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Estimation of tooth agenesis risks between tooth types in orthodontic patients with non-syndromic oligodontia
orthodontic waves 78 (2019) 49 –55
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/locate/odw
Original article
Estimation of tooth agenesis risks between tooth types in orthodontic patients with non-syndromic oligodontia Ayaka Sato, Kazuhito Arai * Department of Orthodontics, School of Life Dentistry at Tokyo, The Nippon Dental University, Tokyo, Japan
article info
abstract
Article history:
Oligodontia, a severe type of hypodontia generally characterized as tooth agenesis of six or
Received 8 January 2019
more permanent teeth excluding third molars, is known to have a multifactorial etiology
Received in revised form
and the characteristics of orthodontic patients are not fully understood. The aim of the
13 March 2019
present study was to investigate the risks of tooth agenesis between tooth types of
Accepted 5 April 2019
permanent dentition in orthodontic patients with non-syndromic oligodontia. Panoramic
Available online 23 May 2019
radiographs of 292 orthodontic patients (184 females and 108 males) were obtained from one university-based orthodontic clinic and 79 private orthodontic clinics in Japan.
Keywords: Oligodontia Tooth agenesis Multiple logistic regression analysis
Agenesis of permanent teeth excluding third molars was evaluated. Multiple logistic regression analysis was conducted to evaluate the risk of simultaneous tooth agenesis between all tooth type combinations. Significant symmetry of tooth agenesis was observed for all tooth types. Twenty-six tooth type combinations showed a significantly increased risk of simultaneous tooth agenesis [odds ratios (ORs): 1.99–14.51], and 15 tooth type combinations showed a significantly decreased risk of simultaneous tooth agenesis (ORs: 0.11–0.56). These findings suggest early detection to establish appropriate multidisciplinary treatment planning and prediction of the risk for tooth agenesis of non-syndromic oligodontia. © 2019 Published by Elsevier Ltd and The Japanese Orthodontic Society.
1.
Introduction
Tooth agenesis is the most common developmental dental anomaly in humans [1]. The reported incidences of tooth agenesis in orthodontic patients range from 2.3% to 15.7% in the permanent dentition excluding third molars [2]. Tooth agenesis is commonly classified into three categories: hypodontia, oligodontia, and anodontia [1]. Among them,
oligodontia, a severe type of hypodontia, has been generally characterized as the absence of six or more permanent teeth excluding third molars [3,4]. The reported prevalence of oligodontia has ranged from 0.08% to 0.3% [5–8]. Oligodontia is known to have a multifactorial etiology. Some environmental factors including maternal smoking, chemoradiotherapy, and surgical intervention during childhood have been reported to cause agenesis of the permanent tooth [9–11]. Causative genes have also been identified
* Corresponding author at: Department of Orthodontics, School of Life Dentistry at Tokyo, The Nippon Dental University, 1-9-20 Fujimi, Chiyoda-ku, Tokyo 102 8159, Japan. E-mail address: [email protected] (K. Arai). https://doi.org/10.1016/j.odw.2019.04.001 1344-0241/ © 2019 Published by Elsevier Ltd and The Japanese Orthodontic Society.
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orthodontic waves 78 (2019) 49 –55
for some syndromes with tooth agenesis, for example, ectodermal dysplasia [7,12] and Down syndrome [13]. However, variation in the anatomical position of tooth agenesis can be observed even within a family carrying the same genetic mutations for these reported syndromes [7,12]. Oligodontia can occur without known syndromes and is called non-syndromic oligodontia [4]. Reported characteristics of non-syndromic oligodontia are fewer number of missing teeth per individual [4] and higher prevalence of tooth agenesis in maxillary and mandibular first and second premolars and maxillary lateral incisors than other teeth when compared with the syndromic type [4,14,15]. However, tooth agenesis patterns in patients with non-syndromic oligodontia are widely varied [15,16]. When excluding third molars, permanent tooth agenesis is more often found in specific tooth types than other teeth and seems to occur as a non-random phenomenon [6]. Previous studies observed associations between tooth agenesis of different tooth types in patients with hypodontia [17–19]. Conversely, Kirkham et al. [20] statistically evaluated the interactions of the risk of agenesis between tooth types in hypodontia patients using autologistic regression analysis and found a significantly higher risk of tooth agenesis between the same tooth type in the horizontally or vertically opposite quadrant. However, the risk of tooth agenesis between different tooth types in patients with non-syndromic oligodontia has not yet been investigated. Previous studies in patients with non-syndromic oligodontia have mainly investigated the prevalence of agenesis for individual tooth type and tooth agenesis pattern in a quadrant [4,15,21]. Genetic factors are known to play an important role in oligodontia [22–26]. In particular, PAX9, MSX1, and EDA typically affect the molars, premolars, and mandibular incisors, respectively [27,28]. Understanding the associations of agenesis between tooth types might contribute to early detection of tooth agenesis pattern of non-syndromic oligodontia and provide supportive information for the complex treatment planning of difficult cases that require multidisciplinary care, including orthodontics. The purpose of the present study was to investigate the risks of tooth agenesis between tooth types in the permanent dentition excluding third molars in orthodontic patients with non-syndromic oligodontia.
2.
Materials and methods
The protocol of this study (NDU-T 2017-32) was approved by the ethics committee of Nippon Dental University.
2.1.
Patient Selection
We collected digital panoramic radiographs of non-syndromic oligodontia patients from 79 private orthodontic clinics and the Division of Orthodontics, Nippon Dental University Hospital, between April 1, 2011 and January 31, 2018. Inclusion criteria included patient age 7years. Age, and dental-medical records were obtained for all patients. Patients with any
congenital abnormalities such as cleft lip/palate or ectodermal dysplasia were excluded.
