Provides general dental practitioners with:
Current knowledge on the aetiological basis of human hypodontia.
Clinical features and classification of this common dental anomaly.
A summary of the syndromic forms of this condition.
The congenital absence of teeth is one of the commonest developmental abnormalities seen in human populations. Familial hypodontia or oligodontia represents an absence of varying numbers of primary and/or secondary teeth as an isolated trait. While much progress has been made in understanding the developmental basis of tooth formation, knowledge of the aetiological basis of inherited tooth loss remains poor. The study of mouse genetics has uncovered a large number of candidate genes for this condition, but mutations in only three have been identified in human pedigrees with familial hypodontia or oligodontia: MSX1, PAX9 and AXIN2. This suggests that these conditions may represent a more complex multifactorial trait, influenced by a combination of gene function, environmental interaction and developmental timing. Completion of the human genome project has made available the DNA sequence of the collected human chromosomes, allowing the localisation of all human genes and, ultimately, determination of their function. Therefore it is likely that our understanding of this complex developmental process will continue to improve, not only during normal development but also when things go wrong.
There can be few dental surgeons who have not pondered the mysteries surrounding congenital tooth absence at some point in their career. A genetic basis for the embryonic mechanisms underlying tooth formation is clear, even at an anecdotal level. A wide variety of animals have highly adapted and species-specific dentitions; in human populations defects of tooth development often affect particular teeth and these anomalies frequently run in families, while defects in tooth number are often associated with other anomalies of dental development (Table 1). The genetic mechanisms responsible for generating such a regionally diverse but homologous structure as the mature human dentition are still poorly understood, but progress has been made over the last decade, largely with the use of mouse models.1,2,3 In recent years, homologues of some candidate mouse genes have been identified as having a role in human dental development, particularly in the aetiology of congenitally absent teeth.4,5 However, given the large number of candidates and the prevalence of this condition, it is surprising that more genes have not been identified to date.
Hypodontia is often used as a collective term for congenitally missing teeth, although specifically it describes the absence of one to six teeth, excluding third molars (Table 2). Oligodontia refers to the absence of more than six teeth, excluding third molars, while anodontia represents a complete failure of one or both dentitions to develop.6 Hypodontia can either occur with accompanying genetic disease as part of a recognised clinical syndrome, or as a non-syndromic, familial form, which occurs as an isolated trait, affects variable numbers of teeth and appears either sporadically or in a familial fashion within a family pedigree7 (Fig. 1).
Online Mendelian Inheritance in Man (OMIM) lists over 60 different syndromic conditions that include hypodontia as part of their phenotypic spectrum of anomalies8 and candidate genes have been identified for many of these conditions (Table 3). However, possibly of more relevance to the general dental practitioner is the more common non-syndromic or familial form of hypodontia (Fig. 1). This condition can follow autosomal dominant,9,10,11,12 autosomal recessive13,14 or sex-linked15 patterns of inheritance, with considerable variation in both penetrance and expressivity. Indeed, a multifactorial model has been suggested to explain the inheritance of anomalies in both tooth number and size with the phenotypic effect being related to certain thresholds, themselves influenced by both genetic and environmental factors.16,17 Clearly, within this model, the mutation of a major gene may be a significant enough event to result in inherited tooth loss.
It is important for the general dental practitioner to fully assess any patient presenting with hypodontia and referral to a specialist clinic is often desirable. In some cases this condition can be indicative of underlying genetic disease and further referral for genetic testing might be desirable. Treatment of this condition aims to improve both aesthetics and function, and is often facilitated through a multidisciplinary approach.18,19
Non-syndromic hypodontia is by far the most common form of congenital tooth absence and can involve variable numbers of teeth. It is more commonly seen in the secondary dentition, but in the rare cases of missing primary teeth that do occur, there is often a strong tendency towards further tooth absence in the secondary teeth. Anodontia (OMIM #206780) represents the most severe form of non-syndromic hypodontia, but is extremely rare in the absence of accompanying genetic disease,20 while oligodontia (OMIM #604625) is only seen at a level of around 0.25% within European populations.21,22 The more localised incisor-premolar type of hypodontia affects only one or a few teeth (OMIM #106600), but occurs more commonly in around 8% of the population.7 Within these clinical entities, certain teeth fail to develop more often than others. Third molars are the most commonly absent tooth in the dentition, with at least one being absent in anything up to 20-30% of the population. This is followed in Europeans by the mandibular second premolar, maxillary lateral incisor and premolars (around 2%) and the mandibular central incisor (0.2%).23 The absence of canine teeth, first molars and second molars is extremely rare in hypodontia;24 if these teeth are missing, it is usually seen in association with severe forms of syndromic oligodontia.
