Appropriateness of standard cephalometric norms for the assessment of dentofacial characteristics in patients with cleidocranial dysplasia

Objectives: Cleidocranial dysplasia (CCD) is a rare skeletal syndrome affecting craniofacial and dental development. As a consequence, conventional cephalometric landmarks may not be valid for CCD patients, and the appropriateness of norms used for the general population should be critically discussed. Methods: Five patients 9- to 22-year-old (three females, two males) with CCD were included. Lateral-cephalograms, orthopantomographies, and intra-oral photos were retrospectively analysed. Lateral-cephalograms of 50 normal controls (ten for each CCD patient) matched for age and sex were selected from an online database. Cephalometric measurements of each CCD patients were compared with average values of matched controls using Wilcoxon signed-rank test for paired values (α = 0.05). Results: In CCD patients, a shortening of the cranial base was present (ΔSN = −17.1 mm, p = 0.043). Thus, the mandible (ΔSNPg = +9.5°, p = 0.043) and the maxilla (ΔSNA = +11.2°, p = 0.043) showed protrusion compared to the cranial base, despite a reduced maxillary (ΔCo-A = −15.1 mm, p = 0.043) and mandibular (ΔCo-Gn = −15.2 mm, p = 0.080) length. The mandibular divergence was reduced (ΔSN/GoGn = −6.4°, p = 0.043), a reduced overbite was present (ΔOverbite = −2.9 mm, p = 0.043), and the interincisal angle was increased (ΔInterincisalAngle = +13.7°, p = 0.043), mainly due to retro-inclination of lower incisors. Conclusions: Standard cephalometric norms for the assessment of horizontal jaw position may not be applicable to CCD patients because of a reduced anterior cranial base length compared to normal subjects. Vertical relationships may not be affected, and mandibular hypodivergency was confirmed.


Introduction
Cleidocranial dysplasia (CCD) is a rare genetic syndrome with an estimated prevalence of 1:1.000.000 and characterised by autosomal dominant inheritance. 1 It is caused by mutations affecting the core-binding factor subunit alpha-1 (Cbfa1) 2 on the chromosome 6p21. 3 Involved in the differentiation of osteoblasts, 4 Cbfa1 is part of the fibroblast growth factor and bone morphogenetic protein pathways in the development of teeth and bones. 5 Cbfa1 is also a major regulator of chondrocyte differentiation, 6 related to endochondral formation of long bones and vertebrae.
Commonly, the diagnosis of CCD is clinical, and hypoplastic clavicles, open fontanelles, and supernumerary teeth constitute a characteristic triad. 1 In patients with atypical characteristics, molecular analysis can be used for differential diagnosis, 7 as variable loss of function of Cbfa1 may give rise to a clinical variability ranging from isolated primary dental anomalies to classic CCD. 8 Craniofacial abnormalities are expressed in over 80% of the cases, 9 including skeletal class III with mandibular prognathism, [10][11][12] and a short anterior cranial base. 13,14 Furthermore, CCD patients often presents a broad forehead, a depressed nasal bridge, a delayed closure of fontanelles and sutures, reduced paranasal sinuses and even missing parietal and nasal bones. 1,15 Dental signs are expressed in over 90% of patients, 9 including the retention of the deciduous dentition and the presence of supernumerary teeth, 10,11 which compromise normal dental eruption. Such anomalies contribute to crowding and malocclusion often including open-bite 11 and cross-bite. 10,11 Although previous case-reports have described cephalometric characteristics of patients with CCD [10][11][12]14 and reviews have summarised common craniofacial features, 1,9 the literature is lacking of controlled studies. In fact, it seems that only one previous work compared the cephalometric characteristics of CCD patients with normal subjects, concluding that affected individuals have relatively normal jaw proportions in relation to the cranial base. 16 However, CCD patients usually present a limited growth of the cranial base, 13 and it is important to critically analyse the appropriateness of using standard cephalometric norms for these patients. In fact, despite maxillary hypoplasia has been commonly described in CCD patients, 1,9,14 the reported cephalometric values have been contradictory, showing SNA angles close to 90°. 10,11 The objective of the present study was to critically investigate the application of conventional cephalometric analysis in CCD patients, to properly understand craniofacial alterations in these subjects.

