Presence of single nucleotide polymorphisms in transforming growth factor ß and insulin-like growth factor 1 in class II malocclusions due to retrognathic mandible.

AIM: The aim of this study was to evaluate specific single nucleotide polymorphisms (SNP) of transforming growth factor-beta (TGF-ß) (rs1800469) and insulin-like growth factor-1 (IGF-1) (rs17032362) genes in Class II individuals with a normal maxilla and retrognathic (short) mandible.

Systematic review on the genetic factors associated with skeletal Class II malocclusion.

AIM: The aim of this study is to review studies evaluating the role of genetics in skeletal class II malocclusion. OBJECTIVE: To assess the scientific evidence associating the role of genes in skeletal class II malocclusion. Materials and Methods: A complete search across the electronic database through PubMed, Cochrane, LILACS, BMC and manual hand search of orthodontic journals were done till May 2019. The keywords for the search included: "Genetics", "class II malocclusion", "maxillary prognathism", "mandibular retrognathism". DATA COLLECTION AND ANALYSIS: Studies were selected based on PRISMA guidelines. RESULTS: Articles were selected based on the inclusion and exclusion criteria. A total of 11 cross-sectional studies satisfied the inclusion criteria and were analyzed for the role of genes in skeletal class II malocclusion. Almost all the studies except for one revealed a positive correlation of genes with skeletal class II malocclusion. CONCLUSIONS: Out of the 11 studies included, a positive correlation of the genes with the skeletal II malocclusion was found in 10 studies. Genes FGFR2, MSX1, MATN1, MYOH1, ACTN3, GHR, KAT6B, HDAC4, AJUBA were found to be positively linked to skeletal class II malocclusion.

First case of bilateral coronoid hyperplasia in monozygotic twin sisters-a new aetiological perspective?

BACKGROUND: Mandibular coronoid hyperplasia is a rare condition associated with gradual reduction in mouth opening. Its aetiology is unknown but increased temporalis activity, endocrine stimulus, trauma and familial causes have been proposed. CASE REPORT: In this article, we present a case of bilateral coronoid hyperplasia presenting with limited mouth opening in 16-year-old Caucasian twin sisters. DISCUSSION: This report gives a new perspective to the aetiology of coronoid hyperplasia since it describes its occurrence in monozygotic twins and hence provides a strong argument in support of a genetic aetiology.

Avaliação fenotípica em portadores de maloclusão classe II esquelética / Phenotypic evaluation in patients with skeletal class II malocclusion

Objetivo: Avaliar os principais componentes da maloclusão de Classe II esquelética e os seus subgrupos para melhor caracterizar este fenótipo e melhorar o diagnóstico. Foram avaliados 502 prontuários de indivíduos atendidos na clínica de mestrado em Ortodontia do Departamento de Odontopediatria e Ortodontia da Universidade Federal do Rio de Janeiro no período de agosto de 2015 a janeiro de 2016. Para isso, foram incluídos 40 prontuários de indivíduos portadores de maloclusão de Classe II esquelética, caracterizados com ângulo ANB > 4°. Foram excluídos portadores de síndromes, fenda labiopalatina, pacientes em crescimento, prontuários incompletos e radiografias iniciais de paciente realizadas previamente ao tratamento ortodôntico. Para análise estatística foram aplicados os testes do Quiquadrado e/ou exato de Fisher (p<0.05), regressão logística multivariada, análise dos componentes principais e método de Cluster. Os resultados encontrados demonstraram 4 componentes principais morfológicos relacionados a Classe II, sendo avaliados tamanho e posição de maxila e mandíbula, tipo facial definido pela direção de crescimento e perfil tegumentar. Quatro subgrupos foram verificados caracterizando a Classe II. Conclui-se que a maloclusão de Classe II esquelética apresenta 4 principais componentes morfológicos e quatro subgrupos característicos o que pode melhorar o diagnóstico e auxiliar estudos em genética (AU)

