Mesio-Distal and Buccal-Lingual Tooth Dimensions are Part of the Cleft Spectrum: A Pilot for Future Genetic Studies

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1 The Cleft Palate-Craniofacial Journal 50(6) pp November 2013 Copyright 2013 American Cleft Palate-Craniofacial Association ORIGINAL ARTICLE Mesio-Distal and Buccal-Lingual Tooth Dimensions are Part of the Cleft Spectrum: A Pilot for Future Genetic Studies Ticiana Medeiros de Sabóia, D.D.S., M.S.D., Erika Calvano Küchler, D.D.S., M.S.D., Ph.D., Patricia Nivoloni Tannure, D.D.S., M.S.D., Ph.D., Ana Cristina Rey, D.D.S., M.S.D., Jose Mauro Granjeiro, D.D.S., M.S., Ph.D., Marcelo de Castro Costa, D.D.S., Ph.D., Alexandre Rezende Vieira, D.D.S., M.S.D., Ph.D. Objective: Considering that oral clefts and tooth dimensions may be part of the same phenotypic spectrum, the aim of this study was to investigate tooth dimensions in permanent dentition and dental malformations, including tooth size discrepancies, of subjects born with clefts compared with individuals without clefts. Design: Cross-sectional study. Participants: The cleft group was composed of 66 subjects, and the noncleft group consisted of 66 healthy unrelated subjects. Main Outcome Measures: The mesio-distal and buccal-lingual crown diameter of fully erupted permanent teeth outside the cleft area was measured using a digital caliber. Clinical records and radiographs were used to evaluate the type of clefts and dental anomalies. Results: The lower second premolar was significantly reduced in the CLP and CP groups. The upper lateral incisor was found to be significantly smaller in the CP group, only for mesio-distal dimensions (P,.05). Dental agenesis was found in eight (12%) cleft subjects and supernumerary teeth in two (3%). Conclusions: Subjects born with oral clefts presented size reduction in specific dental groups. KEY WORDS: agenesis, cleft lip, cleft palate, tooth crown Oral clefts are the most common craniofacial malformations. They are frequently observed as an isolated manifestation but may occur associated with some syndromes and other clinical anomalies (Scapoli et al., 2008). Oral clefts are a complex phenotype in which two main types of clefts are recognized: cleft lip with or without cleft Dr. de Sabóia is Ph.D. Student, Department of Pediatric Dentistry and Orthodontics, School of Dentistry, Federal University of Rio de Janeiro, RJ, Brazil. Dr. Küchler is Postdoc, Cell Therapy Center, Unit of Clinical Research, Fluminense Federal University, Niterói, RJ, Brazil. Dr. Tannure is Auxiliar Professor, Discipline of Pediatric Dentistry, School of Dentistry, Veiga de Almeida University, Rio de Janeiro, RJ, Brazil. Dr. Rey is Orthodontist, Nossa Senhora do Loreto Hospital, Rio de Janeiro, RJ, Brazil. Dr. Granjeiro is Senior Researcher, Cell Therapy Center, Unit of Clinical Research, Fluminense Federal University, Niterói, RJ, Brazil, and Head of Bioengineering Program, National Institute of Metrology, Quality and Technology, Rio de Janeiro, RJ, Brazil. Dr. Costa is Associate Professor, Department of Pediatric Dentistry and Orthodontics, School of Dentistry, Federal University of Rio de Janeiro, RJ, Brazil. Dr. Vieira is Associate Professor, Department of Oral Biology and Center of Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania. Submitted September 2011; Accepted March Address correspondence to: Dr. Alexandre Rezende Vieira, 614 Salk Hall, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, 3501 Terrace Street, Pittsburgh, PA arv11@pitt.edu. DOI: / palate, which may be either unilateral or bilateral, and isolated cleft palate, which involves only the secondary palate. The etiology