It has been shown that in human embryos and fetuses with cleft lips

SCIENTIFIC FOUNDATION Crown Morphologic Abnormalities in the Permanent: Dentition of Patients With Cleft Lip and Palate Ma amon A. Rawashdeh, BDS, MScD, FDSRCS (En),*Þ and Emad Omar Abu Sirdaneh, BDS, MSÞ Abstract: The purpose of this study was to investigate crown morphologic abnormalities in the permanent dentition of subjects with clefts and unaffected controls. This is a prospective study of 100 patients and 60 control subjects. The study was carried out at the Cleft Lip and Palate Center at the King Abdullah University Hospital and at the Maxillofacial Unit at Jordan University of Science and Technology during the period November 2003 to September 2005. Eleven kinds of crown morphology abnormalities commonly described in the permanent dentition were recorded using the Arizona State University Dental Anthropology System. There were 1525 teeth examined in 100 subjects with clefts, and 203 crown morphologic abnormalities were recorded, resulting in a mean of 2 abnormalities per individual. No significant difference between the unilateral and bilateral cleft lip and palate groups was found; however, the difference between the cleft group and the control group was highly significant. Crown morphologic abnormalities were more frequent in the maxillary cleft teeth than in the mandibular teeth and in the anterior teeth than in posterior teeth, with a statistically significant difference. The most frequently found abnormalities in subjects with clefts were peg-shaped maxillary incisors and missing hypocone, followed by excess mammelons. In conclusion, there was a significant increase in the frequency of crown morphologic abnormalities in individuals with clefts when compared with subjects without clefts. Crown morphologic abnormalities occurred throughout the entire dentition and did not follow any predictable pattern. Key Words: Crown morphologic abnormalities, dental abnormalities, dental development, cleft lip and palate (J Craniofac Surg 2009;20: 465Y470) It has been shown that in human embryos and fetuses with cleft lips and/or palates, the incidence of external and visceral abnormalities was significantly higher than in specimens without cleft. 1,2 Another study showed that the sequence of initial ossification of the bones of the foot deviated from the norm far more frequently in fetuses with From the *Cleft Lip and Palate Center, King Abdullah University Hospital, and Department of Oral and Maxillofacial Surgery, Jordan University of Science and Technology, Irbid, Jordan. Received July 7, 2008. Accepted for publication November 26, 2008. Address correspondence and reprint requests to Ma amon A. Rawashdeh, BDS, MScD, FDSRCS (En), PO Box 3795, Baghdad Street, Irbid 21110, Jordan; E-mail: mamonrawashdeh@yahoo.com This project was supported by a grant (no. 107/2006) from Jordan University of Science and Technology and submitted in partial fulfillment of a master s degree in oral and maxillofacial surgery. Copyright * 2009 by Mutaz B. Habal, MD ISSN: 1049-2275 DOI: 10.1097/SCS.0b013e31819b97bf clefts than in those without. 3 In addition, it has been noted that children with clefts have a higher incidence of dental abnormalities than children without clefts. Dental development and dental irregularities associated with the various expressions of cleft lip and palate have been a source of investigation by several authors. 4Y17 The incidence of abnormal crown morphology in patients with clefts has been scarcely investigated. 