Dental Anomalies: Genetics


Development of teeth is under strict genetic control, which ensures the formation and renewal of a certain number of teeth with specific shapes and positions in a reproducible timetable. Gene mutations can disturb normal dental development and affect tooth number, shape, eruption or formation of the hard tissues, enamel, dentin or cementum. These anomalies are often observed as isolated, that is, only dentition is affected, and especially failure to develop all teeth, tooth agenesis or hypodontia is extremely common. Different dental anomalies are also observed in numerous rare developmental syndromes because the genes and genetic networks that regulate tooth morphogenesis and differentiation are also active in the development of other organs and tissues. Tooth anomalies are especially associated with other ectodermal defects and orofacial clefts. Many examples indicate that teeth are often most sensitive to a reduced activity of a specific genetic pathway which is related to the complexity and self‐organising features of dental development.

Key Concepts:

  • Teeth are specialised ectodermal organs.

  • Development of dentition is regulated by cell interactions by same signalling pathways that are active in other organs and requires modulation of signalling by antagonist factors.

  • Tooth agenesis (failure to develop all teeth) is one of the most common developmental anomalies.

  • Most cases of tooth agenesis and supernumerary teeth are caused by reduced rather than complete inactivation of gene activity.

  • Dental anomalies are often diagnostic indications of a heritable syndrome or systemic disease.

  • Dental hard tissues do not regenerate after an injury and their development involve unique mechanisms.

  • Studies into congenital enamel defects are revealing functions for novel proteins that are involved in cellular regulation in ameloblasts and other cells.

Keywords: tooth agenesis; hypodontia; oligodontia; ectodermal dysplasia; cleft lip; cleft palate; enamel; dentin; tooth eruption

Figure 1.

Schematic presentation of genetic regulation of early tooth morphogenesis. Signalling molecules mediate cellular communication within and between the epithelium and the mesenchyme (epithelial signals, upper arrows; mesenchymal signals, lower arrows). The signals belong to conserved families that regulate the development of practically all tissues and organs (BMP, bone morphogenetic protein; FGF, fibroblast growth factor; SHH, sonic hedgehog; and WNT, homologues of Drosophila Wingless). Placodes and enamel knots are signalling centres in the epithelium which express locally more than 10 different signals regulating morphogenesis. Inactivation of the function of many different genes in mice leads to an arrest in tooth development at a specific stage, and their expression is typically regulated by the signals. Mutations in several of these genes have been shown to cause dental anomalies in humans.

Figure 2.

Radiographs and photographs of dentitions with tooth agenesis or supernumerary teeth. Asterisks mark the missing teeth. (a) Dentition with the common incisor–premolar hypodontia. Mandibular (lower) second premolars and maxillary (upper) right third molar (wisdom tooth) are missing. (b) Dentition with the common incisor–premolar hypodontia. Maxillary lateral incisor on the left side is missing and the one on the right side is peg shaped (arrow). Reproduced with permission from Nieminen . (c) An example of severe taurodontia (apical displacement of the root bifurcation) in molars (arrows). (d) Oligodontia caused by a mutation in PAX9. Missing permanent and second deciduous molars in a 7‐year‐old boy. Also, three of the second premolars as well as the upper lateral incisors are missing. (e) Oligodontia caused by mutations (compound heterozygote) in WNT10A. 15 permanent teeth are missing and the maxillary lateral incisor is peg shaped (arrow). Deciduous maxillary right canine and mandibular incisors and canines are retained at the age of 13 years. (f) Dentition of a boy with HED/EDA. Most of the permanent teeth are congenitally missing. Reproduced with permission from Nieminen . (g) Dentition of a patient diagnosed with Rieger syndrome. Nine permanent teeth are missing and the deciduous upper central incisors persist. Maxillary lateral incisors are peg shaped (arrows). (h) Supernumerary incisor, mesiodens, in an inverted position between the maxillary central incisors of a 9‐year‐old girl (arrow). (i) Dentition in a 15‐year‐old girl with cleidocranial dysplasia. Supernumerary teeth were depicted with arrows. (a), (b), (e), (f), (g) and (i) Courtesy of Sirpa Arte, (c) courtesy of Tiina Kuittinen, (d) courtesy of Satu Alaluusua, (h) courtesy of Ulla‐Maija Wesander.