2.2.
Evaluation of panoramic radiographs
Panoramic radiographs were independently evaluated by two orthodontists to identify permanent tooth agenesis excluding third molars. Tooth agenesis was scored as “1” and a tooth present was scored as “0”. During the evaluation, cases with unclear images to identify the tooth germ were excluded (n =4). In cases in which a consensus could not be reached regarding the evaluation results (n =3), the evaluation was determined through discussion amongst the evaluators while referring to the initial diagnosis of the original orthodontist. As a result, panoramic radiographs of 292 orthodontic patients in Japan [184 females and 108 males; age range =7–46 years, mean standard deviation (SD)=14.4 6.4years] were obtained.
2.3.
Analysis
The number of tooth agenesis was counted for each patient based on the evaluation of panoramic radiographs. Mean, SD, range, median, and interquartile range (IQR) were calculated. The number of patients with tooth agenesis in each tooth was counted for the right and left sides and the maxillary and mandibular arches. The pair of permanent tooth agenesis on the right and left sides was evaluated for each tooth type from the central incisor to second molar as I1, I2, C, P1, P2, M1, and M2 for the maxillary and mandibular arches of each patient. Tooth agenesis of right and left sides of each patient was evaluated. Patients were classified into the following four categories and frequencies for each category were calculated: agenesis on both sides, right side only, left side only, and no agenesis for each tooth type. Then Cramér’s measure of association analysis (P<0.05) was performed for each tooth type to evaluate the bilateral symmetry. Because we observed a significant symmetric tendency between the right and left sides for all tooth types, tooth agenesis risk (TAR) was accordingly counted as missing on either left or right side or both sides. Multivariate logistic regression analysis (likelihood ratio) was performed to examine the effects of independent variables on TAR. Probability for stepwise entry and removal was set at entry as 0.05 and removal as 0.10. Hosmer– Lemeshow goodness-of-fit was confirmed at P<0.05. Odds ratios (ORs) and 95% confidence intervals (CIs) were also calculated. Before the multiple logistic regression analysis, Spearman’s regression analysis was conducted for all tooth type combinations. Tooth type combinations indicated as P>0.25 were excluded, and remaining tooth types were set as dependent variables. All 14 tooth types in the maxillary and mandibular arches were individually set as independent variables. The simultaneous possibility of tooth agenesis increases at OR>1; in contrast, the possibility of simultaneous tooth agenesis decreases at OR<1. Statistical analyses were performed using SPSS version 25 software (IBM, Armonk, NY, USA).
orthodontic waves 78 (2019) 49 –55
Table 1 – Frequency distribution of number of patients with oligodontia according to the number of tooth agenesis per patient. Number of tooth agenesis
n
Prevalence (%)
Cumulative (%)
6 7 8 9 10 11 12 13 14 15 16 17 18 19
96 53 48 25 18 16 17 5 4 4 0 2 3 1
32.9 18.1 16.4 8.6 6.2 5.5 5.8 1.7 1.4 1.4 0.0 0.7 1.0 0.3
32.9 51.0 67.4 76.0 82.2 87.7 93.5 95.2 96.6 98.0 98.0 98.7 99.7 100.0
3.
Results
The maximum number of tooth agenesis per patient was 19. MeanSD (medianIQR) of the number of tooth agenesis per patient was 8.22.6 (7.03.0) (Table 1). The highest frequency of tooth agenesis was observed in the second premolars followed by the maxillary first premolars. In contrast, agenesis of the maxillary central incisors, mandibular first molars, and mandibular canines was relatively rare (Fig). Bilateral symmetry calculated for each tooth type was greater than 80% for all tooth types. Significant associations between the right and left sides for each tooth type in the maxillary and mandibular arches were detected by Cramér’s measure of association analysis (Table 2). Table 3 shows the results of multivariate logistic regression analyses. Significant associations were found for 41 (22.5%) of the total 182 tooth type combinations. Among them, 26 tooth type combinations showed significant increases in the risk of simultaneous tooth agenesis (ORs: 1.99–14.51), and 15 tooth type combinations showed significant decreases in the risk of simultaneous tooth agenesis (ORs: 0.11–0.56) (Table 3).
4.