If genes are so important in controlling tooth development, what do we know about potential candidates within the human genome? As with many aspects of mammalian development, the mouse has become one of the principle model organisms for the study of these embryonic processes and a host of genes, encoding members of numerous protein families, are expressed during development of the mouse tooth.1,3,25 Targeted deletion in many such genes within knockout mice can disrupt tooth formation. These data have provided a reference point in the search for candidate genes that may play a role in the aetiology of human forms of hypodontia.26 In particular, two genes that encode members of transcription factor families have attracted considerable attention because of their role in murine tooth development.
Msx1 (Muscle segment homeobox) is a member of a distinct sub-family of homeobox genes, which is expressed in spatially restricted regions of the head during early development, localising to regions of condensing embryonic connective tissue or ectomesenchyme in the tooth germ27,28 (Fig. 2). Furthermore, analysis of mice lacking a functional Msx1 gene reveals that all tooth development arrests at the bud stage.29 These findings demonstrate that in the mouse at least, Msx1 is essential for normal odontogenesis. Pax9 encodes a member of another transcription factor protein family, characterised by the presence of a DNA-binding paired-box domain. In the mouse embryo, Pax9 is also expressed in the prospective mesenchymal compartment of developing teeth30 (Fig. 2) and is essential during later stages of tooth development; mice with targeted mutations in Pax9 also exhibit tooth arrest at the bud stage.31 These two genes are therefore excellent candidates for human forms of hypodontia and have been the subject of intense scrutiny within human pedigrees affected by non-syndromic tooth loss.
Consistent with the mouse phenotype, mutations in the human MSX1 gene have been associated with familial oligodontia12,32 and certain forms of syndromic hypodontia;33,34 however, associations with the more common incisor-premolar form of familial hypodontia are less common.7,35 The relationship of MSX1 to familial incisor-premolar hypodontia was originally investigated in five Finnish families, with a total of 20 affected individuals; but no linkage was identified.7 However, these findings did not rule out a defect in MSX1 being associated with other forms of hypodontia and analysis of a family affected with oligodontia identified a causative locus on chromosome 4p where the MSX1 gene resides.12 Sequence analysis demonstrated a missense mutation within a critical region of the MSX1 protein in all affected family members. This protein was subsequently found to be inactive in vivo and haploinsufficiency concluded to be the probable cause of the phenotype.36 A frameshift mutation in MSX1 has been identified in a family demonstrating non-syndromic hypodontia with absence of all second premolars and mandibular central incisors.37 Further studies have also demonstrated a role for MSX1 in the aetiology of some forms of syndromic hypodontia. A Dutch family showing various combinations of cleft lip, cleft palate and tooth agenesis were identified with a nonsense mutation in exon 133 and a further nonsense mutation has been shown to be responsible for Witkop syndrome (OMIM #189500), an autosomal dominant form of ectodermal dysplasia involving nail dysplasia and variable numbers of congenitally missing permanent and/or primary teeth.34
A number of mutations38,39,40,41,42,43 and polymorphisms in the upstream promoter region44 of the human PAX9 gene have been identified in association with variable forms of oligodontia, that particularly affect the molar dentition. A family exhibiting hypodontia of most permanent molars and variable absence of second premolars and mandibular incisors were originally identified with a single base insertion that produced a frame-shift mutation and premature termination of the PAX9 protein.38 Significantly, this mutation alters the amino acid sequence within the highly conserved (paired box) region of the gene, producing reduced DNA binding of the mutant protein.45 However, another frame-shift insertional mutation outside this region can also produce hypodontia.40 Further single basepair mutations in PAX9 have since been identified in association with molar hypodontia, including nonsense39 and missense;41 in addition to a large 288 basepair insertion.41 Interestingly, while molar tooth development does seem to be particularly sensitive to alterations in PAX9 function, a PAX9 mutation has also been associated with a non-familial form of oligodontia affecting third molars, premolars and some incisor teeth.42 Haploinsufficiency of PAX9 seems to be the underlying cause of the hypodontia in these affected pedigrees, a finding reinforced by the identification of a rare father and daughter kindred affected by complete primary and permanent molar hypodontia with a deletion of one copy of their PAX9 gene.46
MSX1 and PAX9?