Purpose: To evaluate the main components of skeletal Class II malocclusion and its subgroups to better characterize the phenotype and to improve the diagnosis. Methods: We evaluated 502 medical records of patients who were attended the Pediatric dentistry and Orthodontics Department of the Federal University of Rio de Janeiro, between August 2015 and January 2016. We excluded individuals with Syndromes, cleft lip and palate, incomplete records, growing patients and the initial radiograph realized after the orthodontic treatment be conducted. Forty medical records were included, which comprised patients with skeletal Class II malocclusion, according to Steiner measurements, ANB> 4°. Statistical analysis were carried out trough chi-square and / or Fisher exact test (p <0.05), multivariate logistic regression, principal component analysis and cluster method. Results: We found 4 morphological main components related to skeletal Class II, that were related to the size and to the position of the maxilla and mandible, facial type was defined by the direction of growth and soft tissue profile. Four subgroups were evaluated underlying the skeletal Class II malocclusion. Thereby, we concluded that the skeletal Class II malocclusion presented four main morphological components and four subgroups with similar features, which can improve the diagnosis and to add genetic studies (AU)

Candidate Gene Analyses of Skeletal Variation in Malocclusion.

This study evaluated associations between craniofacial candidate genes and skeletal variation in patients with malocclusion. Lateral cephalometric radiographs of 269 untreated adults with skeletal classes I, II, and III malocclusion were digitized with 14 landmarks. Two-dimensional coordinates were analyzed using Procrustes fit and principal component (PC) analysis to generate continuous malocclusion phenotypes. Skeletal class classifications (I, II, or III) were used as a categorical phenotype. Individuals were genotyped for 198 single-nucleotide polymorphisms (SNPs) in 71 craniofacial genes and loci. Phenotype-genotype associations were tested via multivariate linear regression for continuous phenotypes and multinomial logistic regression for skeletal malocclusion class. PC analysis resulted in 4 principal components (PCs) explaining 69% of the total skeletal facial variation. PC1 explained 32.7% of the variation and depicted vertical discrepancies ranging from skeletal deep to open bites. PC1 was associated with a SNP near PAX5 (P = 0.01). PC2 explained 21.7% and captured horizontal maxillomandibular discrepancies. PC2 was associated with SNPs upstream of SNAI3 (P = 0.0002) and MYO1H (P = 0.006). PC3 explained 8.2% and captured variation in ramus height, body length, and anterior cranial base orientation. PC3 was associated with TWIST1 (P = 0.000076). Finally, PC4 explained 6.6% and detected variation in condylar inclination as well as symphysis projection. PC4 was associated with PAX7 (P = 0.007). Furthermore, skeletal class II risk increased relative to class I with the minor alleles of SNPs in FGFR2 (odds ratio [OR] = 2.1, P = 0.004) and declined with SNPs in EDN1 (OR = 0.5, P = 0.007). Conversely, skeletal class III risk increased versus class I with SNPs in FGFR2 (OR 2.2, P = 0.005) and COL1A1 (OR = 2.1, P = 0.008) and declined with SNPs in TBX5 (OR = 0.5, P = 0.014). PAX5, SNAI3, MYO1H, TWIST1, and PAX7 are associated with craniofacial skeletal variation among patients with malocclusion, while FGFR2, EDN1, TBX5, and COL1A1 are associated with type of skeletal malocclusion.

Phenotype-genotype correlations of facial width and height proportions in patients with Class II malocclusion.

OBJECTIVES: To characterize soft-tissue facial height and width variation in Class II malocclusion and test for correlations with genes HMGA2, AJUBA, and ADK. SETTING AND SAMPLE POPULATION: Nine facial proportions were estimated from 2D frontal repose photographs of 330 Caucasian adults with Class II malocclusion. MATERIAL AND METHODS: After adjustments for age and gender, the facial proportions were submitted to a principal component analyses (PCA). The most meaningful phenotypic variations were correlated with SNPs rs7924176 (ADK), rs17101923 (HMGA2), and rs997154 (AJUBA) genotyped in 106 individuals. RESULTS: Principal component analyses resulted in four principal components (PCs), which explained 75% of total variation. PC1 captured variation in the intercanthus distance and explained 28% of total variation. PC2 explained 21% of the variations in facial taper and facial index. PC3 explained 14% and reflected variations in the vertical dimension of the lower face. PC4 explained 12% and captured variations in distance between the eyes, width of the commissures, and the length of the superior aspect of the lower face height corresponding to the vertical dimension of the philtrum of the upper lip. A suggestive association (p<0.05) was observed between PC4 and rs997154 corroborating the role of AJUBA in variation of facial dimensions. CONCLUSION: 2D frontal photographs can be used to derive quantitative measures of soft-tissue phenotypes that are of clinical relevance. The methods described are suitable for discovery and replication of associations between genotypes and malocclusion phenotypes.

