Case report: Long-term management of occlusion after surgical-orthodontic treatment for a patient with drug-induced open bite developed after the onset of schizophrenia.

Background: Schizophrenia is a major mental disorder, with an estimated incidence of 1%. Since they are sensitive to sensory changes, orthodontic treatment to move teeth should be avoided as aggressively as possible in these patients because of strong concerns about the possibility of causing adverse psychological effects, thus there are few reports on orthodontic treatment for schizophrenia patients. We report a case of severe open bite caused by medication after the onset of schizophrenia, even though the patient's occlusion had been stable for a long time after surgical orthodontic treatment. Medication control and the use of a minimally invasive orthodontic appliance improved the occlusion without adversely affecting the patient's mental health. Case: A 22-year-old woman presented to the clinic with a chief complaint of an anterior open bite. Intraoral findings showed an overbite (vertical overlap of the incisor teeth) of -3.0 mm and an overjet (horizontal overlap of the incisor teeth) of -0.5 mm. The preoperative orthodontic treatment included bilateral extraction of the maxillary first premolars. Subsequently, orthognathic surgery was performed to achieve a harmonized skeletal relationship and occlusion. Occlusion was stable for 3 years after surgery. However, 10 years after surgery, the patient returned to the clinic complaining of an anterior open bite (overbite = -4.0 mm). Six years prior to the return, the patient was diagnosed with schizophrenia. We thought that ignoring the patient's strong desire to treat her open bite might also cause psychological problems; therefore, in addition to medication control, we treated her using a minimally invasive removable orthodontic appliance (retainer with tongue crib). Her anterior open bite improved (overbite, +1.0 mm) to within the normal range. Conclusion: In this case, medication control was thought to be essential to improve her drug-induced open bite. However, minimally invasive orthodontic treatment, such as the use of a removable appliance, might be helpful in promoting her mental stability as well as for improving occlusion. Careful support is required to obtain information about the patient's mental state and medications through close cooperation with psychiatrists.

The role of the histone methyltransferase SET domain bifurcated 1 during palatal development.

The histone methyltransferase SET domain bifurcated 1 (SETDB1) catalyzes the trimethylation of lysine 9 of histone H3, thereby regulating gene expression. In this study, we used conditional knockout mice, where Setdb1 was deleted only in neural crest cells (Setdb1fl/fl,Wnt1-Cre + mice), to clarify the role of SETDB1 in palatal development. Setdb1fl/fl,Wnt1-Cre + mice died shortly after birth due to a cleft palate with full penetration. Reduced palatal mesenchyme proliferation was seen in Setdb1fl/fl,Wnt1-Cre + mice, which might be a possible mechanism of cleft palate development. Quantitative RT-PCR and in situ hybridization showed that expression of the Pax9, Bmp4, Bmpr1a, Wnt5a, and Fgf10 genes, known to be important for palatal development, were markedly decreased in the palatal mesenchyme of Setdb1fl/fl,Wnt1-Cre + mice. Along with these phenomena, SMAD1/5/9 phosphorylation was decreased by the loss of Setdb1. Our results demonstrated that SETDB1 is indispensable for palatal development partially through its proliferative effect. Taken together with previous reports that PAX9 regulates BMP signaling during palatal development which implies that loss of Setdb1 may be involved in the cleft palate development by decreasing SMAD-dependent BMP signaling through Pax9.

Histone methyltransferase SET domain bifurcated 1 negatively regulates parathyroid hormone/parathyroid hormone-related peptide receptor to control chondrocyte proliferation in Meckel's cartilage.

