New Neonatal Classification of Unilateral Cleft Lip and Palate Part 1: To Predict Primary Lateral Incisor Agenesis and Inherent Tissue Hypoplasia

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1 The Cleft Palate Craniofacial Journal 51(4) pp July 2014 Ó Copyright 2014 American Cleft Palate Craniofacial Association ORIGINAL ARTICLE New Neonatal Classification of Unilateral Cleft Lip and Palate Part 1: To Predict Primary Lateral Incisor Agenesis and Inherent Tissue Hypoplasia Christian Delestan, D.D.S., Ph.D., Pedro Montoya, M.D., Ph.D., Jean-Charles Doucet, M.D., D.M.D., M.Sc., Michèle Bigorre, M.D., Caroline Baümler, D.D.S., Christian Herlin, M.D., M.Sc., Jean-Pierre Daures, M.D., Ph.D., Guillaume Captier, M.D., Ph.D. Objectives: To bring a neonatal classification system of unilateral cleft lip and palate (UCLP) and to correlate this classification with the distribution of the primary lateral incisor. Design: Retrospective with longitudinal follow-up. Setting: Tertiary. Patients: One hundred twenty-one patients with treated UCLP. Thirteen plaster casts were used as controls. Main Outcome Measures: The UCLP patients were classified anatomically into four categories: class 1 corresponds to a maxillary arch with a narrow alveolar cleft, class 2 corresponds to a balanced form, class 3 corresponds to a wide cleft and short maxilla, and class 4 corresponds to a wide cleft and long maxilla. Clinical validity was evaluated with a concordance analysis (intra- and interexaminer). This anatomical classification was also corroborated with an automatic classification determined by morphometric parameters measured on neonatal maxillary plaster casts. The class was finally correlated with the distribution of the primary lateral incisor. Results: Clinical classification of UCLP found 12 cases of class 1 (9.9%), 36 cases of class 2 (29.8%), 47 cases of class 3 (38.8%), and 26 cases of class 4 (21.5%). The clinical classification was validated with a good intra- and interexaminer concordance analysis (j..6). The automatic classification was close to the clinical classification in 84%. The correlation was ideal in class 1 (100%), almost perfect in class 4 (92%), but lower for class 2 (74%) and class 3 (70%). The primary lateral incisor was usually duplicated in class 1, whereas class 2 and class 4 were correlated with a primary lateral incisor located on the lateral palatal segment. Class 3 was associated with an agenesis of the primary lateral incisor (P,.001). Conclusions: UCLP can be classified into four different classes at birth, which can all give information about the inherent tissue hypoplasia and the distribution of the primary lateral incisor. KEY WORDS: cleft lip, cleft palate, growth, incisor Dr. Delestan is dentist, Dr. Montoya (deceased) was pediatric plastic surgeon, Dr. Doucet is oral and maxillofacial surgeon, Dr. Bigorre is pediatric plastic surgeon, Dr. Baümler is orthodontist, Dr. Herlin is orthodontist, and Dr. Captier is pediatric plastic surgeon, Département de chirurgie orthop edique et plastique p ediatrique, Hopital ˆ Lapeyronie, CHRU Montpellier, France. Dr. Doucet is oral and maxillofacial surgeon, Department of Oral and Maxillofacial Surgery, Dalhousie University, Halifax, Canada. Dr. Daures is epidemiologist and public health professor and Dr. Captier is professor, Cleft and Craniofacial Pediatric Plastic Surgery Department, Labroratoire d epid emiologie, statistiques et recherche cliniques, IURC, Université Montpellier, France. Ethics: This research has followed the principles outlined in the Declaration of Helsinki. Paper presented at 7 e congrès de l association francophone des fentes faciales, March 23 to 24, 2012, Paris, France Financial disclosure: No commercial associations or financial disclosures for all authors. Submitted May 2012; Revised October 2012, January 2013; Accepted January Address correspondence to: Dr. Guillaume Captier, Unit e de Chirurgie Plastique P ediatrique, Hopital ˆ Lapeyronie, 371 avenue du doyen Gaston Giraud, Montpellier, France. g-captier@ chu-montpellier.fr. DOI: / The anatomo-clinical classification of facial clefts of Kernahan and Stark (Kernahan and Stark, 1958) adopted in 1967 is currently used. The American Cleft Palate Association committee on nomenclature recognizes three principal classes: (1) clefts of the primary palate (cleft lip 6 alveolus), (2) clefts of the secondary palate (cleft palate), and (3) the combination of both (cleft lip and palate; Whitaker et al., 1981). Midfacial growth is multifactorial and depends on the initial anatomo-clinical form, the treatment protocol and surgical techniques, and the inherent growth potential of the child, explaining interindividual variations (Bardach, 1990; Friede, 1998; Peltomaki et al., 2001; Reiser et al., 2010). To better understand the prognosis and effects of treatments on maxillary growth, long-term follow-up is essential. It is thus important to establish a very precise initial evaluation 392

