Congenital Tooth Agenesis Research Articles

Etiology and clinical treatment strategies for second primary molars without permanent tooth germs

Congenital tooth agenesis is a type of craniofacial developmental anomaly with reduced number of teeth, which is caused by disturbances in tooth germ development. If the number of missing teeth is less than six (excluding the third molars), it is termed as hypodontia. The second premolars are most commonly affected. When the second premolars are missing, the second primary molars are more prone to suffer from retention, infraocclusion, caries, pulpitis, or periapical periodontitis. Without timely prevention and appropriate treatment, congenital loss of second premolars may cause adverse effects on the patients' tooth arrangement, occlusal function, craniofacial development, and even future prosthetic treatment. This review summarises the aetiological and diagnostic features of the agenesis of second premolars, and discusses the clinical considerations of retaining or extracting the second primary molars without permanent tooth germs, when the absence of permanent tooth germs is fully established or not, so as to provide references for dentists.

Congenital Tooth Agenesis and Risk of Early-Onset Cancer

There is some evidence that tooth agenesis (congenital absence of 1 or more teeth) is associated with cancer risk, especially carcinomas of the colon and ovaries, but results of previous studies are conflicting, and associations have not yet been evaluated in a population-based setting. To examine the association between tooth agenesis and specific cancer types before 40 years of age. This population-based cohort study used linking data from nationwide registries in Denmark to assess all Danish live-born singletons born from January 1, 1977, to December 31, 2018, and followed up for up to 40 years. Data were analyzed from January through June 2023. Tooth agenesis as documented by the Danish Central Registry of Odontology (Danish municipal pediatric dental care) from January 1, 1988, to December 31, 2018, and from hospital encounters in the Danish National Patient Registry within the entire study period. The primary outcome was first cancer diagnosis before 40 years of age obtained from the Danish Cancer Registry. Associations between tooth agenesis and specific cancers were estimated by Cox proportional hazards regression as hazard ratios (HRs) with 95% CIs. Analyses were split into age groups: younger than 1 year, 1 to younger than 3 years, 3 to younger than 10 years, 10 to younger than 20 years, 20 to younger than 30 years, and 30 to younger than 40 years. Associations with nonsyndromic tooth agenesis were evaluated after exclusion of individuals with known syndromes. Among 2 501 715 included individuals (1 284 292 [51.3%] male), 70 288 (2.8%) had a diagnosis of tooth agenesis (mean [SD] age at diagnosis, 13.2 [4.1] years) and 26 308 (1.1%) had a diagnosis of early-onset cancer within the study period; 778 individuals had co-occurrence of tooth agenesis and cancer. Overall, tooth agenesis was positively associated with several cancer types, including neuroblastoma (age 1 to <3 years; HR, 4.20; 95% CI, 2.24-7.88), nephroblastoma (age 1 to <3 years; HR, 4.59; 95% CI, 2.37-8.91), hepatoblastoma (age 1 to <3 years; HR, 7.10; 95% CI, 2.70-18.68), osteosarcoma (age 10 to <20 years; HR, 2.19; 95% CI, 1.11-4.32), colorectal carcinomas (age 30 to <40 years; HR, 2.81; 95% CI, 1.38-5.71), and carcinomas of bladder (age 20 to <30 years; HR, 3.35; 95% CI, 1.35-8.30). This cohort study found associations between congenital tooth agenesis and several cancer types, from childhood to early adulthood. Further evaluation of these associations is needed to assess possible clinical implications.

Novel frameshift variant of WNT10A in a Japanese patient with hypodontia

Congenital tooth agenesis is caused by the impairment of crucial genes related to tooth development, such as Wnt signaling pathway genes. Here, we investigated the genetic causes of sporadic congenital tooth agenesis. Exome sequencing, followed by Sanger sequencing, identified a novel single-nucleotide deletion in WNT10A (NC_000002.12(NM_025216.3):c.802del), which was not found in the healthy parents of the patient. Thus, we concluded that the variant was the genetic cause of the patient’s agenesis.

