Chinese multiplex families. American Journal of Human Genetics 71: 349–364.

McGrath JA, Duijf PH, Doetsch V, et al. (2001) Hay–Wells syndrome is caused by heterozygous missense mutations in the SAM domain of p63. Human Molecular Genetics 10: 221–229.

Prescott NJ, Lees M, Winter RM and Malcolm S (2000) Identification of susceptibility loci for nonsyndromic cleft lip with or without cleft palate in a two stage genome scan of affected sib pairs. Human Genetics 106: 345–350.

Satokata I and Maas R (1994) MSX1 deficient mice exhibit cleft palate and abnormalities of craniofacial and tooth development. Nature Genetics 6: 348–356.

Sözen MA, Suzuki K, Tolarova MM, et al. (2001) Mutation of PVRL1 is associated with sporadic, nonsyndromic cleft lip/palate in northern Venezuela. Nature Genetics 29: 141–142.

Suzuki K, Hu D, Bustos T, et al. (2000) Mutations of PVRL1, encoding a cell–cell adhesion molecule/herpesvirus receptor, in cleft lip/palate‐ectodermal dysplasia. Nature Genetics 25: 427–430.

Further Reading

Brewer C, Holloway S, Zawalnyski P, Schinzel A and Fitzpatrick D (1998) A chromosomal deletion map of human malformations. American Journal of Human Genetics 63: 1153–1159.

Christensen K and Mitchell LE (1996) Familial recurrence‐pattern analysis of nonsyndromic isolated cleft palate: a Danish registry study. American Journal of Human Genetics 58: 182–190.

Farrall M and Holder S (1992) Familial recurrence‐pattern analysis of cleft lip with or without cleft palate. American Journal of Human Genetics 50: 270–277.

Lindsay EA (2001) Chromosomal microdeletions: dissecting de122q11 syndrome. Nature Reviews Genetics 2: 858–868.

Mitchell LE (1997) Transforming growth factor alpha locus and nonsyndromic cleft lip with or without cleft palate: a reappraisal. Genetic Epidemiology 14: 231–240.

Mitchell LE and Risch N (1992) Mode of inheritance of nonsyndromic cleft lip with or without cleft palate: a reanalysis. American Journal of Human Genetics 51: 323–332.

Murray JC (2002) Gene/environment causes of cleft lip and/or palate. Clinical Genetics 61: 248–256.

Sharpe J, Ahlgren U, Perry P, et al. (2002) Optical projection tomography as a tool for 3D microscopy and gene expression studies. Science 296: 541–545.

Van Bokhoven H and Brunner HG (2002) Splitting p63. American Journal of Human Genetics 71: 1–13.

Wilkie AOM and Morriss‐Kay GM (2001) Genetics of craniofacial development and malformation. Nature Reviews Genetics 2: 458–468.

Web Links

Interferon regulatory factor 6 (IRF6); Locus ID: 3664. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=3664

msh Homeo box homolog 1 (Drosophila) (MSX1); Locus ID: 4487. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=4487

Transforming growth factor, alpha (TGFA); Locus ID: 7039. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=7039

Transforming growth factor, beta 3 (TGFB3); Locus ID: 7043. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=7043

Interferon regulatory factor 6 (IRF6); MIM number: 607199. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?607199

msh Homeo box homolog 1 (Drosophila) (MSX1); MIM number: 142983. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?142983

Transforming growth factor, alpha (TGFA); MIM number: 190170. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?190170

Transforming growth factor, beta 3 (TGFB3); MIM number: 190230. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?190230

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How to Cite close
Dixon, Michael J, and Murray, Jeffrey C(Jan 2006) Orofacial Clefting. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1038/npg.els.0006028]