Subjects
Lateral-cephalograms, orthopantomographies, and intra -oral photos of Caucasian patients affected by CCD from the Dental School of the hospital Spedali Civili di Brescia were retrospectively analysed. Five patients, three females (9-, 13-and 22-years-old) and two males (14-and 16-years-old), were included in the study. In addition, ten lateral-cephalograms matched for sex and age (same year) were selected as controls for each patient with CCD, for a total of 50 controls. Controls were subjects with Angle class I occlusion, which were obtained from the online database of the Craniofacial Growth Legacy Collection. 17 The study design was modified from Kreiborg et al., which was structured for the comparison of a limited number of rare syndromic cases with a larger control group. 13 The study was approved by the internal review board of the hospital Spedali Civili di Brescia (Approval number: SINDCRAN NP2882).

Analysis of lateral radiographs
The cephalometric analysis was performed using a computer software (OpenCeph 3.3.0, developed by Dr Bruno Oliva). No correction was applied for the X-ray magnification. Horizontal skeletal measurements, vertical skeletal measurements, dento-skeletal measurements, and dento-dental measurements were recorded according to the European Board of Orthodontics guidelines, 18 with additional parameters from the analysis of Jacobson, 19 McNamara, 20 and Jarabak 21 (Table 1 and Figure 1A).

Statistical analysis
After an initial calibration on five lateral cephalograms, measurements were taken by one assessor (F.D.R.), who repeated the measurements after a wash-out period of about one month. The single measure intraclass correlation coefficient (ICC) for absolute agreement was used to calculate the intra -assessor agreement. 22 ICC was considered "poor" if <0.5, "fair" from 0.5 to 0.7, "good" from 0.7 to 0.8, and "excellent" if >0.8. 23 The method error was estimated with Dahlberg's formula. 24 The average between the two repeated measurements was calculated and used for analysis. Results were reported as mean and standard deviation (SD). The data of each CCD patient were compared with the average value of 10 matched controls. Non-parametric tests were adopted, and the two groups were compared with the Wilcoxon signed-rank test for paired values. Data analysis was performed with statistical software (SPSS © V23.0, IBM, US) at significance level α = 0.05. Orthopantomographies and intra -oral photos of CCD patients were used for further qualitative description of dental and facial characteristics.

Results
The intra -assessor agreement was generally lower for measurements involving the incisors and higher for the others, ranging between 0.628 (IncInf/GoGn) and 0.908 (SNA) for angular measurements, and between 0.428 (Overbite) and 0.995 (SN) for linear measurements. The method error ranged between 1.6° (ANPg) and 4.8° (InterincisalAngle) for angular measurements, and between 0.4 mm (Wits) and 2.0 mm (Co-Gn) for linear measurements. Table 1 Identification of anatomical points adopted in the cephalometric analysis

Dental characteristics
In CCD patients, the interincisal angle was significantly higher compared to controls (ΔInterincisalAngle =+13.7°, p = 0.043), mainly due to retro-inclination of the lower incisors (ΔIncInf/GoGn = −9.1°). An anterior open-bite (overbite = −0.4 mm) was also present in CCD patients compared to controls ( Table 2, Figures 1B and 3), as confirmed by the intra-oral photos (Supplementary Material 1). All patients presented one or multiple retained deciduous teeth. One patient showed impacted upper central and lateral incisors, and one patient an impacted upper second premolar. Furthermore, one patient presented supernumerary upper central incisors (Table 3).

