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Prevalence and patterns of tooth agenesis in Angle Class II Division 2 malocclusion in Japan
ORIGINAL ARTICLE
Prevalence and patterns of tooth agenesis in Angle Class II Division 2 malocclusion in Japan Kanako Otaa and Kazuhito Araib Tokyo, Japan
Introduction: The purpose of this study was to evaluate the prevalence and patterns of tooth agenesis in subjects with Angle Class II Division 2 malocclusion compared with general orthodontic patients in Japan. Methods: Panoramic radiographs, dental casts, and cephalograms of 76 patients with Class II Division 2 malocclusions (52 female, 24 male) and 270 orthodontic patients as the control group (168 female, 102 male) who were 14 years of age or older were selected. The prevalences of tooth agenesis in this cohort and in each tooth type were calculated and compared between the groups with the chi-square test. Odds ratios and corresponding 95% confidence intervals were also calculated. Results: The prevalence of tooth agenesis excluding the third molars was significantly higher in the Class II Division 2 group (22.4%) than in the control group (11.9%) (P \0.05); the odds ratio was 2.14 (95% CI, 1.12-4.12). A higher prevalence of tooth agenesis excluding the third molars was observed in the Class II Division 2 group for the mandibular second premolar (P \0.05) and the maxillary lateral incisor (P \0.01). The prevalence of third molar agenesis was also significantly higher in the Class II Division 2 group (42.1%) compared with the control group (26.7%) (P \0.05); the odds ratio was 2.00 (95% CI, 1.18-3.40). Conclusions: Compared with the general orthodontic patient population, permanent tooth agenesis was observed approximately 2 times more frequently, and a distinctive agenesis pattern was found in the Class II Division 2 group in Japan. (Am J Orthod Dentofacial Orthop 2015;148:123-9)
A
ccording to Angle,1 Class II Division 2 malocclusion is characterized by a distal position of the mandibular arch with retroclination of the maxillary incisors; this is the result of longer contact with the lips during normal respiratory function of the oral environment, rather than genetic factors. Consequently, lip pressure has been found to be significantly greater in patients with Class II Division 2 malocclusion than in those with Class I malocclusion.2 However, research studies,3,4 a review article,5 and case reports of twins and triplets6 have suggested the heritability of Class II Division 2 malocclusion. Peck et al3 identified a characteristic pattern of heritable skeletal and tooth-size features in patients with Class II Division 2 cover-bite malocclusion and suggested a strong genetic influence on the formation of this pattern. From the Department of Orthodontics, School of Life Dentistry, Nippon Dental University, Tokyo, Japan. a Clinical research fellow. b Professor and chair. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest, and none were reported. Address correspondence to: Kazuhito Arai, Department of Orthodontics, School of Life Dentistry at Tokyo, Nippon Dental University, 1-9-20 Fujimi, Chiyoda-ku, Tokyo 102-8159, Japan; e-mail, [email protected]. Submitted, October 2014; revised and accepted, February 2015. 0889-5406/$36.00 Copyright Ó 2015 by the American Association of Orthodontists. http://dx.doi.org/10.1016/j.ajodo.2015.02.023
Subsequently, Basdra et al4 evaluated 267 Class II Division 2 patients in Germany and found a higher prevalence of heritable dental anomalies, including tooth agenesis, compared with other epidemiologic studies of general populations in Europe and the United States. In addition, the researchers observed a high prevalence of agenesis of the maxillary lateral incisor. In another recent study in Portugal, Pereira et al7 examined 115 Class II Division 2 subjects without maxillary lateral incisor agenesis and classified them into 2 groups on the basis of maxillary incisor retroclination. These researchers found a higher prevalence of tooth agenesis in the group with retroclination of all 4 maxillary incisors than in the group with retroclination of bilateral maxillary central incisors. The authors suggested that different etiologic factors contribute to the different manifestations of Class II Division 2 malocclusion. Developmental dental anomalies, including tooth agenesis, have been suggested to be an anatomic characteristic of patients with Class II Division 2 malocclusion. Therefore, an analysis of the prevalence and patterns of tooth agenesis may provide additional evidence of possible genetic factors contributing to Class II Division 2 malocclusion. In a recent review article, Hartsfield et al5 reported an increased risk of Class II Division 2 malocclusion in first-degree relatives of Class 123
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II Division 2 probands compared with the general population. Their findings suggested that the Class II Division 2 malocclusions resulted from a polygenic, complex etiology rather than from variations in a single gene. They also suggested the need to investigate possible common etiologic factors, including genes associated with tooth development and tooth agenesis in patients with Class II Division 2 malocclusion and environmental etiologies. However, a direct comparison of the prevalence and patterns of tooth agenesis between patients with Class II Division 2 malocclusion and those with general malocclusion has not been performed until now. The prevalence of Class II Division 2 malocclusion has been studied worldwide, and wide geographic variations have been observed. The wide variations in prevalence among geographic regions suggest the possible influence of genetic background on the etiology of Class II Division 2 malocclusion. However, in Japan, previous studies of Class II Division 2 malocclusion were limited to evaluation of the skeletal and dental morphologies, and few studies have investigated the heritability of this malformation.8 The purpose of this study was to evaluate the prevalence and patterns of permanent tooth agenesis in Japanese patients with Class II Division 2 malocclusion compared with general orthodontic patients in Japan and with previous studies in other countries. MATERIAL AND METHODS
For our Class II Division 2 group, the relationship of the first molars and the inclination of the maxillary incisors were evaluated by clinical intraoral and dental cast observations from a total population of approximately 3000 patients at the Nippon Dental University Hospital and private clinics in metropolitan Tokyo, and from a total population of approximately 1000 students at Nippon Dental University and other colleges for dental hygienists and dental technicians. One hundred four subjects with Angle Class II Division 2 malocclusion (Class II molar relationship, end to end or worse on at least 1 side in maximum intercuspation, and retroclination of bilateral maxillary central incisors with deep overbite) and no syndromes were selected by intraoral examinations or dental cast observations. Subjects with extracted permanent teeth or uncertain dental history were excluded. Subsequently, panoramic radiographs, cephalograms, and dental casts were evaluated and further selected according to the following inclusion criteria: U1-SN less than 90 , overbite deeper than 3 mm, no previous orthodontic treatment, no prosthetic crowns, and age 14 years or older. Tooth agenesis was evaluated by 2 dentists (K.O. and K.A.); in case of a
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divergence of opinion between the evaluators, the subject was excluded. Overall, 76 subjects with a mean age of 21.0 6 6.9 years, including 52 female subjects with a mean age of 21.4 6 6.5 years and 24 male subjects with a mean age of 20.6 6 8.0 years, were selected as the Class II Division 2 group. The maximum age in this group was 41.9 years. The protocol of this study (NDUT2011-34) was approved by the ethics committee of Nippon Dental University. For the control group, panoramic radiographs and dental casts from the diagnostic records of approximately 1000 orthodontic patients from private clinics in metropolitan Tokyo were evaluated according to the following inclusion criteria: no previous orthodontic treatment, no prosthetic crowns, and age 14 years or older. Subjects with extracted permanent teeth or uncertain dental history were excluded. In addition, if the evaluations of tooth agenesis by the 2 evaluators did not agree, the subject was excluded. As the control group, 270 orthodontic patients with no syndromes and a mean age of 18.2 6 4.8 years (168 female subjects with a mean age of 18.5 6 5.0 years, 102 male subjects with a mean age of 17.3 6 4.7 years) were selected. The maximum age in this group was 44.0 years. The numbers of subjects with tooth agenesis and their tooth types were evaluated. The numbers of absent teeth were counted for each tooth type in the maxilla and the mandible. The prevalence of tooth agenesis among all subjects and the prevalence of agenesis for each tooth type were calculated and compared between the 2 groups using the chi-square test (P\0.05). The results are presented as odds ratios with the corresponding 95% confidence intervals (CIs). The prevalences of agenesis of at least 1 third molar in both groups and agenesis in the maxillary and mandibular arches were calculated and compared between the 2 groups using the chi-square test (P \0.05). The results are presented as odds ratios with the corresponding 95% CI. Additionally, the prevalence of agenesis was compared between the maxillary and mandibular arches within each group using the chi-square test (P \0.05). Furthermore, subjects with agenesis of at least 1 third molar were divided into 4 subgroups according to the number of absent third molars for each subject, and the prevalence for each subject was compared between the 2 groups using the chi-square test (P \0.05). Sample size estimation (2 3 2 for independent samples, chi-square test) was performed using the SPSS Sample Power version 3 in the SPSS statistics package (version 21.1; IBM, Armonk, NY). Based on a previous study in which the prevalence values of tooth agenesis between different Class II Division 2 malocclusion
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Table I. Prevalence of agenesis excluding the third molars and third molar agenesis in the 2 groups and comparisons with the chi-square test Tooth agenesis excluding third molars Third molar agenesis
Class II Division 2 group, n 5 76 17 (22.4%) 32 (42.1%)
Control group, n 5 270 32 (11.9%) 72 (26.7%)
Chi-square value 5.396 6.724
P value 0.020* 0.010*
*P \0.05.