OBJECTIVE: The aim of this study is to show that the proliferation of chondrocytes is regulated by SET domain bifurcated 1 (SETDB1) along with the downregulation of parathyroid hormone (PTH)/parathyroid hormone-related peptide (PTHrP) receptor in Meckel's cartilage. DESIGN: Setdb1 was knocked down or overexpressed in a mouse chondrogenic ATDC5 cells, by transfecting the cells with short interfering RNA against Setdb1 or wild-type Setdb1 expression vector, respectively. Cell proliferation was detected by bromodeoxyuridine incorporation. Setdb1 was conditionally deleted in neural crest cells with Wnt1-Cre (Setdb1 conditional knockout mice). Immunofluorescence staining of paraffin sections of embryonic days 13.5 and 14.5 Setdb1 conditional knockout mice or transfected ATDC5 cells was performed to detect PTH/PTHrP receptor. Protein kinase B (AKT) phosphorylation inhibitor was added to both siRNA-transfected ATDC5 cultures to determine whether AKT activation induces PTH/PTHrP receptor expression after Setdb1 knockdown or vice versa. RESULTS: Setdb1 knockdown in ATDC5 cells showed increased cell proliferation and parathyroid hormone receptor 1 expression. Contrasting results were observed in the Setdb1-overexpressed wild-type cells. Immunofluorescence staining showed the highly expressed PTH/PTHrP receptor in Setdb1-knocked down ATDC5 cells and in the chondrocytes of Setdb1 conditional knockout embryonic Meckel's cartilage, indicating the negative regulation of SETDB1 on PTH/PTHrP receptor. Strong staining of phosphorylated AKT was observed in Setdb1-knocked down ATDC5 cells. However, the inhibition of AKT phosphorylation significantly reduced both the PTH/PTHrP receptor staining and the Setdb1-knockdown-induced increase in ATDC5 cell proliferation. CONCLUSIONS: Our findings contribute new insights on SETDB1 function in relation with AKT and PTH/PTHrP receptor during chondrocyte proliferation.

Case Report: Iatrogenic Dental Progress of Phantom Bite Syndrome: Rare Cases With the Comorbidity of Psychosis.

Introduction: Phantom bite syndrome (PBS) is considered as the preoccupation with dental occlusion and the continual inability to adapt to changed occlusion. These patients constantly demand occlusal corrections and undergo extensive and excessive dental treatments. We present three cases with PBS-suspected iatrogenic concerns and the attribution to underlying psychosis. Case Presentation: A 70-year-old female demanded orthodontic retreatment and complained of tightness and cramped sensation of teeth in the oral cavity, uncomfortable occlusion, and pain in her neck and legs that she was convinced was induced by orthodontic treatment. However, even earlier than the orthodontic treatment, she had kept doctor shopping for over 35 years, not merely dentists but also psychiatrists, neurologists, and so on; she was diagnosed with bipolar disorder. A 48-year-old female complained of malaligned improper occlusion and demanded occlusal adjustment. These symptoms occurred in the absence of a dental trigger and were worsened by orthodontic treatment. She underwent psychiatric treatment for 15 years with a diagnosis of bipolar disorder. A 38-year-old female, who had a history of schizophrenia for over 20 years, complained of occlusal discomfort and revisited with a complaint of abnormal occlusion due to excessive dental procedures. In the last two cases, requests for dental procedures had reduced owing to the collaboration between the psychiatrists and dentists. All the cases first visited our clinic following a succession of dental visits. They were strongly convinced that occlusal correction was the only solution to their symptoms, including the symptoms of discomfort in other body parts. Their misleading perceptions were uncorrectable, and repeated dental treatments exacerbated their complaints. Moreover, the dentists overlooked the psychotic histories of the patients, while the comorbid psychosis resulted in a strict demand for dental treatment by the patients. Conclusions: The presented PBS cases with psychosis suggest that repeated dental treatments and comorbid psychosis exacerbate PBS. Moreover, their persistent demands reflecting comorbid psychosis led dentists to perform numerous procedures. Early detection of underlying psychosis and the prompt collaboration between psychiatrists and dentists are integral to help prevent complications in PBS cases with psychosis.

3D evaluation of the morphological and volumetric changes of the tongue and oral cavity before and after orthognathic surgery for mandibular prognathism: a preliminary study.

