Investigation of the fungiform papillae number in children with tooth number anomalies.

OBJECTIVE: This cross-sectional study investigated the association between fungiform papillae (FP) numbers and tooth number anomalies in children, considering variables related to hypodontia and hyperdontia. The aim was to explore this association while adjusting for age and sex differences. MATERIALS AND METHODS: A total of 144 children (aged 8-10) were categorized into hypodontia (n = 48), hyperdontia (n = 48), and control groups (n = 48). Clinical and radiographic diagnoses were used to classify tooth number anomalies. Hypodontia was categorized by number and location, while hyperdontia was categorized by number, shape, and location. FP were assessed using the Denver Papillae Protocol. Data analyses were performed using NCSS software, with p < 0.05 considered statistically significant. RESULTS: The hypodontia group (22.5 ± 8.4) exhibited significantly lower FP than the control group (30.4 ± 9.2) and the hyperdontia group (27.9 ± 7.8) (p < 0.0005, p = 0.003, respectively). No significant difference existed between the hyperdontia and control groups. FP numbers in hypodontia subgroups showed no significant differences based on teeth agenesis numbers or locations. Similarly, hyperdontia subgroup analyses revealed no significant differences in FP numbers based on supernumerary teeth shapes (supplemental, conical, tuberculoid, paramolar) or the numbers of supernumerary teeth. CONCLUSIONS: The lower FP numbers in children with hypodontia suggested an association between teeth and FP number. However, the non-significant difference in FP numbers with hyperdontia underscored the complexity of tooth development, warranting further investigations. CLINICAL RELEVANCE: Children with hypodontia may exhibit distinct FP numbers compared to those without tooth number anomalies.

Genetic Variants in KCTD1 Are Associated with Isolated Dental Anomalies.

KCTD1 plays crucial roles in regulating both the SHH and WNT/ß-catenin signaling pathways, which are essential for tooth development. The objective of this study was to investigate if genetic variants in KCTD1 might also be associated with isolated dental anomalies. We clinically and radiographically investigated 362 patients affected with isolated dental anomalies. Whole exome sequencing identified two unrelated families with rare (p.Arg241Gln) or novel (p.Pro243Ser) variants in KCTD1. The variants segregated with the dental anomalies in all nine patients from the two families. Clinical findings of the patients included taurodontism, unseparated roots, long roots, tooth agenesis, a supernumerary tooth, torus palatinus, and torus mandibularis. The role of Kctd1 in root development is supported by our immunohistochemical study showing high expression of Kctd1 in Hertwig epithelial root sheath. The KCTD1 variants in our patients are the first variants found to be located in the C-terminal domain, which might disrupt protein-protein interactions and/or SUMOylation and subsequently result in aberrant WNT-SHH-BMP signaling and isolated dental anomalies. Functional studies on the p.Arg241Gln variant are consistent with an impact on ß-catenin levels and canonical WNT signaling. This is the first report of the association of KCTD1 variants and isolated dental anomalies.

Three-dimensional changes in the cranial base associated with soft-diet feeding.

BACKGROUND: Masticatory activity affects the morphology of the maxillo-mandibular complex, however, its influence on the cranial base remains to be elucidated. The recent integration of quantitative morphometric analysis with 3D imaging enabled a comprehensive and high-resolution morphological characterization of the craniofacial complex. We aimed to investigate the influence of masticatory activity on the morphology of the growing cranial base by three-dimensional (3D) geometric morphometric approach using micro-CT. METHODS: The micro-CT data was reanalyzed to illustrate the 3D shape of the cranial base, and wireframe models were generated by connecting landmarks on the images. In the original study, mice were fed a soft diet (SD) of powdered pellets or a conventional hard diet (HD) for 6 weeks from 3 to 9 weeks of age, immediately after weaning. A principal component (PC) analysis analyzed shape variations and assessed their significance, while canonical variate (CV) analysis facilitated the comparison and differentiation of groups based on shape, unveiling meaningful shape distinctions. RESULTS: Three PCs were extracted that significantly separated the SD and HD groups among those explaining variations in shape. These PCs were related to the length of the sphenoid bone, the width of the anterior part of the sphenoid bone, and the length of the cranial base. Furthermore, one CV effectively distinguished SD from HD, and CV analysis showed that the sphenoid was shortened in the length and narrowed at the border of the temporal bone in SD mice. CONCLUSIONS: Masticatory loading affects the skeletal development of the cranial base. The morphology of the sphenoid bone was affected in both the sagittal and transverse axes.