Table II. Prevalence of tooth agenesis excluding the third molars in the 2 groups Class II Division 2 group, n 5 76 Tooth type Mn I2 Mn P2 Mx P2 Mn I1 Mx M1 Mx C Mx P1 Mn P1 Mx I2 Mn M1 Mx M2 Total
Number of subjects (%) 6 (7.9) 7 (9.2) 3 (3.9) 0 0 0 0 1 (1.3) 4 (5.3) 1 (1.3) 1 (1.3)
Number of teeth (%) 9 (28.1) 9 (28.1) 4 (12.5) 0 0 0 0 1 (3.1) 7 (21.9) 1 (3.1) 1 (3.1) 32 (100)
Control group, n 5 270 Number of subjects (%) 12 (4.4) 8 (3.0) 7 (2.6) 5 (1.9) 3 (1.1) 2 (0.7) 1 (0.4) 1 (0.4) 1 (0.4) 0 0
Number of teeth (%) 15 (25.9) 12 (20.7) 11 (19.0) 6 (10.3) 7 (12.1) 4 (6.9) 1 (1.7) 1 (1.7) 1 (1.7) 0 0 58 (100)
Statistical comparison between the groups Chi-square value 1.432 5.582 0.388 0.922 9.969 -
P value 0.232 NS 0.018* 0.533 NS 0.337 NS 0.002y -
Mn, Mandibular; Mx, maxillary; I1, central incisor; I2, lateral incisor; C, canine; P1, first premolar; P2, second premolar; M1, first molar; M2, second molar; NS, not significant. *P \0.05; yP \0.01.
groups were 19% and 41%, with power greater than 80% and an alpha of 5% significance (2-tailed), it was determined that a sample size of 70 would be required in each group.7 To confirm the consistency of the subjects of the Class II Division 2 group, the prevalences of tooth agenesis excluding the third molars and third molar agenesis were compared between the orthodontic patients (n 5 59) and the dental students (n 5 17) using chi-square tests, and no statistically significant difference was observed (chi-square value 5 1.418; P 5 0.234; and chi-square value 5 0.008, P 5 0.930, respectively). RESULTS
The prevalence of tooth agenesis excluding third molars in the Class II Division 2 group (22.4%, n 5 17/76) was significantly higher than in the control group (11.9%, n 5 32/270) according to the chi-square test (chi-square value 5 5.396, P \0.05) (Table I); the odds ratio was 2.14 (95% CI, 1.12-4.12). The highest prevalence of tooth agenesis excluding third molars was found in the mandibular second premolar, mandibular lateral incisor, and maxillary lateral
incisor in the Class II Division 2 group and in the mandibular lateral incisor, mandibular second premolar, and maxillary second premolar in the control group. A significantly higher prevalence was found in the mandibular second premolar and maxillary lateral incisor in the Class II Division 2 group than in the control group (Table II). The prevalence of at least 1 absent third molar in the Class II Division 2 group (42.1%, n 5 32/76) was significantly higher than in the control group (26.7%, n 5 72/ 270) according to the chi-square test (chi-square value 5 6.724, P \0.05) (Table I); the odds ratio was 2.00 (95% CI, 1.18-3.40). The prevalences of third molar agenesis in the maxillary and mandibular arches were higher in the Class II Division 2 group than in the control group (Table III). Compared with the Class II Division 2 group, the prevalence of third molar agenesis was higher in the maxillary arch than in the mandibular arch in the control group (Table III). The prevalence of third molar agenesis was significantly higher in the Class II Division 2 group than in the control group for the subgroup lacking all 4 third molars (Table IV).
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Table III. Prevalence of agenesis of at least 1 third molar and agenesis in the maxillary and mandibular arches in the 2
groups with comparisons between groups and arches with the chi-square test Maxilla Mandible Chi-square value P value
Class II Division 2 group, n 5 76 27 (35.5%) 19 (25.0%) 1.995 0.158 NS
Control group, n 5 270 58 (21.5%) 35 (13.0%) 6.872 0.009y
Chi-square value 6.313 6.524
P value 0.012* 0.011*
NS, Not significant. *P \0.05; yP \0.01.
Table IV. Prevalence of third molar agenesis in the 4 subgroups divided by the number of absent third molars for each
subject in the Class II Division 2 and control groups and comparisons with the chi-square test Number of absent third molars in each subject Group Class II Division 2 group, n 5 76 Control group, n 5 270 Class II Division 2 vs control
One 8 (25.0%) 25 (34.7%) c2 5 0.110 P 5 0.740 NS
Two 12 (37.5%) 30 (41.7%) c2 5 1.217 P 5 0.270 NS
Three 5 (15.6%) 9 (12.5%) c2 5 1.609 P 5 0.205 NS
Four 7 (17.1%) 8 (11.1%) c2 5 5.582 P 5 0.018*
NS, Not significant. *P \0.05.
