Tooth Agenesis Patterns in Bilateral Cleft Lip and Palate

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Theodosia N. Bartzela1, Carine E.L. Tooth agenesis patterns in bilateral Carels2, Ewald M. Bronkhorst3, Elisabeth Rønning4, Sara Rizell5, cleft lip and palate Anne Marie Kuijpers-Jagtman1,6 1Department of Orthodontics and Oral Biology, Radboud University Nijmegen Medical Centre, 2 Bartzela TN, Carels CEL, Bronkhorst EM, Rønning E, Rizell S, Kuijpers-Jagtman AM. Nijmegen, the Netherlands; Department of Orthodontics, Catholic University of Leuven, Tooth agenesis patterns in bilateral cleft lip and palate. Eur J Oral Sci 2010; 118: 47–52. Leuven, Belgium; 3Department of Cariology 2010 The Authors. Journal compilation 2010 Eur J Oral Sci and Preventive Dentistry, Radboud University Nijmegen, Medical Centre, Nijmegen, the Individuals with cleft lip and palate present significantly more dental anomalies, even Netherlands; 4Oslo Cleft Team, Department of Plastic Surgery, National Hospital, and Bredtvet outside the cleft area, than do individuals without clefts. Our aim was to evaluate the 5 prevalence of tooth agenesis and patterns of hypodontia in a large sample of patients Resource Centre, Oslo, Norway; Section of Jaw Orthopedics, University Clinics of with complete bilateral cleft lip and palate (BCLP). Serial panoramic radiographs (the Odontology, Gothenburg, Sweden; 6Cleft first radiograph was taken at 10.5–13.5 yr of age) of 240 patients with BCLP (172 male Palate Craniofacial Unit, Radboud University patients, 68 female patients) were examined. Third molars were not included in the Nijmegen Medical Centre, Nijmegen, the evaluation. Agenesis of at least one tooth was present in 59.8% of patients. Upper Netherlands laterals and upper and lower second premolars were missing most frequently. Using the tooth agenesis code (TAC), 52 different agenesis patterns were identified, of which Anne Marie Kuijpers-Jagtman, Department of simultaneous agenesis of 12, 22, 15, 25, 35, and 45 was the most frequent pattern. Nine Orthodontics and Oral Biology, Radboud of the 240 patients showed combined BCLP and oligodontia. University Nijmegen Medical Center, 309 Dentistry, PO Box 9101, 6500 HB Nijmegen, the Netherlands Telefax: +31–24–3540631 E-mail: [email protected] Key words: bilateral cleft lip and palate; cleft palate; dental agenesis; prevalence Accepted for publication October 2009

The prevalence of tooth agenesis (excluding third mo- dentition are small, ranging from 10 to 125, and often lars) in the general population differs according to con- involve other cleft types in addition to BCLP. The most tinent and gender, and ranges from 3.2 to 5.5% for men frequently missing single teeth in patients with BCLP are and from 4.6 to 7.6% for women (1). The mandibular the maxillary lateral incisors (9–11). Furthermore, few second premolar is the tooth most commonly affected studies have identified tooth agenesis patterns as op- (2.9–3.2%), followed by the maxillary lateral (1.6–1.8%), posed to reporting the prevalence of single missing teeth and the maxillary second premolar (1.4–1.6%). In (3, 11, 12), and only one study determined tooth agenesis patients with cleft lip and palate (CLP), as well as in their patterns for the entire dentition, but the sample size was non-affected siblings, tooth agenesis is more common small (12). Pattern recognition of tooth agenesis is than in the general population (2), which can be important because careful subphenotyping of CLP explained by the close relationship between tooth and patients based on dental development characteristics cleft formation with respect to developmental timing and might identify cleft subgroups, which could help to anatomical location. The maxillary lateral incisors are determine specific genetic contributions and identify the teeth most commonly missing in the cleft area, with a disease-causing alleles (5). prevalence ranging from 56.1 to 74% (3, 4). The preva- Therefore, the aim of this study was to investigate the lence of tooth agenesis outside the cleft region in cleft prevalence of agenesis for each tooth type and to identify patients is 27% (2, 5), with the second premolars being hypodontia patterns in patients with complete BCLP. affected most often (5, 6). The frequency of dental anomalies seems to be linked to the severity of the cleft malformation (2, 7). In the Material and methods most severe type of non-syndromic clefts, complete bilateral cleft lip and palate (BCLP) , the prevalence of Participants missing teeth reaches 100% (8). However, little data are The study comprised radiographs of 240 patients with available for this type of cleft. Table S1 provides an complete BCLP from the Cleft Palate Centers in Gothen- overview of the existing studies on BCLP. In general, burg (Sweden), Nijmegen (the Netherlands), and Oslo sample sizes of studies concerning the permanent (Norway). Inclusion criteria were as follows: 48 Bartzela et al.