2 Delestan et al., NEONATAL CLASSIFICATION OF UCLP: PART of the malformation to avoid comparing different entities and making errors of appreciation. All types of unilateral cleft lip and palate (UCLP) do not resemble each other. In general, the criteria used to establish these differences are based on the extent of the nasolabial deformity, the width of the cleft, and the cleft palate severity. These criteria used for the surgical treatment give little information about the prognosis of maxillary growth in teenagers and young adults. Furthermore, normal dental development is one of the important determining factors for maxillary growth. In UCLP, dental agenesis of the lateral incisor occurs in about halfofthecases(delestan et al., 1998; Tsai et al., 1998; Lourenco Ribeiro et al., 2003; Tortora et al. 2008), which makes orthodontic treatment and prosthetic dental rehabilitation more difficult. Teeth are also a marker of maxillary embryological development (Couly and Monteil, 1982), and their absence can be viewed as a sign of worse prognosis. Even if not consensual, Tsai et al. (1998) proposed a classification of UCLP based on the presence or absence of the primary lateral incisor and its localization on the large or small segment. The purpose of our work is to establish a neonatal classification system of UCLP that can initially indicate the severity of the UCLP and predict the growth potential of the maxilla. We hypothesized that the maxillary arch form at birth can predict the maxillary growth potential and can be indicative of permanent lateral incisor agenesis. In this first article, the aims of are (1) to report a classification of UCLP based on the analysis of the initial deformities (size of the cleft and shape of the maxilla) and (2) to correlate this classification with the distribution pattern of the primary lateral incisor. The second article will correlate the initial deformities with the sagittal growth of the maxilla and the distribution of the permanent lateral incisor. MATERIALS AND METHODS This retrospective study reviewed cleft patients with strict longitudinal follow-up, from birth until the age of 6 to 7 years, treated at the Lapeyronie Hospital, Montpellier, France. All of the consecutively treated cleft lip and palate (CLP) patients, between 1978 and 2004, were reviewed. This research has followed the principles outlined in the Declaration of Helsinki. The inclusion criteria were UCLP patients with longitudinal follow-up, born at term, and operated by the same surgeon with the same treatment protocol, which was performed until 2005 (Montoya et al., 2002). A maxillary plaster cast taken within 1 week after birth as well as a panoramic radiograph and maxillary cast taken at the age of 6 to 7 years were required for the chart to be complete. Incomplete files, bilateral CLP, patients lost to follow-up, and syndromic cleft patients were excluded from the study. Incomplete CLP and CLP with Simonart s bands were also excluded. A series of 13 maxillary plaster casts of term infants free from any craniofacial pathology were used as controls for the morphometric study. Anatomical Classification of the Maxillary Arch at Birth Although the malformation is of the same type, a morphological diversity of the maxillary arch exists in the UCLP, as it was already proposed by Foster (1980). Using the clinical team s experience and observations of plaster casts, the anatomical shape of the maxillary arch of UCLP patients can be classified into four different categories (Fig. 1). Class 1: corresponds to a maxillary arch with a very narrow alveolar cleft. The two cleft margins are sometimes in closed contact with a tiny bridge. Class 2: corresponds to a balanced form in which the shape of the maxillary arch is close to the controls. The cleft is narrow, and the small segment (lateral palatal segment) is not displaced, presenting a harmonious curve without a sagittal shift compared with the large segment. Class 3: corresponds to a wide and short form. In this case, the transverse distance of the maxillary arch is definitely more important than its sagittal length when compared with the controls. Furthermore, the nasal septum is significantly deviated anteriorly with a torque effect. Class 4: corresponds to a wide and long form. The transverse distance is close to class 3, but the sagittal length of the arch is increased when compared with the controls. The septum is rectilinear. The clinical classification was initially carried out by two examiners: a cleft surgeon and a cleft team