4Y6,8 Bon 4 published an extensive study focusing on the maxillary teeth in the area of the cleft. Jordan et al, 5 Karus et al, 6 and Schroeder and Green 8 were the only studies to investigate the crown morphologic abnormalities of the dentitions of subjects with clefts. When Jordan et al 5 compared the tooth buds of human fetuses with and without clefts and the dentition of individuals with and without clefts, 12 different types of crown morphologic abnormalities occurred with significantly higher frequency in subjects with clefts than in those without. The crown morphologic abnormalities occurred throughout the entire dentition and not merely in the maxillary unit in the immediate area of the cleft. Moreover, both deciduous and permanent dentitions were affected. 5,6,8 Bon 4 and Olin 18 attributed dental abnormalities to the physical damage and insufficiency of tissue due to the cleft itself. Other investigators suggested that underlying embryonic disturbance leading to the cleft was widespread and could affect other tissues and organs of the body in various unpredictable ways. 5Y9,16 The purpose of this study was to investigate the distribution and the frequency of crown morphologic abnormalities in the permanent dentition of Jordanian subjects with unilateral (UCLP) and bilateral cleft lip and palate (BCLP) and unaffected controls treated at the Cleft Lip and Palate Center and the Oral and Maxillofacial Surgery Department of the King Abdullah University Hospital (KAUH)/Jordan University of Science and Technology. SUBJECTS AND METHODS Subjects The sample consisted of 100 Jordanian patients presented with unilateral (UCLP) and bilateral cleft lip and palate (BCLP) deformities at the Cleft Lip and Palate Center at the KAUH and the Oral and Maxillofacial Surgery Department at KAUH/Jordan University of Science and Technology during the period November 2003 to September 2005. Individuals with diagnosed syndromes (eg, Crouzon syndrome and hemifacial microsomia) were excluded. The individuals with clefts and the control group were born of Jordanian parents and grew up in Jordan. Methods and Measurements The study was approved by the Department of Oral Medicine and the oral surgery and dental school research committees and conducted in full accordance with the ethical principles of the World Medical Association Declaration of Helsinki. The study was explained to the parents, and upon consenting to participating in the study, the patient s name, date of birth, sex, and cleft type were recorded. Alginate impression was taken in a suitable perforated tray for upper and lower dental arches and then casted in dental stone. All teeth with occlusal wear, caries, and dental restorations were eliminated. The Journal of Craniofacial Surgery & Volume 20, Number 2, March 2009 465

Rawashdeh and Abu Sirdaneh The Journal of Craniofacial Surgery & Volume 20, Number 2, March 2009 The Arizona State University Dental Anthropology System (ASUDAS) was used for collecting nonmetric dental data. 19 This system currently consists of more than 36 tooth crowns and root traits that are scored with the aid of 23 reference plaques. A complete set of plaques was obtained, at cost, from the Department of Anthropology, Arizona State University, for the purpose of the current study. Turner et al 19 emphasized the importance of using plaques, not photographs, for making observation so that a threedimensional appreciation of the characters may be obtained. A written description of each trait is used in conjunction with reference plaques to facilitate accurate assessment of variation. Because many of the ASUDAS crown traits are scored on multiple teeth (eg, M 1,M 2, and M 3 ) 19 within a tooth field (incisors, canines, premolars, and molars) and because the ASUDAS includes morphologic characters on the tooth roots, the cranium and mandible (tori and rocker jaw), as well as the presence of supernumerary teeth, there are potentially a very large number (more than 300) of observations that could be made on each individual. Turner et al 19 indicated that of these, 29 features best characterize genetic affinity. These 29 traits are least likely to be strongly influenced by environment when scored on key teeth as defined by the morphogenetic field concept. 