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Objectives: Temporomandibular joint disorder (TMD) is a complex condition with pain and dysfunction in the temporomandibular joint and related muscles. Scientific evidence indicates both genetic and environmental factors play a crucial role in TMD. In this study, we aimed to discover the genetic changes in individuals from 4 generations of an Iranian family with signs and symptoms of TMD and malocclusion Class III., Materials and Methods: Whole Exome Sequencing (WES) was performed in 4 patients (IV-8, IV-9, V-4, and V-6) with TMD according to (DC/TMD), along with skeletal Class III malocclusion. Then, PCR sequencing was performed on 23 family members to confirm the WES., Results: In the present study, WES results analysis detected 6 heterozygous non-synonymous Single Nucleotide Variants (SNVs) in 5 genes, including CRLF3, DNAH17, DOCK1, SEPT9, and VWDE. A heterozygous variant, c.2012T > A (p.F671Y), in Exon 20 of the DOCK1 (NM_001290223.2) gene was identified. Then, this variant was investigated in 19 other members of the same family. PCR-Sequencing results showed that 7/19 had heterozygous TA genotype, all of whom were accompanied by malocclusion and TMD symptoms and 12/19 individuals had homozygous TT genotype, 9 of whom had no temporomandibular joint problems or malocclusion. The remaining 3 showed mild TMD clinical symptoms. The 5 other non-synonymous SNVs of CRLF3, DNAH17, SEPT9, and VWDE were not considered plausible candidates for TMD., Conclusions: The present study identified a heterozygous nonsynonymous c.2012T > A (p.F671Y) variant of the DOCK1 gene is significantly associated with skeletal class III malocclusion, TMD, and its severity in affected individuals in the Iranian pedigree., Clinical Relevance: The role of genetic factors in the development of TMD has been described. The present study identified a nonsynonymous variant of the DOCK1 gene as a candidate for TMD and skeletal class III malocclusion in affected individuals in the Iranian pedigree., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Skeletal Class III (SCIII) is among the most challenging craniofacial dysmorphologies to treat. There is, however, a knowledge gap regarding which syndromes share this clinical phenotype. The aims of this study were to: (i) identify the syndromes affected by the SCIII phenotype; (ii) clarify the involvement of maxillary and/or mandibular structures; (iii) explore shared genetic/molecular mechanisms. A two-step strategy was designed: [Step#1] OMIM, MHDD, HPO, GeneReviews and MedGen databases were explored; [Step#2]: Syndromic conditions indexed in [Step#1] were explored in Medline, Pubmed, Scopus, Cochrane Library, WOS and OpenGrey. Eligibility criteria were defined. Individual studies were assessed for risk of bias using the New Ottawa Scale. For quantitative analysis, a meta-analysis was conducted. This scoping review is a hypothesis-generating research. Twenty-two studies met the eligibility criteria. Eight syndromes affected by the SCIII were targeted: Apert syndrome, Crouzon syndrome, achondroplasia, X-linked hypohidrotic ectodermal dysplasia (XLED), tricho-dento-osseous syndrome, cleidocranial dysplasia, Klinefelter and Down syndromes. Despite heterogeneity between studies [p < 0.05], overall effects showed that midface components were affected in Apert and Down Syndromes, lower face in Klinefelter Syndrome and midface and lower face components in XLED. Our review provides new evidence on the craniofacial characteristics of genetically confirmed syndromes exhibiting the SCIII phenotype. Four major regulatory pathways might have a modulatory effect on this phenotype. IMPACT: What does this review add to the existing literature? To date, there is no literature exploring which particular syndromes exhibit mandibular prognathism as a common trait. Through this research, it was possibly to identify the particular syndromes that share the skeletal Class III phenotype (mandibular prognathism) as a common trait highlighting the common genetic and molecular pathways between different syndromes acknowledging their impact in craniofacial development., (© 2024. The Author(s).)

This study aimed to identify evidence from animal studies examining genetic variants underlying maxillomandibular discrepancies resulting in a skeletal Class III (SCIII) malocclusion phenotype. Following the Manual for Evidence Synthesis of the JBI and the PRISMA extension for scoping reviews, a participant, concept, context question was formulated and systematic searches were executed in the PubMed, Scopus, WOS, Scielo, Open Gray, and Mednar databases. Of the 779 identified studies, 13 met the selection criteria and were included in the data extraction. The SCIII malocclusion phenotype was described as mandibular prognathism in the Danio rerio, Dicentrarchus labrax, and Equus africanus asinus models; and as maxillary deficiency in the Felis silvestris catus, Canis familiaris, Salmo trutta, and Mus musculus models. The identified genetic variants highlight the significance of BMP and TGF-β signaling. Their regulatory pathways and genetic interactions link them to cellular bone regulation events, particularly ossification regulation of postnatal cranial synchondroses. In conclusion, twenty genetic variants associated with the skeletal SCIII malocclusion phenotype were identified in animal models. Their interactions and regulatory pathways corroborate the role of these variants in bone growth, differentiation events, and ossification regulation of postnatal cranial synchondroses., (© 2023 The Authors. Journal of Experimental Zoology Part B: Molecular and Developmental Evolution published by Wiley Periodicals LLC.)

Non-syndromic skeletal Class III malocclusion is a major craniofacial disorder characterized by genetic and environmental factors. Patients with severe skeletal Class III malocclusion require orthognathic surgery to obtain aesthetic facial appearance and functional occlusion. Recent studies have demonstrated that susceptible chromosomal regions and genetic variants of candidate genes play important roles in the etiology of skeletal Class III malocclusion. Here, we provide a comprehensive review of our current understanding of the genetic factors that affect non-syndromic skeletal Class III malocclusion, including the patterns of inheritance and multiple genetic approaches. We then summarize the functional studies on related loci and genes using cell biology and animal models, which will help to implement individualized therapeutic interventions., (© 2022 Wiley Periodicals LLC.)