In addition to mutational analysis and the identification of candidate genes, biologists are now attempting to understand some of the molecular interactions underlying tooth development failure. There is now evidence to suggest that PAX9 and MSX1 interact during odontogenesis at both the gene and protein levels. Clues to this relationship are present in mice; expression of these genes co-localise in the developing tooth (Fig. 2), odontogenesis arrests at the bud stage in both mouse knockouts29,31 and this phenotype is also accompanied by a marked reduction in expression of the gene encoding Bone morphogenetic protein 4 (Bmp4) in both mouse lines. Bmp4 encodes a signalling molecule with a key role during transition of the tooth germ from bud to cap stage.28,47 Initial evidence of an interaction in humans came from a genetic epidemiological study48 and has since been confirmed by biochemical analyses; mammalian Pax9 is able to form a physical association with Msx1.49 This interaction takes the form of a heterodimeric protein complex, which enhances the ability of Pax9 to activate both Msx1 and Bmp4 gene expression during tooth development. Importantly, simulation of a known Pax9 mutation has also been shown to lack the ability to activate transcription of these target genes, even though a physical interaction with Msx1 still occurs.49
The identification of a four-generation Finnish family affected by autosomal dominant oligodontia has recently provided a rather unexpected further insight into the genetics of inherited tooth loss. Within this family, 11 members were identified as lacking at least eight permanent teeth and rather surprisingly, further investigation of this pedigree suggested that among these individuals affected by oligodontia, a significant risk of developing colorectal neoplasia was also present.50 Linkage analysis of this pedigree identified a candidate region on chromosome 17, which contained approximately 80 genes, among which was a gene called AXIN2 (Axis inhibition protein-2). AXIN2 was selected as a strong candidate gene for this condition for several reasons: its position within this particular chromosomal region, a previously identified association with colorectal carcinoma and the fact that AXIN2 is also a known regulator of the Wnt signalling pathway. The Wnt family of secreted proteins form part of a large family of signalling molecules that have a wide-ranging role during embryonic development and demonstrate regionally restricted expression in the tooth.51 Suppression of Wnt signal transduction in mutant mice or over-expression in wild type jaw explants can inhibit tooth development.52,53 Crucially, when further sequence analysis was carried out, all the affected family members within this pedigree had a nucleotide transition within exon 7 of AXIN2, which produced a nonsense mutation and premature termination of the encoded protein.50 Several novel polymorphisms or variants of AXIN2 have since been identified, which when present, also carry an increased risk of tooth agenesis to the individual.54
Given the large number of candidate genes that have been provided from studies in the mouse,25 it is perhaps surprising that mutations in so few have been identified in human family pedigrees affected by hypodontia.26 This suggests that in many cases, familial human hypodontia may represent a more complex, multifactorial condition. A number of subtle traits are apparent within human pedigrees possessing identifiable gene mutations in association with hypodontia. MSX1 function is predominantly associated with premolar and occasionally molar agenesis, while PAX9 mutations are almost always associated with missing molar and only occasionally premolar teeth. In contrast, hypodontia associated with AXIN2 mutations involves a wider range of tooth types. These observations suggest that the combined and overlapping expression domains of genes expressed within the tooth-forming regions are important for normal development of the dentition, a finding consistent with observations in the mouse.55,56 This threshold model is useful in explaining the lack of phenotypic penetrance and variability found in many pedigrees affected by hypodontia. However, it also provides some explanation for the observations that teeth along the margins of each field are more commonly absent (lateral incisors, second premolars, third molars).57 It is the peripheral domains of gene expression that are most important in delineating tooth class, but also the most susceptible to perturbations in function.