20 When studying the dentition, the expression of each trait is scored on each tooth in the morphologic field, but only the expression on the key tooth is used in the analyses. In the current study, 11 kinds of crown morphology abnormalities commonly described in the permanent dentition were recorded. 5,6,8 These crown abnormalities were thick curved maxillary central incisors (TCMI), excess mammelons, exaggerated mammelons, peg-shaped anterior teeth, T-shaped lateral incisors, malformed mandibular first molars, abnormal maxillary first molars (missing hypocones, reduced hypocones, fused prolocone, and metacone), malformed bicuspids, and incisal fissure. RESULTS The study sample consisted of 100 cleft lip and palate cases (68 UCLP and 32 BCLP) and 60 control cases. Of the 100 cleft cases, there were 68 cases of UCLP and 32 cases of BCLP. The UCLP group consisted of 33 male and 35 female children, whereas the BCLP group consisted of 17 male and 15 female children. The control group consisted of 26 male and 34 female children of unaffected Jordanian subjects. The mean ages were 13.4 years for the cleft group and 14.6 years for the control group. Overall Distribution of the Crown Morphologic Abnormalities in the UCLP and BCLP Groups and the Controls The number of teeth available for examination in the UCLP group (68 patients) was 1030 teeth, and the number of crown morphologic abnormalities recorded was 148, resulting in a mean of 2.2 abnormalities per individual. In the BCLP group (32 patients), the 495 teeth examined had 55 crown morphologic abnormalities with a mean number per individual of 1.7 abnormalities. The total cleft teeth (UCLP and BCLP) examined were 1525 teeth having 203 crown morphologic abnormalities and a mean of 2 abnormalities per individual. The 982 teeth of the control group (60 patients) had 20 crown morphologic abnormalities yielding a mean of 0.33 abnormalities per individual. A W 2 test showed no significant difference between the UCLP and BCLP groups (P = 0.078); however, the difference between the cleft group and the control group was highly significant (P G 0.001). The percentages of the crown morphologic abnormalities recorded in the total number of teeth in the UCLP group, BCLP group, all cleft group, and control group were 14.4%, 11.1%, 13.3%, and 2%, respectively (Table 1). Distribution of the Crown Morphologic Abnormalities According to Arch, Arch Segment, and Cleft Type The percentage of the recorded crown morphologic abnormalities in the total maxillary cleft teeth (17.6%) was almost twice that of the mandibular teeth (9.4%). This difference was statistically significant (P G 0.001) when the maxillary and mandibular teeth were compared using the W 2 test. Crown morphologic abnormalities recorded in the anterior cleft teeth (19.2%) were almost 3 times that recorded in the posterior teeth (6.9%), yielding a statistically significant difference (P G 0.001). A similar pattern was observed when the data for the subjects with UCLP and BCLP were examined separately. The anterior and posterior teeth of the subjects with UCLP of both arches had higher percentages of abnormalities than those of subjects with BCLP (Table 1). The highest percentage of crown morphologic abnormalities in subjects with clefts was recorded in the maxillary anterior teeth (29%) of the UCLP group, and the lowest (3.7%) was recorded in the posterior teeth in the BCLP group. In the control group, the percentages of crown morphologic abnormalities in both arches and the different arch segments were relatively similar (0.7%Y3%; Table 1). TABLE 1. Distribution