of oral clefts is not yet well understood, and multiple genetic and environmental factors are involved (Vieira, 2008). Oral clefts are caused by failure of fusion between the medial nasal process and the maxillary process, or between the palatal processes, during embryogenesis (Jugessur et al., 2009). The formation of tooth germs and the occurrence of cleft lip and/or palate defects have a close relationship in terms of timing, anatomical position (Tsai et al., 1998), neural crest cell origin (Ewings and Carstens, 2009), and genetic background (Vieira, 2003, 2008; Vieira et al., 2008). Dental anomalies (Dewinter et al., 2003; Letra et al., 2007; Menezes and Vieira, 2008; Küchler et al., 2011) and the reduction in the tooth size (Rawashdeh and Bakir, 2007; Akcam et al., 2008; Walker et al., 2009) are frequently observed in subjects born with oral clefts. We suggested that dental anomalies may represent an additional clinical marker for oral clefts, suggesting that isolated cleft lip and palate can be subphenotyped based on dental development (Letra et al., 2007; Menezes and Vieira, 2008; Küchler et al., 2011). We hypothesize that tooth sizes reductions may also be part of the oral cleft phenotypic spectrum. Therefore, the aim of this study was to investigate tooth dimensions in the permanent dentition 678

2 Sabóia et al., TOOTH DIMENSIONS ARE PART OF THE CLEFT SPECTRUM 679 of subjects born with clefts compared with individuals born without clefts. MATERIALS AND METHODS Ethical approval was obtained from the Central Research Ethics Committee (113/09) of the Health Department of the city of Rio de Janeiro, Brazil, and the University of Pittsburgh Institutional Review Board ( ). To confirm the proposed hypothesis, we used a crosssectional design with 66 subjects born with oral clefts and 66 subjects born without clefts or dental anomalies. Pretreatment orthodontic dental study casts, clinical records, and orthopantomographs were assessed. The cleft group was composed of subjects with nonsyndromic oral clefts treated since they were born at the Nossa Senhora do Loreto Hospital, Rio de Janeiro, Brazil. All subjects born with clefts received primary surgical treatment for reconstruction of the orofacial cleft during early childhood and presented a clinical dental record completely filled. They also had no signs of an underlying syndrome. The comparison group consisted of healthy unrelated subjects, recruited at the Department of Pediatric Dentistry and Orthodontics, Federal University of Rio de Janeiro, Brazil. This group was selected to ensure it matched the group born with clefts in age (10 to 45 years), gender, and geographic distribution. Both institutions are located within 10 km of each other to avoid selection bias. The population included in this study resides in the metropolitan area of Rio de Janeiro, Brazil, and was composed of a mix of Caucasians (mainly European descendants, 53.6%) and African descendants (obviously mixed Portuguese, 33.6%, or not obviously mixed Africans, 12.3%). The remaining 0.5% of the population was Amerindian or Asian descendants. The determination of the cleft phenotype was based on the description in the clinical records that included type of cleft (cleft lip only, cleft lip with cleft palate, and cleft palate only) and laterality (unilateral and bilateral). Tooth agenesis and supernumerary teeth were radiographically diagnosed (Küchler et al., 2008). Dental casts were used to obtain data regarding tooth dimensions. Dental casts were excluded from assessment if they met one of the following criteria: teeth with restorations extending both for the mesio-distal and for the buccal-lingual