DISCUSSION
The minimum cutoff age for tooth agenesis excluding the third molars has been controversial.9 A recent meta-analysis of the prevalence of tooth agenesis excluding the third molars on panoramic radiographs recommended that the minimum age of study subjects should be over 12 years to prevent classifying late formation of the second premolar tooth germ as agenesis.10 Garn and Lewis11 suggested that it is not possible to confirm third molar agenesis on radiographs before the age of 14. Therefore, in this study, we included only subjects who were 14 years of age or older for both tooth agenesis analyses. However, no significant difference using the maximum cutoff age was obtained in the meta-analysis.10 When older subjects were included, the risk of including some with tooth extractions increased. Therefore, in our study, subjects with an uncertain dental history were excluded. The significantly higher prevalence of tooth agenesis excluding third molars in the Class II Division 2 group than in the control group of general orthodontic patients (Table I) that we observed was consistent with previous studies conducted in Japan (Table V).12,13 In Germany, Basdra et al4 also reported a higher prevalence of tooth agenesis in subjects with Class II Division 2 malocclusion than in other epidemiologic studies of the general population. A higher prevalence of tooth agenesis can usually be expected in an orthodontic patient population than in the general population.10 A
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higher prevalence of tooth agenesis excluding the third molars (approximately 30%-60%) has also been reported in other anomalies caused by gene mutations, such as Apert syndrome,14 Down syndrome,15 Crouzon syndrome,16 and cleft lip and palate.17 These findings support the hypothesis of a genetic etiology of Class II Division 2 malocclusion.3-6 Over 200 genes are expressed during tooth development18; therefore, more than 1 genetic mutation may be involved in the many factors that contribute to a specific malocclusion type such as Class II Division 2 malocclusion.3 However, another recent study in Turkey reported a lower prevalence of tooth agenesis, although without a statistically significant difference, in patients with Class II Division 2 malocclusion than in other Angle malocclusions, suggesting a regional difference.19 Consequently, it remains unclear whether the same genetic factors that are associated with the higher prevalence in the Class II Division 2 sample in Japan are the same factors that affect Class II Division 2 patients with tooth agenesis in Europe and the United States. Polder et al9 conducted a meta-analysis of the prevalence of congenitally missing teeth in a sample of 112,334 people from a variety of ethnic groups and found that agenesis of the mandibular second premolar was most common, followed by the maxillary lateral incisor. However, in a sample of Class II Division 2 patients in Germany, Basdra et al4 found that the prevalence of tooth agenesis was highest for the maxillary
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Table V. Comparison of the prevalence (%) of tooth agenesis excluding the third molars
Study Present study Endo et al12 (1 study) Kure and Arai13 (meta-analysis)
Basdra et al4 Polder et al9 (meta-analysis)
Sample characteristics Class II Division 2 Orthodontic patients Orthodontic patients General population Orthodontic patients General population Orthodontic patients Class II Division 2 General population
Ethnic group Japanese Japanese Japanese White German Mixed
Total sample size (n) 76 270 3,358 79,006 22,431 54,815 6,212 267 112,334
Prevalence of tooth agenesis (%) 22.4 11.9 8.5 5.3 9.6 5.8 9.7 NA 2.5-6.9*
Prevalence of agenesis for each tooth (%) Mx I2 21.9 1.7 10.5 13.4 15.5 22.2 23.8 26.1 22.9
Mx P2 12.5 19.0 15.7 14.4 15.0 21.1 19.5 13.3 21.2
Mn I2 28.1 25.9 10.9 16.2 13.4 2.4 1.9 3.5 2.5
Mn P2 28.1 20.7 27.8 22.6 23.2 40.5 41.7 25.2 41.0
Mx I2, Maxillary lateral incisor; Mx P2, maxillary second premolar; Mn I2, mandibular lateral incisor; Mn P2, mandibular second premolar; NA, not available in the study. *Range of means in the various ethnic groups.
lateral incisor, followed by the mandibular second premolar, and suggested that the higher prevalence of maxillary lateral incisor agenesis is 1 characteristic of a Class II Division 2 malocclusion. In our study, a significantly higher prevalence of tooth agenesis was also found in the maxillary lateral incisor in the Class II Division 2 group than in the control group. Therefore, although our sample size was limited, the higher prevalence of agenesis of the maxillary lateral incisor may be a universal agenesis pattern characteristic of a Class II Division 2 malocclusion.4 Distinct patterns of agenesis of permanent teeth have also been frequently observed in heritable congenital anomalies in various geographic regions. For example, the most frequently absent teeth in patients with cleft lip and palate are the maxillary lateral incisor and the maxillary second premolar.20 In patients with Down syndrome, the most frequently absent teeth are the maxillary lateral incisor, followed by the mandibular second premolar and the mandibular incisors.15 Additionally, higher frequencies of agenesis for specific teeth have been explained as selective tooth agenesis: ie, a specific pattern of tooth agenesis that is related to a specific gene mutation.21,22 For instance, PAX9 and MSX1 mutations mainly affect the molars and premolars, respectively.23,24 Missing mandibular incisors are also known as the chief manifestation of Ectodysplasin A (EDA)-associated nonsyndromic oligodontia, which has mostly been studied in Asian countries.25 In this study, a relatively higher prevalence of tooth agenesis was found in the mandibular lateral incisor in both groups, but that difference was not statistically significant. This finding is similar to the results of previous studies of general orthodontic patients in Japan (Table V).12,13 Therefore, the pattern of tooth
agenesis observed in patients with Class II Division 2 malocclusion may be influenced significantly by the ethnic background of the study population. Combined with the published literature, our results suggest that the cause of tooth agenesis is not the mutation of a single gene and that tooth agenesis is influenced by multiple genes related to tooth development. Additionally, 1 gene mutation may be specific to a group of genes associated with ethnic phenotypes, including skeletal, dental, and soft-tissue morphologies. Based on radiographic evaluations of general orthodontic patients, a higher prevalence of at least 1 third molar agenesis has been reported in Japan, ranging from 22.2% to 32.3%,26 than in the United States and Europe (Table VI), with a range between 5.8%27 and 20.9%,28 respectively. Similar to these previous studies, the prevalence of third molar agenesis in the control group in this study was 26.7%. In a recent study with exclusion of maxillary lateral incisor agenesis in Portugal, a significantly higher third molar agenesis was observed in a Class II Division 2 malocclusion group with retroclined maxillary lateral incisors (35.9%) compared with a group with proclined maxillary lateral incisors (14.3%).7 This finding suggested a biologic relationship between third molar agenesis and Class II Division 2 malocclusion. However, Basdra et al4 determined the prevalence of third molar agenesis of Class II Division 2 patients in Germany (22.0%) but found no differences with other studies in the same area. In contrast to the findings of these studies,4,7 in our study, the prevalence of third molar agenesis in the Class II Division 2 group was significantly higher than in the control group (Tables I and III). A high prevalence of third molar agenesis (74%-84.4%) has also been reported in studies of Down syndrome populations.15,29