Discussion
The results of previous studies on hypodontia [26,29–31] and non-syndromic oligodontia [4,30] have generally observed tooth agenesis as a bilaterally symmetrical phenomenon. Genetic factors are hypothesized to have an influence on the symmetry of tooth agenesis in non-syndromic oligodontia [21]. The present study first statistically evaluated the bilateral symmetry of tooth agenesis excluding third molars according to each tooth type in orthodontic patients with non-syndromic oligodontia and also found significant agreement of tooth agenesis between right and left sides for all tooth types in the maxillary and mandibular arches. Some researchers have studied the genotypes and phenotypes in hypodontia and oligodontia patients and have
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recently begun to reveal the possible relationships between the responsible genetic mutations and agenesis in specific tooth types [26,28,30,32]. Although the genotypes and phenotypes do not always correspond [33], a recent meta-analysis suggests relationships between specific tooth type and causative genetic mutation [28]. In the present study, we observed significant increases in TAR between 26 combinations of different tooth types among 182 possible combinations in orthodontic patients with non-syndromic oligodontia. This finding may support previous studies, which suggested biological associations as the causes of tooth agenesis at different tooth sites [17–19,34]. This finding also suggests the possibility of early detection of oligodontia and could be considered a clinical sign of a possible unidentified genetic syndrome including severe pathologies, for example, colorectal [35] and ovarian [36] cancers. However, orthodontists should carefully consult and cooperate with clinical geneticists during the diagnostic process in orthodontic treatment of children with oligodontia [22,37]. In the present study, significant increases in TAR were observed between the same tooth types in the antagonistic arches excluding central incisors. This finding supports a previous study in hypodontia patients [20]. Furthermore, this finding at least partly supports studies that observed similar tendencies in premolar agenesis for MSX1 mutations [30], in molar agenesis for PAX9 mutations, and in canine and molar agenesis for multiple causative gene mutations [28,32]. However, we also observed a significantly increased TAR between the maxillary and mandibular lateral incisors in orthodontic patients with non-syndromic oligodontia. These findings suggest unknown causes including genetic or environmental factors of tooth agenesis for lateral incisors. The present study also revealed that maxillary lateral incisor agenesis increases the possibility of mandibular central and lateral incisor agenesis by approximately two-fold. These findings may be related to the higher prevalence of agenesis of mandibular incisors in the Japanese population [16,38,39]. Among the combinations of adjacent tooth types, significant associations were found only in five combinations (between the first and second premolars in the maxillary arch and the first and second molars in the mandibular arch; and a one-way relationship from the central to lateral incisors in the mandibular arch). In addition, this finding also suggests a higher possibility of simultaneous agenesis in these three sites and indicates that orthodontic closure would be difficult in such a large space. Therefore, consecutive multidisciplinary treatment including prosthetics for orthodontic patients with non-syndromic oligodontia may be often required. Significantly decreased TAR was observed between three combinations of tooth type in the maxillary first premolar and first and second molars in orthodontic patients with nonsyndromic oligodontia. These teeth were adjacent to the maxillary second premolar, which showed an approximately 80% prevalence of agenesis. This tendency could be useful information for prosthodontic treatment planning for maxillary posterior teeth. Our study had several limitations, even though the sample size was larger than in previous studies of
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Table 2 – Number of missing teeth excluding third molars for the right and left sides in maxillary and mandibular arches. Number and percentage of patients with symmetric and asymmetric tooth agenesis in maxillary and mandibular arches and pooled data. Unilateral agenesis
Tooth Number of missing teeth
Present bilaterally
Bilateral agenesis
Symmetric Right Left side Asymmetric Statistical analyses side only only
Right
Left
n
n
(%)
n
(%)
n
(%)
n
(%)
(%)
n
(%)
Cramér’s V P value
Maxilla
I1 I2 C P1 P2 M1 M2
3 94 66 162 237 31 64
3 91 72 153 234 29 217
289 179 212 107 36 255 216
(99.0) (61.3) (72.6) (36.6) (12.3) (87.3) (74.0)
3 72 58 130 215 23 55
(1.0) (24.7) (19.9) (44.5) (73.6) (7.9) (18.8)
292 251 270 237 252 278 271
(100) (86.0) (92.5) (81.2) (86.0) (95.2) (92.8)
0 22 8 32 22 8 9
(0) (7.5) (2.7) (11.0) (7.5) (2.7) (3.1)
0 19 14 23 19 6 12
(0) (6.5) (4.8) (7.9) (6.5) (2.1) (4.1)
0 41 22 55 41 14 21
(0) (14.0) (7.5) (18.8) (14.0) (4.8) (7.2)
1.00 0.68 0.79 0.62 0.55 0.74 0.79
0.000* 0.000* 0.000* 0.000* 0.000* 0.000* 0.000*
Mandible
I1 I2 C P1 P2 M1 M2
64 14 230 104 20 48 59
66 54 18 98 242 14 67
220 226 266 167 32 274 218
(75.3) (77.4) (91.1) (57.2) (11.0) (93.8) (74.7)
53 36 12 77 212 10 57
(18.2) (12.3) (4.1) (26.4) (72.6) (3.4) (19.5)
273 262 278 244 244 284 275
(93.5) (89.7) (95.2) (83.6) (83.6) (97.3) (94.2)
6 12 8 27 18 4 7
(2.1) (4.1) (2.7) (9.2) (6.2) (1.4) (2.4)
13 18 6 21 30 4 10
(4.5) (6.2) (2.1) (7.2) (10.3) (1.4) (3.4)
19 30 14 48 48 8 17
(6.5) (10.3) (4.8) (16.4) (16.4) (2.7) (5.8)
0.81 0.65 0.61 0.64 0.48 0.70 0.83
0.000* 0.000* 0.000* 0.000* 0.000* 0.000* 0.000*
n: Number of patients, I1: central incisor, I2: lateral incisor, C: canine, P1: first premolar, P2: second premolar, M1: first molar, and M2: second molar. “Symmetric” is the summation of “Present bilaterally” and “Bilateral agenesis.” “Asymmetric” is the summation of “Right side only” and “Left side only” of “Unilateral agenesis.” Cramér’s measure of association analysis was performed for each tooth type to evaluate the bilateral symmetry. * P <0.05.
