Objectives. This review aims to evaluate the effect of orthodontic therapy on periodontal health. Data. Original articles that reported on the effect of orthodontic therapy on periodontal health were included. The reference lists of potentially relevant review articles were also sought. Sources. A literature search was conducted using the databases, Medline, EMBASE, Cochrane Library, Web of Science, Google Scholar, and Scopus databases for relevant studies. The search was carried out by using a combined text and the MeSH search strategies: using the key words in different combinations: “periodontal disease,” “orthodontics” and “root resorption.” This was supplemented by hand-searching in peer-reviewed journals and cross-referenced with the articles accessed. Articles published only in English language were included. Letters to the Editor, historical reviews and unpublished articles were not sought. Conclusions. Within the limitations of the present literature review, it was observed that there is a very close inter-relationship between the periodontal health and the outcome of orthodontic therapy.

Objectives: To investigate the relationship between salivary alkaline phosphatase activity (ALP), protein concentration, and chronological age with cervical vertebral maturation stages (CVMS) as noninvasive biomarkers for skeletal maturity assessment. Materials and Methods: This cross-sectional study included 79 subjects (48 females, 31 males; 7 to 23 years old) categorized into five CVMS based on lateral cephalographs evaluated by three examiners. ALP activity and protein concentration in unstimulated whole saliva were compared among five CVMS. The association between age and CVMS was assessed and five multinomial logistic regression models were utilized to predict CVMS based on salivary ALP activity, protein concentration, and chronological age. Results: Salivary ALP reached the peak at early pubertal stage and then declined with a significant difference between CVMS I and CVMS II (P < .001) and between CVMS I and CVMS V (P = .004). A significant positive correlation between age and CVMS was found (rs = 0.763, P < .001). The models' overall correct classification rates for predicting CVMS were 32.9% using protein concentration, 35.4% using ALP activity, and 53.2% using both ALP activity and age. Conclusions: The combination of salivary ALP activity and chronological age may provide the best CVMS prediction.

Irf6 and Esrp1 are important for palate development across vertebrates. In zebrafish, we found that irf6 regulates the expression of esrp1. We detailed overlapping Irf6 and Esrp1/2 expression in mouse orofacial epithelium. In zebrafish, irf6 and esrp1/2 share expression in periderm, frontonasal ectoderm, and oral epithelium. Genetic disruption of irf6 and esrp1/2 in zebrafish resulted in cleft of the anterior neurocranium. The esrp1/2 mutant also developed cleft of the mouth opening. Lineage tracing of cranial neural crest cells revealed that cleft resulted not from migration defect, but from impaired chondrogenesis. Analysis of aberrant cells within the cleft revealed expression of sox10, col1a1 and irf6 and were adjacent to cells krt4 and krt5 positive. Breeding of mouse Irf6;Esrp1;Esrp2 compound mutants suggested genetic interaction, as the triple homozygote and the Irf6;Esrp1 double homozygote was not observed. Further, Irf6 heterozygosity reduced Esrp1/2 cleft severity. These studies highlight the complementary analysis of Irf6 and Esrp1/2 in mouse and zebrafish and captured a unique aberrant cell population expressing sox10, col1a1 and irf6. Future work characterizing this cell population will yield additional insight into cleft pathogenesis.

Wnt signaling plays a critical role in craniofacial patterning, as well as tooth and bone development. Rspo2 and Rspo3 are key regulators of Wnt signaling. However, their coordinated function and relative requirement in craniofacial development and odontogensis are poorly understood. We showed that in zebrafish rspo2 and rspo3 are both expressed in osteoprogenitors in the embryonic craniofacial skeleton. This is in contrast to mouse development, where Rspo3 is expressed in osteoprogenitors while Rspo2 expression is not observed. In zebrafish, rspo2 and rspo3 are broadly expressed in the pulp, odontoblasts and epithelial crypts. However, in the developing molars of the mouse, Rspo3 is largely expressed in the dental follicle and alveolar mesenchyme while Rspo2 expression is restricted to the tooth germ. While Rspo3 ablation in the mouse is embryonic lethal, zebrafish rspo3-/- mutants are viable with modest decrease in Meckel’s cartilage rostral length. However, compound disruption of rspo3 and rspo2 revealed synergistic roles of these genes in cartilage morphogenesis, fin development, and pharyngeal tooth development. Adult rspo3−/− zebrafish mutants exhibit a dysmorphic cranial skeleton and decreased average tooth number. This study highlights the differential functions of Rspo2 and Rspo3 in dentocranial morphogenesis in zebrafish and in mouse.