Objective: This study aimed to evaluate whether sex and genetic polymorphisms impact the oral health-related quality of life (OHRQoL) preoperatively and the difference between preoperative and postoperative OHRQoL in skeletal Class III patients submitted to orthognathic surgery., Materials and Methods: This longitudinal study consisted of ninety-nine patients with skeletal Class III malocclusion who required orthognathic surgery. The Oral Health Impact Profile-14 (OHIP-14) is a questionnaire used to assess the OHRQoL with a 5-point Likert-type scale, covering seven domains related to physical and psychosocial factors. The questionnaire was applied in the preoperative and postoperative periods, and the difference scores were calculated to assess the OHRQoL after orthognathic surgery. The DNA was extracted from oral mucosa cells to evaluate genetic polymorphisms in ANKK1, DRD2, ESR1, and ESR2 through real-time PCR., Results: There was an improvement in all OHRQoL domains following orthognathic surgery (p < 0.05). In the preoperative evaluation, women presented worse OHRQoL (p < 0.05) than men. There was no statistical difference between sex and the OHRQoL after surgery (p > 0.05). When evaluating the polymorphisms and preoperative OHIP-14 scores, CT genotype patients for rs1800497 (ANKK1) had a worse perception of the physical pain domain than CC genotype (p = 0.026), and CC genotype patients for rs1256049 (ESR2) had a worse perception of the functional limitation domain than CT genotype (p = 0.002). In the analysis between polymorphisms and postoperative and preoperative difference scores, CT genotype patients for rs1256049 (ESR2) had a greater improvement in the perception of the physical pain domain than the CC genotype (p = 0.031). In rs6275 and rs6276 (DRD2), patients with the CC genotype worsened the perception of the functional limitation domain than the TT genotype (p = 0.045), and AA genotype patients worsened the perception of the functional limitation domain than GG genotype (p = 0.048) after surgery, respectively. In addition, patients with the CT genotype for rs1800497 (ANKK1) had a greater improvement of OHRQoL perception in the total scale than the TT genotype (p = 0.018), and CT genotype patients had a greater improvement in the perception of function limitation domain than TT genotype (p = 0.017)., Conclusion: Women have a worse perception of OHRQoL in the preoperative period of orthognathic surgery. Furthermore, polymorphisms in the ANKK1, DRD2, and ESR2 genes could be involved with OHRQoL in the preoperative period and following orthognathic surgery., Clinical Relevance: The knowledge of the genetic background concerning OHRQoL in skeletal class III patients would aid in clinical practice to screen for associated genetic factors and prevent OHRQoL deterioration, especially after orthognathic surgery, considering that patients' genetic profiles would soon be available., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Skeletal deformities and malocclusions being heterogeneous traits, affect populations worldwide, resulting in compromised esthetics and function and reduced quality of life. Skeletal Class III prevalence is the least common of all angle malocclusion classes, with a frequency of 7.2%, while Class II prevalence is approximately 27% on average, varying in different countries and between ethnic groups. Orthodontic malocclusions and skeletal deformities have multiple etiologies, often affected and underlined by environmental, genetic and social aspects. Here, we have conducted a comprehensive search throughout the published data until the time of writing this review for already reported quantitative trait loci (QTL) and genes associated with the development of skeletal deformation-associated phenotypes in different mouse models. Our search has found 72 significant QTL associated with the size of the mandible, the character, shape, centroid size and facial shape in mouse models. We propose that using the collaborative cross (CC), a highly diverse mouse reference genetic population, may offer a novel venue for identifying genetic factors as a cause for skeletal deformations, which may help to better understand Class III malocclusion-associated phenotype development in mice, which can be subsequently translated to humans. We suggest that by performing a genome-wide association study (GWAS), an epigenetics-wide association study (EWAS), RNAseq analysis, integrating GWAS and expression quantitative trait loci (eQTL), micro and small RNA, and long noncoding RNA analysis in tissues associated with skeletal deformation and Class III malocclusion characterization/phenotypes, including mandibular basic bone, gum, and jaw, in the CC mouse population, we expect to better identify genetic factors and better understand the development of this disease.

Objective: The current study aimed to assess the association between collagen type II alpha 1 chain (COL2A1) single nucleotide polymorphism (SNP: rs2070739; C>T; G1405S) and mandibular skeletal malocclusions in the population of Mazandaran (North Iran)., Design: During 13 months, 102 control samples, 81 samples with skeletal Class III malocclusion contributed by mandibular prognathism and 82 samples with skeletal Class II malocclusion contributed by mandibular retrognathism were screened. Cephalometric analysis was performed to determine the type of abnormalities. COL2A1-G1405S genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The HOPE tool was used to investigate the effect of COL2A1-G1405S on the three-dimensional structure of protein., Results: Results showed that there is no significant correlation between genotypes and alleles related to COL2A1-G1405S and mandibular prognathism (CT genotype: p-value= 0.210; T allele: p-value= 0.222). On the other hand, an association was observed between COL2A1-G1405S and mandibular retrognathism (CT genotype: p-value= 0.008; T allele: p-value= 0.011). The outputs of the HOPE tool also showed that COL2A1-G1405S can disrupt the NC1 domain of the protein., Conclusions: Here, we provide evidence that COL2A1-G1405S polymorphism may have positive correlation with the risk of skeletal Class II malocclusion contributed by mandibular retrognathism in the population of Mazandaran. Given that the COL2A1-G1405S occurs in NC1 domain, it is possible that this domain plays an important role in signaling pathways related to ossification. So, we suggest that the study of COL2A1 SNPs can help researchers understand the significant role of this collagen in mandibular skeletal malocclusions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objectives: To evaluate the association of three single-nucleotide polymorphisms (SNPs) of growth hormone receptor (GHR) gene with mandibular prognathism (MP) and relationships between mandibular morphology and GHR gene SNPs in the Korean population., Materials and Methods: A total of 325 subjects were divided into two groups based on sagittal maxillomandibular relationship by the lateral cephalography: the MP and control groups. From the SNPs in the GHR gene, three SNPs (rs6180, rs6182 and rs6184) were selected. SNP genotyping was performed using direct sequencing. The craniofacial measurements of lateral cephalography were analysed., Results: We found a lack of association between GHR and MP. However, in the analysis according to the values of cephalometric measurements, rs6180 was significantly associated with ANB, SNB, effective mandibular length and SNMP in females. Additionally, rs6182 and rs6184 were significantly associated with ramal height in males., Conclusion: Growth hormone receptor SNPs may affect not only the sagittal development of mandible but also the vertical development of ramal height, and GHR SNPs may gender-differently influence mandibular morphology. This finding supports that the GHR might be susceptible on mandibular morphogenesis in the Korean population., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To investigate SNPs in bone- and cartilage-related genes and their interaction in the aetiology of sagittal and vertical skeletal malocclusions., Settings and Sample Population: This study included 143 patients and classified as follows: skeletal class I (n = 77), class II (n = 47) and class III (n = 19); maxillary retrusion (n = 39), protrusion (n = 52) and well-positioned maxilla (n = 52); mandibular retrognathism (n = 50), prognathism (n = 50) and well-positioned mandible (n = 43); normofacial (n = 72), dolichofacial (n = 55) and brachyfacial (n = 16)., Materials and Methods: Steiner's ANB, SNA, SNB angles and Ricketts' NBa-PtGn angle were measured to determine the skeletal malocclusion and the vertical pattern. Nine SNPs in BMP2, BMP4, SMAD6, RUNX2, WNT3A and WNT11 were genotyped. Chi-squared test was used to compare genotypes among the groups. Multifactor dimensionality reduction (MDR) and binary logistic regression analysis, both using gender and age as co-variables, were also used. We performed Bonferroni correction for multiple testing., Results: Significant associations at P < .05 were observed for SNPs rs1005464 (P = .042) and rs235768 (P = .021) in BMP2 with mandibular retrognathism and for rs59983488 (RUNX2) with maxillary protrusion (P = .04) as well as for rs708111 (WNT3A) with skeletal class III (P = .02; dominant model), rs1533767 (WNT11) with a brachyfacial skeletal pattern (P = .01, OR = 0.10; dominant model) and for rs3934908 (SMAD6) with prognathism (P = .02; recessive model). After the Bonferroni correction, none of the SNPs remained associated. The MDR predicted some interaction for skeletal class II, dolichofacial and brachyfacial phenotypes., Conclusion: Our results suggest that SNPs in BMP2, BMP4, SMAD6, RUNX2, WNT3A and WNT11 could be involved in the aetiology of sagittal and vertical malocclusions., (© 2020 The Authors. Orthodontics & Craniofacial Research published by John Wiley & Sons Ltd.)