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Table VI. Comparison of the prevalence (%) of third molar agenesis
Study Present study Endo et al26 Basdra et al4 Barka et al28 Harris and Clark27
Sample characteristics Class II Division 2 Orthodontic patients Orthodontic patients Class II Division 2 Orthodontic patients Orthodontic patients Orthodontic patients
Ethnic group Japanese Japanese German Greek African American White American
Specific regions of chromosome 21 contribute to the phenotypic features of Down syndrome, but the high prevalence of third molar agenesis appears to result from specific genetic mutations.29 A higher prevalence of third molar agenesis has also been observed in subjects with the MSX1 missense mutation,21 which is also related to craniofacial anomalies, including cleft lip and palate.22 However, the reported prevalence of third molar agenesis in patients with cleft lip and palate ranges from 7% to 26%, which is not much higher than that of the general population.30 Therefore, whether the gene mutations that affect tooth development in Class II Division 2 malocclusion and other hereditary craniofacial anomalies are directly related remains an important topic for future research. In the control group, the prevalence of third molar agenesis in the maxillary arch was higher than in the mandibular arch (Table III). This tendency is similar to the findings of other studies conducted in Asian countries but differs from findings in European and North American countries, suggesting a regional difference.26 Higher frequencies of agenesis of maxillary third molars in patients with Down syndrome29 and mandibular third molars in patients with Pierre Robin sequence31 have been associated with environmental factors such as a smaller maxilla and mandible, respectively. However, the skeletal pattern of Class II Division 2 malocclusion in Japanese orthodontic patients remains unclear.8 Therefore, in Class II Division 2 malocclusion, the relationship between third molar agenesis and environmental factors, including the skeletal pattern with local terminal vascularization and the growth of related nerve branches for developing tooth buds,32 should be investigated in future studies. Endo et al12 compared the prevalence of permanent tooth agenesis between 1905 female subjects and 1453 male subjects in Japan and observed no significant difference. In our study, there was also no statistically significant sex difference in the prevalence; this led us to pool the sexes for analysis. However, a recent meta-analysis reported sex differences in the prevalence of permanent tooth agenesis.10 Accordingly,
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Subjects with at least 1 third molar agenesis (n) 32 72 417 56 46 35 184
Total subjects (n) 76 270 1,291 255 220 600 1,100
Prevalence of third molar agenesis (%) 42.1 26.7 32.3 22.0 20.9 5.8 16.7
further study on this issue may be necessary with a larger sample size. This study was conducted to evaluate the characteristics of permanent tooth agenesis in patients with Class II Division 2 malocclusion in Japan. Therefore, we focused on patients with Class II Division 2 malocclusion and compared them with a group of general orthodontic patients. However, there is evidence that Class III malocclusion also has a genetic component.5 In addition, although the sampling technique was different from that of our study, a higher prevalence of tooth agenesis in Class III malocclusion compared with Class I and Class II malocclusions was previously observed in an Iranian orthodontic population.33 Therefore, comparing the prevalence and pattern of permanent tooth agenesis in probands and first-degree relatives among Angle classifications, as well as analyzing the associations with DNA genetic markers, may provide insights into the genetic etiology of malocclusion. Regarding the diagnosis of Class II Division 2 malocclusion patients, in addition to the problem of the sagittal molar relationship, deep overbite, smaller tooth size,3 and lip function, the tooth agenesis pattern that we observed may further complicate this malocclusion type. For early detection, it is important to consider the patient's family history of dental anomalies34 and ethnic background. In addition, panoramic radiographs of the early mixed dentition can identify tooth agenesis excluding the third molars in more than 20% of Class II Division 2 patients in Japan. CONCLUSIONS
1.
2.
The prevalence of permanent tooth agenesis was approximately 2 times higher in the Class II Division 2 group than in general orthodontic patients in Japan. Higher prevalences of tooth agenesis in the mandibular second premolar and the maxillary lateral incisor were observed in the Class II Division 2 group.
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The prevalence of third molar agenesis was significantly higher in the Class II Division 2 group than in the control group only for the subgroup lacking all 4 third molars.
ACKNOWLEDGMENT
We thank Dr Sheldon Peck (former clinical professor, Harvard School of Dental Medicine, Boston, Mass) for his discussion and constructive comments regarding this research. REFERENCES 1. Angle EH. Classification of malocclusion. Dent Cosmos 1899;41: 248-64. 2. Lapatki BG, Mager AS, Schulte-Moenting J, Jonas IE. The importance of the level of the lip line and resting lip pressure in Class II, Division 2 malocclusion. J Dent Res 2002;81:323-8. 3. Peck S, Peck L, Kataja M. Class II Division 2 malocclusion: a heritable pattern of small teeth in well-developed jaws. Angle Orthod 1998;68:9-20. 4. Basdra EK, Kiokpasoglou M, Stellzig A. The Class II Division 2 craniofacial type is associated with numerous congenital tooth anomalies. Eur J Orthod 2000;22:529-35. 5. Hartsfield JK, Morford LA, Otero LM, Fardo DW. Genetics and nonsyndromic facial growth. J Pediatr Genet 2013;2:1-12. 6. Markovic MD. At the crossroads of oral facial genetics. Eur J Orthod 1992;14:469-81. 7. Pereira PM, Ferreira AP, Tavares P, Braga AC. Different manifestations of Class II Division 2 incisor retroclination and their association with dental anomalies. J Orthod 2013;40:299-306. 8. Deguchi T, Togari A, Matsui K, Ozawa M, Teramachi K, Matsuda Y. Morphological variation of Angle Class II Division 2 in Japanese male adults. Nihon Kyosei Shika Gakkai Zasshi 1981;40:300-7. 9. Polder BJ, Van't Hof MA, Van der Linden FP, KuijpersJagtman AM. A meta-analysis of the prevalence of dental agenesis of permanent teeth. Community Dent Oral Epidemiol 2004;32: 217-26. 10. Rakhshan V. Meta-analysis and systematic review of factors biasing the observed prevalence of congenitally missing teeth in permanent dentition excluding third molars. Prog Orthod 2013; 14:1-12. 11. Garn SM, Lewis AB. The relationship between third molar agenesis and reduction in tooth number. Angle Orthod 1962;32:14-8. 12. Endo T, Ozoe R, Kubota M, Akiyama M, Shimooka S. A survey of hypodontia in Japanese orthodontic patients. Am J Orthod Dentofacial Orthop 2006;129:29-35. 13. Kure K, Arai K. A meta-analysis of tooth agenesis pattern of permanent teeth. Orthod Waves Japanese Ed 2012;70:184-96. 14. Stavropoulos D, Bartzela T, Bronkhorst E, Mohlin B, Hagberg C. Dental agenesis patterns of permanent teeth in Apert syndrome. Eur J Oral Sci 2011;119:198-203.
