Skeletal Class III phenotype: Link between animal models and human genetics: A scoping review.

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-ß 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.

Long-term evaluation of the upper airway following mandibular setback surgery in the patients with mandibular prognathism.

OBJECTIVE: The aim of this study was to evaluate the changes in the upper airway following mandibular setback surgery. METHODS: The patients underwent mandibular setback surgery and cone-beam computed tomography scan data obtained at four time points: before surgery, immediately after surgery, short- and long-term follow-up. Upper airway geometries were segmented and extracted at each time point. Time-averaged airflow through the upper airway was evaluated at each time point. The measurements of airway volume and minimum cross-sectional areas were obtained at four time points. RESULTS: The airway volume and cross-sectional areas of airway significantly decreased immediately after surgery (p = 0.013 for airway volume and 0.016 for cross-sectional area). At short-term follow-up, the decreased airway volume and cross-sectional areas still showed statistically significant difference to original dimension (p = 0.017 for airway volume and 0.006 for cross-sectional area). At long-term follow-up, although there were no statistical significances (p = 0.859 for airway volume and 0.721 for cross-sectional area), the airway volume and cross-sectional areas had increased slightly compared to those at short-term follow-up. CONCLUSIONS: Although the airflow and dimensional parameters of the upper airway worsened following mandibular setback surgery, there was a tendency to gradually recover during long-term follow-up.

Genetic effect of single nucleotide polymorphisms in growth hormone receptor gene on the risk of non-syndromic mandibular prognathism in the Korean population.

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.

Clinical significance of postoperative skeletal relapse in the treatment of mandibular prognathism: Receiver operating characteristic curve analysis.

BACKGROUND/PURPOSE: Postoperative skeletal relapse is the most important issue in patients undergoing orthognathic surgery. This study aimed to investigate clinical skeletal relapse (≥2 mm) after mandibular setback surgery (intraoral vertical ramus osteotomy: IVRO) using receiver operating characteristic curve (ROC curve) analysis. METHODS: Serial cephalograms of 40 patients with mandibular prognathism were obtained at different time points: (1) before surgery (T1), (2) immediately after surgery (T2), and (3) at least with a 2-year follow-up postoperatively (T3). The menton (Me) was used as the landmark for measuring the amount of mandibular setback and postoperative skeletal relapse. Postoperative stability (T32) was divided into groups A and B by skeletal relapse ≥2 mm and <2 mm, respectively. The area under the ROC curve (AUC) was used to determine the cut-off point for mandibular setback. RESULTS: At the immediate surgical setback (T21), the amount of setback in group A (15.55 mm) was significantly larger than in group B (10.97 mm). Group A (T32) showed a significant relapse (4.07 mm), while group B showed a significant posterior drift (1.23 mm). The amount of setback had the highest AUC area (0.788). The cut-off point was 14.1 mm (T21) that would lead to a clinical relapse of 2 mm (T32). CONCLUSION: In IVRO, the postoperative mandibular positions reveal posterior drift and anterior displacement (relapse). The experience of clinical observation and patient perception of postoperative skeletal relapse was ≥2 mm. In the ROC curve analysis, the cut-off point of setback was 14.1 mm.

Genes and Pathways Associated with Skeletal Sagittal Malocclusions: A Systematic Review.

Skeletal class II and III malocclusions are craniofacial disorders that negatively impact people's quality of life worldwide. Unfortunately, the growth patterns of skeletal malocclusions and their clinical correction prognoses are difficult to predict largely due to lack of knowledge of their precise etiology. Inspired by the strong inheritance pattern of a specific type of skeletal malocclusion, previous genome-wide association studies (GWAS) were reanalyzed, resulting in the identification of 19 skeletal class II malocclusion-associated and 53 skeletal class III malocclusion-associated genes. Functional enrichment of these genes created a signal pathway atlas in which most of the genes were associated with bone and cartilage growth and development, as expected, while some were characterized by functions related to skeletal muscle maturation and construction. Interestingly, several genes and enriched pathways are involved in both skeletal class II and III malocclusions, indicating the key regulatory effects of these genes and pathways in craniofacial development. There is no doubt that further investigation is necessary to validate these recognized genes' and pathways' specific function(s) related to maxillary and mandibular development. In summary, this systematic review provides initial insight on developing novel gene-based treatment strategies for skeletal malocclusions and paves the path for precision medicine where dental care providers can make an accurate prediction of the craniofacial growth of an individual patient based on his/her genetic profile.

Rehabilitation of Occlusal Vertical Dimension in a Patient with Acromegaly: A Clinical Report.

Acromegaly is a rare acquired disorder caused by excessive growth hormone production. Dentists play an important role in the diagnosis of this disorder because of intraoral and extraoral symptoms such as extreme growth of the mandible, enlargement of the maxilla, diastema between teeth, a tendency toward malocclusion, a wide and thick nose, a marked malar bone, and thick lips. The prosthetic treatment of these patients is challenging because growth in the condyles and rami can lead to the development of a severe class III jaw relationship. This case report describes the prosthetic treatment of a patient with acromegaly. A decreased occlusal vertical dimension and class III jaw relationship were determined by intraoral and extraoral examinations and cephalometric radiography. The occlusal vertical dimension was reestablished by increasing it approximately 10 mm, as per the esthetic and functional needs of the patient. Four years after treatment, the patient was functioning well, and neither occlusal disharmony nor temporomandibular disorder was observed.