Objectives: The present systematic review aims to report and critically assess the findings of the available scientific evidence from genetic association studies examining the genetic variants underlying skeletal class III malocclusion and its sub-phenotypes., Material and Methods: A pre-piloted protocol was registered and followed. The PubMed, Scopus, WOS, Cochrane Library, Gray Open literature, and CADTH databases were explored for genetic association studies following PICOS-based selection criteria. The research was reported in accordance with PRISMA statement and HuGE guidelines. The Q-genie tool was applied to assess the quality of genetic studies. Meta-analysis of genetic association studies was done by means of Meta-Genyo tool., Results: A total of 8258 articles were retrieved, of which 22 were selected for in-depth analysis. Most of the studies did not differentiate between sub-phenotypes, and the cohorts were heterogeneous regarding ethnicity. Four to five principal components of class III malocclusion explained the phenotypic variation, and gene variants at MYO1H(rs10850110), BMP3(rs1390319), GHR (rs2973015,rs6184, rs2973015), FGF7(rs372127537), FGF10(rs593307), and SNAI3(rs4287555) (p < .05) explained most of the variation across the studies, associated to vertical, horizontal, or combined skeletal discrepancies. Meta-analysis results identified a statistically significant association between risk of class III malocclusion of A allele of the FBN3 rs7351083 [OR 2.13; 95% CI 1.1-4.1; p 0.02; recessive model]., Conclusion: Skeletal class III is a polygenic trait substantially modulated by ethnicity. A multicentric approach should be considered in future studies to increase sample sizes, applying multivariate analysis such as PCA and cluster analysis to characterize existing sub-phenotypes warranting a deeper analysis of genetic variants contributing to skeletal class III craniofacial disharmony., Clinical Relevance: Grasping the underlying mechanisms of this pathology is critical for a fuller understanding of its etiology, allowing generation of preventive strategies, new individualized therapeutic approaches and more accurate treatment planification strategies.

Background: The "Habsburg jaw" has long been associated with inbreeding due to the high prevalence of consanguineous marriages in the Habsburg dynasty. However, it is thought that mandibular prognathism (MP) is under the influence of a dominant major gene. Aim: To investigate the relationship between the "Habsburg jaw" and the pedigree-based inbreeding coefficient ( F ) as a relative measure of genome homozygosity. Subjects and methods: The degree of MP and maxillary deficiency (MD) of 15 members of the Habsburg dynasty was quantified through the clinical analysis of 18 dysmorphic features diagnosed from 66 portraits. Results: A statistically significant correlation ( r  = 0.711, p  = 0.003) between MP and MD was observed among individuals. Only MP showed a statistically significant positive regression on F as evidenced from univariate analysis ( b  = 6.36 ± 3.34, p  = 0.040) and multivariate analysis (PCA) performed from single dysmorphic features ( b  = 14.10 ± 6.62, p  = 0.027, for the first PC). Conclusion: Both MP and MD are generally involved in the "Habsburg jaw." The results showed a greater sensitivity to inbreeding for the lower third of the face and suggest a positive association between the "Habsburg jaw" and homozygosity and therefore a basically recessive inheritance pattern.

Introduction: Mandibular prognathism (MP) is subject to major polygenic influence and segregates within families in autosomal dominance with variable expressivity and incomplete penetrance. We aimed to identify the inheritance pattern and genes and loci involved in the development of MP in Mediterranean families and to evaluate the dentoskeletal characteristics of affected individuals., Methods: Fifty-one eastern Mediterranean families with individuals affected by MP were identified. Data and biospecimens were collected from 14 of the families, including clinical examination, lateral cephalography (on subjects with Class III malocclusion), and 5 mL blood drawn from consenting affected and nonaffected relatives. Next-generation sequencing (NGS) was performed on 8 families (7 Lebanese, 1 Lebanese/Syrian), including large numbers of affected individuals over many generations and severe conditions, with the use of whole-exome sequencing., Results: Most pedigrees suggested autosomal-dominant inheritance with an equal number of affected male and female individuals. Affected individuals had macrognathic and prognathic mandibles with dentoalveolar compensation. Genetic screening did not correspond with previously reported MP-linked genes, but yielded 3 novel genes (C1orf167, NBPF8, NBPF9) on chromosome 1 potentially responsible for mandibular development and macrognathism., Conclusions: In this first genetic study with the use of NGS on the largest reported number of families with MP, novel genes (C1orf167, NBPF8, NBPF9) were associated with familial MP in the eastern Mediterranean population., (Copyright © 2019 American Association of Orthodontists. Published by Elsevier Inc. All rights reserved.)

Mandibular prognathism is characterized by a prognathic or prominent mandible. The objective of this study was to find the gene responsible for mandibular prognathism. Whole exome sequencing analysis of a Thai family (family 1) identified the ADAMTSL1 c.176C>A variant as the potential defect. We cross-checked our exome data of 215 people for rare variants in ADAMTSL1 and found that the c.670C>G variant was associated with mandibular prognathism in families 2 and 4. Mutation analysis of ADAMTSL1 in 79 unrelated patients revealed the c.670C>G variant was also found in family 3. We hypothesize that mutations in ADAMTSL1 cause failure to cleave aggrecan in the condylar cartilage, and that leads to overgrowth of the mandible. Adamtsl1 is strongly expressed in the condensed mesenchymal cells of the mouse condyle, but not at the cartilage of the long bones. This explains why the patients with ADAMTSL1 mutations had abnormal mandibles but normal long bones. This is the first report that mutations in ADAMTSL1 are responsible for the pathogenesis of mandibular prognathism., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Since the 19th century, and in every field of medicine, monozygotic twins have been studied to assess the involvement of genetic and environmental factors in phenotypic expression. The phenotype/genotype relationship remains the leading problem in contemporary biology. In dentofacial orthopedics, this relationship is of relevance in the three-dimensional approach to the face, in both diagnosis and treatment. The present study of two monozygotic twins presenting skeletal class III malocclusions which were genetic yet different is a clear illustration of the interaction of genotype and epigenetic factors with environmental influences. We will demonstrate that treatment can reduce phenotypic differences., (Copyright © 2017. Published by Elsevier Masson SAS.)