and Percentages of Crown Morphologic Abnormalities According to Cleft Type and Arch Segment UCLP BCLP All Cleft Control T Abn, n (%) T Abn, n (%) T Abn, n (%) T Abn, n (%) Maxillary anterior 237 69 (29.1) 115 26 (22.6) 352 95 (27) 260 8 (3) Maxillary posterior 250 25 (10) 124 8 (6.5) 374 33 (8.8) 228 2 (0.7) Total maxillary 487 94 (19.3) 239 34 (14.2) 726 128 (17.6) 488 10 (2) Mandibular anterior 290 40 (13.8) 148 17 (11.5) 438 57 (13) 288 6 (2.1) Mandibular posterior 253 14 (5.5) 108 4 (3.7) 361 18 (5) 204 4 (1.9) Total mandibular 543 54 (9.9) 256 21 (8.2) 799 75 (9.4) 490 10 (2) Total anterior 527 109 (20.7) 263 43 (16.3) 790 152 (19.2) 548 14 (2.5) Total posterior 503 29 (5.8) 232 12 (5.2) 735 51 (6.9) 432 6 (1.4) Total anterior and posterior 1030 148 (14.4) 495 55 (11.1) 1525 203 (13.3) 982 20 (2) Abn indicates numbers (percentages) of teeth with crown morphologic abnormalities; T, total number of teeth. 466 * 2009 Mutaz B. Habal, MD

The Journal of Craniofacial Surgery & Volume 20, Number 2, March 2009 Crown Morphologic Abnormalities in Cleft TABLE 2. Distribution and Percentages of Crown Morphologic Abnormalities in Anterior Teeth According to Cleft Type Central Lateral Canine Total T Abn, n (%) T Abn, n (%) T Abn, n (%) T Abn, n (%) UCLP Maxillary 101 33 (32.7) 70 27 (38.7) 66 9 (13.6) 237 69 (29.1) Mandibular 96 25 (26) 105 10 (9.5) 89 5 (5.6) 290 40 (13.8) Total 197 58 (29.4) 175 37 (21.1) 155 14 (9) 527 109 (20.7) BCLP Maxillary 50 13 (26) 36 13 (36.1) 29 0 (0) 115 26 (22.6) Mandibular 52 12 (23) 50 3 (6) 46 2 (4.3) 148 17 (11.5) Total 102 25 (24.5) 86 16 (18.6) 75 2 (2.7) 263 43 (16.3) All cleft Maxillary 151 46 (30.5) 106 40 (37.7) 95 9 (9.5) 352 95 (27) Mandibular 148 37 (25) 155 13 (8.4) 135 7 (5.2) 438 57 (13) Total 299 83 (27.7) 261 53 (20.3) 230 16 (6.9) 790 152 (19.2) Control Maxillary 120 0 (0) 96 8 (8.3) 44 0 (0) 260 8 (3.1) Mandibular 120 0 (0) 120 6 (5) 48 0 (0) 280 6 (2.1) Total 240 0 (0) 216 14 (6.5) 92 0 (0) 540 14 (2.6) Distribution of the Crown Morphologic Abnormalities According to Arch and Class of Teeth The cleft central incisors, maxillary and mandibular combined, showed the largest percentage (27.7%) of crown morphologic abnormalities. However; in the maxillary arch, the lateral incisors had the highest percentage of recorded abnormalities (37.7%), whereas in the mandibular arch, the central incisor had the highest percentage of 25%. Abnormalities recorded in the maxillary canine (9.5%) of subjects with clefts were almost twice those of the mandibular canine (5.2%; Table 2). The difference between the maxillary anterior and mandibular anterior teeth was statistically significant (P G 0.001). No crown morphologic abnormalities were seen in the maxillary premolars, whereas the percentage of abnormalities for the mandibular premolars was 6.8%. The percentage of crown morphologic abnormalities in the maxillary first permanent molar (21%) was 8 times that of the mandibular first molar (2.6%; Table 3). The application of the W 2 test to the cleft maxillary posterior and cleft mandibular posterior teeth resulted in P = 0.041. Distribution of the Crown Morphologic Abnormalities According to Cleft Type and Class of Teeth The maxillary anterior teeth in the UCLP group showed the highest percentage of abnormalities (29.1%), which was slightly higher than that of the subjects with BCLP (22.6%). Among the anterior teeth, the maxillary lateral incisor of the UCLP subjects had the highest percentage of crown morphologic abnormalities (38.7%), followed by the maxillary lateral incisor of the BCLP group (36.1%) and maxillary central incisor of the UCLP group (32.7%). The mandibular central incisor of the UCLP group and the maxillary and mandibular central incisors of the BCLP group had similar percentages of abnormalities (26%, 26%, and 