oligodontia. First, we conducted a retrospective study, which may be subject to selection bias and detection bias. Second, the present study focused on patients with nonsyndromic oligodontia who visited orthodontists. Thus, our results may not be generalizable to patients with other types of oligodontia, including agenesis of more than 19 teeth. Previous research has demonstrated results can vary according to patient characteristics, e.g., patients of prosthodontics, special needs dentistry, or from the general population [4,15], thus warranting further investigation on non-syndromic oligodontia in the general population. Third, women were overrepresented in our cohort, as the subjects of this study were orthodontic patients. Identifying and elucidating sex differences may also deepen our knowledge of tooth agenesis patterns of non-syndromic oligodontia patients [6,40]. Fourth, although the present study was conducted in Japan, ethnic background of each patients was not confirmed. Regional differences have been reported on missing teeth [26] and existing biases require investigations in a broader range of populations, as the majority of reports on oligodontia to date are from the United States and European countries [4,5,12,14]. Fifth, it is usually not appropriate to wait until a patient is 13 years old before evaluating tooth agenesis for orthodontic diagnosis and treatment planning. Therefore, in the present study, non-syndromic oligodontia was assessed in subjects as young as 7 years old. A previous meta-analysis and systematic review of hypodontia [41] recommended sampling children aged 12 years or older in order to avoid false
positive errors introduced by delayed dental bud development for epidemiological studies. In the clinical setting, however, careful evaluations with regular radiographic examinations, especially for second premolars, are important [42]. Studies with longitudinal observations for oligodontia patients are required to confirm this. Lastly, it is currently difficult to use genetic testing to differentiate between non-syndromic and syndromic oligodontia in the orthodontic clinic due to the technology involved, costs, and ethical concerns. Nonetheless, the present study may contribute to the future investigation of genotype-phenotype associations to broaden our understanding of the etiology of oligodontia [12,22].
5.
Conclusions
Significant symmetry of tooth agenesis was observed for all tooth types. Maxillary lateral incisor agenesis significantly increased the probability of mandibular central and lateral incisor agenesis by approximately two-fold, suggesting ethnic characteristics of the population. Significant tooth type combinations of OR<1 implied genetic causes for some combinations but also suggested that unidentified factors contribute to tooth agenesis in non-syndromic oligodontia. These findings suggest possibilities for early detection to establish appropriate multidisciplinary treatment planning, prediction of the risk for tooth agenesis of non-syndromic oligodontia, and future elucidation of causes for non-syndromic oligodontia.
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Table 3 – Results of multiple logistic regression analysis. Independent variables for each dependent variable were ordered by the level of significance. Dependent variable
Independent variable
Odds ratio
95% confidence interval Lower limit
Upper limit
P value
MxI1 MxI2
MxM1 MnI1 MnI2 MnP1
14.51 2.63 2.78 0.54
1.28 1.49 1.54 0.32
164.26 4.65 5.00 0.91
0.031* 0.001* 0.001* 0.021*
MxC
MnC MnP2 MnM1
11.88 0.36 0.11
4.40 0.16 0.01
32.10 0.84 0.90
0.000* 0.017* 0.039*
MxP1
MnP1 MxM1 MxM2 MxP2
4.60 0.25 0.41 2.47
2.51 0.11 0.22 1.10
8.42 0.60 0.75 5.56
0.000* 0.002* 0.004* 0.029*
MxP2
MnI2 MxP1 MnP2
0.18 2.91 3.40
0.09 1.35 1.36
0.39 6.25 8.45
0.000* 0.006* 0.009*
MxM1
MnM1 MnP2 MxP1
11.97 0.11 0.20
3.65 0.04 0.09
39.30 0.29 0.48
0.000* 0.000* 0.000*
MxM2
MnM2 MxP1 MnP1
9.89 0.45 0.45
5.18 0.23 0.21
18.87 0.88 0.93
0.000* 0.020* 0.030*
MnI1
MxI2 MnC MxM1 MnI2
2.71 3.76 2.81 1.99
1.51 1.56 1.29 1.04
4.85 9.08 6.14 3.80
0.001* 0.003* 0.009* 0.037*
MnI2
MxP2 MxI2 MnM2
0.20 2.90 2.41
0.10 1.59 1.28
0.44 5.28 4.55
0.000* 0.001* 0.006*
MnC
MxC MnI1
11.81 4.41
4.42 1.79
31.56 10.86
0.000* 0.001*
MnP1
MxP1 MxM2 MxI2
4.78 0.38 0.56
2.63 0.19 0.33
8.68 0.73 0.95
0.000* 0.004* 0.032*
MnP2
MxM1 MxI2 MxP2
0.12 0.33 3.33
0.05 0.14 1.23
0.31 0.79 8.99
0.000* 0.013* 0.018*
MnM1
MxM1 MnM2
8.07 7.39
2.62 2.16
24.90 25.25
0.000* 0.001*
MnM2
MxM2 MnI2 MxM1 MnM1
10.15 2.74 2.83 4.39
5.23 1.34 1.11 1.08
19.73 5.59 7.18 17.88
0.000* 0.006* 0.029* 0.039*
Forward multiple logistic regression analysis with a likelihood ratio was performed, and odds ratios and 95% confidence interval with significant relationships are shown. Probability for stepwise entry and removal were set at entry= 0.05 and removal =0.10. Hosmer–Lemeshow goodness-of-fit was confirmed at P 0.05. Mx: Maxillary arch, Mn: mandibular arch, I1: central incisor, I2: lateral incisor, C: canine, P1: first premolar, P2: second premolar, M1: first molar, and M2: second molar. Significant correlations between dependent and independent variables found are listed. * P < 0.05.
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Ethical approval The protocol of this study (NDU-T 2017-32) was approved by the ethics committee of Nippon Dental University.
Conflict of interest The authors have no conflicts of interest to disclose.
Acknowledgements The authors would like to thank the members of the Japanese Association of Orthodontists and Alumni Society of Department of Orthodontics, The Nippon Dental University.
