[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.

[Is there more to hypodontia then missing teeth?] / Ernstige hypodontie: meer dan alleen ontbrekende gebitselementen?

Dental care professionals regularly see patients with hypodontia. Hypodontia can be acquired, for example through chemotherapy or radiation at a young age, but is hereditary in most patients. Due to an error (pathogenic variant) in one of the many genes that control odontogenesis, the formation of the tooth germ is disrupted at an early stage. The genes involved are not only crucial for tooth development, but they also play an important role in other physical processes. This article provides background information on hypodontia. Based on an inventory of gastrointestinal complaints in patients with hypodontia and a case description of the simultaneous occurrence of a coagulation disorder and hypodontia, the importance of a broad view of this patient group is illustrated. It is concluded that, in addition to a dental assessment, examination of these patients should include a limited physical examination and the medical history of the patient and his close relatives.

Child Neurology: Hypotonia and Delayed Teeth Eruption in a 2-Year-Old Girl.

POLR3-related disorders are rare hypomyelinating leukodystrophies associated with hypodontia. We present a female patient, who was referred to pediatric neurology at 2 years of age for tremor, low tone, and motor delays. In addition, she was noted to have a delay in her teeth eruption and myopia. Neurologic examination was significant for ataxic features and global developmental delay. Laboratory workup was unrevealing. MRI was significant for hypomyelination. Genetic testing confirmed a pathogenic variant of POLR3B POLR3-related leukodystrophies should be considered in patients who present with hypotonia, ataxia, and hypodontia. There are many different subtypes of POLR-related leukodystrophies each with distinguishing phenotypic and radiographic features. Although MRI can be helpful in initial evaluation, genetic testing is needed for confirmatory diagnosis and to guide prognosis.

A novel EDAR missense mutation identified by whole-exome sequencing with non-syndromic tooth agenesis in a Chinese family.

BACKGROUND: Causative variants in genes of the EDA/EDAR/NF-κB pathway, such as EDA and EDARADD, have been widely identified in patients with non-syndromic tooth agenesis (NSTA). However, few cases of NSTA are due to ectodysplasin-A receptor (EDAR) variants. In this study, we investigated NSTA-associated variants in Chinese families. METHODS: Peripheral blood samples were collected from the family members of 24 individuals with NSTA for DNA extraction. The coding region of the EDA gene of the 24 probands was amplified by PCR and sequenced to investigate new variants. Whole-exome sequencing and Sanger sequencing were then performed for probands without EDA variants detected by PCR. RESULTS: A novel missense variant EDAR c.338G>A (p.(Cys113Tyr)) was identified in one family. In addition, three known EDA variants (c.865C>T, c.866G>A, and c.1013C>T) were identified in three families. Genotype-phenotype correlation analysis of EDAR gene mutation showed that NSTA patients were most likely to lose the maxillary lateral incisors and the maxillary central incisors were the least affected. The phenotype of mutations at codon 289 of EDA in NSTA affected patients was characterized by lateral incisors loss, rarely affecting the maxillary first molars. CONCLUSION: A novel EDAR missense variant c.338G>A (p.(Cys113Tyr)) was identified in a family with NSTA, extending the mutation spectrum of the EDAR gene. Genotype-phenotype correlation analyses of EDAR and EDA mutations could help to improve disease status prediction in NSTA families.

Missense mutations in EDA and EDAR genes cause dominant syndromic tooth agenesis.

BACKGROUND: Hypohidrotic ectodermal dysplasia (HED) is the most common form of ectodermal dysplasia and is mainly associated with mutations in the EDA, EDAR, and EDARADD responsible for the development of ectodermal-derived structures. HED displays different modes of inheritance according to the gene that is involved, with X-linked EDA-related HED being the most frequent form of the disease. METHODS: Two families with tooth agenesis and manifestations of HED underwent clinical examination and EDA, EDAR, and EDARADD genetic analysis. The impact of the novel variant on the protein was evaluated through bioinformatics tools, whereas molecular modeling was used to predict the effect on the protein structure. RESULTS: A novel missense variant was identified in the EDAR (c.287T>C, p.Phe96Ser) of a female child proband and her mother, accounting for autosomal dominant HED. The genetic variant c.866G>A (p.Arg289His) in EDA, which has been previously described, was observed in the male proband of another family confirming its role in X-linked HED. The inheritance model of the missense mutation showed a different relationship with X-linked HED and non-syndromic tooth agenesis. CONCLUSION: Our findings provide evidence of variable expression of HED in heterozygous females, which should be considered for genetic counseling, and different modes of inheritance related to tooth development.

De novo stop-loss variants in CLDN11 cause hypomyelinating leukodystrophy.

Claudin-11, a tight junction protein, is indispensable in the formation of the radial component of myelin. Here, we report de novo stop-loss variants in the gene encoding claudin-11, CLDN11, in three unrelated individuals presenting with an early-onset spastic movement disorder, expressive speech disorder and eye abnormalities including hypermetropia. Brain MRI showed a myelin deficit with a discrepancy between T1-weighted and T2-weighted images and some progress in myelination especially involving the central and peripheral white matter. Exome sequencing identified heterozygous stop-loss variants c.622T>C, p.(*208Glnext*39) in two individuals and c.622T>G, p.(*208Gluext*39) in one individual, all occurring de novo. At the RNA level, the variant c.622T>C did not lead to a loss of expression in fibroblasts, indicating this transcript is not subject to nonsense-mediated decay and most likely translated into an extended protein. Extended claudin-11 is predicted to form an alpha helix not incorporated into the cytoplasmic membrane, possibly perturbing its interaction with intracellular proteins. Our observations suggest that stop-loss variants in CLDN11 expand the genetically heterogeneous spectrum of hypomyelinating leukodystrophies.

