8.1 AGENESIS AND VARIATION OF TEETH

I. INTRODUCTION

Agenesis of one or more teeth is one of the most common of human developmental anomalies. Failure of one or more of the third molars to form occurs in 20% of the population. The reported incidence of teeth other than third molars being missing varies from 1.6% to 9.6%.

Polygenesis, the formation of one or more supernumerary teeth occurs much less frequently than agenesis. For humans, the most frequent site for these occurrences are the maxillary central and lateral incisor regions. Such teeth may have a highly aberrant form, tucked-in to the lingual of the normal tooth row. They may take on the form of neighboring teeth. Supernumerary teeth often do not erupt; therefore, any survey of living or fossil individuals must necessarily include panoramic radiography to reveal unerupted teeth.

Agenesis and polygenesis has been reported for the apes and Old World monkeys. The frequency of agenesis amongst the hominoids is highest in humans and is found most frequently in the molar region.

There are several terms used to describe dental anomalies that are often not familiar to the practicing dentist. These are reviewed in a brief appendix at the end of this article.

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II. EPIDEMIOLOGY OF AGENESIS

Tooth agenesis occurs more frequently amongst a few specific teeth and clinically this is often considered a normal variant. Familial tooth agenesis is transmitted as an autosomal dominant, recessive, or X-linked condition. Affected members within a family often exhibit significant variability with regard to the location, symmetry and number of teeth involved. Residual teeth can vary in their size, shape or rate of development. The permanent dentition is more affected than the primary dentition.

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Tooth agenesis for primary teeth is reported to be in the range of 0.5% to 0.9%. Besides missing teeth, supernumeraries, geminated teeth and fused teeth are also found in the deciduous dentition. Anomalies occur most often in the anterior region of the maxilla or mandible.

Anomalies of the corresponding permanent teeth are a frequent finding. As a general rule, when a deciduous tooth is missing, its permanent counterpart is also absent. Occurrence of other anomalies in the deciduous dentition is a good predictor of anomalies in the corresponding teeth in the permanent teeth, although not necessarily of the same type.

The close relationship between the deciduous and permanent dentitions has implications for clinical treatment and understanding the underlying cause of these defects.

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The absence of four or more teeth (other than third molars) occurs in the general population at 0.25%. The incidence of tooth agenesis varies with tooth class. The third molar is the most frequent at 20%. Next in frequency of absence are the upper lower second premolars (3.4%) followed by the maxillary lateral incisors (2.25%). Absence of just a single premolar happens frequently. Maxillary lateral incisors were the most frequently missing teeth when only one or two teeth were absent, whereas second premolars were the most frequently missing teeth when more than two teeth where absent.

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The absence of third molars has been associated with an increased incidence of other missing teeth. When a third molar is absent, agenesis of the remaining teeth is 13 time more likely. This is an important statement and it has this implication: reductions in tooth number should never be considered alone, but always in relation to the presence or absence of the third molar. Third molar reduction is far from an isolated dental abnormality. When one or more third molar teeth are congenitally absent, the probability of other teeth being missing rises thirteen-fold. Once again this has a clinical application and a research implication. When a third molar is missing on a panoramic radiographic film, the prudent examiner should look for other missing teeth. It is significant that other tooth germs beyond those in the molar field are affected. This implies a more general underlying genetic cause and that agenesis is more than just a localized chance event.

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Third molar agenesis also seems to predispose for reduced size of the remaining teeth and the delayed development of certain teeth. If a third molar is absent, the molars and premolars of the same quadrant are delayed in formation and eruption. This is especially true for the most distal tooth in each class.

Third molar agenesis has also been linked to diminished stablity of specific molar cuspal patterns. Reduction of the Carabelli cusp has been associated with third molar agenesis. A relationship between absent teeth and abnormal morphology of remaining teeth has been observed within other types of agenesis. As can be confirmed by many clinicians, agenesis of one lateral incisor is often accompanied by a small lateral on the contralateral side.

Agenesis of the mandibular third molar is associated with delayed calcification of the posterior teeth. The distal cusp on the lower first permanent molar occurs less frequently when at least one third molar has not formed. It is again apparent that third molar agenesis is not an isolated anomaly.

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Third molar agenesis is associated with crown-size reduction, particularly crown size reduction of the lateral incisors, the second premolars, and inevitably with 'peg-shaped' lateral incisors. This is more true in the female than the male.

There is even evidence of reduced body size and an increased incidence of prematurity, suggesting a reduction of prenatal growth rates in affected individuals.

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You would expect that the teeth most adjacent to the missing third molar would be the one most affected by size reduction. It is the other way around. It is the anterior teeth, not the posterior teeth that are the most affected by third molar agenesis.

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III. CLINICAL GENETICS

Twin studies have been used to show the importance of the genetic component acting during tooth development to control both tooth size and tooth form. Monozygotic twins have been concordant and have shown variation is the expressivity of the trait observed.