矿物质和膳食补充剂对先天缺牙的影响：双样本孟德尔随机化分析

矿物质和膳食补充剂对先天缺牙的影响：双样本孟德尔随机化分析

Measurement and analysis of the crown conical degree of maxillary incisors in patients with congenital tooth agenesis caused by different gene mutations

Objective: To measure the crown conical degree of the remaining maxillary incisors in patients with congenital tooth agenesis, and to analyze the influence of different gene mutations on the crown conical degree of patients. Methods: Whole exome sequencing was performed on 85 patients with congenital tooth agenesis (50 males, 35 females, median age 19 years old) who visited the Department of Prosthodontics, Peking University School and Hospital of Stomatology from January 2019 to January 2023. The pathogenic gene was identified. The width of the crowns of the maxillary central and lateral incisors at the incisal 1/3 and gingival 1/3 were measured on the panoramic radiograph, and the ratio was defined as the crown conical degree. The smaller the ratio is, the more likely is the crown to be peg shaped teeth. The control group was matched by age and gender with 85 other patients with intact maxillary permanent incisors who were treated in the Department of Prosthodontics, Peking University School and Hospital of Stomatology from January 2019 to January 2023. The conical degree of the tooth agenesis group was compared with the control group by t-test, and the differences in the crown conical degree in different gene mutation groups were compared using one-way analysis of variance, and the multiple comparisons among gene groups were carried out using the LSD method. Results: Among the 85 tooth agenesis patients, the numbers of patients in each gene mutation group were 20 in ectodysplasin A (EDA) group, 8 in ectodysplasin A receptor (EDAR) group, 15 in wingless-type MMTV integration site family, member 10A (WNT10A) group, 16 in paired box 9 (PAX9) group, 10 in Msh homeobox 1 (MSX1) group, 10 in low-density Lipoprotein receptor related protein 6 (LRP6) group, and 6 in bone morphogenetic protein4 (BMP4) group. The number of missing teeth were 1-27, median number 15 among the tooth agenesis patients. There was no significant difference in the conical degree between the left and right homonymous teeth in the congenital tooth agenesis group and the control group (P>0.05). The crown conical degree of maxillary central incisor and lateral incisor in the congenital missing teeth group (0.95±0.24, 0.90±0.22) was significantly smaller than that in the control group (1.12±0.09, 1.13±0.09) (t=-8.50, P<0.001; t=-11.47, P<0.001). In WNT10A mutants, the conical degree of lateral incisors (0.89±0.18) was less than that of central incisors (1.07±0.15)(t=3.68, P<0.001). The conical degree of central incisors and lateral incisors (0.70±0.23, 0.57±0.15) of EDA mutants was significantly lower than that in patients with other gene mutations (P>0.05). Conclusions: Compared with the normal control group, the remaining maxillary central and lateral incisors of the seven gene mutation groups of patients with congenital tooth agenesis all had different degrees of conical crown. Among them, the crown conical degree of maxillary central and lateral incisors of the EDA mutation was the most severe, and the WNT10A mutation affected the maxillary lateral incisors more specifically.

Advances in tooth agenesis and tooth regeneration.

The lack of treatment options for congenital (0.1%) and partial (10%) tooth anomalies highlights the need to develop innovative strategies. Over two decades of dedicated research have led to breakthroughs in the treatment of congenital and acquired tooth loss. We revealed that by inactivating USAG-1, congenital tooth agenesis can be successfully ameliorated during early tooth development and that the inactivation promotes late-stage tooth morphogenesis in double knockout mice. Furthermore, Anti- USAG-1 antibody treatment in mice is effective in tooth regeneration and can be a breakthrough in treating tooth anomalies in humans. With approximately 0.1% of the population suffering from congenital tooth agenesis and 10% of children worldwide suffering from partial tooth loss, early diagnosis will improve outcomes and the quality of life of patients. Understanding the role of pathogenic USAG-1 variants, their interacting gene partners, and their protein functions will help develop critical biomarkers. Advances in next-generation sequencing, mass spectrometry, and imaging technologies will assist in developing companion and predictive biomarkers to help identify patients who will benefit from tooth regeneration.