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[36] Chalothorn LA, Beeman CS, Ebersole JL, Kluemper GT, Hicks EP, Kryscio RJ, et al. Hypodontia as a risk marker for epithelial ovarian cancer: a case-controlled study. J Am Dent Assoc 2008;139:163–9. [37] Carlson DS. Evolving concepts of heredity and genetics in orthodontics. Am J Orthod Dentofac Orthop 2015;148:922–38. [38] Endo T, Yoshino S, Ozoe R, Kojima K, Shimooka S. Association of advanced hypodontia and craniofacial morphology in Japanese orthodontic patients. Odontology 2004;92:48–53. [39] Ota K, Arai K. Prevalence and patterns of tooth agenesis in Angle Class II Division 2 malocclusion in Japan. Am J Orthod Dentofac Orthop 2015;148:123–9.
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Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/locate/odw
Original article
Estimation of tooth agenesis risks between tooth types in orthodontic patients with non-syndromic oligodontia Ayaka Sato, Kazuhito Arai * Department of Orthodontics, School of Life Dentistry at Tokyo, The Nippon Dental University, Tokyo, Japan
article info
abstract
Article history:
Oligodontia, a severe type of hypodontia generally characterized as tooth agenesis of six or
Received 8 January 2019
more permanent teeth excluding third molars, is known to have a multifactorial etiology
Received in revised form
and the characteristics of orthodontic patients are not fully understood. The aim of the
13 March 2019
present study was to investigate the risks of tooth agenesis between tooth types of
Accepted 5 April 2019
permanent dentition in orthodontic patients with non-syndromic oligodontia. Panoramic
Available online 23 May 2019
radiographs of 292 orthodontic patients (184 females and 108 males) were obtained from one university-based orthodontic clinic and 79 private orthodontic clinics in Japan.
Keywords: Oligodontia Tooth agenesis Multiple logistic regression analysis
Agenesis of permanent teeth excluding third molars was evaluated. Multiple logistic regression analysis was conducted to evaluate the risk of simultaneous tooth agenesis between all tooth type combinations. Significant symmetry of tooth agenesis was observed for all tooth types. Twenty-six tooth type combinations showed a significantly increased risk of simultaneous tooth agenesis [odds ratios (ORs): 1.99–14.51], and 15 tooth type combinations showed a significantly decreased risk of simultaneous tooth agenesis (ORs: 0.11–0.56). These findings suggest early detection to establish appropriate multidisciplinary treatment planning and prediction of the risk for tooth agenesis of non-syndromic oligodontia. © 2019 Published by Elsevier Ltd and The Japanese Orthodontic Society.
1.
Introduction
Tooth agenesis is the most common developmental dental anomaly in humans [1]. The reported incidences of tooth agenesis in orthodontic patients range from 2.3% to 15.7% in the permanent dentition excluding third molars [2]. Tooth agenesis is commonly classified into three categories: hypodontia, oligodontia, and anodontia [1]. Among them,
oligodontia, a severe type of hypodontia, has been generally characterized as the absence of six or more permanent teeth excluding third molars [3,4]. The reported prevalence of oligodontia has ranged from 0.08% to 0.3% [5–8]. Oligodontia is known to have a multifactorial etiology. Some environmental factors including maternal smoking, chemoradiotherapy, and surgical intervention during childhood have been reported to cause agenesis of the permanent tooth [9–11]. Causative genes have also been identified
* Corresponding author at: Department of Orthodontics, School of Life Dentistry at Tokyo, The Nippon Dental University, 1-9-20 Fujimi, Chiyoda-ku, Tokyo 102 8159, Japan. E-mail address: [email protected] (K. Arai). https://doi.org/10.1016/j.odw.2019.04.001 1344-0241/ © 2019 Published by Elsevier Ltd and The Japanese Orthodontic Society.
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for some syndromes with tooth agenesis, for example, ectodermal dysplasia [7,12] and Down syndrome [13]. However, variation in the anatomical position of tooth agenesis can be observed even within a family carrying the same genetic mutations for these reported syndromes [7,12]. Oligodontia can occur without known syndromes and is called non-syndromic oligodontia [4]. Reported characteristics of non-syndromic oligodontia are fewer number of missing teeth per individual [4] and higher prevalence of tooth agenesis in maxillary and mandibular first and second premolars and maxillary lateral incisors than other teeth when compared with the syndromic type [4,14,15]. However, tooth agenesis patterns in patients with non-syndromic oligodontia are widely varied [15,16]. When excluding third molars, permanent tooth agenesis is more often found in specific tooth types than other teeth and seems to occur as a non-random phenomenon [6]. Previous studies observed associations between tooth agenesis of different tooth types in patients with hypodontia [17–19]. Conversely, Kirkham et al. [20] statistically evaluated the interactions of the risk of agenesis between tooth types in hypodontia patients using autologistic regression analysis and found a significantly higher risk of tooth agenesis between the same tooth type in the horizontally or vertically opposite quadrant. However, the risk of tooth agenesis between different tooth types in patients with non-syndromic oligodontia has not yet been investigated. Previous studies in patients with non-syndromic oligodontia have mainly investigated the prevalence of agenesis for individual tooth type and tooth agenesis pattern in a quadrant [4,15,21]. Genetic factors are known to play an important role in oligodontia [22–26]. In particular, PAX9, MSX1, and EDA typically affect the molars, premolars, and mandibular incisors, respectively [27,28]. Understanding the associations of agenesis between tooth types might contribute to early detection of tooth agenesis pattern of non-syndromic oligodontia and provide supportive information for the complex treatment planning of difficult cases that require multidisciplinary care, including orthodontics. The purpose of the present study was to investigate the risks of tooth agenesis between tooth types in the permanent dentition excluding third molars in orthodontic patients with non-syndromic oligodontia.
2.
Materials and methods
The protocol of this study (NDU-T 2017-32) was approved by the ethics committee of Nippon Dental University.
2.1.