Genetics of the dentofacial variation in human malocclusion.

Malocclusions affect individuals worldwide, resulting in compromised function and esthetics. Understanding the etiological factors contributing to the variation in dentofacial morphology associated with malocclusions is the key to develop novel treatment approaches. Advances in dentofacial phenotyping, which is the comprehensive characterization of hard and soft tissue variation in the craniofacial complex, together with the acquisition of large-scale genomic data have started to unravel genetic mechanisms underlying facial variation. Knowledge on the genetics of human malocclusion is limited even though results attained thus far are encouraging, with promising opportunities for future research. This review summarizes the most common dentofacial variations associated with malocclusions and reviews the current knowledge of the roles of genes in the development of malocclusions. Lastly, this review will describe ways to advance malocclusion research, following examples from the expanding fields of phenomics and genomic medicine, which aim to better patient outcomes.

Long-term surgical versus functional Class II correction: a comparison of identical twins.

The purpose of this twin case comparison was to assess the short- and long-term effects of nonsurgical treatment vs orthognathic surgical treatment for Class II correction. Two identical twins (age 13 years 3 months) were treated for Class II correction where one patient was treated nonsurgically using a fixed functional appliance, while the other was treated using orthognathic mandibular advancement surgery. The patients were recalled and evaluated 5 years in retention. Comparing changes in the short and long term, surgical treatment led to superior skeletal results compared to the nonsurgical twin. However, the soft tissue profile was remarkably similar for both patients suggesting that soft tissue profile changes may not necessarily follow similar changes in the bony skeletal structures.

ACTN3 R577X genotypes associate with Class II and deepbite malocclusions.

INTRODUCTION: α-Actinins are myofibril anchor proteins that influence the contractile properties of skeletal muscles. ACTN2 is expressed in slow type I and fast type II fibers, whereas ACTN3 is expressed only in fast fibers. ACTN3 homozygosity for the 577X stop codon (ie, changing 577RR to 577XX, the R577X polymorphism) results in the absence of α-actinin-3 in about 18% of Europeans, diminishes fast contractile ability, enhances endurance performance, and reduces bone mass or bone mineral density. We have examined ACTN3 expression and genetic variation in the masseter muscle of orthognathic surgery patients to determine the genotype associations with malocclusion. METHODS: Clinical information, masseter muscle biopsies, and saliva samples were obtained from 60 subjects. Genotyping for ACTN3 single nucleotide polymorphisms, real-time polymerase chain reaction quantitation of muscle gene message, and muscle morphometric fiber type properties were compared to determine statistical differences between genotype and phenotype. RESULTS: Muscle mRNA expression level was significantly different for ACTN3 single nucleotide polymorphism genotypes (P <0.01). The frequency of ACTN3 genotypes was significantly different for the sagittal and vertical classifications of malocclusion, with the clearest association being elevated 577XX genotype in skeletal Class II malocclusion (P = 0.003). This genotype also resulted in significantly smaller diameters of fast type II fibers in masseter muscles (P = 0.002). CONCLUSION: ACTN3 577XX is overrepresented in subjects with skeletal Class II malocclusion, suggesting a biologic influence during bone growth. ACTN3 577XX is underrepresented in subjects with deepbite malocclusion, suggesting that muscle differences contribute to variations in vertical facial dimensions.

Phenotypic diversity in white adults with moderate to severe Class II malocclusion.

