Patterns of Tooth Agenesis in Patients with Crouzon or Apert Syndrome

Abstract

Purpose

Dental agenesis is the most common anomaly of dental development and can be a component of a congenital syndrome. The purpose of this study was to evaluate the prevalence of agenesis and to describe patterns of tooth agenesis in patients with Crouzon or Apert syndrome compared with nonsyndromic controls.

Patients and Methods

Longitudinal records of 67 patients with Crouzon syndrome (n = 39) or Apert syndrome (n = 28) from the Erasmus Medical Centre were examined. Syndromic patients were compared with patients in a nonsyndromic control group (n = 284).

Results

Prevalence of tooth agenesis in patients with Crouzon syndrome (35.9%) and patients with Apert syndrome (46.4%) was significantly higher than the prevalence in control subjects (27.5%) (P < .005). In all groups third molars were the most likely to be agenetic. Tooth agenesis excluding third molars was significantly higher in syndromic patients than in control subjects (P < .001). Bilateral agenesis of mandibular second premolars occurred significantly more often in patients with Crouzon and Apert syndrome than in control subjects (P < .001).

Conclusions

Tooth agenesis is more prevalent in patients with Crouzon or Apert syndrome than in control subjects. Tooth agenesis and mandibular symmetrical patterns of second premolar agenesis are more prevalent in syndromic patients.

Keywords

Apert syndrome Crouzon syndrome dental agenesis syndrome

Tooth agenesis, the most common dental anomaly, is described in different ways: congenitally missing teeth, hypodontia (a few teeth are missing), oligodontia (several teeth are missing), and anodontia (all teeth are missing) (De Coster et al., 2009). In this article, the term tooth agenesis encompasses all of these terms. Excluding the third molars, agenesis of permanent teeth in the general population ranges from 3.2% to 7.6% (Polder et al., 2004). The prevalence of tooth agenesis varies per tooth. Third molar agenesis is the most common, with a prevalence around 20% in population studies (Vastardis, 2000; Polder et al., 2004). The teeth with second most prevalence of agenesis are the lateral maxillary incisor or mandibular second premolar (Polder et al., 2004).

Tooth agenesis can be a nonsyndromic trait or a component of an inherited syndrome (Vastardis, 2000; De Coster et al., 2007). Many syndromes are associated with tooth anomalies, which suggests that common molecular mechanisms are responsible for dental and organ development (Bailleul-Forestier et al., 2008). Tooth agenesis has been reported in syndromic craniosynostosis (premature fusion of the craniofacial sutures), such as in patients with Crouzon or Apert syndrome (Cohen and MacLean, 2000; De Coster et al., 2007). These rare syndromes share common clinical features, genetic features, and craniofacial abnormalities (Wilke et al., 1997; Cohen and MacLean, 2000).

Previous studies describing tooth agenesis often use frequencies to describe which individual tooth is missing in a certain population (Polder et al., 2004). This means that only one tooth at the time is addressed and not the overall pattern of absent teeth. The recently introduced Tooth Agenesis Code (TAC) can be used to describe the number and location of missing teeth (Van Wijk and Tan, 2006). TAC scores of different studies could eventually be combined to describe the overall pattern in tooth agenesis for a specific condition. Therefore, the purpose of this study was to evaluate the prevalence of tooth agenesis and to describe patterns of tooth agenesis in patients with Crouzon or Apert syndrome compared with those in nonsyndromic control subjects.

Materials and Methods

Participants

The sample consisted of 39 patients with Crouzon syndrome (20 boys and 19 girls) and 28 patients with Apert syndrome (10 boys and 18 girls) from the Erasmus MC Craniofacial Center, Sophia Children's Hospital in Rotterdam, The Netherlands. A large mixed-longitudinal data set from the Nijmegen Growth Study was used as a control group (Prahl et al., 1979). From these data a random selection of 284 nonsyndromic children was made (125 boys and 157 girls).