Figure 3.

Radiographs and photographs of aberrations of dental hard tissues. (a) Panoramic tomogram of the dentition of a 12‐year‐old girl affected by dentinogenesis imperfecta type II as a result of a mutation in DSPP. Tooth crowns have a bulbous shape as the cervical regions are constricted and the pulp chambers have been obliterated, that is, filled with mineralising dentin. Attrition is observed in several teeth (arrows). (b) Upper dentition of the previous patient. Enamel has chipped off in several teeth and severe attrition is evident. (c) Panoramic tomogram of the permanent right molars of a 22‐year‐old woman with dentin dysplasia type II. Only a typical thistle‐shaped pulp chamber remains. Reproduced with permission from Nieminen et al.. (d) Schematic presentation of the DSPP gene and the consequences of different types of mutations. Mutations concentrate in exon–intron boundaries and in the code for dentin phosphoptein (DPP). Black arrows and text denote dentinogenesis imperfecta II and blue arrows and text dentin dysplasia II. All types of mutations prevent export and secretion of the DSPP protein. (e) AI, X‐linked hypoplastic type with hypoplastic stripes in the enamel of a 17‐year‐old girl. (f) AI, hypomaturation type. Teeth of an 11‐year‐old girl have a chalky opaque appearance. (g) AI, hypocalcified type. Teeth of a 10‐year‐old girl have a brownish discolouration. (a), (b), (e), (f) and (g) courtesy of Satu Alaluusua, (c) courtesy of Sirpa Arte.



Adaimy L, Chouery E, Megarbane H et al. (2007) Mutation in WNT10A is associated with an autosomal recessive ectodermal dysplasia: the odonto–onycho–dermal dysplasia. American Journal of Human Genetics 81(4): 821–828.

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.

Arte S, Nieminen P, Apajalahti S et al. (2001) Characteristics of incisor–premolar hypodontia in families. Journal of Dental Research 80(5): 1445–1450.

Bailleul‐Forestier I, Gros C, Zenaty D et al. (2010) Dental agenesis in Kallmann syndrome individuals with FGFR1 mutations. International Journal of Paediatric Dentistry 20(4): 305–312.

Bloch‐Zupan A, Jamet X, Etard C et al. (2011) Homozygosity mapping and candidate prioritization identify mutations, missed by whole‐exome sequencing, in SMOC2, causing major dental developmental defects. American Journal of Human Genetics 89(6): 773–781.

Bohring A, Stamm T, Spaich C et al. (2009) WNT10A mutations are a frequent cause of a broad spectrum of ectodermal dysplasias with sex‐biased manifestation pattern in heterozygotes. American Journal of Human Genetics 85(1): 97–105.

Celli J, Duijf P, Hamel BCJ et al. (1999) Heterozygous germline mutations in the p53 homolog p63 are the cause of EEC syndrome. Cell 99(2): 143–153.

Chefetz I, Heller R, Galli‐Tsinopoulou A et al. (2005) A novel homozygous missense mutation in FGF23 causes familial tumoral calcinosis associated with disseminated visceral calcification. Human Genetics 118(2): 261–266.

Cluzeau C, Hadj‐Rabia S, Jambou M et al. (2011) Only four genes (EDA1, EDAR, EDARADD, and WNT10A) account for 90% of hypohidrotic/anhidrotic ectodermal dysplasia cases. Human Mutation 32(1): 70–72.

Decker E, Stellzig‐Eisenhauer A, Fiebig BS et al. (2008) PTHR1 loss‐of‐function mutations in familial, nonsyndromic primary failure of tooth eruption. American Journal of Human Genetics 83(6): 781–786.

El‐Sayed W, Parry DA, Shore RC et al. (2009) Mutations in the beta propeller WDR72 cause autosomal‐recessive hypomaturation amelogenesis imperfecta. American Journal of Human Genetics 85(5): 699–705.