Cobourne M T, Sharpe P T . Tooth and jaw: molecular mechanisms of patterning in the first branchial arch. Arch Oral Biol 2003; 48: 1–14.
Jernvall J, Thesleff I . Reiterative signaling and patterning during mammalian tooth morphogenesis. Mech Dev 2000; 92: 19–29.
Tucker A, Sharpe P . The cutting-edge of mammalian development; how the embryo makes teeth. Nat Rev Genet 2004; 5: 499–508.
Mostowska A, Kobielak A, Trzeciak W H . Molecular basis of non-syndromic tooth agenesis: mutations of MSX1 and PAX9 reflect their role in patterning human dentition. Eur J Oral Sci 2003; 111: 365–370.
Vastardis H . The genetics of human tooth agenesis: new discoveries for understanding dental anomalies. Am J Orthod Dentofacial Orthop 2000; 117: 650–656.
Arte S, Pirinen S . Hypodontia. http://www.orphanet/data/patho/GB/uk-hypodontiapdf. Orphanet 2004.
Nieminen P, Arte S, Pirinen S et al. Gene defect in hypodontia: exclusion of MSX1 and MSX2 as candidate genes. Hum Genet 1995; 96: 305–308.
Online Mendelian Inheritance in Man (OMIM) http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM. 2007.
Alvesalo L, Portin P . The inheritance pattern of missing, peg-shaped and strongly mesio-distally reduced upper lateral incisors. Acta Odontol Scand 1969; 27: 563–575.
Arte S, Nieminen P, Apajalahti S et al. Characteristics of incisor-premolar hypodontia in families. J Dent Res 2001; 80: 1445–1450.
Goldenberg M, Das P, Messersmith M et al. Clinical, radiographic, and genetic evaluation of a novel form of autosomal-dominant oligodontia. J Dent Res 2000; 79: 1469–1475.
Vastardis H, Karimbux N, Guthua S W et al. A human MSX1 homeodomain missense mutation causes selective tooth agenesis. Nat Genet 1996; 13: 417–421.
Ahmad W, Brancolini V, ul Faiyaz M F et al. A locus for autosomal recessive hypodontia with associated dental anomalies maps to chromosome 16q12.1. Am J Hum Genet 1998; 62: 987–991.
Pirinen S, Kentala A, Nieminen P et al. Recessively inherited lower incisor hypodontia. J Med Genet 2001; 38: 551–556.
Erpenstein H, Pfeiffer R A . Sex-linked-dominant hereditary reduction in number of teeth. Humangenetik 1967; 4: 280–293.
Brook A H . A unifying aetiological explanation for anomalies of human tooth number and size. Arch Oral Biol 1984; 29: 373–378.
Suarez B K, Spence M A . The genetics of hypodontia. J Dent Res 1974; 53: 781–785.
Morgan C, Howe L . The restorative management of hypodontia with implants: I. Overview of alternative treatment options. Dent Update 2003; 30: 562–568.
Morgan C, Howe L . The restorative management of hypodontia with implants: 2. Planning and treatment with implants. Dent Update 2004; 31: 22–30.
Gorlin RJ, Herman N G, Moss S J . Complete absence of the permanent dentition: an autosomal recessive disorder. Am J Med Genet 1980; 5: 207–209.
Sarnas K V, Rune B . The facial profile in advanced hypodontia: a mixed longitudinal study of 141 children. Eur J Orthod 1983; 5: 133–143.
Schalk-van der Weide Y, Beemer F A, Faber J A et al. Symptomatology of patients with oligodontia. J Oral Rehabil 1994; 21: 247–261.
