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
Konstantonis et al. Progress in Orthodontics
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
Dimitrios Konstantonis 0 1
Alexandros Alexandropoulos 1
Nikoleta Konstantoni 2
Maria Nassika 1
0 Clinic of Orthodontics and Pediatric Dentistry, University of Zurich , Zurich , Switzerland
1 Department of Orthodontics, School of Dentistry, National and Kapodistrian University of Athens , 2 Thivon st, 115 26 Athens , Greece
2 Center for Advanced Dental Education, Department of Orthodontics, Saint Louis University , Saint Louis, MO , USA
Background: The aim of this study was to investigate the prevalence of tooth agenesis, microdontia, and tooth malformation among non-syndromic oral cleft patients and their potential association with cleft type and gender. Methods: Intraoral records and radiographs of 154 patients (97 males and 57 females) were examined. The variables assessed were tooth agenesis, microdontia, dental malformations, and cleft types. The statistics included chi-square and Fisher's exact tests as well as logistic regression to assess any mutual effects of gender and cleft type on the dental variables. Results: Tooth agenesis occurred in 50% of the sample and microdontia in 18%. Non-statistically significant odds ratios for the association of gender and cleft type with tooth agenesis were obtained. Tooth agenesis was substantially higher at the unilateral right CL + P and the bilateral CL + P in quadrant 1 and at the unilateral left CL + P and bilateral CL + P in quadrant 2. It was also higher, at the isolated cleft palate (CP) in quadrants 3 and 4. These results were attributed to teeth 22 (31.8%) and 12 (21.6%) in the maxilla and to teeth 35 (6.1%) and 45 (5.4%) in the mandible. In unilateral CL + P patients, the cleft quadrant that presented tooth agenesis was associated with the side of the cleft. Conclusions: Interdisciplinary treatment of the oral cleft patients should take into consideration the high prevalence of tooth agenesis and their association with the different cleft types. The most frequently affected teeth by cleft are by far the upper lateral incisors. Results indicate that tooth agenesis appears to be a genetically controlled anomaly related to the orofacial cleft development through various genetic links and not caused by the cleft disruptive process.
Cleft lip and palate; Dental anomalies; Tooth agenesis; Microdontia
Cleft lip and palate (CL + P) is the most common
craniofacial birth defect in the world [
]. 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,
The most frequent dental anomaly among cleft patients
is tooth agenesis [
]. The occurrence of tooth agenesis
among cleft patients is markedly increased in comparison
to the general, non-cleft population [
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
rightsided clefts; the cause still remaining unknown [
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
. Furthermore, the permanent dentition seems to be
more affected than the primary dentition in patients with
unilateral and bilateral CL + P [
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 [
the lateral incisor is reported as the most frequently
missing tooth in cleft patients [
3, 6, 13, 15, 16
according to a recent study, the prevalence of lateral
incisor agenesis increases in respect to the severity of
the cleft . A much higher incidence of agenesis of
second premolars was found in the maxilla rather in the
mandible in CL + P patients [
]. This agenesis was
more frequently observed in the left side and was not
gender- or jaw-dependent . Also, contradictory results
are reported regarding gender-dependent patterns in the
distribution of dental anomalies [
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 [
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
xrays; 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
conebeam 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.
Chisquare 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.
Cleft distribution, tooth agenesis, and structural dental
anomalies among patients
In a total of 154 cleft patients, all cleft types were
present except CL U R. The most frequently observed
cleft type was CL + P U L (n = 59; 38.3%), followed by
CL + P B (n = 39; 25.3%) and CL + P U R (n = 34; 22.1%).
On the other hand, the least frequent cleft types were
CP (n = 16, 10.14%) and CL U L (n = 6; 3.9%). A higher
incidence of CL + P U L was observed in men (44.3%)
compared to women (28.1%), although the overall
association between gender and cleft type was not
statistically significant (p = 0.108) (Fig. 1).
The distribution of tooth agenesis and structural
dental anomalies is presented in Table 1 overall and by
gender. Of the 154 patients, 77 (50%) presented with
tooth agenesis, 28 (18.2%) with microdontia and only
one patient with malformation of one tooth. No gender
differences occurred overall and for each separate dental
Neither the frequency of tooth agenesis nor
microdontia differed between male and female patients.