surfaces, teeth displaced or crowded, and teeth not fully erupted. Second and third molars were excluded because of the younger age of many subjects. Maximum mesio-distal and buccal-lingual dimensions of fully erupted permanent teeth outside the cleft area were measured to the nearest 0.1 mm using a digital Mitutoyo caliper. The dimensions were recorded for each tooth using the method proposed by Moorrees and Reed (1964). Blinding during cast measurements was not implemented since individuals born with the defect have obvious signs of its repair; however, all measurements were undertaken by one operator (T.M.S.) with a strict criterion to reduce variation. Five models were analyzed by day during 2 months to prevent depletion of the operator. Each tooth was measured three times, and if its measurements differed by more than 0.2 mm, it was measured three times again. An intraclass correlation coefficient was calculated to assess random error of intraobserver variability. The dental casts of 10 subjects born with clefts and 10 subjects born without clefts were selected. All tooth measurements were assessed on two occasions at least 2 weeks apart. The level of agreement was equal to 0.99, indicating an excellent level of reproducibility of the tooth dimension measurements. The descriptive values of mesio-distal and buccal-lingual dimensions (means and standard deviations) were recorded. Comparison between the mesio-distal and buccal-lingual dimensions of the cleft and noncleft groups was performed. Subjects born with clefts were analyzed not only as a total group but also by cleft types (CL, CLP, and CP). Student s test with alpha.05 was used to determine if any cleft type was preferentially associated with any dental group. RESULTS A total of 132 dental casts fulfilled the inclusion criteria. The operator measured a total of 2871 permanent teeth. Table 1 presents demographic and clinical characteristics of cleft and noncleft groups. No subjects were Amerindian or Asian descendants. There was no difference between Caucasian and African descent in crown mesio-distal (P 5.59) and buccal-lingual measurements (P 5.16). Table 2 shows the crown mesio-distal and buccal-lingual measurements (mm) of the dental groups (upper central incisor, upper lateral incisor, lower incisors, upper and lower canine, upper and lower first premolar, upper and lower second premolar, upper and lower molars) in cleft and noncleft subjects discriminated by gender. We observed that the combined mean of all permanent teeth in cleft subjects presented a significant reduction when compared with the noncleft group (P,.05). Combined mesio-distal widths were consistently smaller in females in the cleft group (P,.001) when compared with male mesio-distal widths (Table 2). Comparisons between the mesio-distal and buccal-lingual measurements of subjects with different clefts types (CL, CLP, and CP) and nonclefts subjects are seen in Table 3. Lower second premolars were significantly reduced in size (P,.05) in the CLP and CP groups. The upper contralateral lateral incisor was found to be significantly smaller in the CP group for mesio-distal dimensions. Dental agenesis was found in eight (12%) cleft subjects. Supernumerary teeth were observed only in two (3%) cleft cases. DISCUSSION Although some epidemiologic characteristics of oral clefts (incidence, gender distribution, most commonly