Patient Selection
We collected digital panoramic radiographs of non-syndromic oligodontia patients from 79 private orthodontic clinics and the Division of Orthodontics, Nippon Dental University Hospital, between April 1, 2011 and January 31, 2018. Inclusion criteria included patient age 7years. Age, and dental-medical records were obtained for all patients. Patients with any
congenital abnormalities such as cleft lip/palate or ectodermal dysplasia were excluded.
2.2.
Evaluation of panoramic radiographs
Panoramic radiographs were independently evaluated by two orthodontists to identify permanent tooth agenesis excluding third molars. Tooth agenesis was scored as “1” and a tooth present was scored as “0”. During the evaluation, cases with unclear images to identify the tooth germ were excluded (n =4). In cases in which a consensus could not be reached regarding the evaluation results (n =3), the evaluation was determined through discussion amongst the evaluators while referring to the initial diagnosis of the original orthodontist. As a result, panoramic radiographs of 292 orthodontic patients in Japan [184 females and 108 males; age range =7–46 years, mean standard deviation (SD)=14.4 6.4years] were obtained.
2.3.
Analysis
The number of tooth agenesis was counted for each patient based on the evaluation of panoramic radiographs. Mean, SD, range, median, and interquartile range (IQR) were calculated. The number of patients with tooth agenesis in each tooth was counted for the right and left sides and the maxillary and mandibular arches. The pair of permanent tooth agenesis on the right and left sides was evaluated for each tooth type from the central incisor to second molar as I1, I2, C, P1, P2, M1, and M2 for the maxillary and mandibular arches of each patient. Tooth agenesis of right and left sides of each patient was evaluated. Patients were classified into the following four categories and frequencies for each category were calculated: agenesis on both sides, right side only, left side only, and no agenesis for each tooth type. Then Cramér’s measure of association analysis (P<0.05) was performed for each tooth type to evaluate the bilateral symmetry. Because we observed a significant symmetric tendency between the right and left sides for all tooth types, tooth agenesis risk (TAR) was accordingly counted as missing on either left or right side or both sides. Multivariate logistic regression analysis (likelihood ratio) was performed to examine the effects of independent variables on TAR. Probability for stepwise entry and removal was set at entry as 0.05 and removal as 0.10. Hosmer– Lemeshow goodness-of-fit was confirmed at P<0.05. Odds ratios (ORs) and 95% confidence intervals (CIs) were also calculated. Before the multiple logistic regression analysis, Spearman’s regression analysis was conducted for all tooth type combinations. Tooth type combinations indicated as P>0.25 were excluded, and remaining tooth types were set as dependent variables. All 14 tooth types in the maxillary and mandibular arches were individually set as independent variables. The simultaneous possibility of tooth agenesis increases at OR>1; in contrast, the possibility of simultaneous tooth agenesis decreases at OR<1. Statistical analyses were performed using SPSS version 25 software (IBM, Armonk, NY, USA).
orthodontic waves 78 (2019) 49 –55
Table 1 – Frequency distribution of number of patients with oligodontia according to the number of tooth agenesis per patient. Number of tooth agenesis
n
Prevalence (%)
Cumulative (%)
6 7 8 9 10 11 12 13 14 15 16 17 18 19
96 53 48 25 18 16 17 5 4 4 0 2 3 1
32.9 18.1 16.4 8.6 6.2 5.5 5.8 1.7 1.4 1.4 0.0 0.7 1.0 0.3
32.9 51.0 67.4 76.0 82.2 87.7 93.5 95.2 96.6 98.0 98.0 98.7 99.7 100.0
3.
Results
The maximum number of tooth agenesis per patient was 19. MeanSD (medianIQR) of the number of tooth agenesis per patient was 8.22.6 (7.03.0) (Table 1). The highest frequency of tooth agenesis was observed in the second premolars followed by the maxillary first premolars. In contrast, agenesis of the maxillary central incisors, mandibular first molars, and mandibular canines was relatively rare (Fig). Bilateral symmetry calculated for each tooth type was greater than 80% for all tooth types. Significant associations between the right and left sides for each tooth type in the maxillary and mandibular arches were detected by Cramér’s measure of association analysis (Table 2). Table 3 shows the results of multivariate logistic regression analyses. Significant associations were found for 41 (22.5%) of the total 182 tooth type combinations. Among them, 26 tooth type combinations showed significant increases in the risk of simultaneous tooth agenesis (ORs: 1.99–14.51), and 15 tooth type combinations showed significant decreases in the risk of simultaneous tooth agenesis (ORs: 0.11–0.56) (Table 3).
4.