23%, respectively; Table 2). The next most commonly affected tooth was the maxillary first molar in both the UCLP (23.6%) and BCLP subjects (15.7%); however, the mandibular first molar had a comparatively much lower percentages of abnormalities in both types of clefts (UCLP, 2.9%; BCLP, 1.8%; Table 3). The premolars and canines were affected to a much lesser degree than the incisors and first molars in both types of clefts, and the expression of crown morphologic abnormalities was highly variable. Interestingly, the maxillary premolars in both types of clefts and the maxillary canine in BCLP showed no abnormalities (Tables 2 and 3). TABLE 3. Distribution and Percentages of Crown Morphologic Abnormalities Recorded in the Posterior Teeth According to Cleft Type T Premolars First Molar Total Abn, n (%) T Abn, n (%) T Abn, n (%) UCLP Maxillary 144 0 (0) 106 25 (23.6) 250 25 (10) Mandibular 152 11 (7.2) 101 3 (2.9) 253 14 (5.5) Total 296 11 (3.7) 207 28 (13.5) 303 39 (12.9) BCLP Maxillary 73 0 (0) 51 8 (15.7) 124 8 (6.4) Mandibular 53 3 (5.7) 55 1 (1.8) 108 4 (3.7) Total 126 3 (2.4) 106 9 (8.5) 232 12 (5.2) All Cleft Maxillary 217 0 (0) 157 33 (21) 374 33 (8.8) Mandibular 205 14 (6.8) 152 4 (2.6) 357 18 (5) Total 422 14 (3.3) 309 37 (12) 731 51 (7) Control Maxillary 108 0 (0) 120 2 (1.7) 228 2 (0.9) Mandibular 84 2 (2.4) 120 2 (1.7) 204 4 (2) Total 192 2 (1) 240 4 (1.7) 432 6 (1.4) * 2009 Mutaz B. Habal, MD 467

Rawashdeh and Abu Sirdaneh The Journal of Craniofacial Surgery & Volume 20, Number 2, March 2009 Distribution of the Individual Crown Morphologic Abnormalities According to Cleft Type and Class of Teeth In both types of clefts, the most frequently recorded crown morphologic abnormalities were peg-shaped maxillary incisor (UCLP, 11.7%; BCLP, 12.8%) and missing hypocone (UCLP, 11.3%; BCLP, 9.8%). Excess mammelons were the next most commonly observed anomaly in the maxillary (UCLP, 8.8%; BCLP, 8.1%) and the mandibular arches (UCLP, 8.45%; BCLP, 6.7%). Reduced hypocone, malformed mandibular premolars, TCMI, and exaggerated mammelons occurred in relatively similar percentages in both types of clefts (Tables 4 and 5). Peg-shaped maxillary canine occurred only in subjects with UCLP (13.6%); however, in the mandible, peg-shaped canine was seen in both types of clefts (UCLP, 5.6%; BCLP, 4.3%). Interestingly, malformed premolars were only observed in the mandibular arch in both types of clefts (UCLP, 7.2%; BCLP, 5.3%). The least commonly observed abnormalities were T-shaped maxillary lateral incisor, incisal fissure, and fused hypocone (Tables 4 and 5). DISCUSSION It is well documented that teeth in the vicinity of the cleft are commonly malformed or missing; however, little is known about the morphologic dental abnormalities of other permanent teeth in subjects with clefts. 4Y17 In the current study, 11 kinds of crown morphologic abnormalities in the permanent teeth of subjects with clefts and controls were investigated. The mean number of crown morphologic abnormalities per individual in our subjects with clefts was 2 abnormalities per individual, which was higher than that reported by Schroeder and Green 8 (1.02 abnormalities per individual) and Jordan et al 5 (1.29 abnormalities per individual) but less than that reported by Kraus et al 6 (4.8 abnormalities per individual). Of the total 1525 permanent teeth in our cleft sample, 13.3% had crown morphologic abnormalities that were similar to those of the 11% reported by Kraus et al 6 in their cleft sample. In the current study, the crown morphologic abnormalities in the cleft maxillary teeth were almost twice that of the mandibular teeth, and abnormalities in the cleft anterior teeth were 3 times those of the posterior teeth. This is similar to that reported by Kraus et al 6 where cleft maxillary abnormalities