Introduction: The purpose of this study was to extend an association study from chromosome 1 to the whole genome (genome-wide association study) to find susceptibility loci of mandibular prognathism., Methods: Two hundred forty patients diagnosed with mandibular prognathism and 360 healthy controls of Japanese descent were recruited. The typing of microsatellites covering the whole genome was conducted using a pooled DNA method. Upon completion of the first and second screenings with pooled DNA, the positive microsatellite markers from both the first and second typings were retyped using individual-subject DNA samples to confirm the significance of allele frequency., Results: Six microsatellites (D1S0411i, D1S1358i, D3S0810i, D6S0827i, D7S0133i, and D15S0154i) showed differences between allele frequencies of the subjects and controls at P <0.001. D1S0411i, D1S1358i, D3S0810i, D6S0827i, D7S0133i, and D15S0154i were located on chromosomes 1p22.3, 1q32.2, 3q23, 6q23.2, 7q11.22, and 15q22.22, respectively. SSX2IP, PLXNA2, RASA2, TCF21, CALN1, and RORA were suggested as candidate genes., Conclusions: The genome-wide association study using microsatellites suggested that 6 loci (1p22.3, 1q32.2, 3q23, 6q23.2, 7q11.22, and 15q22.22) were susceptibility regions of mandibular prognathism. The locus 1p22.3 was supported by a previous linkage analysis, and the other 5 were novel loci., (Copyright © 2016 American Association of Orthodontists. Published by Elsevier Inc. All rights reserved.)

Mandibular prognathism is defined as an abnormal forward projection of the mandible beyond the standard relation to the cranial base and it is usually categorized as both a skeletal Class III pattern and Angle Class III malocclusion. The etiology of mandibular prognathism is still uncertain, with various genetic, epigenetic, and environmental factors possibly involved. However, many reports on its coexistence in both twins and segregation in families suggest the importance of genetic influences. A multifactorial and polygenic background with a threshold for expression or an autosomal dominant mode with incomplete penetrance and variable expressivity are the most probable inheritance patterns. Linkage analyses have, thus far, shown the statistical significance of such loci as 1p22.1, 1p22.3, 1p32.2, 1p36, 3q26.2, 4p16.1, 6q25, 11q22, 12pter-p12.3, 12q13.13, 12q23, 12q24.11, 14q24.3 to 31.2, and 19p13.2. The following appear among candidate genes: MATN1, EPB41, growth hormone receptor, COL2A1, COL1A1, MYO1H, DUSP6, ARHGAP21, ADAMTS1, FGF23, FGFR2, TBX5, ALPL, HSPG2, EVC, EVC2, the HoxC gene cluster, insulin-like growth factor 1, PLXNA2, SSX2IP, TGFB3, LTBP2, MMP13/CLG3, KRT7, and FBN3. On the other hand, MYH1, MYH2, MYH3, MYH7, MYH8, FOXO3, NFATC1, PTGS2, KAT6B, HDAC4, and RUNX2 expression is suspected to be involved in the epigenetic regulations behind the mandibular prognathism phenotype.

Introduction: Our goal was to verify the association between candidate polymorphisms and skeletal Class III malocclusion in a well-characterized homogeneous sample set., Methods: Thirty-five single-nucleotide polymorphisms were studied from 10 candidate loci in 54 Class III subjects and 120 controls. Skeletal Class III characteristics included ANB angle less than 0°, SNB angle greater than 83° (mandibular prognathism), SNA angle less than 79° (maxillary deficiency), Class III molar relationship, and negative overjet. Inclusion criteria for the controls were ANB angle between 0° and 4°, Class I molar relationship, and normal overjet. Chi-square and Fisher exact tests and principal component (PC) analysis were used to determine overrepresentation of marker alleles with alpha of 0.05. Odds ratios and 95% confidence intervals were calculated., Results: MYO1H (rs10850110 AG) (P = 0.001) with PC2 and between FGF10 (rs593307 A

Mandibular prognathism (MP) is considered to be a cranial-facial disorder resulting from the interaction between genes and environment. Recent studies have demonstrated that susceptible chromosomal regions and candidate genes may be responsible for MP. In this study, the authors present current views on the effect of genetic components in nonsystematic mandibular prognathism, in order to clarify the genetic etiology of MP. Data source were Electronic databases, manual searching, and reference lists checking, up to April 2016. Study selection, level of evidence assessment, and data extraction were done by 2 individuals in duplicate. Ninety-one studies were retrieved in initial electronic and manual search, and based on the established inclusion and exclusion criteria, 15 were selected for the review. In result, loci 1p36, 1q32.2, 1p22.3, 4p16.1, 6q25, 19p13, 14q24.3, 14q31.1, and 14q31.2 were thought to harbor genes that confer susceptibility to MP. Genes Matrilin-1, ADAMTS1, COL2A1, and EPB41 seemed to be strongly associated with MP while gene of growth hormone receptor was in dispute. Genetic components appeared to be associated with MP. However, in view of the variety of populations and results in related publications, further studies are necessary to clarify the genetic etiology of MP.

Background: Class III malocclusion is a maxillofacial disorder that is characterised by a concave profile and can be attributed to both genetic inheritance and environmental factors. It is a clinical challenge due to our limited understanding of its aetiology. Revealing its prototypical diversity will contribute to our sequential exploration of the underlying aetiological information. The objective of this study was to characterize phenotypic variations of Class III malocclusion via a lateral cephalometric analysis in a community of Chinese individuals., Method: One-hundred-and-forty-four individuals (58 males ≥18 and 86 females ≥16) with Class III malocclusion ranging from mild to severe were enrolled in this study. Principal component analysis and cluster analysis were performed using 61 lateral cephalometric measurements., Results: Six principal components were discovered in the examined population and were responsible for 73.7 % of the variability. Four subtypes were revealed by cluster analysis. Subtype 1 included subjects with mild mandibular prognathism with a steep mandibular plane. Subjects in subtype 2 showed a combination of prognathic mandibular and retrusive maxillary with a flat or normal mandibular plane. Subtype 3 included individuals with purely severe mandibular prognathism and a normal mandibular plane. Individuals in subtype 4 had a mild maxillary deficiency and severe mandibular prognathism with the lowest mandibular plane angle., Conclusion: The six principal components extracted among the 61 variables improve our knowledge of lateral cephalometric analysis for diagnoses. We successfully identified four Class III malocclusion subtypes, indicating that cluster analysis could supplement the classification of Class III malocclusion among a Chinese population and may assist in our on-going genetic study.