BACKGROUND: The volumetric ratio of the tongue to the oral cavity has been recognized to be one of the important factors for the maintenance of stable occlusion. Oral cavity capacity is changed after orthognathic surgery in patients with mandibular prognathism; however, the volumetric changes of the oral cavity including the tongue before and after surgery have not been analyzed. The purpose of this study was to evaluate the morphological and volumetric changes of the tongue and oral cavity following orthognathic surgery using a newly developed vinyl polysiloxane impression method. MATERIALS AND METHODS: The study was performed in fifteen subjects who underwent surgical orthognathic treatment. Impressions of the tongue together with the oral cavity were obtained before orthognathic surgery and 1, 3, and 6 months after orthognathic surgery. These impression patterns were scanned using cone-beam computed tomography (CT), and three-dimensional (3D) images of the oral cavity including the tongue, and the upper and lower dental arches were reconstructed. The morphological and volumetric changes in the oral cavity capacity and the tongue volume were examined. RESULTS: The volume of the tongue with the volume of the oral cavity decreased after orthognathic surgery. There was a correlation between the decrease in the oral cavity capacity and tongue volume. The volumetric ratio of the tongue to the oral cavity seems to be maintained before and after orthognathic surgery. CONCLUSION: VPS method, free from radiation exposure, may be useful for investigating the morphological and volumetric changes of the tongue and oral cavity, which may possibly influence the stability of the dental arch and occlusion during surgical orthodontic treatment.

Examination of craniofacial morphology in Japanese patients with congenitally missing teeth: a cross-sectional study.

BACKGROUND: The purpose of this cross-sectional study was to investigate the effects of congenitally missing teeth on craniofacial morphology and to characterize the features of maxillofacial morphology of oligodontia patients associated with individual skeletal maturity by assessment with the cervical vertebrae maturation (CVM) method. METHODS: A total of 106 non-syndromic Japanese patients with congenitally missing teeth (except for third molars) were selected and categorized into two groups according to the severity of congenitally missing teeth (hypodontia group, 1-5 missing teeth [n = 56]; oligodontia group, ≥ 6 missing teeth [n = 50]). A control group included orthodontic patients without either skeletal disharmony or congenitally missing teeth (n = 63). Subjects in oligodontia and control groups were further categorized into two subgroups on the basis of cervical stage (CS): stage I (CS2 or 3; n = 27 and n = 31, respectively) and stage II (CS4 or above; n = 23 and n = 32, respectively). Lateral cephalograms were analyzed by using eight angular and eight linear measurements. Z-scores were formulated on the basis of age and sex and were matched to the Japanese norm. Tukey tests and t tests were performed. RESULTS: Compared with the control group, the hypodontia group had significantly smaller U1 to FH plane angle and A-B plane angle; U1-L1 was significantly larger. The oligodontia group had significantly smaller ANS-Me, L1 to mandibular plane angle, and Ptm-A; U1-L1 was significantly larger. At stage I, the oligodontia group had significantly smaller ANS-Me, gonial angle, and ANS-U1. At stage II, the oligodontia group had significantly smaller U1 to FH plane angle, L1 to mandibular plane angle, Ptm-A, and Go-Pog; it also had significantly larger U1-L1. CONCLUSIONS: The present study suggested that skeletal patterns differ along with the number of congenitally missing teeth and that, in oligodontia patients, skeletal patterns differ before and after growth peak. It is important to consider the skeletal characteristics of tooth agenesis patients when designing a treatment plan.

Frequency of missing teeth and reduction of mesiodistal tooth width in Japanese patients with tooth agenesis.

BACKGROUND: Tooth agenesis can involve one or more congenitally missing teeth (CMT) and is the most common congenital dental anomalies in humans. Tooth agenesis and reduction of mesiodistal tooth width are reportedly associated, suggesting that the pathogenesis of the two conditions is related. The current study analyzed the frequency of tooth agenesis and mesiodistal tooth width in cases of hypodontia (1-5 CMT) and oligodontia (≥ 6 CMT) in Japanese patients based on the hypothesis that reductions in mesiodistal tooth width are more frequently associated with oligodontia than hypodontia. METHODS: Japanese patients with tooth agenesis were divided into hypodontia cases (60 female and 25 male, mean age 19.6 years, mean CMT number 1.31 ± 1.65) and oligodontia cases (26 female and 25 male, mean age 14.6 years, mean CMT number 8.07 ± 2.39). Controls included patients with a skeletal class I relationship and no CMT (female and 60 male, mean age 20.8 years). Dental casts and orthopantomograms were used to analyze the CMT frequency and mesiodistal tooth width for each group. The Kruskal-Wallis test, the Mann-Whitney U test, and Spearman's rank correlation were used for statistical analysis. RESULTS: In the hypodontia group, mandibular second premolars were the most frequently missing tooth type (25.9%), followed by mandibular and maxillary lateral incisors (19.4 and 17.1%, respectively). In the oligodontia group, mandibular second premolars were the most frequently missing tooth type (88.2%), followed by maxillary second premolars (87.3%) and first premolars (63.7%). In female subjects in the hypodontia group, only maxillary lateral incisors and mandibular first molars were significantly smaller than those of the female control subjects. In contrast, in the oligodontia group, more tooth types were significantly smaller than those of the control, for both sexes. Except for maxillary second premolars in female subjects, correlations were apparent for all tooth types in both sexes. CONCLUSIONS: Compared to hypodontia, more tooth types exhibited reduced mesiodistal tooth width in oligodontia. Correlations between CMT number and mesiodistal tooth width support the hypothesis that reduction of mesiodistal tooth width are more frequently observed in Japanese oligodontia patients than in Japanese hypodontia patients.