Neal J J, Bowden D E . The diagnostic value of panoramic radiographs in children aged nine to ten years. Br J Orthod 1988; 15: 193–197.
Simons A L, Stritzel F, Stamatiou J . Anomalies associated with hypodontia of the permanent lateral incisors and second premolar. J Clin Pediatr Dent 1993; 17: 109–111.
Gene Expression in Tooth. http://bite-it.helsinki.fi.
Arte S, Nieminen P, Pirinen S et al. Gene defect in hypodontia: exclusion of EGF, EGFR, and FGF-3 as candidate genes. J Dent Res 1996; 75: 1346–1352.
MacKenzie A, Ferguson M W, Sharpe P T . Hox-7 expression during murine craniofacial development. Development 1991; 113: 601–611.
Tucker A S, Al Khamis A, Sharpe P T . Interactions between Bmp-4 and Msx-1 act to restrict gene expression to odontogenic mesenchyme. Dev Dyn 1998; 212: 533–539.
Satokata I, Maas R . Msx1 deficient mice exhibit cleft palate and abnormalities of craniofacial and tooth development. Nat Genet 1994; 6: 348–356.
Neubüser A, Peters H, Balling R et al. Antagonistic interactions between FGF and BMP signaling pathways: a mechanism for positioning the sites of tooth formation. Cell 1997; 90: 247–255.
Peters H, Neubuser A, Kratochwil K et al. Pax9-deficient mice lack pharyngeal pouch derivatives and teeth and exhibit craniofacial and limb abnormalities. Genes Dev 1998; 12: 2735–2747.
Lidral A C, Reising B C . The role of MSX1 in human tooth agenesis. J Dent Res 2002; 81: 274–278.
van den Boogaard M J, Dorland M, Beemer F A et al. MSX1 mutation is associated with orofacial clefting and tooth agenesis in humans. Nat Genet 2000; 24: 342–343.
Jumlongras D, Bei M, Stimson J M et al. A nonsense mutation in MSX1 causes Witkop syndrome. Am J Hum Genet 2001; 69: 67–74.
Scarel R M, Trevilatto P C, Di Hipolito O, Jr. et al. Absence of mutations in the homeodomain of the MSX1 gene in patients with hypodontia. Am J Med Genet 2000; 92: 346–349.
Hu G, Vastardis H, Bendall A J et al. Haploinsufficiency of MSX1: a mechanism for selective tooth agenesis. Mol Cell Biol 1998; 18: 6044–6051.
Kim J W, Simmer J P, Lin B P et al. Novel MSX1 Frameshift causes autosomal-dominant oligodontia. J Dent Res 2006; 85: 267–271.
Stockton D W, Das P, Goldenberg M et al. Mutation of PAX9 is associated with oligodontia. Nat Genet 2000; 24: 18–19.
Nieminen P, Arte S, Tanner D et al. Identification of a nonsense mutation in the PAX9 gene in molar oligodontia. Eur J Hum Genet 2001; 9: 743–746.
Frazier-Bowers S A, Guo D C, Cavender A et al. A novel mutation in human PAX9 causes molar oligodontia. J Dent Res 2002; 81: 129–133.
Das P, Hai M, Elcock C et al. Novel missense mutations and a 288-bp exonic insertion in PAX9 in families with autosomal dominant hypodontia. Am J Med Genet 2003; 118A: 35–42.
Mostowska A, Kobielak A, Biedziak B et al. Novel mutation in the paired box sequence of PAX9 gene in a sporadic form of oligodontia. Eur J Oral Sci 2003; 111: 272–276.
Mostowska A, Biedziak B, Trzeciak W H . A novel mutation in PAX9 causes familial form of molar oligodontia. Eur J Hum Genet 2006; 14: 173–179.
Peres R C, Scarel-Caminaga R M, do Espirito Santo A R et al. Association between PAX-9 promoter polymorphisms and hypodontia in humans. Arch Oral Biol 2005; 50: 861–871.
Mensah J K, Ogawa T, Kapadia H et al. Functional analysis of a mutation in PAX9 associated with familial tooth agenesis in humans. J Biol Chem 2004; 279: 5924–5933.