Farrington F and Lausten L (2009) Oral findings in ankyloblepharon–ectodermal dysplasia–cleft lip/palate (AEC) syndrome. American Journal of Medical Genetics A 149A(9): 1907–1909.

Ferrante MI, Zullo A, Barra A et al. (2006) Oral‐facial‐digital type I protein is required for primary cilia formation and left‐right axis specification. Nature Genetics 38(1): 112–117.

Fine JD, Eady RA, Bauer EA et al. (2008) The classification of inherited epidermolysis bullosa (EB): report of the third international consensus meeting on diagnosis and classification of EB. Journal of American Academy of Dermatology 58(6): 931–950.

Grahnen H (1956) Hypodontia in the permanent dentition. Odontologisk Revy 7(Suppl. 3): 1–100.

Hart PS, Hart TC, Michalec MD et al. (2004) Mutation in kallikrein 4 causes autosomal recessive hypomaturation amelogenesis imperfecta. Journal of Medical Genetics 41(7): 545–549.

Kantaputra P, Miletich I, Ludecke HJ et al. (2008) Tricho–rhino–phalangeal syndrome with supernumerary teeth. Journal of Dental Research 87(11): 1027–1031.

Karlstedt E, Kaitila I and Pirinen S (1996) Phenotypic features of dentition in diastrophic dysplasia. Journal of Craniofacial Genetics and Developmental Biology 16(3): 164–173.

Kim JW, Lee SK, Lee ZH et al. (2008) FAM83H mutations in families with autosomal‐dominant hypocalcified amelogenesis imperfecta. American Journal of Human Genetics 82(2): 489–494.

Kist R, Watson M, Wang X et al. (2005) Reduction of Pax9 gene dosage in an allelic series of mouse mutants causes hypodontia and oligodontia. Human Molecular Genetics 14: 3605–3617.

Kondo S, Schutte BC, Richardson RJ et al. (2002) Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes. Nature Genetics 32(2): 285–289.

Kotilainen J, Pohjola P, Pirinen S, Arte S and Nieminen P (2009) Premolar hypodontia is a common feature in Sotos syndrome with a mutation in the NSD1 gene. American Journal of Medical Genetics A 149A(11): 2409–2414.

Lagerström M, Dahl N, Nakahori Y et al. (1991) A deletion in the amelogenin gene (AMG) causes X‐linked amelogenesis imperfecta (AIH1). Genomics 10(4): 971–975.

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.

Liu W, Wang H, Zhao S et al. (2001) The novel gene locus for agenesis of permanent teeth (He‐Zhao deficiency) maps to chromosome 10q11.2. Journal of Dental Research 80(8): 1716–1720.

Lukinmaa PL, Ranta H, Ranta K, Kaitila I and Hietanen J (1987) Dental findings in osteogenesis imperfecta: II. dysplastic and other developmental defects. Journal of Craniofacial Genetics and Developmental Biology 7(2): 127–135.

von Marschall Z, Mok S, Phillips MD, McKnight DA and Fisher LW (2012) Rough endoplasmic reticulum trafficking errors by different classes of mutant dentin sialophosphoprotein (DSPP) cause dominant negative effects in both dentinogenesis imperfecta and dentin dysplasia by entrapping normal DSPP. Journal of Bone and Mineral Research 27(6): 1309–1321.

McKnight DA, Hart SP, Hart TC et al. (2008) A comprehensive analysis of normal variation and disease‐causing mutations in the human DSPP gene. Human Mutation 29(12): 1392–1404.

Mornet E (2007) Hypophosphatasia. Orphanet Journal of Rare Diseases 2: 40.

Mory A, Dagan E, Illi B et al. (2012) A nonsense mutation in the human homolog of Drosophila rogdi causes Kohlschutter–Tonz syndrome. American Journal of Human Genetics 90(4): 708–714.

Mundlos S, Otto F, Mundlos C et al. (1997) Mutations involving the transcription factor CBFA1 cause cleidocranial dysplasia. Cell 89(5): 773–779.