Discussion
The results of previous studies on hypodontia [26,29–31] and non-syndromic oligodontia [4,30] have generally observed tooth agenesis as a bilaterally symmetrical phenomenon. Genetic factors are hypothesized to have an influence on the symmetry of tooth agenesis in non-syndromic oligodontia [21]. The present study first statistically evaluated the bilateral symmetry of tooth agenesis excluding third molars according to each tooth type in orthodontic patients with non-syndromic oligodontia and also found significant agreement of tooth agenesis between right and left sides for all tooth types in the maxillary and mandibular arches. Some researchers have studied the genotypes and phenotypes in hypodontia and oligodontia patients and have
51
recently begun to reveal the possible relationships between the responsible genetic mutations and agenesis in specific tooth types [26,28,30,32]. Although the genotypes and phenotypes do not always correspond [33], a recent meta-analysis suggests relationships between specific tooth type and causative genetic mutation [28]. In the present study, we observed significant increases in TAR between 26 combinations of different tooth types among 182 possible combinations in orthodontic patients with non-syndromic oligodontia. This finding may support previous studies, which suggested biological associations as the causes of tooth agenesis at different tooth sites [17–19,34]. This finding also suggests the possibility of early detection of oligodontia and could be considered a clinical sign of a possible unidentified genetic syndrome including severe pathologies, for example, colorectal [35] and ovarian [36] cancers. However, orthodontists should carefully consult and cooperate with clinical geneticists during the diagnostic process in orthodontic treatment of children with oligodontia [22,37]. In the present study, significant increases in TAR were observed between the same tooth types in the antagonistic arches excluding central incisors. This finding supports a previous study in hypodontia patients [20]. Furthermore, this finding at least partly supports studies that observed similar tendencies in premolar agenesis for MSX1 mutations [30], in molar agenesis for PAX9 mutations, and in canine and molar agenesis for multiple causative gene mutations [28,32]. However, we also observed a significantly increased TAR between the maxillary and mandibular lateral incisors in orthodontic patients with non-syndromic oligodontia. These findings suggest unknown causes including genetic or environmental factors of tooth agenesis for lateral incisors. The present study also revealed that maxillary lateral incisor agenesis increases the possibility of mandibular central and lateral incisor agenesis by approximately two-fold. These findings may be related to the higher prevalence of agenesis of mandibular incisors in the Japanese population [16,38,39]. Among the combinations of adjacent tooth types, significant associations were found only in five combinations (between the first and second premolars in the maxillary arch and the first and second molars in the mandibular arch; and a one-way relationship from the central to lateral incisors in the mandibular arch). In addition, this finding also suggests a higher possibility of simultaneous agenesis in these three sites and indicates that orthodontic closure would be difficult in such a large space. Therefore, consecutive multidisciplinary treatment including prosthetics for orthodontic patients with non-syndromic oligodontia may be often required. Significantly decreased TAR was observed between three combinations of tooth type in the maxillary first premolar and first and second molars in orthodontic patients with nonsyndromic oligodontia. These teeth were adjacent to the maxillary second premolar, which showed an approximately 80% prevalence of agenesis. This tendency could be useful information for prosthodontic treatment planning for maxillary posterior teeth. Our study had several limitations, even though the sample size was larger than in previous studies of
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Table 2 – Number of missing teeth excluding third molars for the right and left sides in maxillary and mandibular arches. Number and percentage of patients with symmetric and asymmetric tooth agenesis in maxillary and mandibular arches and pooled data. Unilateral agenesis
Tooth Number of missing teeth
Present bilaterally
Bilateral agenesis
Symmetric Right Left side Asymmetric Statistical analyses side only only
Right
Left
n
n
(%)
n
(%)
n
(%)
n
(%)
(%)
n
(%)
Cramér’s V P value
Maxilla
I1 I2 C P1 P2 M1 M2
3 94 66 162 237 31 64
3 91 72 153 234 29 217
289 179 212 107 36 255 216
(99.0) (61.3) (72.6) (36.6) (12.3) (87.3) (74.0)
3 72 58 130 215 23 55
(1.0) (24.7) (19.9) (44.5) (73.6) (7.9) (18.8)
292 251 270 237 252 278 271
(100) (86.0) (92.5) (81.2) (86.0) (95.2) (92.8)
0 22 8 32 22 8 9
(0) (7.5) (2.7) (11.0) (7.5) (2.7) (3.1)
0 19 14 23 19 6 12
(0) (6.5) (4.8) (7.9) (6.5) (2.1) (4.1)
0 41 22 55 41 14 21
(0) (14.0) (7.5) (18.8) (14.0) (4.8) (7.2)
1.00 0.68 0.79 0.62 0.55 0.74 0.79
0.000* 0.000* 0.000* 0.000* 0.000* 0.000* 0.000*
Mandible
I1 I2 C P1 P2 M1 M2
64 14 230 104 20 48 59
66 54 18 98 242 14 67
220 226 266 167 32 274 218
(75.3) (77.4) (91.1) (57.2) (11.0) (93.8) (74.7)
53 36 12 77 212 10 57
(18.2) (12.3) (4.1) (26.4) (72.6) (3.4) (19.5)
273 262 278 244 244 284 275
(93.5) (89.7) (95.2) (83.6) (83.6) (97.3) (94.2)
6 12 8 27 18 4 7
(2.1) (4.1) (2.7) (9.2) (6.2) (1.4) (2.4)
13 18 6 21 30 4 10
(4.5) (6.2) (2.1) (7.2) (10.3) (1.4) (3.4)
19 30 14 48 48 8 17
(6.5) (10.3) (4.8) (16.4) (16.4) (2.7) (5.8)
0.81 0.65 0.61 0.64 0.48 0.70 0.83
0.000* 0.000* 0.000* 0.000* 0.000* 0.000* 0.000*
n: Number of patients, I1: central incisor, I2: lateral incisor, C: canine, P1: first premolar, P2: second premolar, M1: first molar, and M2: second molar. “Symmetric” is the summation of “Present bilaterally” and “Bilateral agenesis.” “Asymmetric” is the summation of “Right side only” and “Left side only” of “Unilateral agenesis.” Cramér’s measure of association analysis was performed for each tooth type to evaluate the bilateral symmetry. * P <0.05.