The study of the heredity of mandibular proganthism has curiously been initiated by a legend and by the examination of a Brussels tapestry. The hereditary condition of mandibular prognathism was recognized by the study of numerous iconographic documents concerning the Habsburger family. Charles V was the most representative of this anomaly of the lower jaw. Numerous members of the Spanish House and of the Austrian House were afflicted with mandibular prognathism. Family intermarriages promoted the multiplication of mandibular anomaly in those important families.

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., (© International & American Associations for Dental Research 2015.)

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., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Mandibular prognathism (MP) is a recognizable phenotype associated with dentoskeletal class III malocclusion. MP is a complex genetic trait, although familial recurrence also suggests the contribution of single inherited variations. To date, the genetic causes of MP have been investigated using linkage analysis or association studies in pooled families. Here for the first time, next-generation sequencing was used to study a single family with a large number of MP-affected members and to identify MP-related candidate genes. A 6-generation kindred with MP segregating as an autosomal dominant character was recruited. To identify family members affected by MP, a standard cephalometric procedure was used. In 5 MP subjects separated by the largest number of meioses, whole-exome sequencing was performed. Five promising missense gene variants (BMP3, ANXA2, FLNB, HOXA2, and ARHGAP21) associated with MP were selected and genotyped in most other family members. In this family, MP seemed to consist of 2 distinct genetic branches. Interestingly, the Gly1121Ser variant in the ARHGAP21 gene was found to be shared by all MP individuals in the larger branch of the family with nearly complete penetrance. This variant is rare in the Caucasian population (frequency 0.00034) and is predicted as damaging by all bioinformatic algorithms. ARHGAP21 protein strengthens cell-cell adhesions and may be regulated by bone morphogenetic factors, thus influencing mandibular growth. Further studies in both animal models and human patients are required to clarify the significance of this association., (© International & American Associations for Dental Research 2015.)

Objective: To evaluate the allele and genotype frequencies of the P561T and C422F polymorphic sites of the growth hormone receptor (GHR) gene and the relationship between mandibular prognathism (MP) and these two single-nucleotide polymorphisms (SNPs)., Materials and Methods: A total of 99 subjects with severe skeletal Class III MP who planned to undergo orthognathic surgery and 99 subjects with Class I occlusion were examined in this study to evaluate the relationship between MP and two SNPs in exon 10 of the GHR gene. GHR was chosen as a candidate gene because growth hormone plays an important role in cartilage growth. A blood sample was used to extract genomic DNA, and the polymerase chain reaction-restriction fragment length polymorphism method was used to determine genotypes of P561T and C422F. The Minitab 14.0 packet program was used to perform statistical analysis., Results: Allele frequencies of the C422F and P561T variants were determined. Because of the low allele frequency of the control group, statistical analysis could not be performed to test the difference between MP and control groups. Therefore, the data were combined to determine the association between the P561T polymorphism and craniofacial measurements. Effective mandibular length (condylion-gnathion) and lower face height (anterior nasal spina-menton) were associated with the P561T variant., Conclusion: This finding supports that the GHR might be a candidate gene for mandibular morphogenesis in this population.

Objective: To investigate the existence of genetic influences on the incidence of mandibular prognathism (MP) in Korean Class III patients., Materials and Methods: The probands consisted of 100 Class III patients with MP (51 men and 49 women; mean age, 22.1 ± 5.2 years; SNA, 81.2° ± 3.2°; SNB, 84.1° ± 3.9°) who underwent orthognathic surgery. Using three-generation pedigree charts, questionnaires, and clinical examinations, general information and information regarding MP for a total of 3777 relatives of the probands (1911 men and 1866 women) was ascertained. Familial correlations of MP between possible pairs in the pedigree were estimated. Heritability (h(2)) of MP under various models was estimated. Segregation analysis was conducted under the assumption of the nonpolygenic multivariate logistic model and finite polygenic mixed model. One-, two-, and three-susceptibility-type models were evaluated., Results: Among 3777 relatives, 199 (97 men and 102 women) were affected with MP (5.3%). Correlation coefficients of MP incidence in full siblings and in parent-offspring were .2003 and .2036, respectively (all P < .001). The h(2) of MP was estimated as 21.5% after adjusting for sex and founder effects. Two- and three-susceptibility-type models showed that the general model fit better than the other models. MP incidence did not have a major gene transmission model and was influenced by numerous minor effect genes and their additive effects., Conclusion: These results suggest that the inherited susceptibility to MP in Korean Class III patients might be due to the summation of minor effects from a variety of different genes and/or influence of environmental factors, rather than Mendelian transmission of major genes.

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., (Copyright © 2013 American Association of Orthodontists. Published by Mosby, Inc. All rights reserved.)

Class III malocclusion is a common dentofacial phenotype with a variable prevalence according to ethnic background. The etiology of Class III malocclusion has been attributed mainly to interactions between susceptibility genes and environmental factors during the morphogenesis of the mandible and maxilla. Class III malocclusion shows familial recurrence, and family-based studies support a predominance of an autosomal-dominant mode of inheritance. We performed whole-exome sequencing on five siblings from an Estonian family affected by Class III malocclusion. We identified a rare heterozygous missense mutation, c.545C>T (p.Ser182Phe), in the DUSP6 gene, a likely causal variant. This variant co-segregated with the disease following an autosomal-dominant mode of inheritance with incomplete penetrance. Transcriptional activation of DUSP6 has been presumed to be regulated by FGF/FGFR and MAPK/ERK signaling during fundamental processes at early stages of skeletal development. Several candidate genes within a linkage region on chromosome 12q22-q23--harboring DUSP6--are implicated in the regulation of maxillary or mandibular growth. The current study reinforces that the 12q22-q23 region is biologically relevant to craniofacial development and may be genetically linked to the Class III malocclusion.

Integrins are heterodimeric cell surface membrane proteins linking the extracellular matrix to actin. α7B integrin is detected in proliferating and adult myofibers, whereas α7A plays a role in regenerating muscle fibers with a minor function in mature muscle fibers. The expression levels of β1A appear to be very low, whereas β1D appears to be the predominant integrin form in mature muscle. Considering the important features of masseter muscle we have studied integrin expression in masseter muscle specimens of surgical patients with posterior right crossbite and comparing them to left side masseter muscle specimens. Our results showed that the expression of integrins was significantly lower in the crossbite side muscle. Furthermore, the most important finding is that β1A is clearly detectable in adult masseter muscle. This behavior could be due to the particular composition of masseter, since it contains hybrid fibers showing the capacity to modify the contractile properties to optimize the energy efficiency or the action of the muscle during contraction. Moreover, masseter is characterized by a high turnover of muscle fibers producing a regeneration process. This may indicate a longer time to heal, justifying the loss of β1D and the consequential increase of β1A. Thus, our data provide the first suggestion that integrins in masseter muscle play a key role regulating the functional activity of muscle and allowing the optimization of contractile forces.