Evaluation of mandibular trabecular bone by fractal analysis in pediatric patients with hypodontia of the mandibular second premolar tooth.

BACKGROUND: It is still unclear whether the trabecular structure of the jaw is different in individuals with hypodontia than in those without hypodontia; this is important for clinicians. The aim was to determine whether the mandibular trabecular bone structure of children and adolescents with hypodontia differs from the control group by using the fractal analysis (FA) method in this study. METHODS: A total of 138 panoramic radiographs of 69 cases and 69 control subjects (mean age 13.2 ± 10.1) were evaluated. The age and gender of subjects in the case and control groups were matched. Three regions of interest (ROIs) were selected from the panoramic radiographs. ROI1 refers to the center of the ramus rising above the mandibular foramen. ROI2 refers to the area between the apical level of the mandibular molar and the upper border of the mandibular canal. ROI3, the missing tooth region, refers to the apical third of the mesial side of the erupting or fully erupted permanent mandibular first molar. Mann-Whitney U and Wilcoxon tests were used. p < 0.05 was accepted for the significance value. RESULTS: The mean fractal dimension (FD) values of ROI1, ROI2, and ROI3 were 1,25, 1,20, and 1,13, respectively. The means FD values obtained from the ramus region were higher than the other regions (p < 0.05). The FD values did not differ significantly according to gender and age (p > 0.05). The FD values of the case group were lower than the control group for ROI3 (p < 0.05). CONCLUSION: The results of this study showed that the mandibular trabecular bone quality of pediatric patients with one missing tooth was different from the healthy group. The difference in the mean FD values from the ROIs indicates that the ramus has a denser structure than the mandibular corpus. Clinicians should factor this into their dental treatment planning process.

Pre-implant surgery complexity for achieving implant-supported prosthetic rehabilitation in oligodontia patients: a retrospective study.

INTRODUCTION: Oligodontia is a rare dental developmental pathology that requires prolonged, complex and multidisciplinary treatment. Although bone augmentation is frequently required during a complete implant treatment of oligodontia. Therefore, we evaluated the ability to predict pre-implant surgery complexity based on age, number of missing teeth, and number of implants required to achieve implant-supported prosthetic rehabilitation. MATERIAL AND METHODS: This retrospectively registered study included all patients who underwent surgical treatment for oligodontia in our Oral and Maxillofacial Surgery Department between January 2012 and May 2023. Demographic data, number and location of missing teeth, pre- and per-implant surgical procedures, and the number of planned implants were recorded. A quantitative variable called "complexity score of pre-implant surgery" was created. This 10-point score was calculated by adding one point for each preimplant surgical procedure registered. A simple linear regression was calculated to explain the number of targeted implants based on number of missing teeth. A multiple linear regression model was used to explain the complexity score of pre-implant surgery and age, number of missing teeth and number of targeted implants. RESULTS: 119 oligodontia patients were included in the study. The median number of tooth agenesis was 10. A total of 825 implants were placed, 14 (1.7%) of which failed. A significant regression equation was used (F(1,118) = 1098,338; p < 0.0001) to explain the number of targeted implants based on number of missing teeth, with a R2 of 0.903. A significant regression equation was found (F(3,116) = 107,229; p < 0.0001) to explain the complexity score of pre-implant surgery and age, number of missing teeth and number of targeted implants, with a R2 of 0.735. DISCUSSION: These results based on patient data indicate that age, number of missing teeth and number of targeted implants could reliably explain the complexity of pre-implant surgery.

Infraocclusion in the Primary and Permanent Dentition-A Narrative Review.