INTRODUCTION: Class II malocclusion affects about 15% of the population in the United States and is characterized by a convex profile and occlusal disharmonies. The specific etiologic mechanisms resulting in the range of Class II dentoskeletal combinations observed are not yet understood. Most studies describing Class II phenotypic diversity have used moderate sample sizes or focused on younger patients who later in life might outgrow their Class II discrepancies; such a focus might also preclude the visualization of adult Class II features. The majority have used simple correlation methods resulting in phenotypes that might not be generalizable to different samples and thus might not be suitable for studies of malocclusion etiology. The purpose of this study was to address these knowledge gaps by capturing the maximum phenotypic variations in a large sample of white Class II subjects selected with strict eligibility criteria and rigorously standardized multivariate reduction analyses. METHODS: Sixty-three lateral cephalometric variables were measured from the pretreatment records of 309 white Class II adults (82 male, 227 female; ages, 16-60 years). Principal component analysis and cluster analysis were used to generate comprehensive phenotypes to identify the most homogeneous groups of subjects, reducing heterogeneity and improving the power of future malocclusion etiology studies. RESULTS: Principal component analysis resulted in 7 principal components that accounted for 81% of the variation. The first 3 components represented variation on mandibular rotation, maxillary incisor angulation, and mandibular length. The cluster analysis identified 5 distinct Class II phenotypes. CONCLUSIONS: A comprehensive spectrum of Class II phenotypic definitions was obtained that can be generalized to other samples to advance our efforts for identifying the etiologic factors underlying Class II malocclusion.

Epigenetic influence of KAT6B and HDAC4 in the development of skeletal malocclusion.

INTRODUCTION: Genetic influences on the development of malocclusion include heritable effects on both masticatory muscles and jaw skeletal morphology. Beyond genetic variations, however, the characteristics of muscle and bone are also influenced by epigenetic mechanisms that produce differences in gene expression. We studied 2 enzymes known to change gene expressions through histone modifications, chromatin-modifying histone acetyltransferase KAT6B and deacetylase HDAC4, to determine their associations with musculoskeletal variations in jaw deformation malocclusions. METHODS: Samples of masseter muscle were obtained from subjects undergoing orthognathic surgery from 6 malocclusion classes based on skeletal sagittal and vertical dysplasia. The muscles were characterized for fiber type properties by immunohistochemistry, and their total RNA was isolated for gene expression studies by microarray analysis and quantitative real-time polymerase chain reaction. RESULTS: Gene expressions for fast isoforms of myosins and contractile regulatory proteins and for KAT6B and HDAC4 were severalfold greater in masseter muscles from a patient with a deepbite compared with one with an open bite, and genes related to exercise and activity did not differ substantially. In the total population, expressions of HDAC4 (P = 0.03) and KAT6B (P = 0.004) were significantly greater in subjects with sagittal Class III than in Class II malocclusion, whereas HDAC4 tended to correlate negatively with slow myosin type I and positively with fast myosin gene, especially type IIX. CONCLUSIONS: These data support other published reports of epigenetic regulation in the determination of skeletal muscle fiber phenotypes and bone growth. Further investigations are needed to elucidate how this regulatory model might apply to musculoskeletal development and malocclusion.

Obstructive sleep apnea syndrome (OSAS) in children with Class III malocclusion: involvement of the PHOX2B gene.

PURPOSE: The aim of this study is to provide new molecular approaches to the children with obstructive sleep apnea syndrome by evaluating the possible involvement of the PHOX2B gene, notoriously associated to congenital central hypoventilation syndrome (CCHS), in Class III malocclusion. METHODS: Fifty subjects with Class III malocclusion, aged from 8 to 14 years, and with history of sleep apneic episodes, and 20 age-matched controls were submitted to genomic DNA examination from oral cells to specifically analyze the PHOX2B genotype. RESULTS: Point "silent" mutations affecting different nucleotides of the PHOX2B gene were observed in 32 % of patients with Class III malocclusion and never in controls (0 %). CONCLUSION: The genetic data obtained in this study in children with Class III malocclusion and sleep-related breathing disorders provide new information useful to the genetic characterization of this pathology. The PHOX2B gene silent mutations can lead to structural and functional modification of their product providing to a group of children with Class III malocclusion similar features to those of CCHS (sleep apnea episodes and craniofacial malformations).

The class II/1 anomaly of hereditary etiology vs. thumb-sucking etiology.