Nagamine K, Peterson P, Scott HS et al. (1997) Positional cloning of the APECED gene. Nature Genetics 17(4): 393–398.

Nieminen P (2009) Genetic basis of tooth agenesis. Journal of Experimental Zoology Part B Molecular and Developmental Evolution 312B(4): 320–342.

Nieminen P, Kotilainen J, Aalto Y et al. (2003) MSX1 gene is deleted in Wolf–Hirschhorn syndrome patients with oligodontia. Journal of Dental Research 82(12): 1013–1017.

Nieminen P, Morgan NV, Fenwick AL et al. (2011a) Inactivation of IL11 signaling causes craniosynostosis, delayed tooth eruption, and supernumerary teeth. American Journal of Human Genetics 89(1): 67–81.

Nieminen P, Papagiannoulis‐Lascarides L, Waltimo‐Siren J et al. (2011b) Frameshift mutations in dentin phosphoprotein and dependence of dentin disease phenotype on mutation location. Journal of Bone and Mineral Research 26(4): 873–880.

Noor A, Windpassinger C, Vitcu I et al. (2009) Oligodontia is caused by mutation in LTBP3, the gene encoding latent TGF‐beta binding protein 3. American Journal of Human Genetics 84(4): 519–523.

O'Sullivan J, Bitu CC, Daly SB et al. (2011) Whole‐exome sequencing identifies FAM20A mutations as a cause of amelogenesis imperfecta and gingival hyperplasia syndrome. American Journal of Human Genetics 88(5): 616–620.

Opsahl Vital S, Gaucher C, Bardet C et al. (2012) Tooth dentin defects reflect genetic disorders affecting bone mineralization. Bone 50(4): 989–997.

Ozdemir D, Hart PS, Ryu OH et al. (2005) MMP20 active‐site mutation in hypomaturation amelogenesis imperfecta. Journal of Dental Research 84(11): 1031–1035.

Parry DA, Brookes SJ, Logan CV et al. (2012) Mutations in C4orf26, encoding a peptide with in vitro hydroxyapatite crystal nucleation and growth activity, cause amelogenesis imperfecta. American Journal of Human Genetics 91(3): 565–571.

Parry DA, Mighell AJ, El‐Sayed W et al. (2009) Mutations in CNNM4 cause Jalili syndrome, consisting of autosomal‐recessive cone‐rod dystrophy and amelogenesis imperfecta. American Journal of Human Genetics 84(2): 266–273.

Pirinen S (1998) Dental and Oral Aspects in Anhydrotic Ectodermal Dysplasia. Consensus Conference on Ectodermal Dysplasia with Special Reference to Dental Treatment 1998. Jönköping, Sweden: The Institute for Postgraduate Dental Education.

Polder BJ, Van't Hof MA, Van der Linden FP and Kuijpers‐Jagtman AM (2004) A meta‐analysis of the prevalence of dental agenesis of permanent teeth. Community Dentistry and Oral Epidemiology 32(3): 217–226.

Price JA, Bowden DW, Wright JT, Pettenati MJ and Hart TC (1998) Identification of a mutation in DLX3 associated with tricho‐dento‐osseous (TDO) syndrome. Human Molecular Genetics 7(3): 563–569.

Priolo M (2009) Ectodermal dysplasias: an overview and update of clinical and molecular‐functional mechanisms. American Journal of Medical Genetics A 149A(9): 2003–2013.

Rajpar MH, Harley K, Laing C, Davies RM and Dixon MJ (2001) Mutation of the gene encoding the enamel‐specific protein, enamelin, causes autosomal‐dominant amelogenesis imperfecta. Human Molecular Genetics 10(16): 1673–1677.

Rohmann E, Brunner HG, Kayserili H et al. (2006) Mutations in different components of FGF signaling in LADD syndrome. Nature Genetics 38(4): 414–417.

Ruiz‐Perez VL and Goodship JA (2009) Ellis‐van Creveld syndrome and Weyers acrodental dysostosis are caused by cilia‐mediated diminished response to hedgehog ligands. American Journal of Medical Genetics C Seminars in Medical Genetics 151C(4): 341–351.