The gradual movement of a tooth away from the occlusal plane is called infraocclusion or reinclusion. Reincluded teeth are most often deciduous molars, and permanent teeth are less frequently affected. Depending on the level of the infraocclusion, the severity of the disorder is classified as mild, moderate, or severe. The etiology of the phenomenon is not fully known. Tooth submerging can lead to serious complications, such as abnormal position of adjacent teeth, displacement of the bud of the permanent successor, shortening of the dental arch, or developmental disturbances of alveolar process. Early diagnosis of the tooth infraocclusion and regular monitoring of its progression help to avoid serious permanent sequelae. The treatment of reinclusion often involves only observation. However, in some cases, the therapeutic procedure requires interdisciplinary treatment by specialists from various fields of dentistry. This study presents current methods of diagnosis and treatment of patients with submerged teeth.

The prevalence of dental agenesis among children with cleft lip and palate patients in Lahore, Pakistan.

Objective: This retrospective, cross-sectional analytical study investigated the incidence of tooth agenesis in cleft lip and palate (CLP) patients. Cone Beam Computed Tomography (CBCT) radiographs of the CLP children were examined for congenitally missing teeth. Method: This study was conducted at three radiology centers in Lahore, namely, the Pakistan Jinnah MRI and Body Scan Centre, the University of Lahore Radiology Centres, and Fatima Memorial Hospital, from September 2021 to August 2022. The CLP patients were divided into four groups based on the location of the cleft: Cleft Lip and Palate Right (CLPR), Cleft Lip and Palate Left (CLPL), Bilateral Cleft (CLPB), and Midline Cleft (CLPM), inside and outside the cleft region. Two-way ANOVA was employed to compare the means of agenesis. Tukey's test was utilized to ascertain where the difference lies. The significance level was set at p ≤ 0.05. Results: Moreover, a significant number of missing teeth were found inside the cleft. This study observed the CLPL (42.3%) and CLPR (13.6%) types more in number. Maxillary first premolars were found more missing outside the cleft region in CLPL and CLPB types. Although CLPB and CLPM types revealed a pattern of missing teeth, only a few cases were found in this study. Moreover, mean tooth agenesis was highest (4.5 SD.71) in the CLPM group, followed up by CLPB (2.75 SD 2.49), CLPR (1.23 SD 1.27), and CLPL Group (1.15 SD 1.12). Conclusions: Unilateral cleft lip and palate patients reported significant agenesis patttern compared to bilateral and median cleft cases.

Gastrointestinal symptoms in patients with isolated oligodontia and a Wnt gene mutation.

OBJECTIVE: Since Wnt signaling plays an important role in both tooth agenesis and altered intestine homeostasis, the aim was to compare gastrointestinal symptoms in patients with isolated oligodontia caused by a Wnt pathway gene mutation and controls. METHODS: A case-control study was designed to compare self-reported gastrointestinal symptoms among patients with isolated oligodontia, caused by a Wnt signaling gene mutation, and fully dentate controls. The Gastrointestinal Symptom Rating Scale (GSRS) was used to assess gastrointestinal symptoms. Prevalence and severity of gastrointestinal symptoms among patients and age- and gender-matched controls were evaluated. RESULTS: Twenty patients with isolated oligodontia and a pathogenic variant in the wnt pathway genes WNT10A, LRP6, or PAX9 participated. The prevalence of gastrointestinal symptoms was higher in the oligodontia patients compared to their controls (Χ2 (1) = 87.33, p = .008). Mean GSRS total scores (p = .011) and domain scores for "abdominal pain" (p = .022), "reflux" (p = .003) and constipation (p = .030) were higher for these oligodontia patients compared to their controls. CONCLUSION: Gastrointestinal symptoms are more prevalent and more severe in patients with isolated oligodontia and a deficiency in a Wnt pathway-related gene, when compared to controls without tooth agenesis.

CACNA1S mutation-associated dental anomalies: A calcium channelopathy.