dentist. A concordance analysis (intra- and interexaminer) was then performed to verify the reliability and the clinical interest of the neonatal classification. Fifty casts were chosen randomly from the group of 121 patients and classified by four different examiners (one dentist, one orthodontist, one pediatric plastic surgeon, and one oral and maxillofacial surgeon). The intraexaminer reliability was measured by comparing two classifications made by each examiner, with 15 days of interval between the readings. The interexaminer concordance was determined by comparing the results of the four examiners. Measurements of the Maxillary Casts The clinical classification was confronted to a morphometric analysis of the plaster casts. The chosen landmarks in Figure 2 were those classically used for the analysis of the edentulous maxillary arch (Aduss and Pruzansky, 1968; Berkowitz and Pruzansky, 1968; Pruzansky, 1968; Deffez et al., 1975; Huddart et al., 1978; Kriens, 1989). The median incisive point (I), and the right (C) and left (C 0 ) canine points (corresponding to

3 394 Cleft Palate Craniofacial Journal, July 2014, Vol. 51 No. 4 FIGURE 1 Clinical classification of unilateral cleft lip and palate. The class 1 arch is represented by #1; class 2 by #2; class 3 by #3; class 4 by #4. the distal ends of the canine prominences where the lateral sulcus crosses the crest of the ridge) were used to analyze growth of the anterior part of the maxillary arch. The right (T) and left (T 0 ) tuberosity points corresponded to the posterior limit of the maxillary arch at the molar level. In the UCLP, the points P and L, respectively, represented the premaxillary margin of the cleft on the FIGURE 2 Maxillary cast landmarks. large segment and the mesial margin of the lateral palatal segment (small segment). The distance between P and L determined the width of the alveolar cleft. The sectorial analysis of the maxillary arch was performed using the linear distance between two landmarks, corresponding to the chord of the arc. Sectors I-C, C-T, I-P, L-C 0,C 0 -T 0, C-C 0, and T-T 0 were measured. The maxillary arch was then modeled using the polygon I-C-C 0 -T-T 0. All measurements were taken three times with the use of an electronic digital caliper (VAP 6511 electronic) by the same operator, and the mean was calculated. The instrument s precision was of 0.01 mm, and all measurements were made directly on the plaster cast. The isobarycenter (B) of polygon I-C-T-T 0 -C 0 -L-P and the sagittal length of the maxillary arch (corresponding to the height of triangle I-T-T 0 ) were mathematically calculated. The models of each class of UCLP were superposed on the control models. This superposition was made starting from the isobarycenter after size standardization. Automatic classification (cluster analysis) was used to determine the natural classes in a unit characterized by several variables. The four parameters studied were (1) the width of the cleft (P-L), (2) the sagittal length of the maxillary arch (height of triangle I-T-T 0 ), (3) the

4 Delestan et al., NEONATAL CLASSIFICATION OF UCLP: PART TABLE 1 Distances Measured on Neonatal Maxillary Plaster Casts (mm) Control Group (n ¼ 13) Total UCLP (n ¼ 121) Class 1 (n ¼ 12) Class 2 (n ¼ 36) Class 3 (n ¼ 47) Class 4 (n ¼ 26) Sagittal Length C-C T-T C 0 -T P-L intercanine width (C-C 0 ), and (4) the intertuberosity width (T-T 0 ). Distribution of the Primary Maxillary Lateral Incisor on the Cleft Side All patients were followed longitudinally with clinical examinations. At the age of 6 to 7 years, a maxillary cast and a panoramic radiograph were performed. Relationships between dental anomalies and the severity of the anatomical deformity have been previously reported (Pfeifer, 1966; Zilberman, 1973; Ehmann et al., 1976; Delestan et al., 1998). The classification of Tsai et al. (1998) was used to classify the distribution of the primary maxillary lateral incisor on the cleft size. This classification is taking account of the presence or absence of the primary lateral incisor, as well as its localization on the large or small segment. Therefore, the distribution pattern is classified in four groups: (1) AB ¼ agenesis; (2) X ¼ localized on the large segment, mesial to the cleft; (3) Y ¼ localized on the small segment, distal to the cleft; and (4) XY ¼ duplicated, on each side of the cleft. The form of the primary maxillary lateral incisor on the cleft side was not studied. Statistical Analysis The first level of analysis was univariate to allow the simple description of the various parameters. A 95% confidence interval (CI) was used, and a level of P,.05 was considered statistically significant. First, a cluster analysis using the K mean method was realized. The group