were more than 3 times as frequent as the mandibular ones, and anterior teeth are affected 4 times more frequently than the posterior teeth. Kraus et al 6 reported that the maxillary incisors were affected twice as frequently as the mandibular incisors, which is comparable to the finding in our cleft sample. The affected maxillary molars in the study by Kraus et al 6 were more than 5 times as frequent as the affected mandibular molars; however, in the current study, the affected maxillary molars were more than 8 times those of the mandibular molars. Jordan et al 5 and Kraus et al 6 studied 11 crown morphologic abnormalities in subjects with cleft using the same criteria; however, Kraus et al 6 did not report on the frequency or distribution of the individual abnormalities in their subjects with clefts. In the study of Jordan et al, 5 TCMI, peg-shaped incisor, exaggerated mammelons, and reduced hypocone were the most frequent abnormalities, accounting for more than 45% of the total abnormalities. On the other hand, Schroeder and Green 8 studied the 10 crown morphologic abnormalities using the same criteria of Kraus et al 6 and found that 5 of these abnormalities (excessive mammelons, T-shaped lateral incisor, missing hypocones, reduced hypocones, and fused protocone and TABLE 4. Numbers and Percentages of Individual Crown Morphologic Abnormalities Recorded in the Permanent Maxillary Teeth UCLP BCLP All Cleft Control Total Central 101 50 151 120 TCMI 10 (9.9%) 5 (10%) 15 (9.9%) 0 Excess mammelons 7 (6.9%) 4 (8%) 11 (7.3%) 0 Exaggerated mammelons 5 (4.9%) 2 (4%) 7 (4.6%) 0 Peg shape 9 (8.9%) 5 (10%) 14 (9.3%) 0 Incisal fissure 1 (0.99%) 1 (2%) 2 (1.3%) 0 Abnormal central 32 (31.7%) 17 (34%) 49 (32.4%) 0 (%) Total lateral 70 36 106 96 Excess mammelons 8 (11.4%) 3 (8.3%) 11 (10.4%) 2 (2.1%) Exaggerated mammelons 6 (8.6%) 2 (5.5%) 8 (7.5%) 1 (1.0%) Peg shape 11 (15.7%) 6 (16.7%) 17 (16%) 5 (5.2%) Incisal fissure 1 (1.4%) 1 (2.8%) 2 (1.9%) 0 (0%) T shape 1 (1.4%) 1 (2.8%) 2 (1.9%) 0 (0%) Abnormal lateral 27 (38.6%) 13 (36.1%) 40 (37.7%) 8 (8.3%) Total canine 66 29 95 44 Peg-shaped canine 9 (13.6%) 0 (0%) 9 (8.5%) 0 (0%) Total premolars 144 73 217 108 Abnormal premolars 0 0 0 0 (0%) Total first molars 106 51 157 120 Missing hypocone 12 (11.3%) 5 (9.8%) 17 (10.8%) 0 (0%) Reduced hypocone 10 (9.4%) 2 (3.9%) 12 (7.6%) 2 (1.7%) Fused hypocone 3 (2.8%) 1 (1.9%) 4 (2.5%) 0 (0%) Abnormal first molars 25 (23.6%) 8 (15.7%) 33 (21%) 2 (1.7%) 468 * 2009 Mutaz B. Habal, MD

The Journal of Craniofacial Surgery & Volume 20, Number 2, March 2009 Crown Morphologic Abnormalities in Cleft TABLE 5. Numbers and Percentages of Individual Crown Morphologic Abnormalities Recorded in the Permanent Mandibular Teeth UCLP BCLP All Cleft Control Total Central 96 52 148 120 Excess mammelons 13 (13.5%) 6 (11.5%) 19 (12.8%) 0 Exaggerated mammelons 7 (7.3%) 3 (5.8%) 10 (6.7%) 0 Peg shape 4 (4.2%) 2 (3.8%) 6 (4.1%) 0 Incisal fissure 1 (1%) 1 (1.9%) 2 (1.3%) 0 Abnormal central 25 (26%) 12 (23%) 37 (25%) 0 (0%) Total lateral 105 50 155 120 Excess mammelons 4 (3.8%) 1 (2%) 5 (3.2%) 1 (0.83%) Exaggerated mammelons 2 (1.9%) 0 2 (1.3%) 1 (0.83%) Peg shape 3 (2.9%) 2 (4%) 5 (3.2%) 4 (3.3%) Incisal fissure 1 (0.95%) 0 1 (0.6%) 0 T shape 0 (0%) 0 0 0 Abnormal lateral 10 (9.5%) 3 (6%) 13 (8.4%) 6 (5%) Total canine 89 46 135 48 Peg-shaped canine 5 (5.6%) 2 (4.3%) 7 (5.2%) 0 Total premolars 152 53 205 84 Abnormal premolars 11 (7.2%) 3 (5.7%) 14 (6.8%) 2 (2.4%) Total first molars 101 55 156 120 Malformed first molars 3 (3%) 1 (1.8%) 4 (2.5%) 2 (1.7%) metacone) were not present in their subjects with clefts. Among the remaining 5 crown morphologic abnormalities, TCMI and incisal fissures were the most frequently found anomalies in their subjects with clefts. 