Table 1 Schematic representation of the human dentition and application of the binary system used to assign unique values to the pattern of tooth agenesis (13)

Maxilla right (Q1) Maxilla left (Q2)

A 18* 17 16 15 14 13 12 11 21 22 23 24 25 26 27 28* B 128 64 32 16 8 4 2 1 1 2 4 8 16 32 64 128 A 48* 47 46 45 44 43 42 41 31 32 33 34 35 36 37 38*

Mandible right (Q4) Mandible left (Q3) Line A: tooth numbering according to the Fe´de´ration Dentaire Internationale (FDI) tooth numbering system, for maxilla (upper) and mandible (lower). Line B: values associated with missing teeth. Q1, Q2, Q3, Q4: ﬁrst to fourth quadrants of the dentition. *Not included in this study.

(i) Non-syndromic complete BCLP; diagnosis conﬁrmed by the pre-operative record or by neonatal pictures Statistical analysis and/or study models. Patients with Simonart‘s band(s) Intra-observer and interobserver agreements were calcu- were included only if no hard tissue union was present. lated using kappa statistics (Table 2 describes the reliability (ii) No other associated congenital malformations, or statistics). Tooth counts and percentages were used to mental retardation. characterize tooth agenesis. The chi-square test (FisherÕs (iii) Caucasian ethnic background. exact test) was used to evaluate the relationship between (iv) At least 11 yr of age when the data were collected. The the prevalence of agenesis and other dichotomous vari- data collection for the three Cleft Palate Centers had ables, such as gender, left/right quadrant, and upper/lower covered the following time span: Oslo 1969–2008; jaw. Nijmegen 1970–2008; and Gothenburg 1980–2008.

Methods Results Radiographs, taken according to the routine clinical pro- Prevalence cedure of each CLP center, were selected from the patient files. Each radiograph was allocated a random identification Records from 240 patients with BCLP (68 female number. No additional radiographs were taken. At least patients and 172 male patients) were evaluated. three panoramic radiographs [orthopantomograms According to data provided by the centers, a number of (OPTs)], taken at different ages of the patient, were avail- patients were excluded because of ethnicity (six patients able for each patient. Congenitally missing teeth were from Gothenburg cleft center, four patients from identified on OPTs and were verified by dental records to exclude premature extractions. Third molars were not included in the assessment. All radiographs were scored by Table 2 one observer (TB). Sixty radiographs were scored twice to assess intra-observer reliability. For assessing interobserver Kappa values for intra-observer and interobserver agreement for reliability, the same 60 radiographs were scored by three each tooth in the upper and lower arches; corresponding teeth in observers. the right and left quadrants were combined The method developed by van Wijk & Tan (13) was used to describe patterns of tooth agenesis. A binary system was Corresponding Intra-observer Interobserver teeth* agreement agreement applied to establish unique numbers associated with different patterns of tooth agenesis; the scoring was dichotomized Maxilla as presence (0) or absence (1) of teeth. A specific value was 7 0.00 1.00 assigned to each missing tooth type. The values were sum- 6 1.00 0.00 med for each quadrant, giving a unique value for each 5 0.87 0.72 pattern of hypodontia, the so-called tooth agenesis code 4 0.66 0.65 (TAC). According to the TAC, a certain quadrant without 3 1.00 0.67 tooth agenesis would have a TAC value of 0 and a quadrant 2 0.80 0.64 with complete tooth agenesis would have a TAC value of 1 0.90 0.28 255 (Table 1) shows the TAC coding system. The overall Mandible TAC score was used to identify patterns of tooth agenesis 7 0.00 0.00 for the entire mouth. For example, when the TAC = 6 0.00 0.00 100.123.038.001, the number 100 corresponds to the first 5 0.92 0.96 quadrant, 123 corresponds to the second quadrant, 038 4 0.00 0.00 corresponds to the third quadrant, and 001 corresponds to 3 0.00 0.00 the fourth quadrant (14). 2 0.66 0.39 1 0.49 )0.10 This research was been conducted in full accordance with ethical principles, including the World Medical Association *Teeth were numbered according to the Fe´de´ration Dentaire Declaration of Helsinki. Internationale (FDI) system. Tooth agenesis in BCLP 49