Comprehending the three-dimensional mandibular morphology of facial asymmetry patients with mandibular prognathism.

BACKGROUND: The purpose of this study was to elucidate the factors that cause facial asymmetry by comparing the characteristics of the mandibular morphology in patients with mandibular prognathism with or without facial asymmetry using three-dimensional computed tomography (3D-CT). METHODS: We studied 28 mandibular prognathism patients whose menton deviated by ≥ 4 mm from the midline (FA group, n = 14) and those with a < 4-mm deviation (NA group, n = 14). DICOM data from multislice CT images were reconstructed and analysed using 3D image analysing software. Mandibular structures were assessed via linear, angular, or volumetric measurements and analysed statistically. RESULTS: The lengths of the ramal and body components and condylar volume in the FA group were significantly greater on the nondeviated side than those on the deviated side. The mandibular body length of the nondeviated side in the FA group was significantly longer than that of the NA group. Other components of the FA group did not significantly differ from those of the NA group. CONCLUSIONS: Imbalances in the sizes of the ramal and body components as well as the increased body length of the nondeviated side in the FA group compared with that of the NA group may contribute to facial asymmetry in patients with mandibular prognathism.

Histone methyltransferase Setdb1 is indispensable for Meckel's cartilage development.

The histone methyltransferase Setdb1 represses gene expression by catalyzing lysine 9 of histone H3 trimethylation. Given that the conventional knockout of Setdb1 is embryo-lethal at the implantation stage, its role in craniofacial development is poorly understood. Here, we investigated the role of Setdb1, using conditional knockout mice-in which Setdb1 was deleted in the Meckel's cartilage (Setdb1 CKO)-and the mouse chondrogenic cell line ATDC5-in which Setdb1 was inhibited by siRNA. Deletion of Setdb1 in Meckel's cartilage, the supportive tissue in the embryonic mandible, led to its enlargement, instead of the degeneration that normally occurs. Chondrocytes from the Meckel's cartilage of Setdb1 CKO mice showed increased size. Furthermore, at embryonic days 16.5 and 18.5, part of the perichondrium was disrupted and mineralization was observed in the Meckel's cartilage. Proliferation analysis showed that inhibition of Setdb1 caused increased proliferation in chondrocytes in the Meckel's cartilage as well as in ATDC5 cells. Quantitative RT-PCR showed decreased expression of chondrogenic genes, such as Sox9, Mmp13, Collagen II, and Aggrecan, as a result of Setdb1 inhibition in ATDC5 cells. Along with these phenomenons, SMAD-dependent BMP signaling was significantly increased by the loss of Setdb1 in both the Meckel's cartilage of Setdb1 CKO mice and ATDC5 cells. Therefore, the abnormal development of Meckel's cartilage in Setdb1 CKO mice is partly due to the enhanced SMAD-dependent BMP signaling. Overall, to our knowledge, the present study is the first to show that epigenetic regulation by Setdb1 is indispensable for the embryonic development of Meckel's cartilage.

Three-dimensional analysis of hard and soft tissue changes in patients with facial asymmetry undergoing 2-jaw surgery.