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15. Shapira J, Chaushu S, Becker A. Prevalence of tooth transposition, third molar agenesis, and maxillary canine impaction in individuals with Down syndrome. Angle Orthod 2000;70:290-6. 16. Stavropoulos D, Bartzela T, Tarnow P, Mohlin B, Kahnberg KE, Hagberg C. Dental agenesis patterns in Crouzon syndrome. Swed Dent J 2011;35:195-201. 17. Bartzela TN, Carels CE, Bronkhorst EM, Ronning E, Rizell S, Kuijpers-Jagtman AM. Tooth agenesis patterns in bilateral cleft lip and palate. Eur J Oral Sci 2010;118:47-52. 18. Thesleff I. Epithelial-mesenchymal signalling regulating tooth morphogenesis. J Cell Sci 2003;116:1647-8. 19. Uslu O, Akcam MO, Evirgen S, Cebeci I. Prevalence of dental anomalies in various malocclusions. Am J Orthod Dentofacial Orthop 2009;135:328-35. 20. Shapira Y, Lubit E, Kuftinec MM. Hypodontia in children with various types of clefts. Angle Orthod 2000;70:16-21. 21. Vastardis H, Karimbux N, Guthua SW, Seidman J, Seidman CE. A human MSX1 homeodomain missense mutation causes selective tooth agenesis. Nat Genet 1996;13:417-21. 22. Ruf S, Klimas D, Honemann M, Jabir S. Genetic background of nonsyndromic oligodontia: a systematic review and meta-analysis. J Orofac Orthop 2013;74:295-308. 23. Nieminen P, Arte S, Tanner D, Paulin L, Alaluusua S, Thesleff I, et al. Identification of a nonsense mutation in the PAX9 gene in molar oligodontia. Eur J Hum Genet 2001;9:743-6. 24. Vieira AR, Meira R, Modesto A, Murray JC. MSX1, PAX9, and TGFA contribute to tooth agenesis in humans. J Dent Res 2004;83:723-7. 25. Tao R, Jin B, Guo SZ, Qing W, Feng GY, Brooks DG, et al. A novel missense mutation of the EDA gene in a Mongolian family with congenital hypodontia. J Hum Genet 2006;51:498-502. 26. Endo S, Sanpei S, Ishida R, Sanpei S, Abe R, Endo T. Association between third molar agenesis patterns and agenesis of other teeth in a Japanese orthodontic population. Odontology 2015;103:88-96. 27. Harris EF, Clark LL. Hypodontia: an epidemiologic study of American black and white people. Am J Orthod Dentofacial Orthop 2008;134:761-7. 28. Barka G, Tretiakov G, Theodosiou T, Ioannidou-Marathiotou I. Presence of third molars in orthodontic patients from northern Greece. Int J Gen Med 2012;5:441-7. 29. Lomholt JF, Russell BG, Stoltze K, Kjaer I. Third molar agenesis in Down syndrome. Acta Odontol Scand 2002;60:151-4. 30. Hermus RR, van Wijk AJ, Tan SP, Kramer GJ, Ongkosuwito EM. Patterns of tooth agenesis in patients with orofacial clefts. Eur J Oral Sci 2013;121:328-32. 31. Suri S, Ross RB, Tompson BD. Mandibular morphology and growth with and without hypodontia in subjects with Pierre Robin sequence. Am J Orthod Dentofacial Orthop 2006;130:37-46. 32. Suri S, Tompson BD, Atenafu E. Prevalence and patterns of permanent tooth agenesis in Down syndrome and their association with craniofacial morphology. Angle Orthod 2011;81:260-9. 33. Vahid-Dastjerdi E, Borzabadi-Farahani A, Mahdian M, Amini N. Non-syndromic hypodontia in an Iranian orthodontic population. J Oral Sci 2010;52:455-61. 34. Peck S. Dental anomaly patterns (DAP). A new way to look at malocclusion. Angle Orthod 2009;79:1015-6.
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Prevalence and patterns of tooth agenesis in Angle Class II Division 2 malocclusion in Japan Kanako Otaa and Kazuhito Araib Tokyo, Japan
Introduction: The purpose of this study was to evaluate the prevalence and patterns of tooth agenesis in subjects with Angle Class II Division 2 malocclusion compared with general orthodontic patients in Japan. Methods: Panoramic radiographs, dental casts, and cephalograms of 76 patients with Class II Division 2 malocclusions (52 female, 24 male) and 270 orthodontic patients as the control group (168 female, 102 male) who were 14 years of age or older were selected. The prevalences of tooth agenesis in this cohort and in each tooth type were calculated and compared between the groups with the chi-square test. Odds ratios and corresponding 95% confidence intervals were also calculated. Results: The prevalence of tooth agenesis excluding the third molars was significantly higher in the Class II Division 2 group (22.4%) than in the control group (11.9%) (P \0.05); the odds ratio was 2.14 (95% CI, 1.12-4.12). A higher prevalence of tooth agenesis excluding the third molars was observed in the Class II Division 2 group for the mandibular second premolar (P \0.05) and the maxillary lateral incisor (P \0.01). The prevalence of third molar agenesis was also significantly higher in the Class II Division 2 group (42.1%) compared with the control group (26.7%) (P \0.05); the odds ratio was 2.00 (95% CI, 1.18-3.40). Conclusions: Compared with the general orthodontic patient population, permanent tooth agenesis was observed approximately 2 times more frequently, and a distinctive agenesis pattern was found in the Class II Division 2 group in Japan. (Am J Orthod Dentofacial Orthop 2015;148:123-9)
A
ccording to Angle,1 Class II Division 2 malocclusion is characterized by a distal position of the mandibular arch with retroclination of the maxillary incisors; this is the result of longer contact with the lips during normal respiratory function of the oral environment, rather than genetic factors. Consequently, lip pressure has been found to be significantly greater in patients with Class II Division 2 malocclusion than in those with Class I malocclusion.2 However, research studies,3,4 a review article,5 and case reports of twins and triplets6 have suggested the heritability of Class II Division 2 malocclusion. Peck et al3 identified a characteristic pattern of heritable skeletal and tooth-size features in patients with Class II Division 2 cover-bite malocclusion and suggested a strong genetic influence on the formation of this pattern. From the Department of Orthodontics, School of Life Dentistry, Nippon Dental University, Tokyo, Japan. a Clinical research fellow. b Professor and chair. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest, and none were reported. Address correspondence to: Kazuhito Arai, Department of Orthodontics, School of Life Dentistry at Tokyo, Nippon Dental University, 1-9-20 Fujimi, Chiyoda-ku, Tokyo 102-8159, Japan; e-mail, [email protected]. Submitted, October 2014; revised and accepted, February 2015. 0889-5406/$36.00 Copyright Ó 2015 by the American Association of Orthodontists. http://dx.doi.org/10.1016/j.ajodo.2015.02.023
Subsequently, Basdra et al4 evaluated 267 Class II Division 2 patients in Germany and found a higher prevalence of heritable dental anomalies, including tooth agenesis, compared with other epidemiologic studies of general populations in Europe and the United States. In addition, the researchers observed a high prevalence of agenesis of the maxillary lateral incisor. In another recent study in Portugal, Pereira et al7 examined 115 Class II Division 2 subjects without maxillary lateral incisor agenesis and classified them into 2 groups on the basis of maxillary incisor retroclination. These researchers found a higher prevalence of tooth agenesis in the group with retroclination of all 4 maxillary incisors than in the group with retroclination of bilateral maxillary central incisors. The authors suggested that different etiologic factors contribute to the different manifestations of Class II Division 2 malocclusion. Developmental dental anomalies, including tooth agenesis, have been suggested to be an anatomic characteristic of patients with Class II Division 2 malocclusion. Therefore, an analysis of the prevalence and patterns of tooth agenesis may provide additional evidence of possible genetic factors contributing to Class II Division 2 malocclusion. In a recent review article, Hartsfield et al5 reported an increased risk of Class II Division 2 malocclusion in first-degree relatives of Class 123
