Genetics of Congenital Tooth Agenesis

Abstract

Tooth agenesis is the most common congenital anomaly in humans. It has variable expression and most severe forms segregate in families, which allowed for the application of strategies for gene identification. A subset of those cases is caused by mutations in PAX9, MSX1, AXIN2, EDA, EDAR, EDARADD, and WNT10A. However, the vast majority of cases of tooth agenesis is less severe and may be the result of hypomorphic genetic variations in multiple genes. Of particular interest is the association of tooth agenesis with other conditions such as cleft lip and palate and cancer. Individuals born with oral clefts have a much higher chance to have tooth agenesis outside the cleft area. Cases of tooth agenesis caused by mutations in AXIN2 can also develop colorectal cancer. These types of cases suggest the understanding of the aetiology of developmental disruptions of dental development can also impact other relevant fields of medicine.

Key Concepts:

  • Oligodontia (agenesis of six or more teeth excluding third molars) is not common in the population (0.3%).

  • Hypodontia (agenesis of less than six teeth excluding third molars) can be as common as 11% in the population.

  • Mutations in genes such as PAX9, MSX1, and AXIN2 explain just a small percentage of oligodontia cases segregating in an autosomal dominant fashion.

  • Mutations in genes such as WNT10A explain just a small percentage of hypodontia cases segregating in an autosomal dominant fashion.

  • X‚Äźlinked inheritance of isolated oligodontia can be caused by mutations in ectodermal dysplasia genes.

  • Tooth agenesis is four times more common in individuals born with oral clefts, as well as in their relatives.

  • Individuals with oligodontia caused by mutations in AXIN2 are at higher risk for colorectal cancer.

Keywords: hypodontia; oligodontia; cancer; cleft lip and palate; MSX1; PAX9; AXIN2; EDA; WNT10A, ectodermal dysplasia

Figure 1.

Deletion of only one copy of the PAX9 gene leads to oligodontia and suggests haploinsufficiency as the etiologic mechanism (Das et al., ). Note: In NKX2‐9, NK stands for Nirenberg and Kim, the authors of the first paper describing these genes in Drosophila. X indicates this is a homeobox gene. SLC25A stands for solute carrier family 25, a mitochondrial carrier. This gene is also called adenine nucleotide translocator, member 5.

Figure 2.

Schematic representation of unilateral cleft (a) and unilateral cleft with agenesis of the lateral incisor (arrow) on the opposite side of the cleft (b), also referred to as ‘unsuccessful or occult cleft’ according to Letra et al. () (i, central incisor; l, lateral incisor; c, canine; pm, pre‐molar; m, molar).

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References

Ahmad W, Brancolini V, ul Faiyaz MF et al. (1998) A locus for autosomal recessive hypodontia with associated dental anomalies maps to chromosome 16q12.1. American Journal of Human Genetics 62(4): 987–991.

Azeem Z, Naqvi SK, Ansar M et al. (2009) Recurrent mutations in functionally related EDA and EDAR genes underlie X‐linked isolated hypodontia and autosomal recessive hypohidrotic ectodermal dysplasia. Archives of Dermatological Research 301(8): 625–629.

Bergendal B, Klar J, Stecksén‐Blicks C, Norderyd J and Dahl N (2011) Isolated oligodontia associated with mutations in EDARADD, AXIN2, MSX1, and PAX9 genes. American Journal of Medical Genetics A 155(7): 1616–1622.

Bergstrom K (1977) An orthopantomographic study of hypodontia, supernumeraries and other anomalies in school children between the ages of 8–9 years: an epidemiological study. Swedish Dental Journal 1(4): 145–157.

Bingle GJ and Niswander JD (1975) Polydactyly in the American Indian. American Journal of Human Genetics 27(1): 91–99.

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(4): 342–343.

Brook AH (1984) A unifying aetiological explanation for anomalies of human tooth number and size. Archives of Oral Biology 29(5): 373–378.

Callahan N, Modesto A, Deeley K, Meira R and Vieira AR (2009a) Transforming growth factor‐alfa gene (TGFA), human tooth agenesis, and evidence of segmental uniparental isodisomy. European Journal of Oral Sciences 117(1): 20–26.

Callahan N, Modesto A, Meira R et al. (2009b) Axis inhibition protein 2 (AXIN2) polymorphisms and tooth agenesis. Archives of Oral Biology 54(1): 45–49.

Calzolari F, Garani G, Sensi A and Martini A (1999) Clinical and radiological evaluation in children with microtia. British Journal of Audiology 33(5): 303–312.

Celikoglu M, Kazanci F, Miloglu O et al. (2010) Frequency and characteristics of tooth agenesis among an orthodontic patient population. Medicina Oral, Patología Oral y Cirurgía Bucal 15(5): e797–801.

Costa MC, Küchler EC, Filho PF, Modesto A and Vieira AR (2009) Defining subphenotypes for tooth agenesis: does side matter? Journal of Clinical Pediatric Dentistry 34(2): 169–172.

Das P, Stockton DW, Bauer C et al. (2002) Haploinsufficiency of PAX9 in associated with autosomal dominant hypodontia. Human Genetics 110(4): 371–376.

D'souza RN, Kapadia H and Vieira AR (2006) Teeth. In: Stevenson RE and Hall JG (eds) Human Malformations and Related Anomalies, pp. 425–465. New York: Oxford University Press.

Eidelman E, Chosack A and Rosenzweig KA (1973) Hypodontia prevalence among Jewish populations of different origin. American Journal of Physical Anthropology 39(1): 129–133.