Design

This study had a retrospective cross-sectional design. Longitudinal standardized panoramic radiographs of sufficient quality taken in the protocol of diagnosis and treatment of these patients between 1980 and 2011 were analyzed. The clinical diagnosis of Crouzon or Apert syndrome was genetically confirmed. Only Caucasian patients with one or more panoramic radiographs were included. Patients and control subjects were between 11 and 22 years old at the time of the panoramic radiograph examination. If a patient showed no third molar on a panoramic radiograph at a certain age, agenesis was scored when the root length of the second molar was at least equal to crown height on a panoramic radiograph (Liversidge, 2008). Chronological age of at least 15.0 years (if available) (Richardson, 1980) was used as third criterion to score third molar agenesis. Third molar agenesis could not always be determined because some of the syndromic patients or control subjects were younger than 15 years old in 2011, and third molars were still absent. The use of data from human subjects followed an approved protocol and satisfied the requirement of the Institutional Review Board (approval number MEC-2010-304).

Patterns of Tooth Agenesis

The TAC (Van Wijk and Tan, 2006) was used to identify patterns of tooth agenesis. The TAC consists of four numbers (q1, q2, q3, and q4) that describe the number and location of missing teeth in each quadrant. Within each quadrant the teeth are numbered 1 to 8 (Peck and Peck, 1996). Each tooth has a tooth value that can be determined by calculating 2^(n-1), in which n = tooth number. TAC values are derived by calculating the sum of tooth values for the missing teeth in each quadrant (Fig. 1).

Figure 1

Schematic representation of the human dentition that can be used to determine Tooth Agenesis Code (TAC) values. To calculate TAC values (Q1, Q2, Q3, and Q4), simply calculate the sum of the values associated with the missing elements in each quadrant. A, tooth numbering according to the FDI tooth numbering system (Peck and Peck, 1996); B, values associated with missing teeth. FDI, (French) translates World Dental Federation; Q1, quadrant 1; Q2, quadrant 2; Q3, quadrant 3; Q4, quadrant 4.

Procedure

Tooth agenesis was diagnosed by one of two authors (E.O. or B.P-A.) based on clinical examination and after studying the panoramic radiographs, plaster casts, and intraoral photographs. All diagnoses were confirmed twice by one author (J.H.R.) by retrospectively studying the patients' dental charts and panoramic radiographs with an interval between the first and second assessment of at least 1 week. In three patients, discrepancies between the authors were identified and discussed until consensus was achieved. Cohen's κ showed high intraobserver (1.0) and interobserver (0.96) reliability. Both scores are considered very high.

Statistical Analysis

The Statistical Package for the Social Sciences (version 18.0; SPSS Inc., Chicago IL) was used for data analysis. TAC values were analyzed using a website that was specifically developed for this purpose (http://www.toothagenesiscode.com). A chi-square test and independent-samples t test were used for statistical analysis.

Results

Prevalence of Tooth Agenesis and Tooth Agenesis Patterns in Patients with Crouzon Syndrome

Prevalence of tooth agenesis (≥4%) in patients with Crouzon syndrome, including the third molar, was 35.9% (upper jaw 10.3%, lower jaw 7.7%, upper and lower jaw 17.9%) (Table 1). The number of missing teeth ranged from one to six. Patients showing tooth agenesis had an average of 2.8 (SD = 1.3) missing teeth; for the upper and lower jaw the averages were was 1.8 (SD = 0.72) and 1.9 (SD = 0.30), respectively. The most commonly missing teeth were the third molars (TAC value 128), followed by the second premolars (TAC value 16) and lateral incisors (TAC value 2) (Table 1).