8 In the current study, the most frequently found abnormalities in subjects with clefts were peg-shaped maxillary incisor and missing hypocone, followed by excess mammelons. The least commonly observed abnormalities were T-shaped maxillary lateral incisor, incisal fissure, and fused hypocone. An interesting finding in our cleft sample was that malformed premolars were only observed in the mandibular arch. Teeth are sensitive records of the individual growth history because unlike bone, once formed, they do not remodel and are formed throughout most of the years from the second trimester in utero into young adult life. 16 The morphogenesis of teeth is regulated by interactions between the epithelium and mesenchymal tissue components. More than 300 genes have been associated with patterning and morphogenesis, as well as cell differentiation in teeth. Specific categories are currently of particular interest, which are often called master regulatory genes and genes of signaling networks. Molecular genetic studies have shown that mutations in the genes of the signaling networks can result in disruption of several signaling loops and, depending on the molecule and the timing of its required expression, may produce anomalies in different craniofacial structures. The development of the cranial-oral-facial tissues, including teeth, depends on several key mediators of signaling (Fgf and Bmp families) and transcription factors (Dlx1, Dlx2, Msx1, Msx2, Pax9, Lef1, and Runx2/Cfba1). 21Y29 Orofacial clefting has been also associated with defects in the genetic loci for Tgfs, Fgfs, Bmp, Msx1, Msx2, Tp63, T-Box 22, Para, and Bcl3, which have the most supporting data in published significant results and consistent replication. 21,23,26,28,29,30Y32 Although genetic analysis is still going, the current knowledge would suggest that the genes and transcription factors that cause orofacial clefting may also play key roles in the development and morphogenesis of the teeth. The current study and the studies of Jordan et al, 5 Kraus et al, 6 and Schroeder and Green 8 demonstrated a significant increase in the incidence of crown morphologic abnormalities in individuals with clefts when compared with subjects without clefts. It is also notable that crown morphologic abnormalities occurred throughout the entire dentition and not merely in the maxillary teeth in the vicinity of the cleft. Furthermore, crown morphologic abnormalities did not follow any predictable pattern but seemed to occur haphazardly both in type and location. The results of the current study combined with the previously reported results of studies of other dental abnormalities, 4Y6,8,9,11Y13,16,17 external body and visceral malformations, 1Y3 and recent investigations of the molecular mechanisms regulating embryonic development of cranial-oral-facial tissues 21Y32 lend support to the hypothesis that cleft lip/palate is part of a widespread but irregular pattern of disturbance throughout the body. REFERENCES 1. Kraus BS, Kitamura H, Ooe T. Malformations associated with cleft lip and palate in human embryos and fetuses. Am J Obstet Gynecol 1963;86:321Y328 2. Kitamura H, Kraus BS. Visceral variations and defects associated with cleft lip and palate in human fetuses: a macroscopic description. Cleft Palate J 1964;16:99Y115 3. Kraus BS, Ahern S. Deviations in the sequence of appearance of primary centers of ossification in the feet of human fetuses with cleft lip and/or palate. Am J Anat 1966;118:735Y742 4. Bohn A. Dental anomalies in harelip and cleft palate. Acta Odontol Scand 1963;21:1Y109 5. Jordan RE, Kraus BS, Neptune CM. Dental abnormalities associated with cleft lip and/or palate. Cleft Palate J 1966;3:22Y55 6. Kraus BS, Jordan RE, Pruzansky S. Dental abnormalities in the deciduous and permanent dentitions of individuals with cleft lip and palate. J Dent Res 1966;45:736Y746 * 2009 Mutaz B. Habal, MD 469