Novel WNT10A variant in a Japanese case of nonsyndromic oligodontia

Congenital tooth agenesis is one of the most common anomalies in humans. Many genetic factors are involved in tooth development, including MSX1, PAX9, WNT10A, and LRP6. Thus, mutations in these genes can cause congenital tooth agenesis in humans. In this study, we identified a novel nonsense WNT10A variant, NM_025216.3(WNT10A_v001):c.1090A > T, which produces a C-terminal truncated gene product, p.(Lys364*), in a sporadic form of congenital tooth agenesis. The variant was not found in the healthy parents and thus was considered to cause congenital tooth agenesis in the case.

Development of a Novel Antibody Drug to Regenerate Missing Teeth in Patients with Congenital Tooth Agenesis, a Rare Disease -Toward Industrialization of Research Seeds-

Development of a Novel Antibody Drug to Regenerate Missing Teeth in Patients with Congenital Tooth Agenesis, a Rare Disease -Toward Industrialization of Research Seeds-

An in vitro and computational validation of a novel loss-of-functional mutation in PAX9 associated with non-syndromic tooth agenesis.

Congenital tooth agenesis (CTA) is one of the most common craniofacial anomalies. Its frequency varies among different population depending upon the genetic heterogeneity. CTA could be of familial or sporadic and syndromic or non-syndromic. Five major genes are found to be associated with non-syndromic CTA, namely PAX9, MSX1, EDA1, AXIN2, and WNT10A. Very few studies have been carried out so far on CTA on this Indian population making this study unique and important. This study was initiated to identify potential pathogenic variant associated with congenital tooth agenesis in an India family with molar tooth agenesis. CTA was investigated and a novel c.336C > G variation was identified in the exon 3 of PAX9, leading to substitution of evolutionary conserved Cys with Trp at 112th amino acid position located at the functionally significant DNA-binding paired domain region. Functional analysis revealed that p.Cys112Trp mutation did not prevent the nuclear localization although mutant protein had higher cytoplasmic retention. EMSA using e5 probe revealed that mutant protein was unable to bind with the paired-domain-binding site. Subsequently, GST pull-down assay revealed lower binding activity of the mutant protein with its known interactor MSX1. These in vitro results were consistent with the computational results. The in vitro and computational observations altogether suggest that c.336C > G (p.Cys112Trp) variation leads to loss of function of PAX9 leading to CTA in this family.

Investigation into the characteristics of missing patterns and maxillofacial morphology in patients with non-syndromic congenital tooth agenesis of 10 or more teeth

Investigation into the characteristics of missing patterns and maxillofacial morphology in patients with non-syndromic congenital tooth agenesis of 10 or more teeth

A novel LRP6 variant in a Japanese family with oligodontia

Congenital tooth agenesis is a common anomaly in human development. We performed exome sequence analysis of genomic DNA collected from Japanese patients with tooth agenesis and their relatives. We found a novel single-nucleotide insertion in the LRP6 gene, the product of which is involved in Wnt/β-catenin signaling as a coreceptor for Wnt ligands. The single-nucleotide insertion results in a premature stop codon in the extracellular region of the encoded protein.

Novel MSX1 frameshift mutation in a Japanese family with nonsyndromic oligodontia

Congenital tooth agenesis is a common anomaly in humans. We investigated the etiology of human tooth agenesis by exome analysis in Japanese patients, and found a previously undescribed heterozygous deletion (NM_002448.3(MSX1_v001):c.433_449del) in the first exon of the MSX1 gene. The deletion leads to a frameshift and generates a premature termination codon. The truncated form of MSX1, namely, p.(Trp145Leufs*24) lacks the homeodomain, which is crucial for transcription factor function.