Table 1

Patterns of Missing Teeth in Each Quadrant for Each Sample

		q1		q2		q3		q4
TAC	Tooth Type	n	%	n	%	n	%	n	%	Total (n)
Crouzon syndrome
1	I₁	0	0	2	20	2	22.2	2	20	6
2	I₂	0	0	1	10	1	11.1	1	10	3
16	P₂	1	12.5	0	0	4	44.4	5	50	10
20	P₂+C	1	12.5	0	0	0	0	0	0	1
128	M₃	5	62.5	7	70	2	22.2	2	20	16
144	M₃+P₂	1	12.5	0	0	0	0	0	0	1
Total		8	100	10	100	9	100	10	100	37
Apert syndrome
2	I₂	1	11.1	0	0	0	0	0	0	1
16	P₂	1	11.1	2	28.6	5	62.5	5	71.4	13
128	M₃	6	66.7	5	71.4	2	25.0	1	14.3	14
144	M₃+P₂	0	0	0	0	1	12.5	1	14.3	2
192	M₃+M₂	1	11.1	0	0	0	0	0	0	1
Total		9	100	7	100	8	100	7	100	31
Control subjects
2	I₂	3	7.0	2	5.0	1	2.4	1	2.3	7
4	C	2	4.8	3	7.5	0	0	0	0	5
16	P₂	0	0	1	5.0	4	9.8	6	14.0	11
24	P₂+P₁	1	2.4	1	5.0	0	0	0	0	2
128	M₃	34	81.0	32	80.0	36	87.8	34	79.1	136
130	M₃+I₂	2	4.8	1	5.0	0	0	0	0	3
144	M₃+ P₂	0	0	0	0	0	0	2	4.6	2
Total		42	100	40	100	41	100	43	100	166

For the upper jaw, four patterns were found in q1 and three in q2 (Table 2). The whole maxilla showed seven different patterns. The only symmetrical maxillary pattern was a single bilateral third molar (TAC value 128). For the mandible, five different patterns were found (Table 3). Except for one patient (TAC value 16 found in q4), all other patients with agenesis (n = 9) presented symmetrical patterns of one single tooth.

Table 2

Maxillary Patterns of Tooth Agenesis for Patients With Crouzon Syndrome, Patients With Apert Syndrome, and Control Subjects

		Patients with Apert Syndrome, n (%)			Patients with Crouzon Syndrome, n (%)			Control Subjects, n (%) q1
TAC Values	Corresponding Missing Teeth	q1	q2	q1 and q2	q1	q1	q1 and q2	q1	q2	q1 and q2
1	I₁					1 (9.1)
2	I₂	1 (7.7)						1 (2.1)		2 (4.2)
4	C								1 (2.1)	2 (4.2)
16	P₂		1 (7.7)	1 (7.7)	1 (9.1)
128	M₃	2 (15.4)		4 (30.8)		2 (18.2)	4 (36.4)	7 (14.6)	5 (10.4)	26 (54.2)
130	M₃+I₂									1 (2.1)
20.1	C+P₂ (q1) and I₁ (q2)						1 (9.1)
24.16	P₁+P₂ (q1) and P₂ (q2)									1 (2.1)
128.2	M₃ (q1) and I₂ (q2)						1 (9.1)
128.24	M₃ (q1) and P₁+P₂ (q2)									1 (2.1)
130.128	M₃+I₂ (q1) and M₃ (q2)									1 (2.1)
144.128	M₃+P₂ (q1) and M₃ (q2)						1 (9.1)
192.128	M₃+M₂ (q1) and M₃ (q2)			1 (7.7)
Total		3	1	6	1	3	7	8	6	34

Table 3

Mandibular Patterns of Tooth Agenesis for Patients With Crouzon Syndrome, Patients With Apert Syndrome, and Control Subjects

TAC Values	Corresponding Missing Teeth	Patients With Apert Syndrome, n (%)			Patients With Crouzon Syndrome, n (%)			Control Subjects, n (%) q3
TAC Values	Corresponding Missing Teeth	q3	q4	q3 and q4	q3	q4	q3 and q4	q3	q4	q3 and q4
1	I₁						2(20)
2	I₂						1(10)			1 (1.9)
16	P₂	1 (7.7)	1 (7.7)	4 (30.8)		1(10)	4(40)		1 (1.9)	4 (7.5)
128	M₃	1 (7.7)		1 (7.7)			2(20)	10 (18.9)	11 (20.8)	23 (43.4)
144	M₃+P₂			1 (7.7)
16.128	P₂ (q1) and M₃ (q2)									1 (1.9)
144.128	M₃+P₂ (q1) and M₃ (q2)									2 (3.8)
Total		2	1	6		1	9	10	12	31