Tooth agenesis can be isolated or part of a syndrome. Isolated forms may be familial or sporadic. Familial tooth agenesis is often the result of a single dominant gene mutation. However, in other families the mode of inheritance is recessive. Third molar agenesis cannot be explained in the majority of cases with a simple model of autosomal dominant transmission. A polygenic model of inheritance has been speculated.

Peg lateral incisors or rudimentary third molars may reflect incomplete expression expres ion of a gene defect that causes tooth agenesis. Unilateral agenesis may be a result of reduced penetranceon the side affected.

More than 49 syndromes categorized in the On-line Mendelian Inheritance in Man (OMIN) are associated with tooth agenesis. This implies that there are common molecular mechanisms for tooth or other organ development. Agenesis of numerous teeth is often associated with congenital ectodermal dysplasia.

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IV. EVOLUTION AND AGENESIS

In clinical practice, dentists often assume that teeth which are frequently missing or variable in form are 'on the way out' in evolution. Is this a valid statement? If we set it up as a testable hypothesis, it might be stated as follows: teeth destined for evolutionary loss anticipate that condition by increased variability in size, shape, and/or agenesis. Supporting evidence would be strong selective pressure toward loss of a tooth in evolution. Another evidence might be a series of consecutive fossil specimens as evidence of progressive tooth loss. I am not aware of such studies.

Implicit in the proposed hypothesis is that phylogenetic changes in the dentition correlate with functional adaptation. In understanding agenesis we would have to consider it as a functional adaptation. Is reproductive fitness enhanced by missing teeth? Or, is agenensis just a chance mutation with little consequence except minor inconvenience to the person afflicted. I do not have answers to these questions for you.

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What is the dental future for humans? It has been suggested that one incisor, one canine, one premolar, and two molars per quadrant is likely to be the dental profile of future man. This prediction is predicated on progressive loss of the most distal incisor, premolar, and molar. I find this assumption questionable

This topic could be argued endlessly and I will enter into this issue only by mentioning a primate odd-ball, the Aye Aye of Madagascar. The dental formula of this critter is as follows:

This solitary, nocturnal primate exhibits extreme dental reduction and is highly specialized for a life similar to that of a woodpecker (which is absent in Madagascar). If humans are going to undergo great dental reduction. then you would expect a highly specialized diet. This would seem unlikely for an omniverous, wide ranging species like humans. Not only is their wide culinary variation within our culture, there are many things eaten in other cultures we don't even consider as food.

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V. BUTLER'S FIELD THEORY AND TOOTH AGENESIS

The Butler theory attempts to explain why some teeth are stable and others are unstable. According to this hypothesis, the mammalian dentition can be divided into three morphogenic fields corresponding to incisors, canines and the cheek teeth (premolars and molars). You will recall our diagram in 2.1, The Organization of the Dentition.

Within each field there is one tooth that is presumed to be the stable 'best copy'. Moving out from that tooth, flanking teeth are considered progressively less stable. Considering each quadrant separately, the key tooth in the molar/premolar field would be the first molar.

Based on this theory, the third molar and the first premolar would be predicted to be most variable in size and shape. Certainly, the third molar is extremely variable and is often missing. It isn't true for the first premolar--but consider: according to paleontology, the premolars we retain are premolars three and four from the primitive ancestral stock for primates. The lost 'first' and 'second' premolars would have been farthest from the key tooth, the first permanent molar and in an evolutionary sense could be considered unstable.

The terminal or most posterior tooth of the incisors, premolars, and molars are the ones most often missing. Some suggest that we should consider the most posterior tooth as 'vestigial' and of litle practical value. For this to be true, I suggest to you that we need evidence of more favorable reproductive fitness when there are fewer teeth.

Some suggest an anatomical model for agenesis instead of an evolutionary model. We can present those ideas here as follows: certain regions such as adjacent to the junction between the premaxilla and maxilla are unstable regions and this could account for maxillary incisor instability. This fails, however to account for the considerable stability of the canine--also adjacent to that junction.

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VI. ODONTOGENESIS AND EPITHELIAL-MESENCHYMAL INTERACTIONS

The field theory encourages us to think of teeth not as discrete units, but as a continuum from the midline to the end of the tooth row at the distal. Thus far we've considered the field theory as the size, shape, rate of development, and presence or absence of teeth.

Now let us consider it at the tissue and cellular level. (This discussion is cursory; there are many excellent detailed articles on this subject.) Teeth are a product of cooperation between oral epithelium and mesenchyme. The mesenchyme of the jaws is of neural crest origin. Many authors call it ectomesenchyme; in this discussion we will use the traditional nomenclature and just call it mesenchyme.

Consider the following: The epithelial contribution to teeth comes from oral epithelium which ultimately forms the enamel. Mesenchyme contributes dentin, cementum, the pulp and supporting structures of the teeth. Intimate contact between the epithelial and mesenchymal components at the right time in embryogenesis is necessary for tooth development.

If you will accept that tooth forming mesenchyme and epithelium arise from common cell populations, then it is understandable that events such as agenesis of third molars reflect genetic information shared by all of the tooth forming tissues.

