A cross-sectional analysis of the prevalence of tooth agenesis and structural dental anomalies in association with cleft type in non-syndromic oral cleft patients

Cleft lip and palate (CL + P) is the most common craniofacial birth defect in the world [1]. The average prevalence of cleft lip with or without cleft palate is 7.75 and 7.94 per 10,000 live births in the USA and worldwide, respectively, [2].

The most frequent dental anomaly among cleft patients is tooth agenesis [3–7]. The occurrence of tooth agenesis among cleft patients is markedly increased in comparison to the general, non-cleft population [3, 6–11]. Additionally, dental anomalies appear more commonly in the cleft rather than the non-cleft area [4, 10, 12–14]. It is reported that the prevalence of left-sided clefts is higher than right-sided clefts; the cause still remaining unknown [9, 15]. Data from the literature indicate that isolated cleft lip patients (CL) seem to be less affected by dental anomalies outside the cleft area compared to CP or CL + P patients [7]. Furthermore, the permanent dentition seems to be more affected than the primary dentition in patients with unilateral and bilateral CL + P [13].

Other investigations suggest a link between the severity of the cleft type and the number of missing teeth as well as the incidence of dental anomalies [4, 12]. Still, the lateral incisor is reported as the most frequently missing tooth in cleft patients [3, 6, 13, 15, 16]. Also, according to a recent study, the prevalence of lateral incisor agenesis increases in respect to the severity of the cleft [16]. A much higher incidence of agenesis of second premolars was found in the maxilla rather in the mandible in CL + P patients [14, 17]. This agenesis was more frequently observed in the left side and was not gender- or jaw-dependent [9]. Also, contradictory results are reported regarding gender-dependent patterns in the distribution of dental anomalies [4, 18].

It is the aim of this study to identify a contemporary sample of cleft lip and/or palate patients and investigate the prevalence of tooth agenesis and structural dental anomalies and their possible association to the cleft type or gender. Therefore, the null hypothesis of this study was that tooth agenesis and dental structural anomalies are not different between the various types of oral clefts and gender.

The data of this study consisted of consecutive cleft patient records obtained from the graduate clinic of the Department of Orthodontics and Pediatric Dentistry of the School of Dentistry of the National and Kapodistrian University in Athens, Greece. An ethics and research committee approval was also obtained (ref. 312/21.09.2016).

Considering that the proportion of patients with tooth agenesis and structural dental anomalies approaches 60%, we found that approximately 160 individuals are needed to ensure that a 99% confidence interval estimate of the proportion is within 10% of the true proportion [19].

By the end of 2016, a total of 154 cleft patient records were thoroughly examined for tooth agenesis and structural dental anomalies. All patients were born between 1977 and 2006 in Greece. Of them, 97 were males and 57 were females. The inclusion criteria were Caucasian male or female non-syndromic patients with complete records including dental casts, photos, and panoramic x-rays; no history of permanent teeth extractions prior to the initial orthodontic screening; and no previous orthodontic treatment received. Third molars were excluded from our assessment. All patient records were taken prior to secondary alveolar bone grafting. Additionally, no pre-surgical orthopedics, gingivoperiosteoplasty or primary bone grafting were performed so that tooth agenesis as well as structural dental anomalies presented in this sample of patients could not be considered iatrogenic. In order to make sure that the agenesis of second premolars was not mistakenly noted due to individual variation, we evaluated all panoramic radiographs of patients older than 8 years of age. All patients received comprehensive orthodontic treatment in the Orthodontic Graduate Clinic.

Since orofacial cleft patients visit the orthodontic department quite early in life, adequate records of intraoral screening and radiographic assessment were readily available. Specifically, the panoramic and cephalometric radiographs along with the patient’s intraoral photographs, dental casts, and charts were minutely examined. In addition, some of the patients’ files contained a cone-beam computed tomography, which was also assessed. In order to assess the intra and inter examiner repeatability, all the patients’ records were reexamined by the principal investigator and by an independent examiner.

The types of orofacial clefts investigated in this research study were isolated cleft lip at the upper right side (CL U R), isolated cleft lip at the upper left side (CL U L), bilateral cleft lip and palate (CL + P B), unilateral cleft lip and palate at the right side (CL + P U R), and unilateral cleft lip and palate at the left side (CL + P U L) and isolated cleft palate (CP). The dental anomalies examined included tooth agenesis, and teeth with morphological discrepancies in regard to mainly their shape and size (malformation and microdontia).

All analyses were performed using the Stata statistical package (Stata/SE 11.0. for Windows; Stata Corporation, College Station, TX, USA). For descriptive purposes, results are presented as frequency and percentages. Chi-square and Fisher’s exact tests were applied to assess comparisons between tooth agenesis, structural dental anomalies, cleft types, and gender. Logistic regression was performed to further assess any mutually adjusted potential effects of gender and cleft type on tooth agenesis and microdontia and to examine potential confounding. Tooth analysis alone or through comparisons of maxillary and mandibular arches was further carried out using Fisher’s exact test. The significance level was predetermined at 5%. To assess intra and inter examiner repeatability, Cohen’s Kappa statistical tests were performed. The reexamination of all 154 cases by the principal and a second investigator resulted in excellent intra and inter examiner agreement.

The distribution of the cleft types between male and female patients did not vary significantly. These results are in concordance with other research reports [14]. Still, the majority of the patients belonged to the CL + P L group (38.3%) in agreement with relative research investigations [9, 15, 20].