Specifically, 29.9% of the patients had 1 and 14.3% had 2 teeth
missing whereas 5.8% of the patients were found to have
3 or more missing teeth. Microdontia was found in
18.2% of the patients. Of these patients, 14.3% presented
microdontia in 1 tooth and 3.9% in 2 or more teeth
Association of tooth agenesis and structural dental
anomalies with cleft and gender
No tooth agenesis was observed among the 6 patients
with CL U L, and no microdontia among the 16 with
CP. Still, no differences were found between the
different types of clefts in regard to tooth agenesis (p = 0.111)
and microdontia (p = 0.211) (data not shown). After
excluding those cleft types with no dental anomalies from
the corresponding analyses for tooth agenesis (N = 148)
and microdontia (N = 138), we found that only in the
CL + P B group, the male patients were missing
significantly more teeth than the female patients (p = 0.047)
(Figs. 2 and 3). To further explore any potential
confounding, we assessed the mutually adjusted effects of
gender and cleft type on the occurrence of tooth
agenesis or microdontia through logistic regression. Females
appeared to have a lower risk for tooth agenesis by 27%
compared to men after controlling for cleft type, but the
result did not reach statistical significance (OR = 0.73,
95% CI 0.37–1.46). Neither gender nor cleft types were
associated with tooth agenesis or structural dental
anomalies (p values >0.05) (Table 3).
Tooth agenesis, structural dental anomalies, and cleft
type by tooth and by quadrant: inter-quadrant
The highest prevalence of tooth agenesis occurred for
the maxillary left lateral incisor (22), the maxillary right
lateral incisor (12), the maxillary right second premolar
(15), the mandibular left second premolar (35), and the
mandibular right second premolar (45) (Table 4). Both
the upper lateral incisors and lower left second
premolars were significantly missing in this sample of cleft
patients. The upper right lateral incisor was found missing
more in the CL + P R group (38.2%); whereas the upper
left lateral incisor was primarily missing in the CL + P B
group (43.6%) and secondarily in the CL + P L group
(40.7%). Furthermore, the lower left second premolar
was missing more in the CP group (25%). The CL U L
group of patients presented an intact alveolus and no
missing teeth or teeth with structural dental anomalies.
Microdontia occurred only for the maxillary central and
lateral incisors. However, only the upper left lateral
incisors presented microdontia, which was significantly
larger for the CL + P L group (p = 0.028) (Table 5).
Table 6 presents the association between tooth
agenesis by quadrant and by cleft type. Agenesis of teeth in
the upper right quadrant (Q1) occurred mainly in the
CL + P R patients (44.1%, p = 0.014). Similarly, agenesis
of teeth in the upper left quadrant (Q2) occurred mainly
in the CL + P B (48.7%) and CL + P L (40.7%) groups of
patients (p = 0.003). With regard to the mandibular left
(Q3) and right (Q4) quadrant, the CP patients were
found missing more teeth in these quadrants (p = 0.027
and p = 0.050, respectively) than any other cleft group.
A strong association was found between cleft and
non-cleft quadrants in regard to tooth agenesis. More
specifically, the association was statistically significant
between Q1 and Q2 (p = 0.003), Q1 and Q3 (p = 0.051),
and Q3 and Q4 (p < 0.001) (Table 7).
The distribution of the cleft types between male and
female patients did not vary significantly. These results
are in concordance with other research reports [
Still, the majority of the patients belonged to the CL + P
L group (38.3%) in agreement with relative research
9, 15, 20
In current literature, tooth agenesis is also reported
as the most frequent dental anomaly among cleft
]. 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 [
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
] 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 [
excluding the third molars). Lagana [
] 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
A meta-analysis conducted by Polder [
] included 33
studies and investigated the prevalence of
nonsyndromic 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
]. 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 [
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) [
]. 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 [
]. 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 [
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 [
]. Still, several research
projects conclude that agenesis occurs mainly at the cleft
side and the most prevalent missing tooth is the lateral
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 [
]. 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,
*Fisher’s exact test
thus indicating a genetic link between cleft and tooth
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
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 [
Several of these critical genetic controls assume a
mutual part in the development of orofacial clefts [
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
Limitations of the study
The limitations of this study can be primarily attributed
to the small sample size especially for the groups of cleft
lip only (CL U R and CL U L) and cleft palate only (CP).
Still, oral clefts comprise a rare disease and collection of
large samples can be very challenging. Furthermore, all
patients were of Caucasian origin and this constitutes
another limitation. In order to achieve an accurate
representation of the different cleft types, distribution in
non-syndromic oral cleft patients' further investigations
should examine different ethnic groups and obtain larger
The results of this investigation showed that 50% of the
oral cleft patients presented with tooth agenesis and 18%
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
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.
DK conceived the idea of the study, participated in its design and
coordination, and wrote the manuscript. AA was responsible for acquisition
of data and proofread the article. NK performed the statistical evaluation and
participated in the design of the study. MN participated in data acquisition
and helped in the interpretation of the results. All authors read and
approved the final manuscript.
The authors declare that they have no competing interests.
Ethics approval and consent to participate
An ethics and research committee approval from the Committee of Ethics of
the Dental School of the National and Kapodistrian University of Athens in
Athens, Greece, was obtained (ref. 312/21.09.2016) on October 24, 2016.
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
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