The cranial base has a crucial effect on the position of the maxilla and mandible. This study aims to investigate the relationship between the cranial base sagittal and transverse dimensions in different skeletal patterns. This is a retrospective study of pre-existing CBCT images of 132 subjects (60 males and 72 females) from Saudi Arabia with a mean age of 35 years old. The grouping of the subjects was based on the ANB angle of Steiner’s analysis. One-way ANOVA was used to compare the means of the sagittal and transverse dimensions between different skeletal patterns, followed by a post hoc test for individual comparisons. Logistic regression analysis was performed to test the relationship between gender, age, and cephalometric values between the three groups. The significance level was 0.05. One-way ANOVA revealed a statistically significant difference in posterior cranial base length (p < 0.05) and total cranial base length (p < 0.05) among different skeletal patterns. Tukey’s post hoc analysis showed that skeletal class II had a smaller posterior cranial base and total cranial base length when compared to the other groups. The class II skeletal pattern has a smaller posterior cranial base and total cranial base when compared to skeletal class I and class III skeletal patterns.

The contribution of low-frequency variants to the genetic architecture of normal-range facial traits is unknown. We studied the influence of low-frequency coding variants (MAF < 1%) in 8091 genes on multi-dimensional facial shape phenotypes in a European cohort of 2329 healthy individuals. Using three-dimensional images, we partitioned the full face into 31 hierarchically arranged segments to model facial morphology at multiple levels, and generated multi-dimensional phenotypes representing the shape variation within each segment. We used MultiSKAT, a multivariate kernel regression approach to scan the exome for face-associated low-frequency variants in a gene-based manner. After accounting for multiple tests, seven genes (AR, CARS2, FTSJ1, HFE, LTB4R, TELO2, NECTIN1) were significantly associated with shape variation of the cheek, chin, nose and mouth areas. These genes displayed a wide range of phenotypic effects, with some impacting the full face and others affecting localized regions. The missense variant rs142863092 in NECTIN1 had a significant effect on chin morphology and was predicted bioinformatically to have a deleterious effect on protein function. Notably, NECTIN1 is an established craniofacial gene that underlies a human syndrome that includes a mandibular phenotype. We further showed that nectin1a mutations can affect zebrafish craniofacial development, with the size and shape of the mandibular cartilage altered in mutant animals. Findings from this study expanded our understanding of the genetic basis of normal-range facial shape by highlighting the role of low-frequency coding variants in several novel genes.

The contribution of low-frequency variants to the genomic architecture of normal-range facial traits is unknown. Therefore, we studied the influence of 31347 low-frequency coding variants (MAF < 1%) in 8091 genes on multi-dimensional facial shape phenotypes in a European cohort of 2329 healthy individuals. Using three-dimensional facial images, we partitioned the full face into 31 hierarchically arranged segments to model global-to-local features, and generated multi-dimensional phenotypes representing the shape variation within each segment. We used MultiSKAT, a multivariate kernel regression approach to scan the exome for face-associated low-frequency variants in a gene-based manner. After accounting for multiple tests, seven genes (AR, CARS2, FTSJ1, HFE, LTB4R, TELO2, NECTIN1) were significantly associated with morphology of the cheek, chin, nose and philtrum. These genes displayed a wide range of phenotypic effects, with some impacting the full face and others affecting localized regions. Notably, NECTIN1 is an established craniofacial gene that underlies both syndromic and isolated forms of cleft lip and palate. The missense variant rs142863092 in NECTIN1 had a significant individual effect on chin morphology, and it is predicted bioinformatically to be deleterious on the nectin-1 protein. We show that the zebrafish nectin1a mutation affects craniofacial development and leads to abnormal size and shape of the palate and Meckel’s cartilage. These results expand our understanding of the genetic basis of normal-range facial shape by highlighting the role of low-frequency coding variants in novel genes.

ABSTRACTOrofacial clefts are among the most common human congenital malformations. Irf6 and Esrp1 are two key genes important for palate development, conserved across vertebrates. In the zebrafish, we found that irf6 regulates the expression of esrp1. Using RNAscope, we detailed overlapping Irf6 and Esrp1/2 gene expression in the mouse frontonasal prominence ectoderm, lambda joint periderm, palate and lip epithelium. In the zebrafish, irf6 and esrp1/2 share expression in the pre-gastrulation periderm and the embryonic frontonasal ectoderm, oral epithelium ventral to the anterior neurocranium (ANC), and the developing stomodeum. Genetic disruption of irf6 and esrp1/2 in the zebrafish resulted in cleft of the ANC. In the esrp1/2 zebrafish mutant, cleft of the mouth opening formed and appeared to tether into the ANC cleft. Lineage tracing of the anterior cranial neural crest cells revealed that cleft of the ANC resulted not from migration defect, but from impaired chondrogenesis. Molecular analysis of the aberrant cells localized within the ANC cleft revealed that this cell population espresses sox10, col1a1 and irf6 and is adjacent to cells expressing epithelial krt4. Detailed morphogenetic analysis of mouse Irf6 mutant revealed mesenchymal defects not observed in the Esrp1/2 mutant. Analysis of breeding compound Irf6;Esrp1;Esrp2 mutant suggests that these genes interact where the triple mutant is not observed. Taken together, these studies highlight the complementary analysis of Irf6 and Esrp1/2 in mouse and zebrafish models and captured an unique aberrant embryonic cell population that contributes to cleft pathogenesis. Future work characterizing this unqiue sox10+, col1a1+, irf6+ cell population will yield additional insight into cleft pathogenesis.