number was fixed at 5 to verify the concordance between the clinical and morphometric classification. The relationship between the clinical classes and the position of the primary lateral incisor was then analyzed using a factorial correspondence analysis on a Burch table. The Kappa (j) coefficient of Cohen (with a 95% CI) was used for the statistical concordance analysis. The concordance was considered to be very good with a j.8, good with a j between.6 and.8, average with a j between.6 and.4, and poor with a j,.4 (Landis and Koch, 1977). All statistical analyses were realized using the Statistical Analysis System software and Syste` me Portable pour l Analyse des Donn ees software of the Institut Universitaire de Recherche Clinique and the Biostatistique Epid emiologie Sant e Publique et Information Médicale software of the teaching hospital of Nımes. ˆ RESULTS Of 713 clefts operated between 1974 to 2004, 399 were UCLP and a total of 121 charts met the inclusion criteria (79 boys, 42 girls). Of these, 81 were left UCLP and 40 were right UCLP. Anatomical Classification of the UCLP The clinical classification of UCLP maxillary arches found 12 cases of class 1 (9.9%), 36 cases of class 2 (29.8%), 47 cases of class 3 (38.8%), and 26 cases of class 4 (21.5%). The width of the cleft (P-L) ranged from 0 to 16.5 mm, with an average of mm (n ¼ 121). The average distance was of mm in class 1 cases, mm in class 2 cases, mm in class 3 cases, and in class 4 cases (Table 1). A positive correlation was present between the width of the cleft and transverse measurements (C-C 0 and T- T 0 ). The intertuberosity widths T-T 0 were similar in each class, apart for slightly lower values for class 1 cases. The intercanine widths C-C 0 increased progressively from class 1 to class 4 cases. This distance was lower than the intertuberosity width T-T 0 in classes 1 and 2 but equal or greater in class 3 and 4. The sagittal length (height of triangle I-T-T 0 ) was different in each class. These differences were secondary to the overall shape of the maxillary arch and were especially due to the deformation and sagittal shift of the premaxillary segment. Septal deviation was probably partly responsible for this situation. Automatic Classification and Superposition Cluster analysis was carried out in 134 cases: 121 UCLP and 13 controls (Table 2). The results showed that the automatic classification was close to the clinical classification in 84% of the cases. A total of 22 cases were classified differently. An ideal concordance was found in class 1 (100%), with the 12 maxillary arches classified clinically also corresponding to a distinct

5 396 Cleft Palate Craniofacial Journal, July 2014, Vol. 51 No. 4 TABLE 2 Distribution Between Clinical Classification (Arch Class) and Automatic Classification of the Arches Based on Morphometric Analysis (Cluster)* Cluster n (%) n (%) Arch Class 0 17 (12.7) 13 (9.7) (9.0) 12 (9.0) (24.6) 36 (26.9) (29.1) 47 (35.1) (24.6) 26 (19.4) 4 Total Total * Arch class 0 corresponds to the control population. cluster based on morphometric classification. This concordance was almost perfect in class 4 (92%), with 24 of the 26 class 4 cases classified clinically corresponding to the same cluster. This concordance was lower for class 2 (74%), and class 3 (70%). Four UCLP cases were classified as normal with the automatic classification. The superposition of different classes of UCLP maxillary arches on the control group is illustrated in Figure 3. The arches of classes 1 and 2 were similar. Their isobarycenter was shifted posteriorly compared with the controls. Class 3 cases were wide and short compared with the controls. The superposition of the intertuberosity width T-T 0 compared with the isobarycenter showed a relative hypoplasia of the anterior maxillary arch, which was severe in class 3 and moderate in classes 1 and 2. Class 4 cases were broader and longer than the controls. Concordance Analysis to Validate the Classification The reliability and the clinical interest of the neonatal classification were validated with the concordance analysis of 50 casts. The interexaminer concordance (between four judges) was found to be good, with an average Kappa of.63 (j ¼.40 to.83; 95% CI ¼.45 to.81). Similarly, the intra-examiner concordance was also good, with an average Kappa of.71 (j ¼.63 to.91; 95% CI ¼.66 to.76), showing the simplicity and reproducibility of the classification in the cleft team. Class 2 and class 4 were most often confounded during this FIGURE 3 Morphometric analysis of the four classes of unilateral cleft lip and palate. The polygon of each class of cleft patients (in gray; thick line corresponding to the alveolar cleft P-L) is superposed on the polygon of normal newborn babies (white).