OBJECTIVE: We studied 3-dimensionally how hard and soft tissues of patients with facial asymmetry were changed by 2-jaw surgery. STUDY DESIGN: Nine patients diagnosed with mandibular prognathism and facial asymmetry who underwent 2-jaw surgery were enrolled. Three-dimensional (3-D) computed tomographic images taken before and after surgery were superimposed by 3-D imaging software. Linear and angular measurements of hard and soft tissues were performed and compared before and after surgery. RESULTS: Along with improved roll rotations of the hard and soft tissues of the facial structures by surgery, both hard and soft tissue mentons were moved toward the nonshifted side. Only the hard tissue mentons, however, were important for improving the roll rotation of the mandible. Variations in the wing of the nose and lip were significant for shaping the maxilla. CONCLUSIONS: The 3-D analysis in this study enabled us to understand hard and soft tissues quantitatively, thereby providing helpful information for treatment planning.

Retinoic acid inhibits histone methyltransferase Whsc1 during palatogenesis.

Cleft lip with or without palate (CL/P) is a common congenital anomaly in humans and is thought to be caused by genetic and environmental factors. However, the epigenetic mechanisms underlying orofacial clefts are not fully understood. Here, we investigate how the overdose of retinoic acid (RA), which can induce cleft palate in mice and humans, regulates histone methyltransferase, Wolf-Hirschhorn syndrome candidate 1 (WHSC1) during palatal development in mice. We treated mouse embryonic fibroblasts (MEFs) with 1 µM all-trans RA and discovered that the global level of H3K36me3 was downregulated and that expression of the H3K36 methyltransferase gene, Whsc1, was reduced. The expression level of WHSC1 in embryonic palatal shelves was reduced during palatogenesis, following maternal administration of 100 mg/kg body weight of RA by gastric intubation. Furthermore, the expression of WHSC1 in palatal shelves was observed in epithelial and mesenchymal cells at all stages, suggesting an important role for palatal development. Our results suggest that the pathogenesis of cleft palate observed after excessive RA exposure is likely to be associated with a reduction in the histone methyltransferase, WHSC1.

The function and regulation of TBX22 in avian frontonasal morphogenesis.

The frontonasal mass gives rise to the facial midline and fuses with the maxillary prominence to form the upper lip. Here we focus on the regulation and function of TBX22, a repressor dynamically expressed in the frontonasal mass. Both FGF and Noggin (a BMP antagonist) strongly induce gTBX22, however, each has opposite effects on morphogenesis - Noggin inhibits whereas FGF stimulates growth. To determine whether TBX22 mediates these effects, we used retroviruses to locally increase expression levels. RCAS::hTBX22 decreased proliferation, reduced expression of MSX2 and DLX5 and caused cleft lip. Decreased levels of endogenous gTBX22 were also observed but were not the primary cause of the phenotype as determined in rescue experiments. Our data suggest that genetic or environmental insults such as those affecting the BMP pathway could lead to a gain-of-function of TBX22 and predispose an individual to cleft lip.

Expression and regulation of the decoy bone morphogenetic protein receptor BAMBI in the developing avian face.

Here, we examine the expression and regulation of the gene BAMBI, a kinase-deficient decoy receptor capable of interacting with type I bone morphogenetic protein (BMP) receptors in avian embryos. Initially, expression was limited to the endoderm during neurula and pharyngula stages. From embryonic day 3.5 (stage 20) and onward, BAMBI expression almost perfectly overlapped with known expression patterns for BMP4, particularly in the face and limbs. We performed bead implant experiments in the face to see which signals could be repressing or promoting expression of BAMBI. Our data point to retinoids and BMPs as being major positive regulators of BAMBI expression; however, fibroblast growth factor 2 acts to repress BAMBI. Furthermore, retinoic acid is likely to act directly on BAMBI as induction occurs in the presence of cycloheximide. The data suggested that BAMBI could be used to regulate Bmp signaling during tissue interactions that are an integral part of facial morphogenesis.

Orthodontic treatment of a patient with Stickler syndrome.