Local application of Usag-1 siRNA can promote tooth regeneration in Runx2-deficient mice

Runt-related transcription factor 2 (Runx2)-deficient mice can be used to model congenital tooth agenesis in humans. Conversely, uterine sensitization-associated gene-1 (Usag-1)-deficient mice exhibit supernumerary tooth formation. Arrested tooth formation can be restored by crossing both knockout-mouse strains; however, it remains unclear whether topical inhibition of Usag-1 expression can enable the recovery of tooth formation in Runx2-deficient mice. Here, we tested whether inhibiting the topical expression of Usag-1 can reverse arrested tooth formation after Runx2 abrogation. The results showed that local application of Usag-1 Stealth small interfering RNA (siRNA) promoted tooth development following Runx2 siRNA-induced agenesis. Additionally, renal capsule transplantation of siRNA-loaded cationized, gelatin-treated mouse mandibles confirmed that cationized gelatin can serve as an effective drug-delivery system. We then performed renal capsule transplantation of wild-type and Runx2-knockout (KO) mouse mandibles, treated with Usag-1 siRNA, revealing that hindered tooth formation was rescued by Usag-1 knockdown. Furthermore, topically applied Usag-1 siRNA partially rescued arrested tooth development in Runx2-KO mice, demonstrating its potential for regenerating teeth in Runx2-deficient mice. Our findings have implications for developing topical treatments for congenital tooth agenesis.

Anti-USAG-1 therapy for tooth regeneration through enhanced BMP signaling.

Uterine sensitization-associated gene-1 (USAG-1) deficiency leads to enhanced bone morphogenetic protein (BMP) signaling, leading to supernumerary teeth formation. Furthermore, antibodies interfering with binding of USAG-1 to BMP, but not lipoprotein receptor-related protein 5/6 (LRP5/6), accelerate tooth development. Since USAG-1 inhibits Wnt and BMP signals, the essential factors for tooth development, via direct binding to BMP and Wnt coreceptor LRP5/6, we hypothesized that USAG-1 plays key regulatory roles in suppressing tooth development. However, the involvement of USAG-1 in various types of congenital tooth agenesis remains unknown. Here, we show that blocking USAG-1 function through USAG-1 knockout or anti-USAG-1 antibody administration relieves congenital tooth agenesis caused by various genetic abnormalities in mice. Our results demonstrate that USAG-1 controls the number of teeth by inhibiting development of potential tooth germs in wild-type or mutant mice missing teeth. Anti-USAG-1 antibody administration is, therefore, a promising approach for tooth regeneration therapy.

Pediatric Dentist-Pediatrician Cooperation in Early Diagnosis of Congenital Tooth Agenesis

Pediatric Dentist-Pediatrician Cooperation in Early Diagnosis of Congenital Tooth Agenesis

Detection and functional analysis of BMP2 gene mutation in patients with tooth agenesis

To screen for BMP2 mutation with functional impact in patients with congenital tooth agenesis and to make oral and skeletal phenotype record and functional analysis with in vitro experiments. We enrolled eighteen patients with congenital tooth agenesis. The medical and dental history was collected,and clinical and dental examinations including the X-ray examination of oral-facial and skeletal bone were performed for the phenotypic analysis. Blood samples were collected to extract DNA and whole exome sequencing was conducted. The genes involved in oral-facial development and congenital skeletal diseases were investigated for mutation screening. The mutations with functional impact were then investigated. In one patient, the BMP2 mutation with putative functional impact was selected for functional analysis. Wild type and mutant BMP2 plasmids with green fluorescent protein (GFP) tag were constructed and transfected into HEK293T cells. Subcellular protein distribution was observed under laser scanning confocal microscope. The activation of downstream SMAD1/5/9 phosphorylation by BMP2 was detected by Western blotting to investigate the functional impact and genetic pathogenicity. BMP2 mutation NM_001200.3:c.393A>T (p.Arg131Ser), rs140417301 was detected in one patient with congenital tooth agenesis, while for other genes involved in oral-facial development and congenital skeletal diseases, no functionally significant mutation was found. The proband's parents didn't carry this mutation. The father had normal dentition, while the mother lacked one premolar, and both the parents showed normal palate and maxilla. The patient also had maxillary hypoplasia in both sagittal and coronal planes, palatal dysmorphology, and malocclusion, and was diagonsed with osteopenia after the X-ray examnination of his skeletal bone. Functional analysis showed this mutation had normal subcelluar localization but reduced phosphorylation of SMAD1/5/9 (reduction by 32%, 22%, and 27% in three independent replicates). Taken together with family co-segregation, this mutaion was considered as "likely pathogenic". BMP2 mutation c.393A>T (p. Arg131Ser) affects bone morphogenetic protein signaling activity, and may affect the number of teeth, growth of maxilla and palate, and bone mineral density.