3 680 Cleft Palate Craniofacial Journal, November 2013, Vol. 50 No. 6 TABLE 1 Demographic and Clinical Characteristics of Study Subjects Cleft Noncleft P Value CL(16) CLP(35) CP(15) Mean age, y (SD) 17.0 (67.2) 20.1 (66.6).013* Gender (%) Male { Female Ethnicity (%) Caucasian { African descendant Cleft group characteristics Laterality (%) Right 5 9 Left 8 19 Bilateral 3 7 Gender (%) Male Female * t test was used. { Chi-square was used. affected side) are known, minor clinical findings related to the dentition, which could be used as markers for molecular studies, remain largely unexplored. In this study, we evaluated dental casts and radiographs of subjects born with clefts to explore in more detail the clinical presentation of the dentition, investigating the presence of specific patterns of dental dimensions. The digital caliper was used because it is considered the gold standard (Hunter and Priest, 1960; Bolton, 1962) among the different techniques for the measurement of erupted teeth on dental casts. Our results agree with previous studies that showed individuals born with clefts generally have smaller tooth sizes for both arches compared with unaffected individuals (Rawashdeh and Bakir, 2007; Akcam et al., 2008; Walker et al., 2009), suggesting that the results are not due to type I error. Although multiple testing is always an issue to be considered, dental formation is the result of a number of factors, and caution has to be exercised to not increase type II errors and consequently ignore possible true associations that may explain contributions to specific dental groups. It is important to emphasize that anatomically affected maxillary central and lateral incisors and canines were not included in our analysis because such anomalies may be the consequence of developmental alterations at the cleft side (Letra et al., 2007). When the 10 cases with dental anomalies were evaluated regarding their tooth dimensions, suggestive evidence of site-specific tooth reductions emerged. Three cases with agenesis of one upper lateral incisor had reduced dimensions of the contralateral corresponding tooth. This pattern of agenesis opposite to the cleft side has been suggested previously as a possible indication of an incomplete bilateral cleft lip (Letra et al., 2007; Menezes and Vieira, 2008). Another case with agenesis of the right first upper premolar had reduced dimensions of the teeth anterior to the agenesis (right upper central and lateral incisors and canine). This pattern of reduced tooth sizes of the remaining teeth in cases with dental agenesis was reported in a family with a missense mutation in PAX9 and oligodontia (Brook et al., 2009). In this family, most teeth were significantly reduced in size in the individuals affected. In contrast with our study, it is unlikely a PAX9 defect is contributing to the tooth agenesis pattern seen, but these results in aggregate suggest the phenotype is more complex, including not only dental agenesis but also reduced tooth sizes, which may be part of the cleft phenotypic spectrum. In our study, we noted a strong association between smaller lower second premolar and oral clefts, with these results likely driven by cleft palate only cases. The relationship between lower premolar agenesis and oral clefts has been previously noted (Larson et al., 1998; Letra et al., 2007; Menezes and Vieira, 2008; Küchler et al., 2011). In a previous study, cleft palate only subjects were also more affected by second premolar agenesis (Menezes and Vieira, 2008). However, the exact nature of this association remains largely unknown. We suggest that smaller premolars could be a phenotypic variability of premolar agenesis. Although it is accepted that cleft lip with or without cleft palate and cleft palate only are distinct entities, in some cases both of these cleft types segregate in the same pedigree, suggesting that they might share a common genetic background (Koillinen et