6 Delestan et al., NEONATAL CLASSIFICATION OF UCLP: PART FIGURE 4 Association between maxillary arch class and the distribution of the primary maxillary lateral incisor on the cleft side. concordance analysis. Class 1 and class 3 were easily identified. Association Between the Maxillary Arch Class and the Distribution of the Primary Maxillary Lateral Incisor on the Cleft Side Results of associations between the anatomical class and the distribution pattern of the primary lateral incisor (independent to its form) are shown in Figure 4 and Table 3. The primary maxillary lateral incisor on the cleft side was absent in 24% (n ¼ 29), duplicated in 14% (n ¼ 17), localized on the large segment in 8% (n ¼ 10), and localized on the small segment in 54% (n ¼ 65). This distribution differed according to the anatomical class of the maxillary arch (P,.001). A link was found between class 1 and a duplicated lateral incisor (XY group). Class 3 cases were associated with missing lateral incisors (AB group). Classes 2 and 4 were correlated with a lateral incisor located on the small segment (Y group). DISCUSSION Based on the shapes of neonatal maxillary arches, the identification of four classes of UCLP can be described clinically. Classes 1 and 2 were balanced with a width-tolength ratio similar to the controls. The shape of the arch is not ruptured, and no anteroposterior shifts are present. Class 3 cases are characterized by a wide and short arch. The nasal septum is strongly deviated anteriorly, and anterior maxillary hypoplasia appears to be present. Finally, class 4 cases are broad and long, with no deviation of the nasal septum. After morphometric analysis (size and shape), two groups of maxillary arch can be distinguished: the balanced forms, represented by classes 1 and 2, and the unbalanced forms, represented by classes 3 and 4. Interestingly, the sagittal length and the intercanine width were the most discriminating parameters. As shown by the concordance analysis, classes 2 and 4 could be confounded, but classes 1 and 3 were easily distinguished. It turns out that there is therefore a challenge to correctly separate classes 2 and 4 since they are clinically confused, even if they are morphometrically not identical. Indeed, even if class 4 is wider and longer than the controls, this difference is not always easy to visualize clinically without any measurement. On the other hand, classes 2 and 3, which may have relatively similar sizes, are easier to distinguish clinically because of their very distinctive outline. To the best of our knowledge, this is the first study that accounted for the form of the nasal septum as a discriminating parameter in UCLP. Septal deviation is usually present when the arch is sagittally short. It seems that the septum has to bend to adapt the small maxilla. Characterization of the anatomical class at birth is thus possible by associating the width of the cleft with the arch form, the curvature of the septum, and the overall sagittal dimension of the maxilla. The neonatal clinical classification is practical, easy, and reproducible, which was shown by a good intra- and interexaminer concordance analysis. This classification also tends to highlight a relationship between the neonatal severity of the UCLP and the distribution pattern of the primary maxillary lateral incisor on the cleft side. Duplications of the primary lateral incisor are correlated with class 1, which is the least severe form. Agenesis of the primary lateral incisor is associated with class 3, which is the most severe form. On the other hand, its presence on the lateral palatal segment (small segment) is found in classes 2 or 4, which can be differentiated from each other by using the width of the cleft and the arch dimensions. Some forms can also be difficult to classify, but the longitudinal follow-up of these patients will permit one to confirm or change the initial class. The advantage of this classification is to identify potentially difficult cases, to better inform the parents TABLE 3 Distribution of the Primary Maxillary Lateral Incisor on the Cleft Side Primary Lateral Incisor X Y XY AB Class 1 0 (0%) 4 (33%) 8 (67%)* 0 (0%) Class 2 2 (6%) 27 (75%)* 4 (11%) 3 (8%) Class 3 6 (13%) 17 (36%) 3 (6%) 21 (45%)* Class 4 2 (8%) 17 (65%)* 2 (8%) 5 (19%) P value,.001* * Statistically significant.