Stickler syndrome (MIM 108300, 604841, 184840) is an autosomal dominant disease characterized by midfacial flattening and variable disorders of vision, hearing and articulation. There are three types of the syndrome caused by mutations in different genes (type 1, COL2A1; type 2, COL11A1; and type 3, COL11A2). About 20% of type 1 patients have cleft palate or bifid uvula, but there have been no case reports of orthodontic treatment of this syndrome so far. The Japanese female patient presented here with Stickler syndrome was characterized by a flat midface and had high myopia, sensorineural hearing loss, enlarged joints, and cleft of the soft palate. She had fairly small SNA and SNB angles and a steep mandibular plane with an enlarged gonial angle. The incisors of both arches were retroclined, and a large overjet and overbite were noted. Orthodontic treatment was initiated at 11 years of age using a lingual arch appliance followed by an edgewise multibracket appliance. Stable functional occlusion was obtained after the treatment. Most of the other seven Stickler syndrome patients exhibited pretreatment characteristics of small SNA and SNB angles, steep mandibular planes, enlarged gonial angles, and retroclined incisors of both arches, demonstrating the characteristic skeletal and occlusal features of this syndrome.

Unique CCT repeats mediate transcription of the TWIST1 gene in mesenchymal cell lines.

TWIST1, a basic helix-loop-helix transcription factor, plays critical roles in embryo development, cancer metastasis and mesenchymal progenitor differentiation. Little is known about transcriptional regulation of TWIST1 expression. Here we identified DNA sequences responsible for TWIST1 expression in mesenchymal lineage cell lines. Reporter assays with TWIST1 promoter mutants defined the -102 to -74 sequences that are essential for TWIST1 expression in human and mouse mesenchymal cell lines. Tandem repeats of CCT, but not putative CREB and NF-kappaB sites in the sequences substantially supported activity of the TWIST1 promoter. Electrophoretic mobility shift assay demonstrated that the DNA sequences with the CCT repeats formed complexes with nuclear factors, containing, at least, Sp1 and Sp3. These results suggest critical implication of the CCT repeats in association with Sp1 and Sp3 factors in sustaining expression of the TWIST1 gene in mesenchymal cells.

Functional analysis of natural mutations in two TWIST protein motifs.

The basic helix-loop-helix protein Twist, a transcriptional repressor, is essential for embryogenesis in both invertebrates and vertebrates. Haploinsufficiency of the human TWIST1 gene, which causes the craniosynostosis disorder Saethre-Chotzen syndrome (SCS), is related to failure to repress transcription of CDKN1A (which encodes p21/WAF1/CIP1), promoting osteoblast differentiation. We have examined the functional significance of natural TWIST1 variants present in craniosynostosis patients and in their healthy relatives. Both deletion and duplication variants of the glycine-rich tract Gly5AlaGly5 inhibited E2A (E12/E47)-dependent transcription of CDKN1A to a similar degree as wild-type protein, indicating that the length of this glycine tract is not critical for efficient transcriptional repression. We also evaluated a newly identified heterozygous TWIST1 variant (c.115C>G, encoding p.Arg39Gly), located within a putative nuclear localization signal (NLS), that was present in a child with mild SCS and her clinically unaffected father and grandmother. Unlike wild-type protein, this mutant required cotransfected E12 to localize to the nucleus, indicating that the NLS, including amino acid 39, is essential for nuclear localization; inhibition of E2A-dependent transcription of CDKN1A occurred normally. This analysis further dissects the structure-function relationships of TWIST and corroborates with phenotypic observations of disease expressivity.

[Regulation of p21(WAF1/CiP1) expression during cellular differentiation].

In the present study, the molecular mechanisms regulating p 21(WAF1/CiP1) expression by basic helix-loop-helix (bHLH) factors during cellular differentiation were investigated. The cyclin dependent kinase inhibitor p 21 plays crucial roles during differentiation of osteoblasts and myoblasts. In the osteoblastic cell line MG 63, expression of the p 21 gene has been shown to be upregulated by E2A factors, members of the bHLH factor family. In addition, E2A-dependent activation of p21 promoter can be inhibited by another bHLH factor, TWIST. Using reporter assays with mutant p 21 promoters, a novel element was identified in the p21 promoter, which is essential for E2A-dependent activation and TWIST-mediated inhibition. Interestingly, in the myoblastic cell line C2C12, this sequence was not involved in E2A-dependent activation of p21 expression. Gel mobility shift assays showed a specific complex of the novel p21 promoter element with nuclear factor(s) of MG 63 cells. Complex formation was inhibited by the addition of anti-TWIST antibody. In contrast no complexes could be identified with C2C12 cells. These results raise the possibility that interactions of the bHLH factors with the novel p21 promoter element are cell type specific. This suggests a novel mechanism regulating p 21 expression.