al., 2005). In our study, the significant association between upper lateral incisor reduction and cleft palate only raises interesting possibilities. Our previous study suggested that the high prevalence of upper lateral incisor agenesis opposite to the cleft side in subjects with unilateral cleft lip may be a form of bilateral cleft (Letra et al., 2007). We also have published data suggesting that cleft palate only individuals may have defects on the orbicular oris muscle that can be detected by ultrasound (Weinberg et al., 2008). Following a similar pattern, these lateral incisor reductions could reflect the possibility that, in some instances, cleft palate only associated with a smaller upper lateral incisor may be a not fully expressed cleft lip with cleft palate.

4 Sabóia et al., TOOTH DIMENSIONS ARE PART OF THE CLEFT SPECTRUM 681 TABLE 2 Crown Mesio-Distal and Buccal-Lingual Measurements (mm) of the Dental Groups in Cleft and Noncleft Subjects, Discriminated by Gender{ Dimension Measured Cleft Group (n 5 66) Noncleft Group (n 5 66) P Value Male Cleft Group (n 5 36) Male Noncleft Group (n 5 27) P Value Female Cleft Group (n 5 30) Female Noncleft Group (n 5 39) P Value All teeth (MD) 7.73 (0.47) 7.92 (0.45).016* 7.93 (0.45) 8.04 (0.40) (0.39) 7.84 (0.46).001* Maxillary teeth (MD) Combined teeth 8.14 (0.53) 8.29 (0.60) (0.49) 8.42 (0.54) (0.47) 8.19 (0.63).046 Central incisor 8.66 (0.62) 8.78 (0.67) (0.62) 8.98 (0.57) (0.53) 8.73 (0.65).045* Lateral incisor 6.99 (0.66) 7.12 (0.56) (0.65) 7.28 ( 0.60) (0.61) 7.06 (0.50).052 Canine 7.74 (0.46) 8.19 (0.55),.001* 7.89 (0.48) 8.49 (0.48),.001* 7.59 (0.39) 7.99 (0.50).002* First premolar 7.35 (0.51) 7.40 (0.45) (0.47) 7.49 (0.36) (0.48) 7.34 (0.50).099 Second premolar 6.92 (0.51) 7.10 (0.48).050* 7.00 (0.51) 7.26 (0.35).031* 6.83 (0.50) 6.98 (0.53).216 Molars (0.73) (0.59).012* (0.70) (0.57) (0.61) (0.59).001* Mandible teeth (MD) Combined teeth 7.42 (0.55) 7.56 (0.36) (0.51) 7.67 (0.34) (0.49) 7.49 (0.37).002* Incisors 5.80 (0.37) 5.99 (0.70).048* 5.92 (0.30) 6.14 (1.01) (0.39) 5.89 (0.34).007* Canine 6.99 (0.51) 7.09 (0.48) (0.42) 7.34 (0.44) (0.40) 6.92 (0.44).026* First premolar 7.36 (0.47) 7.48 (0.42) (0.43) 7.57 (0.33) (0.45) 7.41 (0.46).030* Second premolar 7.37 (0.46) 7.61 (0.48).005* 7.52 (0.44) 7.72 (0.43) (0.42) 7.53 (0.51).004* Molars (0.64) (0.63) (0.54) (0.68) (0.54) (0.59).001* All teeth (BL) 8.35 (0.91) 8.41 (0.47) (0.50) 8.60 (0.56) (1.25) 8.27 (0.35).967 Maxillary teeth (BL) Combined teeth 9.08 (0.79) 8.88 (0.48) (0.67) 9.10 (0.54) (0.83) 8.73 (0.37).748 Central incisor 7.27 (0.96) 7.38 (0.56) (0.95) 7.50 (0.55) (0.91) 7.30 (0.56).092 Lateral incisor 6.66 (0.86) 6.59 (0.62) (0.80) 6.79 (0.61) (0.83) 6.45 (0.59).526 Canine 7.68 (0.89) 8.29 (0.75),.001* 7.94 (1.08) 8.59 (0.79).017* 7.42 (0.56) 8.08 (0.67),.001* First premolar 9.29 (1.03) 9.65 (0.68).025* 9.40 (1.21) 9.94 (0.61).047* 9.17 (0.79) 9.47 (0.67).1 Second premolar 9.46 (0.96) 9.68 (0.91) (1.05) (0.73) (0.81) 9.40 (0.93).496 Molars (0.74) (0.65).017* (0.73) (0.74) (0.56) (0.53),.001* Mandible teeth (BL) Combined teeth 7.72 (0.59) 7.94 (0.51).022* 7.87 (0.46) 8.11 (0.61) (0.68) 7.82 (0.36).031 Incisors 6.04 (0.48) 6.26 (0.48).009* 5.92 (0.30) 6.35 (0.55) (0.41) 6.21(0.43).005* Canine 7.09 (0.68) 7.40 (0.75).017* 7.22 (0.72) 7.78 (0.81).007* 6.95 (0.61) 7.13 (0.57).206 First premolar 7.95 (0.63) 8.07 (0.66) (0.69) 8.39 (0.76) (0.46) 7.88 (0.51).148 Second premolar 8.60 (0.69) 8.73 (0.85) (0.75) 8.99 (0.99) (0.51) 8.55 (0.69).214 Molars (0.65) (0.60) (0.64) (0.70) (0.45) (0.50).005* * Statistically significance differences. { Comparison was performed between the cleft group and noncleft group (t test).