Other characteristics
In four subjects, the nasal bones were difficult to identify on cephalometric radiographs, probably due to their underdevelopment or absence. No other evident abnormality of craniofacial bones was noticed. Although the frontal sinus was not recognisable on cephalometric radiographs, the maxillary sinuses appeared normally developed on cephalometric and panoramic radiographs. No palatoschisis was noticed from radiographs or intra-oral photos (Supplementary Material 1).

Skeletal characteristics
The present study showed a mean SNA angle of 92.8° in CCD patients, which was significantly higher compared to controls (+11.2°), indicating maxillary protrusion with respect to a normal value of about 81.0°. 25 Accordingly, previous studies analysing CCD patients reported SNA values ranging from 87.4° to 97.0°, 10-12 confirming a forward position of the maxilla with respect to the anterior cranial base. Since the SNA angle may not discriminate the contribution of maxillary size to the overall maxillary position, the maxillary length was also measured. Perhaps surprisingly, and in disagreement with a high SNA angle, a significantly shorter maxilla was shown in CCD patients compared to controls (ΔCo-A = −15.1 mm), in agreement with the published literature. 1,[9][10][11]14 Regarding the mandible, the present study showed a mean SNPg value of 91.1°, which was significantly higher than the controls (+9.5°). Accordingly, previous studies reported CCD patients to present SNB values      [10][11][12] supporting the presence of the prognathic mandible described in the literature. 1,14,16 However, the Co-Gn values did not show significant differences respect to controls and suggested a norma-or even hypoplasti-mandible instead. Therefore, the clinically evident class III tendency may be more attributable to the marked midface hypoplasia rather than mandibular hyperplasia. 14 Yet, the ANPg value (1.7°) did not show significant differences compared to controls and previous studies in CCD patients reported ANB values ranging between 0.0° and 3.0°, 10,12 which are compatible with a norm of about 3.0°. 25 In addition, the Wits value (1.5 mm) did not show significant differences compared to controls. These two aspects could be explained by the fact that the ANB angle increases if Nasion is positioned more posteriorly, while the Wits appraisal increases if the occlusal plane is rotated counter clockwise. 26 In fact, the anterior cranial base is short in CCD patients, 1,11,13,14 leading to a posterior position of Nasion. Previous authors reported an average anterior cranial base length in CCD adults of 63.1 mm for females and 70.3 mm for males, compared to 70.4 mm and 73.4 mm in normal controls, respectively. 13 Other authors showed cases of CCD patients with anterior cranial base as short as 57.6 mm at 12-year-old, and 58.4 mm at 14-year-old. 11 In the present study, the average length of the anterior cranial base was 60.0 mm, with a shortening of 17.1 mm compared to controls. Since the whole mid-face of CCD patients is usually poorly developed and further compromised by small or absent nasal bones, 1 the anterior cranial base may not be a suitable reference for the assessment of antero -posterior jaw relationships in these patients. As reported by Jarvinen for CCD, 12 and also supported by Jacobson for skeletal class III, 27 the ANB angle can be erroneous in presence of facial prognathism and "the impression of normal or nearly normal sagittal relation between the jaws [in CCD patients] is regarded as misleading". 12 Similarly, ANPg values may be increased due to a shortening of the anterior cranial base. Accordingly, Binder demonstrated a change of 2.5° in the ANB angle for a 5.0 mm horizontal displacement of Nasion, 28 and Mills suggested a correction of the ANB angle of −0.5° for each degree of deviation of the SNA angle above the upper normative value (81°+3°). 29 Alternative cephalometric methods that use the forehead as a reference 30 may be not advisable as well, as the forehead position is also likely to be affected by CCD. Instead, establishing a coordinate system originating from Sella may offer advantages, such as in patients affected by craniosynostosis. 31 Beside the controversial assessment of antero -posterior relationships, a mandibular hypodivergence in CCD patients has been consistently reported in the literature with SN/Go-Gn values of 23.4°1 0 and 21.1°, 16 compared to a norm of about 29.0°. 25 The present study confirmed a counter clockwise mandibular rotation, showing an average SN/GoGn angle of 24.2° that was significantly reduced compared to controls (−6.4°). Such forward rotation of the mandible might be caused by a reduced vertical development of the midface, which may be related to hypoplasia of facial bones and underdevelopment of paranasal sinuses. 1 In fact, nasal bones were difficult to identify on cephalometric radiographs of most patients, and a depressed nasal bridge was present. In addition, the vertical facial growth may be decreased due to a reduced alveolar bone development related to lack of eruption of permanent teeth, 16 eventually contributing to a brachifacial phenotype. Thus, clinicians may consider spontaneous or orthodontic-guided eruption, and prosthodontic rehabilitation for increasing the lower anterior facial height and the mandibular divergence. 11