Introduction: Several candidate loci have been suggested as influencing mandibular prognathism (1p22.1, 1p22.2, 1p36, 3q26.2, 5p13-p12, 6q25, 11q22.2-q22.3, 12q23, 12q13.13, and 19p13.2). The goal of this study was to replicate these results in a well-characterized homogeneous sample set., Methods: Thirty-three single nucleotide polymorphisms spanning all candidate regions were studied in 44 prognathic and 35 Class I subjects from the University of Pittsburgh School of Dental Medicine Dental Registry and DNA Repository. The 44 subjects with mandibular prognathism had an average age of 18.4 years; 31 were female and 13 male; and 24 were white, 15 African American, 2 Hispanic, and 3 Asian. The 36 Class I subjects had an average age of 17.6 years; 27 were female and 9 male; and 27 were white, 6 African American, 1 Hispanic, and 2 Asian. Skeletal mandibular prognathism diagnosis included cephalometric values indicative of Class III such as an ANB smaller than 2°, a negative Wits appraisal, and a positive A-B plane. Additional mandibular prognathism criteria included negative overjet and visually prognathic (concave) profile as determined by the subject's clinical evaluation. Orthognathic subjects without jaw deformations were used as the comparison group. The mandibular prognathic and orthognathic subjects were matched by race, sex, and age. Genetic markers were tested by polymerase chain reaction with TaqMan chemistry. Chi-square and Fisher exact tests were used to determine overrepresentation of marker allele with an alpha of 0.05., Results: An association was unveiled between a marker in MYO1H (rs10850110) and the mandibular prognathism phenotype (P = 0.03). MYO1H is a Class I myosin that is in a different protein group than the myosin isoforms of muscle sarcomeres, which are the basis of skeletal muscle fiber typing. Class I myosins are necessary for cell motility, phagocytosis, and vesicle transport., Conclusions: More strict clinical definitions might increase homogeneity and aid the studies of genetic susceptibility to malocclusions. We provide evidence that MYO1H can contribute to mandibular prognathism., (Copyright © 2012 American Association of Orthodontists. Published by Mosby, Inc. All rights reserved.)

The role played by genetic components in the etiology of the Class III phenotype, a class of dental malocclusion, is not yet understood. Regions that may be related to the development of Class III malocclusion have been suggested previously. The aim of this study was to search for genetic linkage with 6 microsatellite markers (D1S234, D4S3038, D6S1689, D7S503, D10S1483, and D19S566), near previously proposed candidate regions for Class III. We performed a two-point parametric linkage analysis for 42 affected individuals from 10 Brazilian families with a positive Class III malocclusion segregation. Analysis of our data indicated that there was no evidence for linkage of any of the 6 microsatellite markers to a Class III locus at = zero, with data supporting exclusion for 5 of the 6 markers evaluated. The present work reinforces that Class III is likely to demonstrate locus heterogeneity, and there is a dependency of the genetic background of the population in linkage studies.

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., (Copyright © 2011 Formosan Medical Association & Elsevier. Published by Elsevier B.V. All rights reserved.)

To present current views that are pertinent to the investigation of the genetic etiology of Class III malocclusion. Class III malocclusion is thought to be a polygenic disorder that results from an interaction between susceptibility genes and environmental factors. However, research on family pedigrees has indicated that Class III malocclusion might also be a monogenic dominant phenotype. Recent studies have reported that genes that encode specific growth factors or other signaling molecules are involved in condylar growth under mechanical strain. These genes, which include Indian hedgehog homolog (IHH), parathyroid-hormone like hormone (PTHLH), insulin-like growth factor-1 (IGF-1), and vascular endothelial growth factor (VEGF), and variations in their levels of expression play an important role in the etiology of Class III malocclusion. In addition, genome-wide scans have revealed chromosomal loci that are associated with Class III malocclusion. It is likely that chromosomal loci 1p36, 12q23, and 12q13 harbor genes that confer susceptibility to Class III malocclusion. In a case-control association study, we identified erythrocyte membrane protein band 4.1 (EPB41) to be a new positional candidate gene that might be involved in susceptibility to mandibular prognathism. Most of the earlier studies on the genetic etiology of Class III malocclusion have focused on the patterns of inheritance of this phenotype. Recent investigations have focused on understanding the genetic variables that affect Class III malocclusion and might provide new approaches to uncovering the genetic etiology of this phenotype.

Despite the prevalence of craniofacial disorders, the genetic contribution remains poorly understood. Class III malocclusion represents a specific craniofacial problem that can be handicapping, both functionally and socially. We hypothesized that the Class III phenotype is genetically linked to specific loci that regulate maxillary or mandibular growth. To determine the region linked to the Class III phenotype in four Hispanic families, we performed a genome-wide scan and linkage analysis using 500 microsatellite markers. Pedigree and linkage analyses revealed that the Class III phenotype (primarily maxillary deficiency) segregates in an autosomal-dominant manner, and that 5 loci (1p22.1, 3q26.2, 11q22, 12q13.13, and 12q23) are suggestive of linkage. Candidate genes within the 12q23 region (ZLR=2.93) include IGF1, HOXC, and COL2A1. Chromosome 1 results (ZLR=2.92) were similar to those reported previously in an Asian cohort with mandibular prognathism, suggesting that a common upstream genetic element may be responsible for both mandibular prognathism and maxillary deficiency.

Popliteal pterygium syndrome (PPS) is a rare malformation disorder characterized by autosomal dominant inheritance, highly variable expressivity and incomplete penetrance. The disorder is caused by the mutation of the IRF6 gene and the respective protein, which belongs to a family of nine transcription factors and is involved in the differentiation and proliferation of keratinocytes. Mutations in the IRF6 gene give rise to popliteal pterygium syndrome, Van Der Woude syndrome and nonsyndromic orofacial clefts. The anomalies from which affected patients suffer can be subdivided into alterations of the orofacial region, the musculoskeletal system and the genitals. Diagnosis is difficult, as is differential diagnosis, due to the variability of the manifestations. Prenatal diagnosis is possible by means of sequence analysis of the IRF6 gene in DNA extracted from the chorionic villus or amniotic fluid, or by means of intrauterine ultrasound. The prognosis is generally good, with normal mental development and the possibility to correct most of the alterations through targeted surgery. The case presented in this study involves two patients: a father and daughter who suffer from PPS, of whom the former was not diagnosed at birth. The two patients have undergone numerous operations over the years on various parts of the body and sequence analysis of the IRF6 gene, which revealed the presence of a mutation in the target site.