Das P, Stockton D W, Bauer C et al. Haploinsufficiency of PAX9 is associated with autosomal dominant hypodontia. Hum Genet 2002; 110: 371–376.
Chen Y, Bei M, Woo I et al. Msx1 controls inductive signaling in mammalian tooth morphogenesis. Development 1996; 122: 3035–3044.
Vieira A R, Meira R, Modesto A et al. MSX1, PAX9, and TGFA contribute to tooth agenesis in humans. J Dent Res 2004; 83: 723–727.
Ogawa T, Kapadia H, Wang B et al. Studies on Pax9-Msx1 protein interactions. Arch Oral Biol 2005; 50: 141–145.
Lammi L, Arte S, Somer M et al. Mutations in AXIN2 cause familial tooth agenesis and predispose to colorectal cancer. Am J Hum Genet 2004; 74: 1043–1050.
Sarkar L, Sharpe P T . Expression of Wnt signalling pathway genes during tooth development. Mech Dev 1999; 85: 197–200.
Sarkar L, Cobourne M, Naylor S et al. Wnt/Shh interactions regulate ectodermal boundary formation during mammalian tooth development. Proc Natl Acad Sci USA 2000; 97: 4520–4524.
van Genderen C, Okamura R M, Farinas I et al. Development of several organs that require inductive epithelial-mesenchymal interactions is impaired in LEF-1-deficient mice. Genes Dev 1994; 8: 2691–2703.
Mostowska A, Biedziak B, Jagodzinski P P . Axis inhibition protein 2 (AXIN2) polymorphisms may be a risk factor for selective tooth agenesis. J Hum Genet 2006; 51: 262–266.
Sharpe P T . Homeobox genes and orofacial development. Connect Tissue Res 1995; 32: 17–25.
Sharpe P T . Neural crest and tooth morphogenesis. Adv Dent Res 2001; 15: 4–7.
Thesleff I . Two genes for missing teeth. Nat Genet 1996; 13: 379–380.
Kere J, Srivastava A K, Montonen O et al. X-linked anhidrotic (hypohidrotic) ectodermal dysplasia is caused by mutation in a novel transmembrane protein. Nat Genet 1996; 13: 409–416.
Amiel J, Bougeard G, Francannet C et al. TP63 gene mutation in ADULT syndrome. Eur J Hum Genet 2001; 9: 642–645.
van Bokhoven H, Hamel B C, Bamshad M et al. p63 Gene mutations in eec syndrome, limbmammary syndrome, and isolated split hand-split foot malformation suggest a genotype-phenotype correlation. Am J Hum Genet 2001; 69: 481–492.
Colige A, Sieron A L, Li S W et al. Human Ehlers-Danlos syndrome type VII C and bovine dermatosparaxis are caused by mutations in the procollagen I Nproteinase gene. Am J Hum Genet 1999; 65: 308–317.
Smahi A, Courtois G, Vabres P et al. Genomic rearrangement in NEMO impairs NF-kappaB activation and is a cause of incontinentia pigmenti. The International Incontinentia Pigmenti (IP) Consortium. Nature 2000; 405: 466–472.
Semina E V, Reiter R, Leysens N J et al. Cloning and characterisation of a novel bicoidrelated homeobox transcription factor gene, RIEG, involved in Rieger syndrome. Nat Genet 1996; 14: 392–399.
About this article
Cite this article
Cobourne, M. Familial human hypodontia – is it all in the genes?. Br Dent J 203, 203–208 (2007). https://doi.org/10.1038/bdj.2007.732
The influence of mild versus severe hypodontia on facial soft tissues? A three-dimensional optical laser scanning-based cohort study
Journal of Orthodontics (2021)
International Journal of Paleopathology (2021)
Acta Odontologica Turcica (2021)
Are developmentally missing teeth a predictive risk marker of malignant diseases in non-syndromic individuals? A systematic review
Journal of Orthodontics (2021)
Minerva Dental and Oral Science (2021)