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VII. MOLECULAR MARKERS OF ODONTOGENESIS

The molecular mechanisms involved in normal tooth development in humans remain largely unknown. Studies in other vertebrates, however, have implicated several homeobox proteins in tooth organogenesis. In mice, two transcription factors, Msx1 and Msx2 have direct epithelial-mesenchymal interations that initiate tooth formation. Msx1 is expressed in mouse embryonic tissues derived from the neural folds and adjacent crest cells. Msx1-deficient mice exhibit multiple craniofacial abnormalities including cleft secondary palate, abnormalities of several facial bones and the malleus in the middle ear, in addition to complete tooth agenesis.

The thesis by Vastardis (1996) provides the first direct evidence that tooth structure and patterning is controlled by specific transcription factors.

To identify genes involved in human tooth development, a family with autosomal dominant tooth agensis was studied. All affected individuals lacked both maxillary and mandibular second premolars and third molars; some individuals also lacked other teeth. When Vastardis (1996) mapped the autosomal dominant agensis of second premolars and third molars, it was located on chromosomes 4p16.1. In the family studied there was evidence than an Arg Pro substitution withing the homeodomain of human MSX1 causes selective tooth agenesis in that family. The asl suggestedthat the normal, highly conserved Arg31 residue of the homeodomain is necessary for MSX1 functions that are required for second molar and third molar formation. The reader is referred to the Vastardis (1996) thesis and Vastardis et al (1996) for a full description of this research endeavor.

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Sources and further reading

Baum, B. and Cohen, M. 'Studies on Agenesis in the Permanent Dentition' Am. J. Phys. Anthrop., 35: 125-128.

Garn, S. et al 'Third molar Polymorphism and Its Significance to Dental Genetics' J. Dent. Res. Supplement to No. 6. 42: 1344-1363 (1963).

Garn, S. and Lewis, A. 'The Relationship Between Third Molar Agenesis and Reduction in Tooth Number' Angle Orthodont. 32: 14-18 (1962).

Garn, S. and Lewis, A. 'The Gradient and the Pattern of Crown Size Reduction in Simple Hypodontia' Angle Orthodont. 50: 51-57 (1970).

Garn, S. 'Third Molar Agenesis and Reduction in the Number of Other Teeth' J. Dent. Res. 41: 714 (1962b).

Graber, L. 'Congenital Absence of Teeth: a Review with Emphasis on Inheritance Patterns' JADA. 96: 266-275 (1978).

Hillson, S. Dental Anthropology. New York: Cambridge University Press. 1996.

Lavelle, C. and Moore, W. 'The Incidence of Agenesis and Polygenesis in the Primate Dentition' Am. J. Phys. Anthrop. 38: 671-680.

Peck, S. et al 'Prevalence of Tooth Agenesis nd Peg-shaped Maxillary Lateral Incisor Associated with Palatally Displaced Canine (PDC) Anomaly' Am. J. Orthod. Dentofac. Orthop. 110: 441-443 (1996).

Vastardis, H. 'Genetic Approaches to Understanding Tooth Development: A Human MSX1 Homeodomain Missense Mutation Causes Selective Tooth Agenesis' Doctoral Thesis, Oral Biology, Harvard University, May, 1996.

Vastardis, H. et al 'A Human MSX1 homeodomain missense mutation causes selective tooth agenesis' in Nature Genetics 13: pp 417-421 (13 August 1996).

Whittington, B. and Durward, C. 'Survey of Anomalies in Primary Teeth and Their Correlation with the Permanent Dentition' New Zealand Dental Journal 92: 4-8 (1996).

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Appendix on Dental Terminology

Oligodontia literally means 'few teeth'. Anodontia: is an extreme expression of oligodontia; it denotes the complete absence of teeth. Frequently, the term partial anodontia is used synonymously with oligodontia. Hypodontia is used to indicate a more complex entity, involving not only aberrations in number, size, and shape of the remaining teeth but also abnormalities in the overall rate of dental development and time of eruption. The term "congenitally" missing teeth is partially misleading. Teeth are not present in the mout at birth even though they are being developed in the jaws. Agenesis is a more informative term because it also implies an underlying developmental defect.

Source: Vastardis, H. 'Genetic Approaches to Understanding Tooth Development: A Human MSX1 Homeodomain Missense Mutation Causes Selective Tooth Agenesis' Doctoral Thesis, Oral Biolody, Harvard University, May, 1996.

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Gemination is the partial development of two teeth from a single tooth bud following incomplete division. Fusion is the union between either the dentin or enamel, or both, of two or more separate developing teeth.

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Source:

Whittington, B and Durward, C. 'Survey of Anomalies in Primary Teeth and Their Correlation with the Permanent Dentition' New Zealand Dental Journal: 92: 4-8 (1996).

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Special recognition here is due Heleni Vastardis for her excellent literature review and doctoral research; her document was very helpful in assembling this article.