Table 3 Table 4 Tooth agenesis code (TAC), frequency and percentage of TAC, Thirty unique tooth agenesis code (TAC) patterns (frequency 1, corresponding missing teeth, and number (n) of missing teeth in 0.4%) with corresponding missing tooth/teeth, and number (n) of the whole mouth missing teeth per patient

TAC Frequency % Tooth/teeth missing N TAC Frequency % Tooth/teeth missing N

0.0.0.0 96 40.0 None 0 0.16.0.16 1 0.4 25, 45 2 2.2.0.0 25 10.4 12, 22 2 0.2.0.16 1 0.4 22, 45 2 2.0.0.0 19 7.9 12 1 0.2.1.0 1 0.4 22, 31 2 0.2.0.0 14 5.8 22 1 0.2.16.16 1 0.4 22, 35, 45 3 0.16.0.0 5 2.1 25 1 0.26.0.0 1 0.4 22, 24, 25 3 16.16.0.0 5 2.1 15,25 2 0.8.0.0 1 0.4 24 1 18.18.0.0 5 2.1 12,15, 22, 25 4 1.2.0.0 1 0.4 11, 22 2 16.0.0.0 4 1.7 15 1 12.8.8.8 1 0.4 22, 24, 34, 44 4 18.18.16.16 4 1.7 12,15, 22, 25, 35, 45 6 16.16.0.16 1 0.4 15, 25, 45 3 18.2.0.0 4 1.7 12,15, 22 3 16.16.16.16 1 0.4 15, 25, 35, 45 4 0.18.0.0 3 1.2 22, 25 2 16.16.8.8 1 0.4 15, 25, 34, 44 4 16.2.0.0 3 1.2 15, 22 2 16.18.0.0 1 0.4 15, 22, 25 3 2.18.0.0 3 1.2 12, 22, 25 3 16.24.16.16 1 0.4 15, 24, 25, 35, 45 5 0.0.0.16 2 0.8 45 1 18.18.17.16 1 0.4 12, 15, 22, 25, 31, 35, 45 7 0.0.16.0 2 0.8 35 1 18.18.64.64 1 0.4 12, 15, 22, 25, 37, 47 6 0.0.16.16 2 0.8 35, 45 2 18.2.16.16 1 0.4 12, 15, 22, 35, 45 5 0.0.2.0 2 0.8 32 1 2.0.0.16 1 0.4 12, 45 2 0.16.16.16 2 0.8 25, 35, 45 3 2.0.16.0 1 0.4 12, 35 2 0.2.2.0 2 0.8 22, 32 2 2.18.0.16 1 0.4 12, 22, 25, 45 4 1.0.0.0 2 0.8 11 1 2.2.0.16 1 0.4 12, 22, 45 3 16.16.16.0 2 0.8 15, 25, 35 3 2.2.0.64 1 0.4 12, 22, 47 3 16.18.16.16 2 0.8 15,12, 25, 35, 45 5 2.2.2.2 1 0.4 12, 22, 32, 42 4 2.2.16.16 2 0.8 12, 22, 35, 45 4 22.22.4.4 1 0.4 12, 13, 15, 22, 23, 25, 33, 43 8 Total 210 88 24.16.0.0 1 0.4 14, 15, 24 3 24.20.16.16 1 0.4 14, 15, 23, 25, 35, 45 6 24.24.0.0 1 0.4 14, 15, 24, 25 4 64.64.0.0 1 0.4 17, 27 2 65.0.0.0 1 0.4 11, 17 2 Nijmegen cleft center, and seven patients from Oslo cleft 8.0.0.0 1 0.4 14 1 center). The mean age of the patients at the first recorded 90.66.72.73 1 0.4 12, 14, 15, 17, 22, 11 examination was 12.4 yr (range: 10.5–13.5 yr). Agenesis 27, 34, 37, 41, 43, 47 of at least one tooth was found in 59.8% of patients. The Total 30 12 number of missing teeth ranged from 1 to 11 (Tables 3 and 4). Oligodontia, defined as agenesis of 6 or more teeth, was found in nine patients (3.8%) (Tables 3 and 4). and tooth agenesis pattern was found (chi-square test, Table 5 shows the prevalence of agenesis according to P ‡ 0.307). tooth type. The teeth most commonly absent were upper Whether absence of a tooth in one quadrant was laterals and upper and lower second premolars. No dif- related to the absence of the corresponding tooth in the ference in the number of missing teeth between the left other quadrant was also evaluated. This relationship was and right quadrant of the same jaw was observed (chi- statistically significant for 13 of 14 combinations square test, lowest P = 0.123). Because of this high level (P < 0.001–0.21); however, this relationship was not of symmetry and the corresponding increase in statistical statistically significant for the lower central incisors power, right and left quadrants were not distinguished (P = 1.0), reflecting the low prevalence of agenesis of when the relationship between gender and tooth agenesis the lower central incisors. The difference in the preva- patterns was analyzed; no relationship between gender lence of tooth agenesis for the upper and lower arches