Schossig A, Wolf NI, Fischer C et al. (2012) Mutations in ROGDI cause Kohlschutter–Tonz Syndrome. American Journal of Human Genetics 90(4): 701–707.

Semina EV, Reiter R, Leysens NJ et al. (1996) Cloning and characterization of a novel bicoid‐related homeobox transcription factor gene, RIEG, involved in Rieger syndrome. Nature Genetics 14(4): 392–399.

Shapira J, Chaushu S and Becker A (2000) Prevalence of tooth transposition, third molar agenesis, and maxillary canine impaction in individuals with Down syndrome. Angle Orthodontics 70(4): 290–296.

Shields ED (1983) A new classification of heritable human enamel defects and a discussion of dentin defects. Birth Defects Original Article Series 19(1): 107–127.

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.

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(4): 427–430.

Tipton RE and Gorlin RJ (1984) Growth retardation, alopecia, pseudo‐anodontia, and optic atrophy – The GAPO syndrome: report of a patient and review of the literature. American Journal of Medical Genetics 19(2): 209–216.

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.

Wang XP and Fan J (2011) Molecular genetics of supernumerary tooth formation. Genesis 49(4): 261–277.

Xiao S, Yu C, Chou X et al. (2001) Dentinogenesis imperfecta 1 with or without progressive hearing loss is associated with distinct mutations in DSPP. Nature Genetics 27(2): 201–204.

Further Reading

van Bokhoven H and McKeon F (2002) Mutations in the p53 homolog p63: allele‐specific developmental syndromes in humans. Trends in Molecular Medicine 8(3): 133–139.

van den Boogaard MJ, Creton M, Bronkhorst Y et al. (2012) Mutations in WNT10A are present in more than half of isolated hypodontia cases. Journal of Medical Genetics 49(5): 327–331.

Chan HC, Estrella NM, Milkovich RN et al. (2011) Target gene analyses of 39 amelogenesis imperfecta kindreds. European Journal of Oral Sciences 119(Suppl. 1): 311–323.

Eerens K, Vlietinck R, Heidbuchel K et al. (2001) Hypodontia and tooth formation in groups of children with cleft, siblings without cleft, and nonrelated controls. Cleft Palate Craniofacial Journal 38(4): 374–378.

Järvinen E, Salazar‐Ciudad I, Birchmeier W et al. (2006) Continuous tooth generation in mouse is induced by activated epithelial Wnt/beta‐catenin signaling. Proceedings of the National Academy of Sciences of the USA 103(49): 18627–18632.

Jensen BL and Kreiborg S (1990) Development of the dentition in cleidocranial dysplasia. Journal of Oral Pathology and Medicine 19(2): 89–93.

Jernvall J and Thesleff I (2012) Tooth shape formation and tooth renewal: evolving with the same signals. Development 139(19): 3487–3497.

Lu MF, Pressman C, Dyer R, Johnson RL and Martin JF (1999) Function of Rieger syndrome gene in left–right asymmetry and craniofacial development. Nature 401(6750): 276–278.

Nie X, Luukko K and Kettunen P (2006) FGF signalling in craniofacial development and developmental disorders. Oral Diseases 12(2): 102–111.

Tummers M and Thesleff I (2009) The importance of signal pathway modulation in all aspects of tooth development. Journal of Experimental Zoology Part B Molecular and Developmental Evolution 312B(4): 309–319.

Web Links

Gene Expression in Tooth. Graphical database: http://bite‐

HUGO Gene Nomenclature Committee.

Mouse Models of Human Inherited Facial Dysmorphologies. The Jackson Laboratory.

Online Mendelian Inheritance in Man. Online database cataloging human genes and genetic disorders.

Phenotypic and Genotypic Features of Familial Hypodontia. Thesis by Sirpa Arte, University of Helsinki.

UCSC Genome Browser, University of California, Santa Cruz.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Nieminen, Pekka(Mar 2013) Dental Anomalies: Genetics. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0006088.pub2]