Ferguson CA, Tucker AS, Heikinheimo K et al. (2001) The role of effectors of the activin signalling pathway, activin receptors IIA and IIB, and Smad2, in patterning of tooth development. Development 128(22): 4605–4613.

Fogh‐Andersen P (1942) Inheritance of harelip and cleft palate. Copenhagen: Arnold Busck.

Graber LW (1978) Congenital absence of teeth: a review with emphasis on inheritance patterns. Journal of American Dental Association 96(2): 266–275.

Hu G, Vastardis H, Bendall AJ et al. (1998) Haploinsufficiency of MSX1: a mechanism for selective tooth agenesis. Molecular and Cell Biology 18(10): 6044–6051.

Kantaputra P and Sripathomsawat W (2011) WNT10A and isolated hypodontia. American Journal of Medical Genetics A 155(5): 1119–1122.

Küchler EC, Menezes R, Callahan N et al. (2011) MMP1 and MMP20 contribute to tooth agenesis in humans. Archives of Oral Biology 56(5): 506–511.

Lammi L, Arte S, Somer M et al. (2004) Mutations in AXIN2 cause familial tooth agenesis and predispose to colorectal cancer. American Journal of Human Genetics 74(5): 1043–1050.

Letra A, Menezes R, Granjeiro JM and Vieira AR (2007) Defining subphenotypes for oral clefts based on dental development. Journal of Dental Research 86(10): 986–991.

Li S, Li J, Cheng J et al. (2008) Non‐syndromic tooth agenesis in two Chinese families associated with novel missense mutations in the TNF domain of EDA (ectodysplasin A). PLoS One 3(6): e2396.

Lundström A (1960) Asymmetries in the number and size of the teeth and their aetiological significance. Transactions. European Orthodontic Society 1960(1): 167–185.

Markovic M (1982) Hypodontia in twins. Swedish Dental Journal 15(Supp.): 153–162.

Muller TP, Hill IN, Petersen AC and Blayney JR (1970) A survey of congenitally missing permanent teeth. Journal of American Dental Association 81(1): 101–107.

Palmer AR and Strobeck C (1997) Fluctuating asymmetry and developmental stability: heritability of observable variation vs. heritability of inferred cause. Journal of Evolutionary Biology 10(1): 39–49.

Peres RC, Scarel‐Caminaga RM, Espírito Santo AR and Line SR (2005) Association between PAX‐9 promoter polymorphisms and hypodontia in humans. Archives of Oral Biology 50(10): 861–871.

Qiu M, Bulfone A, Ghattas I et al. (1997) Role of the Dlx homeobox genes in proximodistal patterning of the branchial arches: mutations of Dlx‐1, Dlx‐2, and Dlx‐1 and ‐2 alter morphogenesis of proximal skeletal and soft tissue structures derived from the first and second arches. Developmental Biology 185(2): 165–184.

Rayan GM and Frey B (2001) Ulnar polydactyly. Plastic and Reconstructive Surgery 107(6): 1449–1454.

Scutt D, Lancaster GA and Manning JT (2006) Breast asymmetry and predisposition to breast cancer. Breast Cancer Research 8(2): R14.

Stockton DW, Das P, Goldenberg M, D'Souza RN and Patel PI (2000) Mutation of PAX9 is associated with oligodontia. Nature Genetics 24(1): 18–19.

Thesleff I (2006) The genetic basis of tooth development and dental defects. American Journal of Medical Genetics A 140(23): 2530–2535.

Vastardis H, Karimbux N, Guthua SW, Seidman JG and Seidman CE (1996) A human MSX1 homeodomain missense mutation causes selective tooth agenesis. Nature Genetics 13(4): 417–421.

Vieira AR (2003) Oral clefts and syndromic forms of tooth agenesis as models for genetics of isolated tooth agenesis. Journal of Dental Research 82(3): 162–165.

Vieira AR, Meira R, Modesto A and Murray JC (2004) MSX1, PAX9, and TGFA contribute to tooth agenesis in humans. Journal of Dental Research 83(9): 723–727.

Vieira AR, Modesto A, Meira R et al. (2007) Interferon regulatory factor 6 (IRF6) and fibroblast growth factor receptor 1 (FGFR1) contribute to human tooth agenesis. American Journal of Medical Genetics A 143(6): 538–545.

Vieira AR, Seymen F, Patir A and Menezes R (2008) Evidence of linkage disequilibrium between polymorphisms at the IRF6 locus and isolate tooth agenesis, in a Turkish population. Archives of Oral Biology 53(8): 780–784.

Whittington BR and Durward CS (1996) Survey of anomalies in primary teeth and their correlation with the permanent dentition. New Zealand Dental Journal 92(407): 4–8.

Further Reading

Butler PM and Joysey KA (1974) Development, Function and Evolution of Teeth, p. 523. New York: Academic Press.

Smith P and Tchernov E (1992) Structure, Function, and Evolution of Teeth, p. 570. London: Freund Publishing House Ltd.

Teaford MF, Smith MM and Ferguson MW (2000) Development, Function, and Evolution of Teeth, p. 314. Cambridge: Cambridge University Press.

Weinberg RA (2006) The Biology of Cancer, p. 850. Milton Park: Garland Science.

Wyszynski DF (2002) Cleft Lip and Palate. From Origin to Treatment, p. 548. New York: Oxford University Press.

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Vieira, Alexandre R(May 2012) Genetics of Congenital Tooth Agenesis. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0023576]