Table 5 Prevalence of absence per tooth type (percentage) in 240 patients with complete bilateral cleft lip and palate (BCLP)

Maxilla right (Q1) Maxilla left (Q2)

1.2% 0.0% 17.5% 2.5% 0.8% 30.4% 1.7% 0.0% 34.2% 0.8% 2.1% 18.8% 0.0% 0.8% 8*76543 211 234 5678* 1.2% 0.0% 10.8% 1.2% 0.4% 0.4% 0.4% 0.8% 2.1% 0.4% 1.2% 9.6% 0.0% 0.8%

Mandible right (Q4) Mandible left (Q3) Teeth are numbered 1–8 per quadrant (Q) according to the Fe´de´ration Dentaire Internationale (FDI) system. *Not included in this study. 50 Bartzela et al.

Table 6 Frequency and percentage of tooth agenesis patterns (TAC) per quadrant (Q)

Q1 Q2 Q3 Q4 TAC Tooth type n % n % N % n %

0 None 136 56.7 133 55.4 206 85.8 207 86.2 1I1 3 1.2 0 0 1 0.4 0 0 2I2 55 22.8 58 24.1 5 2.1 1 0.4 4 C 0 0 0 0 1 0.4 1 0.4 8P1 1 0.4 2 0.8 2 0.8 2 0.8 12 C+P1 10.400 00 00 16 P2 21 8.7 19 7.9 22 9.1 26 10.8 17 I1 +P2 00 00 10.400 18 I2 +P2 16 6.6 21 8.7 0 0 0 0 20 P2 +C 00 10.400 00 22 P2 + C+I2 1 0.4 1 0.4 0 0 0 0 24 P2 +P1 3 1.2 2 0.8 0 0 0 0 26 P2 +P1 +I2 00 10.400 00 64 M2 1 0.4 1 0.4 1 0.4 2 0.8 65 M2 +I1 10.400 00 00 66 M2 +I2 00 10.400 00 72 M2 +P1 00 00 10.400 73 M2 +P1 +I1 00 00 00 10.4 90 M2 +P2 +P1 +I2 10.400 00 00 Total 240 100.0 240 100.0 240 100.0 240 100.0