In current literature, tooth agenesis is also reported as the most frequent dental anomaly among cleft patients [3–7]. Interestingly, in the CL + P B group, the frequency of tooth agenesis was significantly higher among males. All the other cleft groups showed no differences in the distribution of dental anomalies neither among them nor between genders. Other authors have also reported no differences in dental anomalies between genders [14, 21].

Tooth agenesis in the non-cleft population ranges at considerably smaller numbers than the 50% found in our study. In a cross-sectional study conducted by Lagana [22] in a large sample of 5005 individuals, the prevalence of tooth agenesis was 7,1%, which is in similar range with the reports of Rakhshan [23] (0.15–16.2% excluding the third molars). Lagana [24] also reported that the missing dental units are often the distal teeth in each group of homogeneous teeth: the upper and lower third molars, lateral incisors, and lower second premolars.

A meta-analysis conducted by Polder [25] included 33 studies and investigated the prevalence of non-syndromic tooth agenesis. The results showed that the prevalence of dental agenesis in females was 1.37 times higher than in males. Most individuals were missing one or two permanent teeth, with very few missing more than six. Also, the mandibular second premolar was the most affected tooth, followed by the maxillary lateral incisor and the maxillary second premolar.

The results of our study confirm Dermijian’s reports who postulated that the mechanisms controlling dental development are independent of sexual and somatic maturity thus being influenced by other etiologic factors as clefts [26]. Baek and Kim also reported no differences in the distribution of dental anomalies between Korean male and female patients; whereas Wangsrimongkol et al. examining a sample of 280 Thai patients suggested a gender-dependent pattern in the agenesis of maxillary lateral incisors and maxillary second premolars [4, 18].

In regard to the association of the investigated dental anomalies with the type of cleft, our results showed no differences between the cleft groups coming, thus in contrast with those of Paranaiba et al., where patients with unilateral cleft lip and palate (CLP U) were more frequently affected by dental anomalies than those with bilateral cleft lip and palate (CLP B) [7]. In the same study, CLP U and CLP B were significantly more affected by tooth agenesis than other cleft types. Additionally, Menezes and Vieira reported that in a sample of 146 cleft patients the CL+ P B patients presented more dental anomalies than individuals with incomplete CLP [27]. According to another group of researchers CL + P U had a higher prevalence of tooth agenesis, even in the non-cleft area, in comparison to the normal population [15].

In our sample, the upper lateral incisors followed by the upper right premolar were found missing most frequently in the cleft area. Still, a strong association between the side of the cleft and tooth agenesis was found for the two maxillary quadrants (Q1 and Q2) in CL + P L and in CL + P R patients and for the two mandibular quadrants (Q3 and Q4) in CP patients. In regard to the missing laterals, the findings are in accordance with a study conducted with 203 cleft patients in Brazil stating that agenesis of lateral incisors in CLP U patients was much more frequently noted in the cleft side rather than in the non-cleft side [14]. Still, several research projects conclude that agenesis occurs mainly at the cleft side and the most prevalent missing tooth is the lateral incisor [4, 10, 14–16]. Even in cases of isolated soft tissue cleft lip (the alveolus being intact), dental abnormalities, including tooth agenesis, were significantly more frequent in the cleft side [12]. In agreement with our results, several studies report the maxillary second premolars followed by their mandibular counterparts as the most frequent missing teeth outside the cleft area, thus indicating a genetic link between cleft and tooth agenesis [6, 14, 17].

However, the association between the maxillary right (Q1) and left quadrants (Q2) regarding tooth agenesis was found to be significant. A large percentage (52.5%) of the 40 patients presenting with tooth agenesis in Q1 presented tooth agenesis also in Q2. These results indicate that if a patient presents with tooth agenesis in Q1 is more likely to have agenesis in Q2 compared to a patient who does not present with agenesis in Q1. Still, a strong association was found between Q1 and Q3 indicating that individuals with tooth agenesis at Q1 are more likely to have tooth agenesis also in Q3. To our knowledge in current literature, there are no similar reports examining the association of tooth agenesis quadrants.

The quadrant association findings indicate that tooth agenesis is not directly related to the disruptive osseous defect which occurs at the cleft side but is rather a genetically controlled anomaly related to the orofacial cleft possibly through multifactorial genetic links. These results confirm findings of previous research investigations, which suggest that tooth agenesis encompassing multiple missing teeth has been clearly identified under genetic control of multifactorial inheritance [28–30]. Several of these critical genetic controls assume a mutual part in the development of orofacial clefts [31].

The results of our study will be of valuable help to the clinicians who treat non-syndromic orofacial cleft patients in developing improved interdisciplinary treatment protocols. The high prevalence of tooth agenesis occurred especially in the maxillary arch could be further investigated with the use of the tooth agenesis code (TAC) method.

The results of this investigation showed that 50% of the oral cleft patients presented with tooth agenesis and 18% with microdontia.

The highest prevalence of tooth agenesis occurred for teeth 22, 12, 15, 35, and 45.

No gender differences were noted overall and for each separate dental anomaly apart from the CL + P B patients where the frequency of tooth agenesis was significantly higher among men.

In CL + P U patients, the cleft quadrant presented tooth agenesis associated with the side of the cleft whereas CP patients showed tooth agenesis in the mandibular arch.

The significant association between quadrants with tooth agenesis and quadrants with no tooth agenesis indicates that tooth agenesis is not directly related to the disruptive osseous defect occuring at the cleft side but is rather a genetically controlled anomaly related to the orofacial cleft process.