OBJECTIVES: To identify the molecular etiology of distinct dental anomalies found in eight Thai patients and explore the mutational effects on cellular functions. MATERIALS AND METHODS: Clinical and radiographic examinations were performed for eight patients. Whole exome sequencing, mutant protein modelling, qPCR, western blot analysis, scratch assays, immunofluorescence, confocal analysis, in situ hybridization, and scanning electron micrography of teeth were done. RESULTS: All patients had molars with multiple supernumerary cusps, single-cusped premolars, and a reduction in root number. Mutation analysis highlighted a heterozygous c.865A>G; p.Ile289Val mutation in CACNA1S in the patients. CACNA1S is a component of the slowly inactivating L-type voltage-dependent calcium channel. Mutant protein modeling suggested that the mutation might allow leakage of Ca2+ or other cations, or a tightening, to restrict calcium flow. Immunohistochemistry analysis showed expression of Cacna1s in the developing murine tooth epithelium during stages of crown and root morphogenesis. In cell culture, the mutation resulted in abnormal cell migration of transfected CHO cells compared to wildtype CACNA1S, with changes to the cytoskeleton and markers of focal adhesion. CONCLUSIONS: The malformations observed in our patients suggest a role for calcium signaling in organization of both cusps and roots, affecting cell dynamics within the dental epithelium.

A comparative retrospective study on the prevalence and therapeutic treatment of dental agenesis between healthy children and children with systemic disease or congenital malformation.

BACKGROUND: Dental agenesis (DA) in the permanent dentition is one of the most common dental anomalies, with a prevalence up to 2-10%. Therefore, the aim of this retrospective study was to investigate the prevalence and therapeutic treatment of DA in healthy children (HC) compared to children with systemic disease or congenital malformation (SD/CM). METHODS: Out of 3407 patients treated at the Department of Paediatric Dentistry of the Justus Liebig University Giessen (Germany) between January 2015 and December 2020, a total of 1067 patients (594 female, 473 male) aged between 4.5 and 18 years were included in this study due to DA. Besides the patients' general medical history and therapeutic treatments, panoramic radiographs were analysed. RESULTS: In contrast to the HC group with 9.7% DA, the SD/CM group showed a significantly higher prevalence of DA (19.8%; p < 0.05). The latter group was further classified into children with ectodermal dysplasia (4.4%), down syndrome (8.2%), cleft lip and palate (4.4%), intellectual disability/developmental delay (16.4%), and other genetic/organic diseases without intellectual disability (45.9%). Regarding therapeutic treatments, the HC group (59.5%) was significantly more often treated with an orthodontic gap opening compared to the SD/CM group (42.6%; p < 0.05), followed by orthodontic gap closing 36.5% in the HC group and 22.9% in the SD/CM group (p < 0.05), whereas no treatment was predominantly performed in the SD/CM group (37.7%) compared to the HC group (4%; p < 0.05). Furthermore, 50% in the SD/CM group required general anaesthesia for therapeutic treatment (vs. 8.1% in the HC group; p < 0.05). CONCLUSIONS: Children with SD/CM suffered more often from DA compared to HC that underlines multi- and interdisciplinary treatment of utmost importance. Furthermore, due to intellectual disability, common treatment methods can be complicated by insufficient compliance. This fact underlines the importance of an early attempt to establish the necessary cooperation enabling children with SD/CM to receive therapy.

A novel pathogenic frameshift variant in AXIN2 in a man with polyposis and hypodontia.

BACKGROUND: WNT signaling is pivotal in embryogenesis and tissue homeostasis. Aberrant WNT signaling, due to mutations in components of this pathway, contributes to the development and progression of human cancers, including colorectal cancer. AXIN2, encoded by the AXIN2 gene, is a key negative regulator and target of the canonical WNT signaling pathway. Germline mutations in AXIN2 are associated with absence of permanent teeth (hypo- and oligodontia) and predisposition to gastrointestinal polyps and cancer. The limited number of patients makes an accurate genotype-phenotype analysis currently challenging. CASE PRESENTATION: We present the case of a 55-year-old male with colorectal polyposis and hypodontia. Genetic testing confirmed a novel frameshift germline mutation in exon 8 of the AXIN2 gene. In addition, we provide an updated overview of germline AXIN2 mutations reported in literature. CONCLUSIONS: Although the number of missing teeth is less severe in our patient than in some previously reported cases, our findings provide additional evidence that missing teeth and gastrointestinal neoplasia are associated with rare pathogenic AXIN2 germline mutations.