5 682 Cleft Palate Craniofacial Journal, November 2013, Vol. 50 No. 6 TABLE 3 Tooth Dimensions by Cleft Types{ Tooth Groups Measured Cleft Lip Only, P Value Cleft Lip With Cleft Palate, P Value Cleft Palate Only, P Value All teeth (MD) 7.82 (0.53) (0.43) (0.50).011* Maxillary teeth (MD) Combined teeth 8.23 (0.39) (0.57) (0.51).046* Central incisor 8.75 (0.43) (0.74) (0.54).346 Lateral incisor 7.06 (0.56) (0.75) (0.56).026* Canine 7.86 (0.56) (0.45),.001* 7.81 (0.38).015* First premolar 7.43 (0.42) (0.50) (0.62).198 Second premolar 7.00 (0.32) (0.61) (0.39).105 Molars (0.69) (0.72).010* (0.82).034* Mandible teeth (MD) Combined teeth 7.51 (0.70) (0.48) (0.51).003* Incisors 5.83 (0.37) (0.34) (0.42).132 Canine 7.07 (0.59) (0.48) (0.51).015* First premolar 7.49 (0.42) (0.51) (0.43).062 Second premolar 7.51 (0.51) (0.48).033* 7.16 (0.28).002* Molars (0.73) (0.53) (0.76).024* All teeth (BL) 8.30 (0.65) (0.41) (1.73).537 Maxillary teeth (BL) Combined teeth 9.21 (0.87) (0.70).001* 8.45 (0.61).005* Central incisor 7.49 (1.02) (1.06) (0.69).067 Lateral incisor 6.74 (0.60) (0.95) (0.94).832 Canine 7.93 (1.36) (0.65).002* 7.31 (0.66),.001* First premolar 9.09 (1.51).024* 9.43 (0.79) (0.88).039* Second premolar 9.50 (1.06) (1.06) (0.54).331 Molars (0.81) (0.69) (0.80).033* Mandible teeth (BL) Combined teeth 7.75 (0.48) (0.43).035* 7.69 (0.95).161 Incisors 6.07 (0.42) (0.48).062* 5.89 (0.53).005* Canine 7.09 (0.72) (0.62) (0.69).003* First premolar 8.24 (0.79) (0.41) (0.63).165 Second premolar 8.70 (0.84) (0.67) (0.53).178 Molars (0.49) (0.63) (0.78).029* * Statistically significance differences. { Comparison was performed between the noncleft group and each cleft type (t test). It is known that there is a difference between tooth sizes of males and females, and for this reason, analysis was performed by gender. It is possible that sex-linked genes influence enamel and dentine contributions to crown size (Schwartz and Dean, 2005). It has been suggested that the Y chromosome promotes both tooth crown enamel and dentin growth and that the X chromosome seems to be restricted to enamel formation as a result of observations in dental casts from individuals with various sex chromosome anomalies (Alvesalo, 2009). In our study, differences between males and females (both cleft-affected and -unaffected individuals) support these assumptions. We may interpret this as specific genetic factors that contribute to tooth development may be differentially expressed depending on the gender. Our findings support the hypothesis that oral clefts are part of a complex clinical and genetic malformation resulting from disturbed development of the face and dentition. The knowledge of the genetic processes involved in the etiology of oral clefts depends very much on a detailed phenotypic description. Studies on unaffected relatives of individuals born with clefts will aid the identification of clinical markers that may be part of the cleft spectrum. In the future, these more comprehensive dental descriptions (such as dental anomalies and tooth sizes) may provide new opportunities to identify genetic markers for cleft lip and palate, which may help in genetic counseling. CONCLUSION Subjects born with oral clefts present dental anomalies and tooth size reductions in specific dental groups even in regions not affected by the cleft. Acknowledgments. The authors are indebted to all the staff at the Nossa Senhora do Loreto Hospital. We thank Professor Ronir Raggio Luiz (IESC, UFRJ-RJ) for his help with the statistical analysis. Support for this work was provided by CAPES (T.M.S., P.N.T., and E.C.K.), FAPERJ (M.C.C., J.M.G.), CNPq (J.M.G.), and DECIT/MS (J.M.G.). REFERENCES Akcam MO, Toygar TU, Ozer L, Ozdemir B. Evaluation of 3-dimensional tooth crown size in cleft lip and palate patients. Am J Orthod Dentofacial Orthop. 2008;134:85 92.

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