Hypodontia and WNT10A mutation: a case report

Summary Tooth agenesis is common dentofacial malformation in humans. Its etiology is still not clear. Hypodontia has been regarded as a multifactorial condition influenced by gene function, environmental interaction and developmental timing. More than 300 genes have been related with patterning, morphogenesis and cell differentiation in teeth. According to data WNT10A gene is considered to have an important role in odontogonesis. The aim of this study was to show mutation status in WNT10A gene in a family with two members with diagnosis of hypodontia/oligodontia. In the reported family (father, mother, son, daughter) children were diagnosed with congenital tooth agenesis (son-2 teeth, daughter-11 teeth), while parents negated congenital absence of teeth. We identified a heterozygous missense mutation, c.682T&gt;A (p.Phe228Ile) within the exon 3 of WNT10A in mother and father and the same homozygous mutation was detected in the same region of WNT10A gene in daughter and son. Observed differences in our study, from no symptoms to mild/severe hypodontia, could be the consequence of genetic influence of c.682T&gt;A(p.Phe228Ile) mutation, but also the contribution of many environmental factors during odontogenesis.

WNT10A variants isolated from Japanese patients with congenital tooth agenesis

It has been reported that dozens of WNT10A variants are associated with human isolated tooth agenesis, however, little is known about the precise phenotypes. In 50 Japanese patients with severe congenital tooth agenesis, we identified 11 patients with WNT10A variants. Comparing phenotypes between the tooth agenesis patients carrying the wild-type and variants of WNT10A, we revealed that the development of lateral incisors is relatively susceptive to insufficiency of WNT/β-catenin signaling.

Characterization of PAX9 variant P20L identified in a Japanese family with tooth agenesis.

Transcription factors PAX9 and MSX1 play crucial roles in the development of permanent teeth at the bud stage, and their loss-of-function variants have been associated with congenital tooth agenesis. We sequenced the coding regions of the PAX9 and MSX1 genes from nine patients with non-syndromic tooth agenesis, and identified a missense mutation, P20L, of PAX9 in a single familial case involving three patients in two generations. Identical mutation was previously reported by other authors, but has not been characterized in detail. The mutation was located in a highly conserved N-terminal subdomain of the paired domain and co-segregated as a heterozygote with tooth agenesis. The patients showed defects primarily in the first and second molars, which is typical for cases attributable to PAX9 mutation. Luciferase reporter assay using the 2.3-kb promoter region of BMP4 and electrophoretic mobility shift assay using the CD19-2(A-ins) sequence revealed that P20L substitution eliminated most of the transactivation activity and specific DNA binding activity of PAX9 under the experimental conditions we employed, while some residual activity of the mutant was evident in the former assay. The hypomorphic nature of the variant may explain the relatively mild phenotype in this case, as compared with other PAX9 pathogenic variants such as R26W.

A novel G to A transition at initiation codon and exon-intron boundary of PAX9 identified in association with familial isolated oligodontia

Several studies on experimental animals indicate that the process of organogenesis crucially depends upon the spatiotemporal dose of certain critical bio-molecules. Tooth development is also not an exception. While most of the knowledge regarding the molecular mechanism of tooth development comes from the studies on mouse model, pathogenic variations identified in human tooth agenesis also provide valuable information on mammalian tooth development. Until now five major candidate genes have been identified for tooth agenesis in human. Among them, PAX9 plays the crucial role in tooth development and in non-syndromic congenital tooth agenesis. In this study, microsatellite and SNP based genotyping identifies a disease specific haplotype block, which includes PAX9 gene, segregates with autosomal dominant tooth agenesis phenotype. Direct sequencing of PAX9 identifies a novel heterozygous G to A transition at the third base (c.3G>A) of initiation codon leading to ATG to ATA shift in all affected individuals which is absent in all unaffected relatives and 200 control chromosomes. Further, in vitro functional analysis creating PAX9 minigene construct did apparently show no effect on the splice-site migration. It is therefore proposed that haploinsufficiency of PAX9 is the causal factor for tooth agenesis in this family.