Orthodontic Management of Severe Hypodontia and Impacted Maxillary Second Molars in a Patient with Sotos Syndrome.

Sotos syndrome is a genetic disorder characterized by distinct craniofacial features, overgrowth in childhood, and impaired intellectual development. We herein report the successful orthodontic treatment of a 14-year-old boy with Sotos syndrome caused by a heterozygous mutation in the NSD1 gene. He showed severe hypodontia, impaction of the maxillary second molars and a skeletal Class III jaw-base relationship. Orthodontic management, including space control by protraction of the maxillary first molars and traction of the impacted molars, was performed using fixed appliances and miniscrews. As a result, acceptable occlusion was obtained without any discernible relapse 18 months postretention.

LRP4 mutations, dental anomalies, and oral exostoses.

BACKGROUND: In order to generate a normal set of teeth, fine-tuning of Wnt/ß-catenin signaling is required, in which WNT ligands bind to their inhibitors or WNT inhibitors bind to their co-receptors. Lrp4 regulates the number of teeth and their morphology by modulating Wnt/ß-catenin signaling as a Wnt/ß-catenin activator or inhibitor, depending on its interactions with the partner proteins, such as Sostdc1 and Dkk1. AIM: To investigate genetic etiologies of dental anomalies involving LRP4 in a Thai cohort of 250 children and adults with dental anomalies. DESIGN: Oral and radiographic examinations and whole exome sequencing were performed for every patient. RESULTS: Two novel (p.Leu1356Arg and p.Ala1702Gly) and three recurrent (p.Arg263His, p.Gly1314Ser, and p.Asn1385Ser) rare variants in low-density lipoprotein receptor-related protein 4 (LRP4: MIM 604270) were identified in 11 patients. Oral exostoses were observed in five patients. CONCLUSION: Antagonism of Bmp signaling by Sostdc1 requires the presence of Lrp4. Mice lacking Lrp4 have been demonstrated to have alteration of Wnt-Bmp-Shh signaling and an abnormal number of incisors. Therefore, the LRP4 mutations found in our patients may disrupt Wnt-Bmp-Shh signaling, thereby resulting in dental anomalies and oral exostoses. Root maldevelopment in the patients suggests an important role of LRP4 in root morphogenesis.

The genetic and environmental contributions to variation in the permanent dental arch form: a twin study.

OBJECTIVE: The objective of this study was to examine the relative contributions of genetic and environmental influences on variation in dental arch form in individuals who have largely completed their craniofacial growth. MATERIAL AND METHODS: The subjects of this study comprised dental casts of 50 monozygotic twins and 24 dizygotic twins from the collection of records of twins housed at the Adelaide Dental School, Australia. The subjects were of Western European descent, with an average age of 20.93 ±â€…5.58 years. Dental casts were scanned using a 3D scanner to analyse the dental arch form. Landmark-based inter-arch and intra-arch measurements were performed. Structural equation modelling was employed to analyse the quantitative data using the normal assumptions of the twin model. RESULTS: Genetic modelling revealed that additive genetic and unique environmental factors best explained the observed variation for all occlusal traits measured, except for mandibular intercanine width. High heritability was observed for most intra-arch occlusal variables (0.61-0.85) including the maxillary and mandibular intercanine and intermolar widths, arch depth and perimeter. In contrast, moderate heritability was found for inter-arch occlusal variables (0.52-0.59) such as overjet and overbite. Sexual dimorphism was evident, with males displaying larger posterior arch width than females (P < 0.05). LIMITATIONS: Our sample was limited to individuals of Western European ancestry. CONCLUSION: The predominant source of occlusal variation within this group of Australian twins of Western European descent was controlled by genetic effects, and most were highly heritable. Generally, intra-arch occlusal variables showed greater heritability compared with inter-arch occlusal variables.

Dental anomalies in an Albanian orthodontic sample: a retrospective study.