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II Division 2 probands compared with the general population. Their findings suggested that the Class II Division 2 malocclusions resulted from a polygenic, complex etiology rather than from variations in a single gene. They also suggested the need to investigate possible common etiologic factors, including genes associated with tooth development and tooth agenesis in patients with Class II Division 2 malocclusion and environmental etiologies. However, a direct comparison of the prevalence and patterns of tooth agenesis between patients with Class II Division 2 malocclusion and those with general malocclusion has not been performed until now. The prevalence of Class II Division 2 malocclusion has been studied worldwide, and wide geographic variations have been observed. The wide variations in prevalence among geographic regions suggest the possible influence of genetic background on the etiology of Class II Division 2 malocclusion. However, in Japan, previous studies of Class II Division 2 malocclusion were limited to evaluation of the skeletal and dental morphologies, and few studies have investigated the heritability of this malformation.8 The purpose of this study was to evaluate the prevalence and patterns of permanent tooth agenesis in Japanese patients with Class II Division 2 malocclusion compared with general orthodontic patients in Japan and with previous studies in other countries. MATERIAL AND METHODS
For our Class II Division 2 group, the relationship of the first molars and the inclination of the maxillary incisors were evaluated by clinical intraoral and dental cast observations from a total population of approximately 3000 patients at the Nippon Dental University Hospital and private clinics in metropolitan Tokyo, and from a total population of approximately 1000 students at Nippon Dental University and other colleges for dental hygienists and dental technicians. One hundred four subjects with Angle Class II Division 2 malocclusion (Class II molar relationship, end to end or worse on at least 1 side in maximum intercuspation, and retroclination of bilateral maxillary central incisors with deep overbite) and no syndromes were selected by intraoral examinations or dental cast observations. Subjects with extracted permanent teeth or uncertain dental history were excluded. Subsequently, panoramic radiographs, cephalograms, and dental casts were evaluated and further selected according to the following inclusion criteria: U1-SN less than 90 , overbite deeper than 3 mm, no previous orthodontic treatment, no prosthetic crowns, and age 14 years or older. Tooth agenesis was evaluated by 2 dentists (K.O. and K.A.); in case of a
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divergence of opinion between the evaluators, the subject was excluded. Overall, 76 subjects with a mean age of 21.0 6 6.9 years, including 52 female subjects with a mean age of 21.4 6 6.5 years and 24 male subjects with a mean age of 20.6 6 8.0 years, were selected as the Class II Division 2 group. The maximum age in this group was 41.9 years. The protocol of this study (NDUT2011-34) was approved by the ethics committee of Nippon Dental University. For the control group, panoramic radiographs and dental casts from the diagnostic records of approximately 1000 orthodontic patients from private clinics in metropolitan Tokyo were evaluated according to the following inclusion criteria: no previous orthodontic treatment, no prosthetic crowns, and age 14 years or older. Subjects with extracted permanent teeth or uncertain dental history were excluded. In addition, if the evaluations of tooth agenesis by the 2 evaluators did not agree, the subject was excluded. As the control group, 270 orthodontic patients with no syndromes and a mean age of 18.2 6 4.8 years (168 female subjects with a mean age of 18.5 6 5.0 years, 102 male subjects with a mean age of 17.3 6 4.7 years) were selected. The maximum age in this group was 44.0 years. The numbers of subjects with tooth agenesis and their tooth types were evaluated. The numbers of absent teeth were counted for each tooth type in the maxilla and the mandible. The prevalence of tooth agenesis among all subjects and the prevalence of agenesis for each tooth type were calculated and compared between the 2 groups using the chi-square test (P\0.05). The results are presented as odds ratios with the corresponding 95% confidence intervals (CIs). The prevalences of agenesis of at least 1 third molar in both groups and agenesis in the maxillary and mandibular arches were calculated and compared between the 2 groups using the chi-square test (P \0.05). The results are presented as odds ratios with the corresponding 95% CI. Additionally, the prevalence of agenesis was compared between the maxillary and mandibular arches within each group using the chi-square test (P \0.05). Furthermore, subjects with agenesis of at least 1 third molar were divided into 4 subgroups according to the number of absent third molars for each subject, and the prevalence for each subject was compared between the 2 groups using the chi-square test (P \0.05). Sample size estimation (2 3 2 for independent samples, chi-square test) was performed using the SPSS Sample Power version 3 in the SPSS statistics package (version 21.1; IBM, Armonk, NY). Based on a previous study in which the prevalence values of tooth agenesis between different Class II Division 2 malocclusion
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Table I. Prevalence of agenesis excluding the third molars and third molar agenesis in the 2 groups and comparisons with the chi-square test Tooth agenesis excluding third molars Third molar agenesis
Class II Division 2 group, n 5 76 17 (22.4%) 32 (42.1%)
Control group, n 5 270 32 (11.9%) 72 (26.7%)
Chi-square value 5.396 6.724
P value 0.020* 0.010*
*P \0.05.
Table II. Prevalence of tooth agenesis excluding the third molars in the 2 groups Class II Division 2 group, n 5 76 Tooth type Mn I2 Mn P2 Mx P2 Mn I1 Mx M1 Mx C Mx P1 Mn P1 Mx I2 Mn M1 Mx M2 Total
Number of subjects (%) 6 (7.9) 7 (9.2) 3 (3.9) 0 0 0 0 1 (1.3) 4 (5.3) 1 (1.3) 1 (1.3)
Number of teeth (%) 9 (28.1) 9 (28.1) 4 (12.5) 0 0 0 0 1 (3.1) 7 (21.9) 1 (3.1) 1 (3.1) 32 (100)
Control group, n 5 270 Number of subjects (%) 12 (4.4) 8 (3.0) 7 (2.6) 5 (1.9) 3 (1.1) 2 (0.7) 1 (0.4) 1 (0.4) 1 (0.4) 0 0
Number of teeth (%) 15 (25.9) 12 (20.7) 11 (19.0) 6 (10.3) 7 (12.1) 4 (6.9) 1 (1.7) 1 (1.7) 1 (1.7) 0 0 58 (100)
Statistical comparison between the groups Chi-square value 1.432 5.582 0.388 0.922 9.969 -
P value 0.232 NS 0.018* 0.533 NS 0.337 NS 0.002y -
Mn, Mandibular; Mx, maxillary; I1, central incisor; I2, lateral incisor; C, canine; P1, first premolar; P2, second premolar; M1, first molar; M2, second molar; NS, not significant. *P \0.05; yP \0.01.