Introduction: The cervical column morphology of adults with skeletal Class III malocclusion and mandibular overjet was examined and compared with the cervical column morphology of a control group with neutral occlusion and normal craniofacial morphology., Methods: The mandibular overjet group consisted of 57 patients (32 women, 25 men). The control group consisted of 21 subjects (15 women, 6 men). A visual assessment of the cervical column and measurements of the craniofacial dimensions were performed on a profile radiograph of each subject., Results: In the mandibular overjet group, 61.4% had cervical column fusion, and 12.3% had posterior arch deficiency. Morphologic cervical column deviations occurred significantly more often in the mandibular overjet group than in the control group (P <.001). The most important craniofacial parameters for fusion of the cervical column were maxillary retrognathism (P <.05) and mandibular overjet (P <.05) (R2 = 0.22). The most important factor for posterior arch deficiency was mandibular inclination (P <.05) (R2 = 0.12)., Conclusions: These results are considered an important first step in phenotypic differentiation of skeletal Class III malocclusions that can be associated with different genotypes. This is important for the diagnosis and the correct treatment of these patients.

Unlabelled: Growth factors and growth stimulating genes are main signaling molecules for growth and development in ante- and postnatal period involved in cellular proliferation, differentiation and morphogenesis of tissues and organs during embryogenesis, postnatal growth and adulthood. The aim of this study was to evaluate TGF-beta (transforming growth factor-beta), BMP2/4 (bone morphogenetic protein 2/4), FGFR1 (fibroblast growth factor receptor one), barx1 gene and apoptosis from tissue samples of oro-maxillo-facial region in skeletal class III patients to reveal possible morphopathogenesis of severe skeletal anomalies. The study group included 9 patients with skeletal class III malocclusion. During orthognatic surgery tissue samples from tuber maxillae, ramus mandibulae anterior and posterior part, as well as gingiva from the lower jaw in region of second molar have been taken. Samples were stained with immunohistochemistry for TGF-beta, BMP2/4, FGFR1, apoptosis and barx1 gene. We used also the routine histological staining with haematoxyline and eosine. In tuber maxillae, ramus mandibulae anterior and posterior part staining for TGF-beta was the most relevant. Also BMP2/4, FGFR1 and barx1 showed the highest mean number of positive cells in tuber maxillae. Barx1 was equally expressed in ramus mandibulae, but BMP2/4 and FGFR1 mainly stained its posterior part cells. Apoptosis mostly affected ramus mandibulae anterior part., Conclusions: We suggest about more active stimulation of bone growth in tuber maxilla whereas ramus mandibulae. Apoptosis mainly affects ramus mandibulae anterior part that possibly connects to the lower expression of growth stimulating factors and may indicate lower bone remodelation ability.

Objective: The objective of this study is to characterize the convergences of dentofacial form of skeletal Class III malocclusion in individuals to test the fundamental hypothesis that there are distinct subtypes of Class III malocclusion., Materials and Methods: A detailed phenotypic characterization was performed on a retrospective cohort of 309 subjects using cluster and principal component analyses on 67 cephalometric variables., Results: The results indicated that there are five clusters representing distinct subphenotypes. The principal component analysis suggested that the groupings of variables reflect anteroposterior and vertical dimensions rather than specific craniofacial structures. This may ultimately suggest that different genes are involved in controlling dimension vs structures., Conclusions: Our phenotypic dissection of Class III malocclusion established distinct subtypes in a large sample of patients and will ultimately provide the basis for future familial studies to identify a causative gene.

Purpose: To explore the significance of genetic factor in the pathogenesis of skeletal angle III malocclusion., Methods: A case-control study of 96 probands, 200 controls and their relatives was performed and the data were analyzed with genetic epidemiologic methods. SPSS11.5 software package was used for Chi-square test., Results: The prevalence rates of skeletal angle III malocclusion in the first-degree relatives and second-degree relatives in the proband group were 9.00% and 1.88%,respectively,which were higher than that in the first-degree relatives in the control group(0.96%). The heritability in the first-degree relatives was 0.74+/-0.092.The results of segregation analysis didn't suggest that skeletal angle III malocclusion followed a pattern of autosomal recessive inheritance., Conclusion: Skeletal angle III malocclusion has characteristics of polygenetic disease. Genetic factor might play an important role in the pathogenesis of skeletal angle III malocclusion.

Introduction: Patients with severe mandibular prognathism frequently require orthognathic surgery to correct skeletal disharmony. Genetic and environmental factors are suggested in the etiology of mandibular prognathism, but the precise contribution of these factors is unknown., Methods: To clarify the impact of genetic factors on mandibular prognathism, we gave a questionnaire to 105 subjects with severe skeletal Class III mandibular prognathism who planned to undergo or had undergone orthognathic surgery. The questionnaire assessed mandibular prognathism in 3 generations of each subject's family. All answers were confirmed in a careful interview that included differentiation of "maxillary deficiency" and "mandibular excess." This is the first 3-generation family study of mandibular prognathism in orthognathically treated patients., Results: The average ANB, SNA, and SNB angles in the probands were -3.7 degrees , 80.9 degrees , and 84.6 degrees, respectively. A total of 1480 family members were examined, and 11.2% had mandibular prognathism. Men were slightly more affected than women; 68.6% of families had at least 1 member other than the proband with mandibular prognathism. The affected ratio of first-degree relatives was more than twice that of second-degree relatives (17.5% and 7.6%, respectively). There was no difference in the occurrence between fathers and mothers of probands, and siblings showed a high affected ratio of 25.0%. Falconer's heritability was calculated as 84.3% in first-degree relatives., Conclusions: A high occurrence of mandibular prognathism was seen in families of orthognathically treated skeletal Class III patients, suggesting a profound genetic influence.

Etiology of class-III malocclusion is generally believed to be genetic. A wide range of environmental factors have been suggested as contributing factors for the development of class-III malocclusion. Twin study is one of the most effective methods available for investigating genetically determined variables of malocclusion. Discordancy for class-III malocclusion is a frequent finding in dizygotic twins. However, class-III malocclusion discordancy in monozygotic twins is a rare finding. The purpose of this study of monozygotic twins is to assess the genetic and environmental components of variation within the cranio-dento-facial complex.