RATIONALE: The etiology of class II division 1 Angle anomaly comprises many entities, including heredity and the vicious habit of sucking the finger. A close connection between the etiology and the clinical features needs to be outlined, in order to have a more appropriate treatment approach. AIM: This study aims to find common clinical features for two groups of Class II division 1 etiological factors (heredity and the vicious habit of sucking the finger), outlining a characteristic dento-facial pattern for each etiological factor. MATERIALS AND METHODS: 160 orthodontic cases were studied, taken randomly from the Department of Orthodontics in "Carol Davila" University of Medicine and Pharmacy, between 2005 and 2011. From a total of 46 diagnosed with Class II/1, the following data were noted for each subject in a table: age, sex, etiology, facial symmetry, profile, size of the lower face, stage lip, labiomentonier ditch, menton, form of arches, palate, occlusion in the three plans, Spee curve, other dental anomalies. DISCUSSIONS: The facial asymmetry was found in a greater proportion within the finger-sucking group. Subjects in the finger sucking group have 100% pronounced convex profile, with pronounced lip stage and sharp curve of Spee, being known that the thumb-sucking stops the mandible growth and stimulates the upper jaw protrusion. CONCLUSIONS: The predominant etiological factor is heredity and the clinical features obvious for II/1 Angle anomaly are present in the highest proportion in the thumb-sucking group, but no significant differences were observed between the groups studied according to etiology.

Craniofacial skeletal dysplasia of opposite-sex dizygotic twins.

Craniofacial skeletal dysplasia can lead to different skeletal malocclusions. Both environmental factors and heredity contribute to the formation of malocclusions. There are strong familial tendencies in the development of Angle's Class II and III malocclusions. Cases such as opposite-typed (Class II and III) malocclusions with skeletal and dentoalveolar discordance in siblings or dizygotic (DZ) twins have seldom been reported. We describe the rare case of a pair of opposite-sex DZ twins with completely different skeletal malocclusions, and discuss the clinical considerations for treatment. The patients were twins aged 13 years and 4 months. The girl had mandibular prognathism and a Class III dentoskeletal relationship, whereas the boy had skeletal Class II with mandibular retrusion. Several morphological traits have been implicated with hormonal effect. However, there was no evidence of whether the masculinization effect had any impact on jaw size in the female fetus or whether this effect lasted into adolescence. We suggest that, although DZ twins share the same growth environment, genetic or other unknown extrinsic factors can result in discordance of characteristics of the craniofacial skeleton, dentition, and occlusion.

Supernumerary marker chromosome 15 in a male with azoospermia and open bite deformity.

Supernumerary marker chromosome 15 (sSMC[15]) is the most frequent marker chromosome, and it is generally regarded as unimportant if it does not contain the Prader-Willi/Angelman syndrome critical region (PWACR). The clinical importance of the larger markers in association with the critical region is mentioned in almost all reports related to marker chromosome 15, and smaller markers are solely associated with minor dysmorphic features, azoospermia and recurrent miscarriages. However, these small sSMC(15)s without the PWACR may also determine a specific phenotype. A dysmorphic examination of an azoospermic patient in a genetics clinic was performed and was followed by a peripheral blood lymphocyte chromosomal analysis according to standard cytogenetic methods. Nucleolar region (NOR) banding, C-banding, fluorescence in situ hybridization and a molecular investigation of Y-microdeletions were also performed. The clinical evaluation identified dysmorphic features accompanied with azoospermia and severe 'Angle Class II, Division 1 Open Bite Deformity'. The molecular cytogenetic study revealed the small sSMC(15). In addition, a Y-microdeletion analysis showed that the azoospermia was not the result of a deletion. Although the presented case might represent a coincidental example of supernumerary marker 15 and mandibular anomaly association, the condition may also define a specific phenotype that may be more than azoospermia. This condition may be characterized by infertility, malar hypoplasia, mandibular anomaly, keloid formation and minor dysmorphic features.

Comparison of facial morphology in two populations with complete unilateral cleft lip and palate from two different centers.