Mutant hFGF23(A12D) stimulates osteoblast differentiation through FGFR3.

Fibroblast growth factor (FGF) 23 is a member of the FGF family involved in bone development by interacting with FGFRs. In a previous study, we discovered a mutant human FGF (hFGF) 23 (A12D) in the mandibular prognathism (MP) pedigree. However, the exact role of hFGF23(A12D) during bone formation remains unclear. The aim of this study was to identify the function of hFGF23(A12D) in bone formation. We infected isolated rat calvaria (RC) cells with the recombinant lentivirus containing mutant hFGF23(A12D) and WT hFGF23 respectively. Real-time PCR, western blot and enzyme-linked immunosorbent assay confirmed that hFGF23(A12D) failed to be secreted. We measured cell growth via the CCK-8 assay based on Zsgreen expression, detected cell differentiation ability via alkaline phosphatase staining, performed RT-PCR and found that hFGF23(A12D) inhibited proliferation of RC cells and stimulated the differentiation of RC cells to osteoblasts. Through RNA sequencing, RT-PCR and western blot, we found increased expression of FGFR3. Through co-immunoprecipitation assays and immunofluorescence staining, we revealed that hFGF23(A12D) activated the mitogen-activated protein kinase signalling pathway through interactions with the intracellular domain of FGFR3. In summary, we determined the mechanisms of hFGF23(A12D) involved in osteoblast generation and formation which is specifically due to its interaction with FGFR3.

ADAMTSL1 and mandibular prognathism.

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.

Facial profile and frontal changes after bimaxillary surgery in patients with mandibular prognathism.

BACKGROUND/PURPOSE: Patients are always concerned about their postoperative appearance before surgery for facial deformity correction. The present study investigated the facial profile and frontal changes following two-jaw surgery. METHODS: Forty patients who underwent two-jaw surgery were divided by the amount of mandibular setback (group I: ≤8 mm and group II: >8 mm). Cephalometric radiograms (lateral and frontal) were collected and analyzed at three intervals: preoperatively (T1), immediately postoperatively (T2), and final follow-up (T3). The following points were identified: cheek points (C1-C5), pronasale (Prn, tip of the nose), anterior nasal spine (ANS), subnasal (Sn), point A, labrale superius (Ls), incision superius (Is), labrale inferius (Li), incision inferius (Ii), point B, labiomental sulcus (Si), pogonion (Pog), soft tissue pogonion (PogS), ramus point (RP), and gonion (Go). The immediate postoperative changes (T21), final postoperative changes (T32), and final stability (T31) were calculated and analyzed. RESULTS: In T31, the cheek line showed significant advancements of 2.3 mm (group I) and 1.6 mm (group II). The soft:hard tissue ratios were significantly correlated: Prn:ANS (0.37:1), Prn:A (0.39:1), Sn:A (0.85:1), C3:A (0.82:1), Ls:Is (0.92:1), Li:Ii (0.91:1), Si:B (0.88:1), and PogS:Pog (group I, 0.78:1 and group II, 0.93:1). The intercondylion and intergonial widths of group II (T31) significantly increased 1.8 and 4 mm, respectively. Regarding the postoperative skeletal stability (T32), group I showed significant correlations between amounts of mandibular setback, but group II did not. CONCLUSION: In the facial profile, the cheek line showed significant advancement postoperatively. The frontal mandibular transverse dimensions were significantly increased.

Implant Treatment after Sagittal Splitting Ramus Osteotomy and Alveolar Ridge Augmentation in Patient with Mandibular Prognathism and Multiple Missing Maxillary Teeth.

An abnormal maxillomandibular ridge relationship frequently hinders oral implant treatment in patients with jaw deformities. Here, we describe a patient who was experiencing difficulty using dentures due to multiple maxillary tooth loss and mandibular prognathism. Treatment comprising sagittal splitting ramus osteotomy and alveolar ridge augmentation using bone grafts harvested from the mandibular ramus followed by implant treatment yielded good outcomes. The patient was a 47-year-old woman presenting with an unstable upper partial denture. Although prior prosthetic treatment for mandibular prognathism had resulted in normal overbite, she had since lost an increasing number of teeth due to advanced periodontal disease, impairing support for the denture. She was referred to the Department of Oral Implantology at the Tokyo Dental College Chiba Hospital in October 2008. Subsequent treatment comprised implant treatment following maxillary alveolar ridge augmentation and sagittal splitting ramus osteotomy to correct the maxillary-mandibular relationship. In January 2010, sagittal splitting ramus osteotomy and alveolar bone augmentation using a bone graft from the mandibular ramus were performed under general anesthesia. In July and August 2010, a total of 7 implants were placed in the maxilla and implant superstructure preparation started after 3 months. Taking both the patient's wishes and ease of maintenance into account, retrievable superstructures made of Auro Galvano Crown were fitted in April 2011. The jaw-to-jaw alveolar ridge relationship was improved by sagittal splitting ramus osteotomy, rendering subsequent treatment, from implant placement to superstructure preparation, feasible by conventional methods. The use of surplus bone generated during sagittal splitting ramus osteotomy for bone augmentation avoided the need to harvest bone from another area.