groups were 19% and 41%, with power greater than 80% and an alpha of 5% significance (2-tailed), it was determined that a sample size of 70 would be required in each group.7 To confirm the consistency of the subjects of the Class II Division 2 group, the prevalences of tooth agenesis excluding the third molars and third molar agenesis were compared between the orthodontic patients (n 5 59) and the dental students (n 5 17) using chi-square tests, and no statistically significant difference was observed (chi-square value 5 1.418; P 5 0.234; and chi-square value 5 0.008, P 5 0.930, respectively). RESULTS
The prevalence of tooth agenesis excluding third molars in the Class II Division 2 group (22.4%, n 5 17/76) was significantly higher than in the control group (11.9%, n 5 32/270) according to the chi-square test (chi-square value 5 5.396, P \0.05) (Table I); the odds ratio was 2.14 (95% CI, 1.12-4.12). The highest prevalence of tooth agenesis excluding third molars was found in the mandibular second premolar, mandibular lateral incisor, and maxillary lateral
incisor in the Class II Division 2 group and in the mandibular lateral incisor, mandibular second premolar, and maxillary second premolar in the control group. A significantly higher prevalence was found in the mandibular second premolar and maxillary lateral incisor in the Class II Division 2 group than in the control group (Table II). The prevalence of at least 1 absent third molar in the Class II Division 2 group (42.1%, n 5 32/76) was significantly higher than in the control group (26.7%, n 5 72/ 270) according to the chi-square test (chi-square value 5 6.724, P \0.05) (Table I); the odds ratio was 2.00 (95% CI, 1.18-3.40). The prevalences of third molar agenesis in the maxillary and mandibular arches were higher in the Class II Division 2 group than in the control group (Table III). Compared with the Class II Division 2 group, the prevalence of third molar agenesis was higher in the maxillary arch than in the mandibular arch in the control group (Table III). The prevalence of third molar agenesis was significantly higher in the Class II Division 2 group than in the control group for the subgroup lacking all 4 third molars (Table IV).
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Table III. Prevalence of agenesis of at least 1 third molar and agenesis in the maxillary and mandibular arches in the 2
groups with comparisons between groups and arches with the chi-square test Maxilla Mandible Chi-square value P value
Class II Division 2 group, n 5 76 27 (35.5%) 19 (25.0%) 1.995 0.158 NS
Control group, n 5 270 58 (21.5%) 35 (13.0%) 6.872 0.009y
Chi-square value 6.313 6.524
P value 0.012* 0.011*
NS, Not significant. *P \0.05; yP \0.01.
Table IV. Prevalence of third molar agenesis in the 4 subgroups divided by the number of absent third molars for each
subject in the Class II Division 2 and control groups and comparisons with the chi-square test Number of absent third molars in each subject Group Class II Division 2 group, n 5 76 Control group, n 5 270 Class II Division 2 vs control
One 8 (25.0%) 25 (34.7%) c2 5 0.110 P 5 0.740 NS
Two 12 (37.5%) 30 (41.7%) c2 5 1.217 P 5 0.270 NS
Three 5 (15.6%) 9 (12.5%) c2 5 1.609 P 5 0.205 NS
Four 7 (17.1%) 8 (11.1%) c2 5 5.582 P 5 0.018*
NS, Not significant. *P \0.05.
DISCUSSION
The minimum cutoff age for tooth agenesis excluding the third molars has been controversial.9 A recent meta-analysis of the prevalence of tooth agenesis excluding the third molars on panoramic radiographs recommended that the minimum age of study subjects should be over 12 years to prevent classifying late formation of the second premolar tooth germ as agenesis.10 Garn and Lewis11 suggested that it is not possible to confirm third molar agenesis on radiographs before the age of 14. Therefore, in this study, we included only subjects who were 14 years of age or older for both tooth agenesis analyses. However, no significant difference using the maximum cutoff age was obtained in the meta-analysis.10 When older subjects were included, the risk of including some with tooth extractions increased. Therefore, in our study, subjects with an uncertain dental history were excluded. The significantly higher prevalence of tooth agenesis excluding third molars in the Class II Division 2 group than in the control group of general orthodontic patients (Table I) that we observed was consistent with previous studies conducted in Japan (Table V).12,13 In Germany, Basdra et al4 also reported a higher prevalence of tooth agenesis in subjects with Class II Division 2 malocclusion than in other epidemiologic studies of the general population. A higher prevalence of tooth agenesis can usually be expected in an orthodontic patient population than in the general population.10 A
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higher prevalence of tooth agenesis excluding the third molars (approximately 30%-60%) has also been reported in other anomalies caused by gene mutations, such as Apert syndrome,14 Down syndrome,15 Crouzon syndrome,16 and cleft lip and palate.17 These findings support the hypothesis of a genetic etiology of Class II Division 2 malocclusion.3-6 Over 200 genes are expressed during tooth development18; therefore, more than 1 genetic mutation may be involved in the many factors that contribute to a specific malocclusion type such as Class II Division 2 malocclusion.3 However, another recent study in Turkey reported a lower prevalence of tooth agenesis, although without a statistically significant difference, in patients with Class II Division 2 malocclusion than in other Angle malocclusions, suggesting a regional difference.19 Consequently, it remains unclear whether the same genetic factors that are associated with the higher prevalence in the Class II Division 2 sample in Japan are the same factors that affect Class II Division 2 patients with tooth agenesis in Europe and the United States. Polder et al9 conducted a meta-analysis of the prevalence of congenitally missing teeth in a sample of 112,334 people from a variety of ethnic groups and found that agenesis of the mandibular second premolar was most common, followed by the maxillary lateral incisor. However, in a sample of Class II Division 2 patients in Germany, Basdra et al4 found that the prevalence of tooth agenesis was highest for the maxillary
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Table V. Comparison of the prevalence (%) of tooth agenesis excluding the third molars
Study Present study Endo et al12 (1 study) Kure and Arai13 (meta-analysis)
Basdra et al4 Polder et al9 (meta-analysis)
Sample characteristics Class II Division 2 Orthodontic patients Orthodontic patients General population Orthodontic patients General population Orthodontic patients Class II Division 2 General population
Ethnic group Japanese Japanese Japanese White German Mixed
Total sample size (n) 76 270 3,358 79,006 22,431 54,815 6,212 267 112,334
Prevalence of tooth agenesis (%) 22.4 11.9 8.5 5.3 9.6 5.8 9.7 NA 2.5-6.9*
Prevalence of agenesis for each tooth (%) Mx I2 21.9 1.7 10.5 13.4 15.5 22.2 23.8 26.1 22.9
Mx P2 12.5 19.0 15.7 14.4 15.0 21.1 19.5 13.3 21.2
Mn I2 28.1 25.9 10.9 16.2 13.4 2.4 1.9 3.5 2.5
Mn P2 28.1 20.7 27.8 22.6 23.2 40.5 41.7 25.2 41.0
Mx I2, Maxillary lateral incisor; Mx P2, maxillary second premolar; Mn I2, mandibular lateral incisor; Mn P2, mandibular second premolar; NA, not available in the study. *Range of means in the various ethnic groups.