OBJECTIVE: To identify differences in craniofacial morphology of two populations with a history of complete unilateral cleft lip and palate (UCLP) treated under different protocols. DESIGN: Retrospective longitudinal cohort study. SETTING: Cleft Center of the University of Nijmegen, The Netherlands, and the Cleft Lip and Palate Program, The Hospital for Sick Children, Toronto, Canada. SUBJECTS: Nineteen patients (16 male, 3 female) from Nijmegen and 19 patients (16 male, 3 female) from Toronto. Each patient was matched for sex and age with a patient from the other group. The mean ages at which lateral cephalometric radiographs were available for the Nijmegen group were 5.5, 9.9, and 18.3 years, while for the Toronto group these were available at mean ages of 5.3, 10.1, and 18.3 years, respectively. Eighteen patients from the Nijmegen group received an alveolar bone graft at a mean age of 9.5 years (range 8.2 to 13.5 years). None of the patients from Toronto received bone grafts. MAIN OUTCOME MEASURES: Eighteen cephalometric variables per radiograph were calculated at each time registration, using Dentofacial Planner cephalometric software. Statistical evaluation was performed with repeated-measures analysis of variance. RESULTS: No differences were seen in the maxillary measurements. The patients in the Toronto group had significantly larger mandibles at all three time registrations. CONCLUSIONS: The Nijmegen and Toronto protocols resulted in similar maxillary projections in patients with UCLP. Comparison of data from other studies supports the contention that the larger profile convexity of the Nijmegen group is a reflection of a genetically determined smaller mandibular size in the Dutch population.

Case report: severe infraocclusion ankylosis occurring in siblings.

AIM: This was to report a rare case of strong familiar tendency of ankylosis of maxillary second primary molars. CASE REPORT: Three Caucasian children, male twins of 8.5 years and a sister of 10 years, were diagnosed as having severely infraccluded maxillary second primary molars with underlying second premolars. In all three cases, the early extraction of the infraoccluded molars and an active treatment with cervical extraoral traction allowed the physiologic eruption of second premolars. Follow-up showed that normal vertical relationship and bone height had been obtained. CONCLUSION: Early diagnosis, as well as appropriate treatment and careful follow-up are very important in the presence of severe infraocclusion, when the marginal ridge of affected primary teeth is at or below gingival level.

Tooth agenesis: a report of missing molars in two generations.

A recent review has suggested that tooth agenesis is becoming more evident in society, though it is not known whether this observation is related to better detection methods and patient awareness or whether there is a real trend towards an increase in prevalence. In this paper we report developmental absence of permanent molars in two generations, and discuss the possible clinical implications of this pattern of tooth agenesis.

New oral findings in Cohen syndrome.

Cohen syndrome is a hereditary disorder transmitted as an autosomal-recessive trait. Approximately 100 cases have been reported in the genetic and pediatric literature. Despite the fact that oral alterations are often observed in these cases, only 1 work has been published addressing this specific topic, and it tended to concentrate on periodontal abnormalities. The present study details 2 new patients, 2 brothers (8 and 11 years old), and mainly consists of an analysis of the dentomaxillary anomalies that until now have not been studied in depth. In this study, the mandible, characterized as hypoplastic in Cohen syndrome, appears to be in a normal position; what really exists is a maxillary hyperplasia of genetic origin. We also put forward an observation hitherto undescribed in the literature: dental agenesis.

Congenital tooth anomalies and malocclusions: a genetic link?

The aim of the present study was to investigate putative relationships between different malocclusions such as Class III and Class II division 1, and congenital tooth anomalies. Two-hundred Class III and 215 Class II division 1 patients were examined for the presence of any of the following congenital tooth anomalies: maxillary incisor hypodontia, maxillary canine impaction, transpositions, supernumerary teeth, and tooth agenesis. Their occurrence rates were then calculated as a percentage of the total sample and were compared for statistical differences. The results revealed no statistical difference (P > 0.05) in the occurrence rates of upper lateral incisor agenesis, peg-shaped laterals, impacted canines, or supernumerary teeth between the Class III and the Class II division 1 malocclusions. When the occurrence rate of all congenital tooth anomalies was compared between the two malocclusions, Class III subjects showed significantly higher rates (P < 0.05). Comparison with published surveys on general populations showed similar occurrence rates. It can be concluded that subjects with Class III and Class II division 1 malocclusions show patterns of congenital tooth anomalies similar to those observed in the general population. Congenital tooth anomalies may represent another criterion for the study of malocclusion, with respect to their origin and development.