I1, central incisor; I2, lateral incisor; C, canine; P, premolar; M, molar; subscript 1, first; subscript 2, second. was significant only for the second premolars Serial radiographs were evaluated for each patient. In (P = 0.001) and the lateral incisors (P < 0.001). These addition, patientsÕ files were checked to reduce bias teeth were missing more often in the maxilla than in the regarding delayed dental development and to differenti- mandible. ate between agenesis and extractions for orthodontic purposes. In addition, the age group of the patients included in this study (10.5–13.5 yr) was selected specif- Tooth agenesis patterns ically to prevent misdiagnosis of tooth agenesis in cases The frequency and percentage of tooth agenesis patterns of late mineralization, particularly of the mandibular per quadrant are given in Table 6. second premolar. Late mineralization of these teeth, in Full-mouth data for frequency and percentage of children 10 yr of age, has been observed in the normal TAC, corresponding missing teeth, and number of population (16). A delay in tooth formation of up to missing teeth, are presented in Tables 3 and 4. Maxil- 0.7 yr has been reported for patients with cleft disorders lary lateral and/or maxillary or mandibular second relative to non-cleft controls (17). premolars were involved in 20 of 22 patterns of agen- The range of intra-observer and interobserver kappa esis (Table 3). The mandibular lateral incisor was values was 0.0–1.0, representing strength of agreement involved in only two patients (0.8%). Ultimately, 30 from extremely poor to almost perfect. The low kappa unique patterns (frequency 1) were observed (Table 4). In values for some teeth are explained by the fact that the addition to the maxillary lateral incisors and the second kappa value is influenced by trait prevalence. Agenesis premolars, maxillary and mandibular central incisors, first was very rare for some teeth, in which case the kappa premolars, and second molars were involved in the unique became instable. A single disagreement in scoring patterns. between two observers could determine whether the kappa value is 1.0 or 0.0. The literature contains scant data on tooth agenesis in Discussion patients with complete BCLP. The entire permanent dentition was considered in only six other studies The prevalence of complete BCLP has been reported to (Table S1, marked in grey) with sample sizes ranging from be 0.3 per 1,000 live births, which is lower than the 13 to 125 patients (5, 9, 10, 12, 18, 19). Five other studies prevalence for the more common complete unilateral considered tooth agenesis in specific areas, mainly the cleft lip and palate (UCLP). Only 7% of the entire upper laterals and the upper and lower premolars (3, 6, 8, population with cleft disorders has complete BCLP (15); 11, 20). To our knowledge, only one other study has therefore, only a few centers are likely to have a group of considered tooth agenesis patterns for the entire dentition patients large enough for clinical research. As seen in (12). In the present study, the most common pattern per Table S1, the present study has the largest sample size quadrant was a combination of maxillary agenesis of the (n = 240) yet reported in the literature. lateral incisor and the second premolar in the same Tooth agenesis in BCLP 51 quadrant (Q1, 6.6%; Q2, 8.7%; Table 6). Patterns for the Genetic interactions between genes relevant for oro- entire mouth (described in Tables 3 and 4) were mainly facial cleft formation and tooth agenesis have already patterns of upper laterals with upper and lower second been reported for IRF6 and MSX1, for MSX1 and premolars in all different combinations. Maxillary lateral TGFB3 (28), and for MSX1 and TGFA (30). As it can be incisors were the teeth most often missing in this BCLP assumed that the failure of one or several biological group (Q1, 30.4%; Q2, 34.2%; Table 6); these frequencies mechanisms (such as cellular proliferation, differentia- are somewhat lower than those reported for smaller tion, apoptosis, and adhesion) can lead to cleft formation samples of patients with BCLP (Table S1) but much as well as to tooth agenesis in early craniofacial devel- higher than the prevalence of 1.6–1.8% for the non-cleft opment, these three types of interactions with the MSX1 population (1). By contrast, the prevalence of agenesis of transcription factor pathway add to the hypothesis that lower second premolars in the present study (Q3, 9.1%; some genes or gene loci may contribute to both clefts and Q4, 10.8%) (Table 6) was three times higher than that in dental anomalies (31). Thus, especially in the combined the normal population (2.9–3.2%). This has clinical con- BCLP–oligodontia phenotypes, genetic analysis should sequences for the orthodontic treatment of these patients be performed together with accurate assessment of tooth because the dental complications associated with the cleft agenesis patterns in order to further disclose more and anomaly do not seem to be restricted to the maxilla. specific susceptibility loci for BCLP and to find common Three main factors might contribute to the increased genetic pathways in palatogenesis and tooth formation. prevalence of tooth agenesis in the BCLP patients. First, it has been hypothesized that specific surgical procedures, Acknowledgements – The study, which was part of the PhD such as early periosteoplasty (21) or neonatal closure of thesis of the first author, was fully supported by the Depart- the hard palate (22, 23), might influence tooth formation ment of Dentistry, Radboud University Nijmegen Medical Centre (Nijmegen, the Netherlands). because a lower prevalence of tooth agenesis was found in non-operated individuals with clefts (24). However, other studies have reported that surgical interventions do not seem to affect tooth agenesis (17). Although none of References the centers involved in the present study employed these 1. Polder BJ, VANÕTHof MA, Van der Linden FP, Kuijpers- procedures, it cannot be ruled out that surgery might Jagtman AM. A meta-analysis of the prevalence of dental influence tooth development in the maxilla. Second, the agenesis of permanent teeth. 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