Aim: The prevalence of symptoms of Hoffmeister's "genetically determined predisposition to disturbed development of the dentition" as studied in patients with true skeletal Class III malocclusion; results of the study were compared with those found in the scientific literature regarding samples from the normal population and from orthodontic patients., Patients and Methods: The prevalence of 20 defined symptoms was evaluated in 120 patients with true skeletal Class III malocclusion. The patients were selected on the basis of a positive family history and on the presentation of typical characteristics of a skeletal Class III morphology in a lateral cephalogram. The mean age of the patients evaluated was 12.4 years. The patients' files, 1161 radiographs and plaster casts were analyzed. The prevalence of the individual symptoms was compared by means of the chi(2)-test (p < or = 0.05)., Results: 118 patients (98.3%) were found to have 292 symptoms of "genetically determined predisposition to disturbed development of the dentition". Increased distance between molar buds, atypical tooth bud position and atypical root shape were the symptoms recorded most frequently. With regard to the simultaneous existence of several symptoms, the combination of four such symptoms was most frequent (20.8%), followed by the combination of three symptoms (15.8%), and five symptoms (15.0%). Congenital hypodontia was found in 19.2% of the patients., Conclusion: It should be kept in mind for patients with true skeletal Class III malocclusion that this type of dysgnathia is most likely combined with other symptoms of disturbed development of the dentition. The higher prevalence of those symptoms found in patients with skeletal Class III malocclusion when compared with the normal population and other orthodontic patients renders orthodontic treatment of those patients more difficult and calls for comprehensive clinical and radiological examination prior to any treatment.

A Hispanic family with an unusual clinical and radiological pattern of condylar hyperplasia is presented. Mirror images of condylar hyperplasia, malocclusion of teeth, and shift of midline of the mandible were seen in two brothers. The father had a similar abnormality of his left mandibular condyle. The condylar hyperplasia in this family indicates that mandibular condylar hyperplasias could be genetic in origin, possibly Y-linked or autosomal dominant.

The etiology of mandibular prognathism has been attributed to various genetic inheritance patterns and some environmental factors. The variation in inheritance patterns can be partly due to the use of different statistical approaches in the respective studies. The objective of this study was to investigate the role of genetic influences in the etiology of this trait. We performed segregation analysis on 37 families of patients currently being treated for mandibular prognathism. Mandibular prognathism was treated as a qualitative trait, with cephalometric radiographs, dental models, and photographs used to verify diagnosis. Segregation analysis of a prognathic mandible in the entire dataset supported a transmissible Mendelian major effect, with a dominant mode of inheritance determined to be the most parsimonious.

Case Report: Dizygotic twins, male, 25 years of age, required treatment for an identical orthodontic diagnosis., Diagnosis: Class III malocclusion with mesial molar relation and frontal edge-to-edge bite, lyrate upper dental arch, grouped cross-bite and bilateral open bite in the molar and bicuspid region, retention and lingual inclination respectively of the lower left second bicuspid, mesial inclination of both lower first molars. The severity of the malocclusion differed in the two brothers., Therapy: Orthodontic treatment was successful concerning the transversal expansion and alignment of the maxillary dental arch, the functional relation of the anterior teeth, the transversally correct relation of the upper and lower dental arches and, following surgical removal of the lower second bicuspids, the reduction of crowding in the lower arch. An attempt was made to upright the molars in the mandibular arch and to close the lateral open bite by means of vertical elastics. However, the 10-month period of resistance to the therapy suggested, after a tongue protrusion habit had been ruled out, a diagnosis of ankylosis. Further orthodontic treatment was renounced and a prosthetic solution was pursued instead: the teeth in infraocclusion were treated with full ceramic overlays and, in the regions with residual gaps, with pontics (Empress II, Ivoclar, Schaan, Liechtenstein), after minimally invasive preparation (confined to removal of existing fillings)., Conclusion: This case is particularly interesting because the infrapositioned molars in both brothers were very likely due to ankylosis, suggesting a genetic cause.

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.

The aim of this study is to identify the diagnostic criteria for pseudo-Class III malocclusion and compare it with Class I malocclusion in the southern Chinese population. Sixty-seven patients (mean age, 10.9 +/- 1.8 years) were included in this study; 36 patients represented pseudo-Class III malocclusion. Selection criteria included the following: (1) anterior crossbite (at least 2 incisors with negative overjet and overbite); (2) mandibular displacement; (3) all patients were southern Chinese who had been followed after the growth spurt, none had developed a skeletal Class III malocclusion; (4) the patients were treated for an average of 7 months to procline upper incisors and retrocline lower incisors. None of the cases received any treatment that might affect skeletal growth. Thirty-one patients with Class I malocclusion were included in the Class I malocclusion group for the comparison of dentoskeletal characteristics with the pseudo-Class III malocclusion group. Selection criteria included the following: (1) skeletal Class I malocclusion with normal overjet and overbite, (2) mild to moderate crowding with Class I molar relationship, (3) straight facial profile. The following were included in the assessment of pseudo-Class III malocclusion cases: (1) family history, (2) molar and canine relationships at habitual occlusion and centric relation, and (3) dentoskeletal morphology. The results were that 72% of the examined cases in the pseudo-Class III malocclusion group showed no family history and 75% showed Class I molar relationship at habitual occlusion. Compared with the Class I malocclusion group, subjects in the pseudo-Class III malocclusion group showed a significantly decreased midface length, increased maxillary-mandibular difference, more retroclined upper incisors, and a retrusive upper lip. In conclusion, a pseudo-Class III malocclusion is characterized by retroclined upper incisors, retrusive upper lip, decreased midface length, and increased maxillary-mandibular difference. Findings of this study showed that patients with a pseudo-Class III malocclusion exhibit certain morphologic, dental, and skeletal characteristics that should be of aid in the diagnosis of pseudo-Class III malocclusion.

The spheno-ethmoidal model of midfacial retrognathia suggests that deficient chondrocytic proliferation in the anterior cranial base is associated with inadequate anterior translation of the midfacial complex resulting, for example, in Class III malocclusions. The purpose of this study was to determine whether the morphology of the midface differed in subjects of diverse ethnic origin exhibiting features associated with Class III malocclusions. Lateral cephalographs of 142 children of Korean or European American descent aged between 5 and 11 years were compared. The cephalographs were traced and subdivided into seven age- and sex-matched groups. Average geometries, scaled to an equivalent size, were generated using Procrustes superimposition and subjected to analysis of variance (ANOVA). Graphical analysis using a color-coded finite-element scaling analysis (FESA) program was used to localize differences in morphology. Results indicated that the mean Korean and European American midfacial configurations differed statistically (P < 0.01), and this difference was maintained at most, but not all, age-wise comparisons. Comparing Korean and European American Class III midfacial configurations for local size-change, FESA analysis revealed that while local increases in size were apparent in the posterior palatal regions, the Korean anterior nasal spine regions were generally smaller. For shape-change, the Korean and European American midfacial configurations were predominantly isotropic. Therefore, heterogeneity in appearance may be influenced by morphological variation of the midfacial complex in subjects of diverse ethnic origin, but features of the anterior cranial base may contribute also to the prevalence and severity of Class III malocclusions in Koreans. Moreover, perturbations in endochondral mechanisms of cranio-mandibular growth, and not maxillary intramembranous methods, may be implicated in the etiology of Class III malocclusions in South East Asians.