Rawashdeh and Abu Sirdaneh The Journal of Craniofacial Surgery & Volume 20, Number 2, March 2009 7. Foster T, Lavelle C. The size of the dentition in complete cleft lip and palate. Cleft Palate J 1971;8:177Y184 8. Schroeder DC, Green LJ. Frequency of dental trait anomalies in cleft, sibling, and noncleft groups. J Dent Res 1975;54:802Y807 9. Sofaer JA. Human tooth-size asymmetry in cleft lip with or without cleft palate. Arch Oral Biol 1979;24:141Y146 10. Ranta R. A review of tooth formation in children with cleft lip/palate. Am J Orthod Dentofacial Orthop 1986;90:11Y18 11. Werner S, Harris E. Odontometrics of the permanent teeth in cleft lip and palate systemic size reduction and amplified asymmetry. Cleft Palate J 1989;26:36Y41 12. Harris EF, Hullings JG. Delayed dental development in children with isolated cleft lip and palate. Arch Oral Biol 1990;35:469Y473 13. Harris EF. Timing of cleft insults as viewed from development of the dentition. Am J Phys Anthropol 1993;16(suppl):104 14. Andreson PJ, Moss ALH. Dental findings in parents of children with cleft lip and palate. Cleft Palate J 1996;33:436Y439 15. Narayanan A, Smith S, Townsend G. Dental crown size in individuals with cleft lip and palate. J Dent Res 1999;78:952 16. Harris EF. Dental development and anomalies in craniosynostoses and facial clefting. In: Mooney MP, Siegel MI, eds. Understanding Craniofacial Anomalies: The Etiopathogenesis of Craniosynostosis and Facial Clefting. New York, NY: John Wiley & Sons, 2002:425Y468 17. Rawashdeh MA, Bakir IF. The crown size and sexual dimorphism of permanent teeth in Jordanian cleft lip and palate patients. Cleft Palate Craniofac J 2007;44:155Y162 18. Olin WH. Dental anomalies in cleft lip and palate patients. Angle Orthod 1964;34:119Y123 19. Turner CG II, Nichol CR, Scott GR. Scoring procedures for key morphological traits of the permanent dentition: the Arizona State University Dental Anthropology System. In: Kelley MA, Larsen CS, eds. Advances in Dental Anthropology. New York, NY: Wiley-Liss, 199:13Y31 20. Dahlberg A. The changing dentition of man. J Am Dent Assoc 1945;32:676Y690 21. Thesleff I. The genetic basis of normal and abnormal craniofacial development. Acta Odontol Scand 1998;56:321Y325 22. Thesleff I, Keranen S, Jernvall J. Enamel knots as signaling centers linking tooth morphogenesis and odontoblast differentiation. Adv Dent Res 2001;15:14Y18 23. Slayton RL, Williams L, Murray JC, et al. Genetic association studies of cleft lip and/or palate with hypodontia outside the cleft region. Cleft Palate Craniofac J 2003;40:274Y279 24. Laurikkala J, Kassai Y, Pakkasjarvi L, et al. Identification of a secreted BMP antagonist, ectodin, integrating BMP, FGF, and SHH signals from the tooth enamel knot. Dev Biol 2003;264:91Y105 25. Miletich I, Sharpe PT. Normal and abnormal dental development. Hum Mol Genet 2003;12(special issue 1):R69Y73 26. Vieira AR, Meira R, Modesto A, et al. MSX1, PAX9, and TGFA contribute to tooth agenesis in humans. J Dent Res 2004;83:723Y727 27. Thesleff I. The genetic basis of tooth development and dental defects. Am J Med Genet A 2006;140:2530Y2535 28. De Coster PJ, Mortier G, Marks LA, et al. Cranial suture biology and dental development: genetic and clinical perspectives. J Oral Pathol Med 2007;36:447Y455 29. Arosarena OA. Cleft lip and palate. Otolaryngol Clin North Am 2007;40:27Y60 30. Wyszynski DF, Beaty TH, Maestri NE. Genetics of nonsyndromic oral clefts revisited. Cleft Palate Craniofac J 1996;33:406Y417 31. Schutte BC, Murray JC. The many faces and factors of orofacial clefts. Hum Mol Genet 1999;8:1853Y1859 32. Jugessur A, Murray JC. Orofacial clefting: recent insights into a complex trait. Curr Opin Genet Dev 2005;15:270Y278 470 * 2009 Mutaz B. Habal, MD