7 398 Cleft Palate Craniofacial Journal, July 2014, Vol. 51 No. 4 about the long-term evolution of their child, and, if required, to better adapt the procedures. Naturally, this initial classification needs to be reevaluated at the start of the mixed dentition period to confirm the prognosis (Delestan et al., 2002). A need to better differentiate, within similar malformations, the different varieties of associations between labial, alveolar, and palatal clefts has been present since the development of the first classifications system. This fact explains the multiplicity of proposed classifications (Davis and Ritchie, 1922; Veau and Borel, 1931; Fogh-Andersen and Aagesen, 1942). The embryological approach favored the anatomo-clinical classifications of Kernahan and Stark (1958) and Kernahan (1971). On the other hand, the first computerized classifications were also proposed (Vilar- Sancho, 1962), as well as quantifications of the shape and hypoplasia of the maxillary clefts (Aduss and Pruzansky, 1968; Berkowitz and Pruzansky, 1968; Berkowitz et al., 1974; Hotz and Gnoinski, 1979; Huddart, 1979). However, the main objective of these studies was generally to analyze the results of presurgical orthopedic treatments, without any distinction of the different neonatal clinical classes within each anatomo-clinical form. Moreover, the study population in all of these series was heterogeneous (shown by the importance of the standard deviations). It thus appears difficult to compare or adapt the growth effects of different treatments when different subpopulations exist within the same anatomo-clinical form. The close embryologic relation between skeletal malformations and dental anomalies in clefts has been known for a long time (Tondury, 1950; Pfeifer, 1966; Zilberman, 1973; Ehmann et al., 1976). Interactions between the mesenchyme, originating from neural crest cells, and the dental epithelium are essential for the differentiation of odontoblasts (Hurmerinta and Thesleff, 1981; Thesleff and Hurmerinta, 1981). For teeth at the cleft margins, a positive correlation exists between the width of the cleft and dental agenesis (Ehmann et al., 1976). Consequently, the missing lateral incisor can be considered as the malformative expression of a localized hypoplasia. Contrarily, the presence of a duplication is in favor of a minor hypoplasia of the cleft and thus possibly indicates a good prognosis for growth. Unfortunately, the presence, absence, or duplication of the primary lateral incisor is usually not known at birth because a radiological examination is typically not indicated. Therefore, this distribution pattern cannot be used at birth as a prognostic factor. Fortunately, the classification proposed in our study was closely associated with the distribution pattern of the primary lateral incisor categorized by Tsai et al. (1998). It thus seems possible to use this arch form classification at birth for prediction. Whenashortarchassociatedwithawidecleftispresentat birth, a severe form will ensue with probable agenesis of the primary lateral incisor. On the other hand, the other classes predict a duplication or the presence of the primary lateral incisor on the small segment. For many years, outcome evaluation of different treatment protocols was undertaken with minimal consideration of the neonatal situation. However, the heterogeneity of UCLP demonstrated in this work puts into perspective the role of the treatment protocol. A more detailed analysis of the different subpopulations seems necessary to distinguish between the role of the therapeutic actions and the growth potential of the child. The cleft width has been previously reported to be a negative predictor (Peltomaki et al., 2001; Reiser et al., 2010), but the other predictors that may emerge from this work are of major importance in the treatment of child malformations. Indeed, observations taken at specific ages, confirming the initial classification, will help alleviate some therapeutic sequences to maximize the growth potential of the child. The predictive interest of this classification on the growth potential of UCLP and the presence of the permanent maxillary lateral incisor on the cleft side will be presented in the second part of our work. CONCLUSIONS The width of the cleft is not an isolated prognostic factor. 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