BACKGROUND: To evaluate the prevalence and the distribution of dental anomalies in an Albanian orthodontic sample. METHODS: For this retrospective study, a sample of panoramic radiographs (PR) of n. 779 (456 F and 323 M, mean age of 15.1 ± 5.5 years) Albanian subjects with no genetic syndromes or craniofacial malformations (e.g., cleft lip/palate), history of extraction, trauma or previous orthodontic treatment drawn from the archives of the University Dental Clinic Our Lady of Good Counsel, was examined. The inclusion criteria were: subjects from 8 to 30 years of age, good quality of PRs in order to allow the assessment of crown and root development. For different dental anomalies, both the prevalence and the association were evaluated by using Chi-square test (p < 0.05). RESULTS: 24.4% of the sample had at least one dental anomaly and 4.6% had more than one. The following dental anomalies were most prevalent: hypodontia (9.8%), dental impaction (7.6%), and ectopic eruption (5.3%). No statistically significant correlation was found between males and females (p > 0.05). CONCLUSIONS: The most common anomalies in this group are found to be those of number and position, and only radiological investigations can reveal either of these anomalies. Early diagnosis of dental anomalies can contribute to prevent their complications and to establish the most suitable therapy to achieve a functional occlusion.

Patterns of nonsyndromic tooth agenesis and sexual dimorphism.

BACKGROUND: Sex dimorphism has been implicated in oral health differences and the pathogenesis of oral diseases, such as tooth agenesis, periodontal disease, dental caries, and tooth loss. Tooth agenesis (TA) is one of the most common developmental anomalies in humans, and its prevalence and patterns are different across ethnic groups. The aim of this study was to investigate the phenotypes and sex-associated patterns of nonsyndromic tooth agenesis (TA) in Thai dental patients. METHODS: One thousand ninety panoramic radiographs were examined. One hundred and one subjects (37 males, 64 females, 15-20 years-old) with nonsyndromic TA were evaluated. Differences in TA prevalence between groups were analyzed using the chi-square or Fisher exact test. RESULTS: The TA prevalence, excluding third molars, was 9.3% and more frequently found in the mandible compared with the maxilla. The maxilla demonstrated a higher prevalence of first premolar agenesis than the mandible (P = 0.012), while the mandible had a higher prevalence of second premolar agenesis than the maxilla (P = 0.031). There were significantly more males missing one tooth than females, however, there were more females missing two or more teeth than males (P = 0.042). A missing maxillary left lateral incisor was significantly more frequent in males (P = 0.019), while a missing mandibular right lateral incisor was more frequent in females (P = 0.025). In females, the pattern of two mandibular lateral incisors agenesis was the most common and significantly present in females more than males (P = 0.015). In contrast, the pattern of one mandibular left lateral incisor agenesis was only observed in males and significantly found in males more than females (P = 0.047). CONCLUSIONS: We demonstrate sex-associated differences in nonsyndromic tooth agenesis. The prevalence of single tooth agenesis was higher in males, while that of two or more teeth agenesis was higher in females. We found different patterns of lateral incisor agenesis between males and females.

The quality and reliability of the Internet as a source of information for hypodontia patients.

OBJECTIVES: The aim of this study was to determine the quality, reliability and usability of information on the Internet regarding hypodontia. METHOD: A survey of patients with hypodontia revealed seven key search terms favoured by patients: Hypodontia; Congenitally missing teeth; Missing teeth; Gaps in teeth; Cure of missing teeth; Information on missing teeth; and Treatment of missing teeth. These were entered into four search engines: Google; Ask; Wikipedia; and NHS Choices. Relevant websites were assessed for their overall demographics, author type, country of origin and rank within the search engine. They were then analysed using five validated assessment tools. Intra-examiner reliability was assessed, and statistical analysis of the data was undertaken. RESULTS: Good intra-examiner reliability was observed. A total of 48 websites were included for analysis from an initial 1718. There was no relationship between the ranking of a website on a search engine and the quality of information it contained. When medical search terminology was used, it resulted in websites of better quality than layperson search terms. Most websites were produced by general dental or specialist dental practices but the quality of these was poorer than those developed by private companies and medical organisations. The country of origin was primarily the USA and UK; however, this had no relationship to website quality. Overall, the majority of websites scored poorly for the validated tools and none scored well across multiple tools. A statistical analysis showed a positive relationship between the LIDA and DISCERN instruments but no other correlation between other validated tools was found. CONCLUSION: The quality and reliability of information on the Internet regarding hypodontia is generally poor. There is a need for a reliable online hypodontia resource that can be recommended for patient use.