Prevalence of Tooth Agenesis and Tooth Agenesis Patterns in Patients with Apert Syndrome

Prevalence of tooth agenesis (≥1) in patients with Apert syndrome, including the third molar, was 46.4% (upper jaw 14.3%, lower jaw 10.7%, upper and lower jaw 21.4%) (Table 1). The number of missing teeth ranged from one to six. Patients who showed tooth agenesis had an average of 2.6 (SD = 1.5) missing teeth. For the upper and lower jaw the averages were 1.3 (SD = 0.43) and 1.7 (SD = 0.47), respectively. The most commonly missing teeth were the third molars (TAC value 128), followed by the second premolars (TAC value 16).

For the upper jaw, four unilateral patterns of agenesis were found in the first quadrant (q1) and two patterns in the second quadrant (q2) (Table 2). The maxilla showed six different patterns (Table 2). Half of these maxillary patterns showed a symmetrical single tooth pattern of agenesis. Agenesis of the third molars (TAC value 128; 63.6%) was found bilaterally or unilaterally in q1 (Tables 1 and 2). For the lower jaw, three patterns were found in the third quadrant (q3) and fourth quadrant (q4) (Table 3). The mandible showed nine different patterns of agenesis. In six patients a symmetrical mandibular pattern of a single tooth was found. In all of these patients the mandibular agenesis was found in the second premolars and third molars (TAC values 16 and 128).

Prevalence of Tooth Agenesis and Tooth Agenesis Patterns in Control Subjects

The prevalence of tooth agenesis (≥1) in control subjects, including the third molar, was 27.5% (upper jaw 8.8%, lower jaw 10.6%, upper and lower jaw 8.1%) (Table 1). The number of missing teeth ranged from one to seven. Patients who had tooth agenesis had an average of 2.2 (SD = 1.4) missing teeth. For the upper and lower jaw the averages were 1.6 (SD = 0.48) and 1.4 (SD = 0.50), respectively. The most commonly missing teeth were the third molars, followed by the second premolars and upper lateral incisors.

Five agenesis patterns were found in q1 and six in q2 (Table 2). In the maxilla, 11 different patterns were found. In 64.6% of the symmetrical patients a single bilateral tooth symmetry was found in TAC value 128 (n = 28) and TAC value 2 (n = 3). Of the patients with agenesis, 88.5% was found in the lateral incisors or third molars (TAC value 2 or 128). Unilateral patterns of agenesis were found in q3 (n = 3) and q4 (n = 4) (Table 3). The mandible showed eight different patterns of agenesis, most often in the second premolars and third molars (TAC values 16 and 128).

Comparison of Patients with Crouzon and Apert Syndrome with Control Subjects

Differences between control subjects and patients with Crouzon and Apert syndrome were found in the prevalence of tooth agenesis. Prevalence of agenesis including the third molar was significantly higher in that patients with Apert syndrome (χ²[1] = 4.4; P = .035), but no difference was found for patients with Crouzon syndrome compared with control subjects (χ²[1] = 1.2; P = .27). The prevalence of agenesis, excluding the third molar, among patients with Crouzon syndrome (23.1%) and Apert syndrome (25.0%) was significantly higher than that for control subjects (6.0%) (χ²[2] = 23.8; P < .001). The mean number of missing teeth was significantly higher in patients with Crouzon syndrome compared with control subjects (t[315] = 2.51; P =.013).

Among patients with tooth agenesis, symmetrical maxillary patterns were found more frequently in control subjects than in patients with Crouzon or Apert syndrome, (χ²[2] = 3.23; P = .019). Symmetrical mandibular patterns were found more frequently in patients with Crouzon and Apert syndrome than in control subjects, but these differences were not statistically significant (χ²[2] = 5.04; P= .081) (Tables 2 and 3). In syndromic patients, agenesis of a bilateral second mandibular premolar occurred significantly more often in syndromic patients than in control subjects (χ²[2] = 24.62; P <. 001).

