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RESEARCH REPORT |
1 Department of Orthodontics and
3 Division of Genetics and Molecular Medicine, Kings College London, Dental Institute, Floor 22, Guy’s Tower, St Thomas St., London SE1 9RT, UK, and
2 Faculty of Dental Surgery, University of Malta, Malta, GC
* corresponding author, simon.camilleri{at}kcl.ac.uk, simon.camilleri{at}um.edu.mt
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: tooth eruption • ectopic • cuspid • segregation analysis • Maltese
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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The etiology is controversial. A genetic basis has been suggested (Bjerklin et al., 1992; Peck et al., 1994). Several studies have shown the etiology of ectopic canines to be genetic and associated with other genetically interrelated dental anomalies (Svinhufvud et al., 1988; Bjerklin et al., 1992; Pirinen et al., 1996; Baccetti, 1998). The sex ratio shows a bias toward females (Becker et al., 1981; Ericson and Kurol, 1988), similar to other dental anomalies of genetic origin (Rose, 1966; Davis, 1987). The racial variation, female preponderance, familial occurrence, and association with other dental anomalies imply a polygenic etiology (Kotsomitis and Freer, 1997).
Environmental factors have also been identified. Palatal displacement of the canine may be due to local environmental factors, such as anatomically anomalous or late-developing lateral incisor roots (Becker et al., 1981; Chaushu et al., 2002, 2003). Excess space in the dental arch has been implicated (Paschos et al., 2005). There is evidence that both genetic and environmental factors may be involved. (Ely et al., 2006). Alteration of the local environment by extraction of the deciduous canines will ameliorate the condition (Ericson and Kurol, 1988; Power and Short, 1993).
The prevalence of ectopic canines in Maltese schoolchildren is 4–5.5% (Camilleri, 1995; Camilleri et al., unpublished observations). This is higher than previously published figures (Ericson and Kurol, 1986), possibly due to the ‘founder effect’, since the Maltese population has grown dramatically, from 17,000 in 1535 to over 300,000 today (Blouet, 2004). This relative abundance and familial clustering of cases prompted a study to test the hypothesis that ectopic canines have a genetic etiology.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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We analyzed the pedigree data to assess the familial risk of ectopic canines and other related phenotypes, using the computed familial relative risk.
We used the segregation analysis program Pedigree Analysis Program (PAP) (Hasstedt, 2005) to model the inheritance of ectopic canines throughout the 63 pedigrees. Pedigree members were defined as affected or unaffected with ectopic canines (with no further clinical information used). Genetic models assumed a single locus model with penetrances and mutation frequency maximized for each model. Nested models were compared by the likelihood ratio test, where the difference in -2 ln (likelihood) has a chi-square distribution, with the degrees of freedom equal to the difference in the number of additional parameters fitted in the most general model. Sporadic (no genetic effect), recessive, and dominant models were compared with a co-dominant model. A polygenic model was also tested and compared with the dominant model. An ascertainment correction for the probands in each family was applied.
Five sets of monozygotic and six sets of dizygotic twins were included in the sample. A further two sets of monozygotic twins and one set of triplets were subsequently referred by a colleague. These were not included in the pedigree or segregation analyses; however, they were used in assessments of pairwise concordance.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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The percentage of dental anomalies in the sample for first-degree relatives was noted, and differences against published population prevalences were investigated. The prevalence of ectopic canines was significantly higher in first-degree relatives (15%, p < 0.001) compared with 4.4–5.5% for the Maltese population (Camilleri, 1995; Camilleri et al., unpublished observations). Lateral incisor agenesis was also higher (7.88%, p = 0.01, as opposed to 3.21% for the general population) (Camilleri and Mulligan, 2007).
There were eight cases of maxillary canine transposition in the whole sample. Three were probands, five were first-degree relatives; one was a second-degree relative. Seven were in the upper jaw, giving a prevalence of 1.4%. This is significantly higher (p < 0.001) than the prevalence of 0.27% estimated in a Caucasian population (Yilmaz et al., 2005). Two cases of mandibular canine-lateral incisor transposition were also recorded.
The percentages of first-, second-, and third-degree relatives with ectopic maxillary canines were used to calculate the relative risk (
R) to the first-, second-, and third-degree relatives. This is calculated as (R = 
R/) where is the population prevalence and R is the percentage of relatives affected according to the type of relative, i.e., of the first, second, or third degree (Table 1
). Ascertainment was corrected for by exclusion of the probands from the calculation. We then used the relative risk to plot the drop-off for each decreasing degree of unilineal relationship (Fig. 1), which was close to the theoretical decrease for a genetic disease.
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There was an appreciable sex bias, with the affected Female-to-Male Ratio for first-, second-, and third-degree relatives being 1.78. The sex ratio for the probands was 1.64, and elimination of the probands from the calculation gave a ratio of 1.89. However, there was no appreciable risk difference between relatives of male or female probands (p = 0.77). The proportion of male first-degree relatives affected vs. the proportion of female first-degree relatives was not significant (p = 0.12).
Although there was no evidence of sex-linked transmission, 85% of the three-generation families showed instances where an obligate carrier showed a normal phenotype, although the condition was transmitted to their children (Fig. 2). There was no apparent pattern of augmentation or attenuation of phenotype through the generations.