Solitary median maxillary central incisor in Kabuki syndrome 2 with novel missense mutation of KDM6A and ABCC8 genes.

Kabuki syndrome (KS) is an epigenetic machinery multisystem disorder with peculiar facial gestalt and dental-oral anomalies. This report describes the case of a KS patient with congenital hyperinsulinism, growth hormone deficiency and novel heterogenous missense mutations in exon 25 of the KDM6A (c.3715T>G, p.Trp1239Gly) and exon 1 of the ABCC8 (c.94A>G, p.Asn32Asp) genes. She presented with solitary median maxillary central incisor (SMMCI) and mandibular incisor hypodontia, which could be a unique dental manifestation in KS 2.

Mutations in LRP5 and BMP4 are associated with mesiodens, tooth agenesis, root malformation, and oral exostoses.

WNT/ß-catenin and BMP signaling pathways play important roles in the process of tooth development. Dysregulation of WNT/ß-catenin and BMP signaling is implicated in a number of human malformations, including dental anomalies. Whole exome and Sanger sequencing identified seven patients with LRP5 mutations (p.Asn1121Asp, p.Asp856Asn, p.Val1433Met, and p.Val1245Met) and six patients with BMP4 mutations (p.Asn150Lys, p.Gly168Arg, p.Arg269Gln, and p.Ala42Glu). All patients were affected with isolated dental anomalies (dental anomalies with no other structural defects), including mesiodens, tooth agenesis, unseparated roots, narrow roots, shortened and tapered roots, and taurodontism. Five patients with LRP5 and one with BMP4 mutations had oral exostoses. Protein models of LRP5 mutations indicate the possible functional effects of the mutations. Here we report for the first time that mutations in LRP5 are associated with dental anomalies. LRP5 appears to be the first gene related to pathogenesis of mesiodens. We also show for the first time that in addition to tooth agenesis, mutations in BMP4 are also implicated in root maldevelopment and torus mandibularis. Sharing of the phenotypes of the patients with LRP5 and BMP4 mutations, which include root maldevelopment, tooth agenesis, and torus mandibularis, implicates cross talks between the WNT/ß-catenin and BMP signaling pathways, especially during root development.

WNT10A and RUNX2 mutations associated with non-syndromic tooth agenesis.

The goal of this study was to examine the prevalence of WNT10A and RUNX2 mutations and assess their potential impact on the phenotype of non-syndromic tooth agenesis. The study included 30 participants with non-syndromic tooth agenesis, divided into hypodontia (n = 24) and oligodontia forms (n = 6), and 42 unaffected family members. Genomic DNA from buccal epithelial cells was used for polymerase chain reaction amplification of functionally important exons of the WNT10A and RUNX2 genes. Direct sequencing reactions were performed to confirm the presence of mutations. The trend of increasing prevalence of WNT10A mutations and a slight increase in the prevalence of RUNX2 mutations were revealed in tooth agenesis cases compared to unaffected family members. There was a higher prevalence of hypodontia than oligodontia, increased frequency of females over males with missing teeth, and a wide phenotypic variability was observed in individuals and families analyzed. The common missense mutations (p.Phe228Ile, p.Arg113Cys, p.Asp217Asn, and p.Gly165Arg) and c.114-56T>C in the WNT10A gene and in-frame-deletion/insertions (11A, 24Q, 30Q), synonymous variant c.240G>A, and 424-33dupC in the RUNX2 gene were identified. These findings highlight an important role of WNT10A and RUNX2 mutations in the genetic etiology of non-syndromic tooth agenesis.