Discussion

Prevalence of Tooth Agenesis

The prevalence of agenesis among patients with Crouzon and Apert syndromes was significantly higher than in control subjects and was in agreement with an earlier finding that these syndromes are associated with tooth agenesis (Bailleul-Forestier et al., 2008). The prevalence of third molar agenesis in the present study is very similar to that found in other studies (Kazanci et al., 2010; Celikoglu et al., 2011). Third molar agenesis in patients with Apert syndrome was statistically significant higher than that for control subjects. Third molar agenesis might correlate with an increased prevalence of other missing teeth (Celikoglu et al., 2011). In addition, agenesis of the third molars exhibited maxillary lateral incisor microdontia more frequently and showed higher prevalence of other dental anomalies than in control subjects (De Coster et al., 2009; Celikoglu et al., 2011).

Previous reports (Garn et al. 1962; Gravely, 1965) suggested that the upper age limit for third molar agenesis is 13 years. Additionally, some studies reported that third molar development was as late as age 14 or 15 years (Richardson, 1980). Besides age, third molar agenesis can also be predicted from second molar formation. The probability of a third molar crypt developing decreases as the adjacent second molar root matures. When the root of the second molar is halfway, it is very unlikely for individuals to develop a third molar crypt at a later stage (Liversidge, 2008).

In this study, the prevalence of agenesis, excluding third molars, in control subjects was within the same range as found in other studies (Polder et al., 2004), whereas the prevalence found in patients with Crouzon or Apert syndrome showed much greater prevalence. The second most commonly absent tooth was the mandibular second premolar in all groups, although the prevalence was significantly higher in patients with Crouzon and Apert syndrome than in control subjects.

Patterns of Tooth Agenesis

Among patients with tooth agenesis, a trend of symmetrical maxillary patterns was found more often in control subjects than in patients with Crouzon or Apert syndrome (Tables 1 and 2). In contrast, symmetrical mandibular patterns were found significantly more frequently in patients with Crouzon or Apert syndrome compared with control subjects (Tables 1 and 3). This finding is surprising as tooth agenesis was shown to be more or less equally distributed between maxilla and mandible in each of the three groups. Prevalence of bilateral mandibular second premolar agenesis was significantly higher in syndromic patients than control subjects. In two patients, a combination of TAC values were found, whereas all other symmetrical patterns in mandible or maxilla were combinations of missing bilaterally single teeth (Tables 2 and 3). Although sample sizes are small, it might suggest that there are common molecular mechanisms of the same genetic defect for tooth agenesis and syndromic development (De Coster et al., 2007).

Two Swedish studies also revealed higher prevalence of tooth agenesis in patients with Crouzon syndrome (42.3%; n = 26) (Stavropoulos et al., 2012) or Apert syndrome (34.8%; n = 23) (Stavropoulos et al., 2011), although third molars were excluded. A variety of patterns, mainly asymmetric, were found for patients with Crouzon syndrome (Stavropoulos et al., 2012) in contrast to the mainly symmetrical patterns found in this study. In contrast, the other Swedish study showed mainly symmetrical dental agenesis patterns in patients with Apert syndrome (Stavropoulos et al., 2011). Bilateral tooth agenesis patterns were found for second mandibular premolars and lateral maxillary incisors in patients with Apert syndrome (Stavropoulos et al., 2011). However, in this study the prevalence of maxillary incisors in patients with Apert syndrome was very low (Table 1). It was also apparent that in the Swedish study agenesis occurred in either the maxilla or mandible and not in both arches (Stavropoulos et al., 2011). The prevalence of the second mandibular premolar agenesis was in agreement with this study. Ethnic population differences and the number of patients might explain differences found in this study and the Swedish studies.