lateral incisor, followed by the mandibular second premolar, and suggested that the higher prevalence of maxillary lateral incisor agenesis is 1 characteristic of a Class II Division 2 malocclusion. In our study, a significantly higher prevalence of tooth agenesis was also found in the maxillary lateral incisor in the Class II Division 2 group than in the control group. Therefore, although our sample size was limited, the higher prevalence of agenesis of the maxillary lateral incisor may be a universal agenesis pattern characteristic of a Class II Division 2 malocclusion.4 Distinct patterns of agenesis of permanent teeth have also been frequently observed in heritable congenital anomalies in various geographic regions. For example, the most frequently absent teeth in patients with cleft lip and palate are the maxillary lateral incisor and the maxillary second premolar.20 In patients with Down syndrome, the most frequently absent teeth are the maxillary lateral incisor, followed by the mandibular second premolar and the mandibular incisors.15 Additionally, higher frequencies of agenesis for specific teeth have been explained as selective tooth agenesis: ie, a specific pattern of tooth agenesis that is related to a specific gene mutation.21,22 For instance, PAX9 and MSX1 mutations mainly affect the molars and premolars, respectively.23,24 Missing mandibular incisors are also known as the chief manifestation of Ectodysplasin A (EDA)-associated nonsyndromic oligodontia, which has mostly been studied in Asian countries.25 In this study, a relatively higher prevalence of tooth agenesis was found in the mandibular lateral incisor in both groups, but that difference was not statistically significant. This finding is similar to the results of previous studies of general orthodontic patients in Japan (Table V).12,13 Therefore, the pattern of tooth
agenesis observed in patients with Class II Division 2 malocclusion may be influenced significantly by the ethnic background of the study population. Combined with the published literature, our results suggest that the cause of tooth agenesis is not the mutation of a single gene and that tooth agenesis is influenced by multiple genes related to tooth development. Additionally, 1 gene mutation may be specific to a group of genes associated with ethnic phenotypes, including skeletal, dental, and soft-tissue morphologies. Based on radiographic evaluations of general orthodontic patients, a higher prevalence of at least 1 third molar agenesis has been reported in Japan, ranging from 22.2% to 32.3%,26 than in the United States and Europe (Table VI), with a range between 5.8%27 and 20.9%,28 respectively. Similar to these previous studies, the prevalence of third molar agenesis in the control group in this study was 26.7%. In a recent study with exclusion of maxillary lateral incisor agenesis in Portugal, a significantly higher third molar agenesis was observed in a Class II Division 2 malocclusion group with retroclined maxillary lateral incisors (35.9%) compared with a group with proclined maxillary lateral incisors (14.3%).7 This finding suggested a biologic relationship between third molar agenesis and Class II Division 2 malocclusion. However, Basdra et al4 determined the prevalence of third molar agenesis of Class II Division 2 patients in Germany (22.0%) but found no differences with other studies in the same area. In contrast to the findings of these studies,4,7 in our study, the prevalence of third molar agenesis in the Class II Division 2 group was significantly higher than in the control group (Tables I and III). A high prevalence of third molar agenesis (74%-84.4%) has also been reported in studies of Down syndrome populations.15,29
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Table VI. Comparison of the prevalence (%) of third molar agenesis
Study Present study Endo et al26 Basdra et al4 Barka et al28 Harris and Clark27
Sample characteristics Class II Division 2 Orthodontic patients Orthodontic patients Class II Division 2 Orthodontic patients Orthodontic patients Orthodontic patients
Ethnic group Japanese Japanese German Greek African American White American
Specific regions of chromosome 21 contribute to the phenotypic features of Down syndrome, but the high prevalence of third molar agenesis appears to result from specific genetic mutations.29 A higher prevalence of third molar agenesis has also been observed in subjects with the MSX1 missense mutation,21 which is also related to craniofacial anomalies, including cleft lip and palate.22 However, the reported prevalence of third molar agenesis in patients with cleft lip and palate ranges from 7% to 26%, which is not much higher than that of the general population.30 Therefore, whether the gene mutations that affect tooth development in Class II Division 2 malocclusion and other hereditary craniofacial anomalies are directly related remains an important topic for future research. In the control group, the prevalence of third molar agenesis in the maxillary arch was higher than in the mandibular arch (Table III). This tendency is similar to the findings of other studies conducted in Asian countries but differs from findings in European and North American countries, suggesting a regional difference.26 Higher frequencies of agenesis of maxillary third molars in patients with Down syndrome29 and mandibular third molars in patients with Pierre Robin sequence31 have been associated with environmental factors such as a smaller maxilla and mandible, respectively. However, the skeletal pattern of Class II Division 2 malocclusion in Japanese orthodontic patients remains unclear.8 Therefore, in Class II Division 2 malocclusion, the relationship between third molar agenesis and environmental factors, including the skeletal pattern with local terminal vascularization and the growth of related nerve branches for developing tooth buds,32 should be investigated in future studies. Endo et al12 compared the prevalence of permanent tooth agenesis between 1905 female subjects and 1453 male subjects in Japan and observed no significant difference. In our study, there was also no statistically significant sex difference in the prevalence; this led us to pool the sexes for analysis. However, a recent meta-analysis reported sex differences in the prevalence of permanent tooth agenesis.10 Accordingly,
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Subjects with at least 1 third molar agenesis (n) 32 72 417 56 46 35 184
Total subjects (n) 76 270 1,291 255 220 600 1,100
Prevalence of third molar agenesis (%) 42.1 26.7 32.3 22.0 20.9 5.8 16.7
further study on this issue may be necessary with a larger sample size. This study was conducted to evaluate the characteristics of permanent tooth agenesis in patients with Class II Division 2 malocclusion in Japan. Therefore, we focused on patients with Class II Division 2 malocclusion and compared them with a group of general orthodontic patients. However, there is evidence that Class III malocclusion also has a genetic component.5 In addition, although the sampling technique was different from that of our study, a higher prevalence of tooth agenesis in Class III malocclusion compared with Class I and Class II malocclusions was previously observed in an Iranian orthodontic population.33 Therefore, comparing the prevalence and pattern of permanent tooth agenesis in probands and first-degree relatives among Angle classifications, as well as analyzing the associations with DNA genetic markers, may provide insights into the genetic etiology of malocclusion. Regarding the diagnosis of Class II Division 2 malocclusion patients, in addition to the problem of the sagittal molar relationship, deep overbite, smaller tooth size,3 and lip function, the tooth agenesis pattern that we observed may further complicate this malocclusion type. For early detection, it is important to consider the patient's family history of dental anomalies34 and ethnic background. In addition, panoramic radiographs of the early mixed dentition can identify tooth agenesis excluding the third molars in more than 20% of Class II Division 2 patients in Japan. CONCLUSIONS
1.
2.
The prevalence of permanent tooth agenesis was approximately 2 times higher in the Class II Division 2 group than in general orthodontic patients in Japan. Higher prevalences of tooth agenesis in the mandibular second premolar and the maxillary lateral incisor were observed in the Class II Division 2 group.
American Journal of Orthodontics and Dentofacial Orthopedics
Ota and Arai
3.
The prevalence of third molar agenesis was significantly higher in the Class II Division 2 group than in the control group only for the subgroup lacking all 4 third molars.
ACKNOWLEDGMENT
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American Journal of Orthodontics and Dentofacial Orthopedics
July 2015 Vol 148 Issue 1