Dental characteristics
In the present study, the interincisal angle (145.2°) was significantly larger in CCD patients compared to controls (+13.7°). The marked lingual inclination of lower incisors (82.4°) confirmed the skeletal class III tendency, as noticed by previous authors reporting IncInf/GoGn values from 65.5° to 76.0°. 12 In addition, the anterior open-bite reported in previous studies 10,11 was confirmed by the present findings (ΔOverbite = −2.9 mm). Given the hypodivergent mandibular growth and the brachicephalic skeletal pattern, the open-bite should be considered of dental origin rather than skeletal.
With regard to dental anomalies in CCD patients, hyperdontia is among the most reported in the literature, 32,33 and the presence of supernumeraries may be due to incomplete resorption of the dental lamina. 34 Supernumerary elements can be either uniformly or chaotically located in the jaws, with the upper and lower dentition similarly affected. 35 The altered eruption Table 3 Dental formula and dental history of the analysed CCD cases. Teeth were marked according to FDI World Dental Federation notation Age 18 17 16 15  seems to be consequent to the obstruction created by the lack of resorption of the deciduous teeth roots and respective alveolar bone, which is caused by hyperdontia. 36 Accordingly, the CCD subjects evaluated in the present study exhibited retention of deciduous elements and supernumerary permanent teeth, especially in the frontal region. None of the patients presented agenesis, which have been reported only in few cases. 11

Limitations
The main limitation of the present work was the sample size, which is a common issue in studies analysing CCD patients, given the rare incidence of this syndrome. Despite the wide age-range analysed, the comparison with matched controls ensured a fair assessment accounting for growth differences. However, due to the retrospective nature of the study and the use of a sample from an online database, the acquisition methods of the lateral-cephalograms may have varied. Furthermore, the incisal position was difficult to assess in CCD patients because of the disodontiasis that affected the anterior region, as confirmed by the poor intra -assessor agreement for the overbite and the large method error for the interincisal angle. In addition, some patients were in primary while others in permanent dentition, and one patient received fixed multibracket treatment, which may have influenced the incisal position as well.
Thus, cephalometric data of the incisal area should be considered with caution. Additional studies are needed to understand the underlying growth mechanism related to the described craniofacial characteristics, including radiological assessments of the sutural development. 37 Furthermore, cephalometric assessments may investigate the effects of the craniofacial morphology of CCD patients on the upper airway. 38

Conclusions
In CCD patients, jaws resulted protruded with respect to the anterior cranial base despite the presence of maxillary hypoplasia. However, the anterior cranial base was shorter in CCD patients compared to controls, and normative values used for the diagnosis of antero -posterior jaws position in normal subjects may not be applicable.
In CCD patients, cephalometric analyses using the anterior cranial base as a reference should be critically re-interpreted to avoid misleading diagnosis. Nevertheless, conventional cephalometric analysis may still be valuable for assessing treatment changes.
Supero-inferior values were less affected by the antero -posterior length of the anterior cranial base, and the hypodivergent mandible described in the literature was confirmed.
Further studies are necessary to confirm the present findings and to understand the respective underlying growth mechanism.