Conclusion

•

Prevalence of agenesis excluding the third molar is significantly higher in syndromic patients than in control subjects.

•

Tooth agenesis including the third molar is more prevalent in patients with Apert syndrome than in patients with Crouzon syndrome and control subjects.

•

Symmetrical maxillary patterns of tooth agenesis were found more often in control subjects than in syndromic subjects.

•

Symmetrical mandibular patterns of tooth agenesis seem to occur more often in patients with Crouzon or Apert syndrome often than in control subjects.

•

Prevalence of bilateral tooth agenesis of second mandibular premolars is higher in syndromic patients than in control subjects.

References

Bailleul-Forestier

Berdal

Vinckier

de Ravel

Fryns

J.P.

Verloes

The genetic basis of inherited anomalies of the teeth. Part 2: syndromes with significant dental involvement. Eur J Med Genet. 2008; 51: 383–408.

Celikoglu

Bayram

Nur

Patterns of third-molar agenesis and associated dental anomalies in an orthodontic population. Am J Orthod Dentofacial Orthop. 2011; 140: 856–860.

Cohen

M.M.

MacLean

R.E.

Craniosynostosis: Diagnosis, Evaluation, and Management. New York: Oxford University Press; 2000: 316–365.

De Coster

P.J.

Marks

L.A.

Martens

L.C.

Huysseune

Dental agenesis: genetic and clinical perspectives. J Oral Pathol Med. 2009; 38: 1–17.

De Coster

P.J.

Mortier

Marks

L.A.

Martens

L.C.

Cranial suture biology and dental development: genetic and clinical perspectives. J Oral Pathol Med. 2007; 36: 447–455.

Garn

S.M.

Lewis

A.B.

Vicinus

J.H.

Third molar agenesis and reduction in the number of other teeth. J Dent Res. 1962; 41: 717.

Gravely

J.F.

A radiographic survey of third molar development. Br Dent J. 1965; 119: 397–401.

Kazanci

Celikoglu

Miloglu

Oktay

Third-molar agenesis among patients from the East Anatolian region of Turkey. J Contemp Dent Pract. 2010; 11: E033–E040.

Liversidge

Predicting mandibular third molar agenesis from second molar formation. Acta Stomatol Croat. 2008; 42: 311–317.

10.

Peck

Tooth numbering progress. Angle Orthod. 1996; 66: 83–84.

11.

Polder

BJ.

Van't Hof

M.A.

Van der Linden

F.P.

Kuijpers-Jagtman

A.M.

A meta-analysis of the prevalence of dental agenesis of permanent teeth. Community Dent Oral Epidemiol. 2004; 32: 217–226.

12.

Prahl-Andersen

Kowalski

C.J.

Heyendaal

PHJM

. A Mixed-Longitudinal Interdisciplinary Study of Growth and Development. New York: Academic Press; 1979.

13.

Richardson

Late third molar genesis: its significance in orthodontic treatment. Angle Orthod. 1980; 50: 121–128.

14.

Stavropoulos

Bartzela

Bronkhorst

Mohlin

Hagberg

Dental agenesis patterns of permanent teeth in Apert syndrome. Eur J Oral Sci. 2011; 119: 198–203.

15.

Stavropoulos

Bartzela

Tarnow

Mohlin

Kahnberg

K.E.

Hagberg

Dental agenesis patterns in Crouzon syndrome. Swed Dent J. 2012; 35: 195–201.

16.

Van Wijk

A.J.

Tan

S.P.

A numeric code for identifying patterns of human tooth agenesis: a new approach. Eur J Oral Sci. 2006; 114: 97–101.

17.

Vastardis

The genetics of human tooth agenesis: new discoveries for understanding dental anomalies. Am J Orthod Dentofacial Orthop. 2000; 117: 650–656.

18.

Wilke

T.A.

Gubbels

Schwartz

Richan

J.M.

Expression of fibroblast growth factor receptors (FGFR1, FGFR2, FGFR3) in the developing head and face. Dev Dyn. 1997; 210: 41–52.