oligodontia. First, we conducted a retrospective study, which may be subject to selection bias and detection bias. Second, the present study focused on patients with nonsyndromic oligodontia who visited orthodontists. Thus, our results may not be generalizable to patients with other types of oligodontia, including agenesis of more than 19 teeth. Previous research has demonstrated results can vary according to patient characteristics, e.g., patients of prosthodontics, special needs dentistry, or from the general population [4,15], thus warranting further investigation on non-syndromic oligodontia in the general population. Third, women were overrepresented in our cohort, as the subjects of this study were orthodontic patients. Identifying and elucidating sex differences may also deepen our knowledge of tooth agenesis patterns of non-syndromic oligodontia patients [6,40]. Fourth, although the present study was conducted in Japan, ethnic background of each patients was not confirmed. Regional differences have been reported on missing teeth [26] and existing biases require investigations in a broader range of populations, as the majority of reports on oligodontia to date are from the United States and European countries [4,5,12,14]. Fifth, it is usually not appropriate to wait until a patient is 13 years old before evaluating tooth agenesis for orthodontic diagnosis and treatment planning. Therefore, in the present study, non-syndromic oligodontia was assessed in subjects as young as 7 years old. A previous meta-analysis and systematic review of hypodontia [41] recommended sampling children aged 12 years or older in order to avoid false
positive errors introduced by delayed dental bud development for epidemiological studies. In the clinical setting, however, careful evaluations with regular radiographic examinations, especially for second premolars, are important [42]. Studies with longitudinal observations for oligodontia patients are required to confirm this. Lastly, it is currently difficult to use genetic testing to differentiate between non-syndromic and syndromic oligodontia in the orthodontic clinic due to the technology involved, costs, and ethical concerns. Nonetheless, the present study may contribute to the future investigation of genotype-phenotype associations to broaden our understanding of the etiology of oligodontia [12,22].
5.
Conclusions
Significant symmetry of tooth agenesis was observed for all tooth types. Maxillary lateral incisor agenesis significantly increased the probability of mandibular central and lateral incisor agenesis by approximately two-fold, suggesting ethnic characteristics of the population. Significant tooth type combinations of OR<1 implied genetic causes for some combinations but also suggested that unidentified factors contribute to tooth agenesis in non-syndromic oligodontia. These findings suggest possibilities for early detection to establish appropriate multidisciplinary treatment planning, prediction of the risk for tooth agenesis of non-syndromic oligodontia, and future elucidation of causes for non-syndromic oligodontia.
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Table 3 – Results of multiple logistic regression analysis. Independent variables for each dependent variable were ordered by the level of significance. Dependent variable
Independent variable
Odds ratio
95% confidence interval Lower limit
Upper limit
P value
MxI1 MxI2
MxM1 MnI1 MnI2 MnP1
14.51 2.63 2.78 0.54
1.28 1.49 1.54 0.32
164.26 4.65 5.00 0.91
0.031* 0.001* 0.001* 0.021*
MxC
MnC MnP2 MnM1
11.88 0.36 0.11
4.40 0.16 0.01
32.10 0.84 0.90
0.000* 0.017* 0.039*
MxP1
MnP1 MxM1 MxM2 MxP2
4.60 0.25 0.41 2.47
2.51 0.11 0.22 1.10
8.42 0.60 0.75 5.56
0.000* 0.002* 0.004* 0.029*
MxP2
MnI2 MxP1 MnP2
0.18 2.91 3.40
0.09 1.35 1.36
0.39 6.25 8.45
0.000* 0.006* 0.009*
MxM1
MnM1 MnP2 MxP1
11.97 0.11 0.20
3.65 0.04 0.09
39.30 0.29 0.48
0.000* 0.000* 0.000*
MxM2
MnM2 MxP1 MnP1
9.89 0.45 0.45
5.18 0.23 0.21
18.87 0.88 0.93
0.000* 0.020* 0.030*
MnI1
MxI2 MnC MxM1 MnI2
2.71 3.76 2.81 1.99
1.51 1.56 1.29 1.04
4.85 9.08 6.14 3.80
0.001* 0.003* 0.009* 0.037*
MnI2
MxP2 MxI2 MnM2
0.20 2.90 2.41
0.10 1.59 1.28
0.44 5.28 4.55
0.000* 0.001* 0.006*
MnC
MxC MnI1
11.81 4.41
4.42 1.79
31.56 10.86
0.000* 0.001*
MnP1
MxP1 MxM2 MxI2
4.78 0.38 0.56
2.63 0.19 0.33
8.68 0.73 0.95
0.000* 0.004* 0.032*
MnP2
MxM1 MxI2 MxP2
0.12 0.33 3.33
0.05 0.14 1.23
0.31 0.79 8.99
0.000* 0.013* 0.018*
MnM1
MxM1 MnM2
8.07 7.39
2.62 2.16
24.90 25.25
0.000* 0.001*
MnM2
MxM2 MnI2 MxM1 MnM1
10.15 2.74 2.83 4.39
5.23 1.34 1.11 1.08
19.73 5.59 7.18 17.88
0.000* 0.006* 0.029* 0.039*
Forward multiple logistic regression analysis with a likelihood ratio was performed, and odds ratios and 95% confidence interval with significant relationships are shown. Probability for stepwise entry and removal were set at entry= 0.05 and removal =0.10. Hosmer–Lemeshow goodness-of-fit was confirmed at P 0.05. Mx: Maxillary arch, Mn: mandibular arch, I1: central incisor, I2: lateral incisor, C: canine, P1: first premolar, P2: second premolar, M1: first molar, and M2: second molar. Significant correlations between dependent and independent variables found are listed. * P < 0.05.
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orthodontic waves 78 (2019) 49 –55
Ethical approval The protocol of this study (NDU-T 2017-32) was approved by the ethics committee of Nippon Dental University.
Conflict of interest The authors have no conflicts of interest to disclose.
Acknowledgements The authors would like to thank the members of the Japanese Association of Orthodontists and Alumni Society of Department of Orthodontics, The Nippon Dental University.
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