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). All the genetic models fitted provided a significantly better fit than the sporadic model, confirming that ectopic canines have a genetic basis. The -2log likelihood of the co-dominant model was very similar to the dominant model, but had more parameters. Therefore, the dominant model provided the more parsimonious model, with the -2log (likelihood) for the recessive model being substantially higher. A mixed-dominant model did not provide a sufficiently improved fit, implying that there is no evidence for a polygenic component in addition to the Mendelian locus. These results show that a single dominant gene best accounts for the inheritance of ectopic canines in these pedigrees, with a mutation frequency of 11% and penetrances of 36% in mutation carriers.
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Seven pairs of monozygotic twins were found. Of these, five were completely discordant, in that one twin was unaffected (Fig. 2
). Of the other two pairs, one pair was mirror-image, and the other set had one twin affected unilaterally, the other bilaterally. The pairwise concordance in this sample was 28.6%. Seven pairs of dizygotic twins are also on record, with two showing concordance for ectopic canines, a pairwise concordance rate of 28.6%.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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The prevalence of canine transposition in the sample was far higher than the 0.27% prevalence estimated in a Caucasian population (Yilmaz et al., 2005). The highly significant difference is indicative of canine transposition being an extreme variant of ectopic canine, and is consistent with the highly variable expression exhibited.
The prevalence of lateral incisor agenesis in the Maltese population is 3.21% (Camilleri and Mulligan, 2007). The high figure found in association with ectopic canines suggests that both traits are related, in keeping with previous evidence (Becker et al., 1981; Svinhufvud et al., 1988; Peck et al., 1994; Pirinen et al., 1996; Baccetti, 1998).
Pedigree Analysis
The pattern of transmission was that of an autosomal-dominant trait with low penetrance. Expression was highly variable both within and between families. Incomplete penetrance was evident, with obligate carriers unaffected by ectopic canines. This may be explained by the highly variable expressivity seen, with failure of penetrance in some cases.
Considering the high population prevalence, the figure for R suggests a significant genetic component. When the drop-off in R (decreasing degrees of relation) is plotted as a function of the Relative Risk, the gradual decrease for every decreasing degree of relationship is suggestive of a genetic contribution and does not rule out genetic heterogeneity between families. This analysis cannot distinguish between single-locus or multi-locus inheritance for ectopic canines (Risch, 1990). However, there is no difference in prevalence between families ascertained from one or two probands for first-, second-, or third-degree relatives. Nor is there a difference in the sib-sib/parent-offspring relationships in the two types of families. This is indicative of a single gene, since multiple genes would be expected to give a higher prevalence in families ascertained from two probands.
There was a considerable sex bias toward females, and, surprisingly, elimination of the probands from the calculation produced an increase in the Female-to-Male ratio of the sample. There is no plausible explanation to date for this bias. However, there was no significant difference between the risks to relatives of male or female probands, as expected for an autosomal major gene. Were the trait to be multifactorial, the risk would be higher for the relatives of the less susceptible sex (Farrer and Cupples, 1998).
Segregation Analysis
The inheritance of ectopic canines in the families was modeled assuming a single major gene and with polygenic inheritance. The results of the segregation analysis implied that the sporadic model was rejected compared with all the genetic models. The dominant model fitted equally as well as the co-dominant model, suggesting that a dominant model adequately describes inheritance in these pedigrees. The polygenic model was rejected, and there was no evidence for a polygenic component in addition to a dominantly inherited major gene. The low penetrance (36%) for the dominantly inherited gene allows for the existence of an additional environmental influence, which would determine which genetically susceptible individuals show the phenotype.
Twins
The inclusion of the first five sets of monozygotic and the first six sets of dizygotic twins was serendipitous, since selection was on the basis of affected probands only. The low concordance shown by the monozygotic twins is consistent with epigenetic or environmental factors influencing the eruption of teeth, and is at variance with the epidemiological evidence of a significant genetic component. Furthermore, the incidence of monozygotic twinning for the Maltese Islands is 4.5 per 1000 (Savona-Ventura and Grech, 1988). The prevalence of monozygotic twins selected consecutively in this sample was nearly double that number, and the difference was statistically significant (p = 0.01).
Monozygotic twins share identical DNA sequences; however, they are often discordant for certain phenotypes. Hypodontia, a genetic disorder associated with ectopic canines, is more prevalent in twins. These twins exhibit a high degree of discordance (Keene, 1971; Lapter et al., 1998; Townsend et al., 2005). It is possible that epigenetic events may be responsible for discordant expression in genetically identical individuals. Indeed, certain imprinting-associated diseases, such as Beckwith-Wiedemann Syndrome, are associated with multiple births and discordance in monozygotic twins (Elliott and Maher, 1994). In contrast, ectopic movement of the maxillary canine has been detected in children as young as 5 years of age (McSherry and Richardson, 1999), and the rapidly growing child is susceptible to a multitude of factors that potentially affect intrabony movement of the canine. Evidence for environmental influence on epigenetic mechanisms further clouds the issue (Bird, 2007).
In conclusion, the evidence gathered from analysis of the pedigrees supports the hypothesis of a genetic etiology for ectopic canines, with a single locus being involved, although genetic heterogeneity across pedigrees cannot be ruled out in a modeling study. The most likely mode of transmission is autosomal-dominant. The incomplete penetrance of the dominant locus allows for an environmental component. Further investigation into the molecular etiology of ectopic canines is therefore justified, although the number of monozygotic twins in the sample, plus the discordance of these twins, raises the possibility of gene silencing.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Received March 28, 2007; Last revision January 29, 2008; Accepted February 8, 2008
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REFERENCES |
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