Palatal rugae morphology is associated with variation in tooth number.

This observational study compared palatal rugae morphology in adolescent subjects with normal tooth number and tooth agenesis. Maxillary dental study casts were used to compare rugae number, length and shape. Each study group contained 60 subjects (30 females and 30 males) mean age 13.4 (SD, 1.55) in control and 13.56 (SD, 1.54) years in tooth agenesis groups (p = 0.576). Mean number of missing tooth units in the tooth agenesis group was 2.1. Mean number of primary rugae in the whole sample was 4.35 (SD, 0.98) on the right and 4.33 (SD, 0.92) on the left with no significant differences (p = 0.236 and p = 0.404, respectively). However, the number of secondary rugae on the left (p = 0.006) and fragmentary rugae on the right (p = 0.004) was significantly increased in the tooth agenesis group. The shape of left primary rugae 2 and 3 also differed between groups, tending towards a wavy pattern in the control group and curved in the tooth agenesis group (p = 0.012 and p = 0.004, respectively). In addition, primary rugae 3 was more convergent (p = 0.008) whilst left primary rugae 3 and 5 were orientated in an antero-posterior direction (p = 0.04 for both rugae) in the tooth agenesis group. Subgroup analysis also identified significant associations between patterns of tooth agenesis and rugae number, in addition to shape of primary rugae. The identification of significant differences in rugae pattern between subjects with normal tooth number and agenesis suggests potential commonality in signal pathway disruption during establishment of these structures.

Clinical Orodental Anomalies in Taiwanese Children under Age Six: a Study Based on the 1995-1997 National Dental Survey.

There are few published studies that report the prevalence of intraoral anomalies for young children. The purpose of this study was to investigate the prevalence and distribution of several congenital oral and paraoral anomalies in Taiwanese children under age six. Twenty-five cities and townships were randomly sampled in different areas of Taiwan using the stratified method. These cities and townships represent cross-sectional samples of geographic locations and socioeconomic levels. A total of 981 Taiwanese children under age six were examined with dental mirrors and explorers as part of the national dental survey. The results of this survey indicated an 11.31% prevalence of geographic tongue. This number is higher than that reported in studies previously performed in different countries. The occurrence of double teeth in primary dentition was found to be 2.14%. Ankyloglossia had a frequency of 1.22%, and primary talon cusp a frequency of 0.61%. Seven (0.71%) children exhibited fissured tongues. Thirteen (1.33%) cases of hypodontia were found. These values were different from those reported in several other countries, which may be attributed to differences in the ethnic and racial composition of the population studied.

Anatomical and biochemical evidence for Treponema pallidum in a 19th to early twentieth century skeletal cadaver.

This report summarizes findings relating to the biochemical and skeletal evidence for Treponema pallidum in an unusually old case of congenital syphilis. In 1951, the Milwaukee Public Museum acquired skeletal remains from the Surgical School of Marquette University. The male was identified as a 60-65-year-old, that was suffering from congenital syphilis. His remains are now part of the anthropological collections of Wisconsin Lutheran College (Milwaukee, Wisconsin). Venereal Disease Research Laboratory (VDRL) and Rapid Plasma Reagin (RPR) tests were used to verify the presence of the bacteria-generated antibodies, while mass spectrometry testing provided indirect evidence for the historical treatment of the disease. Notably, antibody detection in human remains of this age is rare. These initial results support what is known of syphilis and its treatment prior to the wide scale, clinical use of penicillin therapy, and describe evidence for long-term skeletal symptoms of congenital syphilis in century-old human remains.

Novel EDAR mutation in tooth agenesis and variable associated features.

Tooth agenesis (TA) is the developmental absence of one or more permanent teeth. We report on 10 members of a Pakistani family afflicted with TA with variable associated features inherited in autosomal dominant fashion with full penetrance. The malformation is bilateral in the majority of cases, and hallmark feature is the absence of lateral and central incisors and canines whereas first and second premolars are involved less often. Affected individuals also have pronounced variable features associated with TA such as diastema between central incisors, overgrown labial frenum, peg-shaped lower incisors, delayed exfoliation, over-erupted upper incisors and malocclusion but have no other signs of ectodermal dysplasia. Through linkage analysis coupled with exome sequencing, we identified novel nonsense variant EDAR c.1302G>A, p.(Trp434*). The variant is deduced to create a premature termination codon that leads to the deletion of the 15 C-terminal residues. Heterozygous EDAR variants most commonly cause hypohydrotic ectodermal dysplasia, but recently one nonsense and 10 missense variants have been reported in nonsyndromic TA, some with few mild features of hypohydrotic ectodermal dysplasia. The phenotype in the family we present, the largest with EDAR-related TA reported to date, is highly variable and without any signs of ectodermal dysplasia.

Number of teeth is associated with facial size in humans.

During human evolution there has been an increase in the size of the brain and the cranium, whereas the size of the face, as well as the size and number of teeth have decreased. In modern humans, the occurrence of missing permanent teeth, namely tooth agenesis, is common. It could be attributed to a biological mechanism of tooth number reduction that has evolved during time and might still be active. Although, if evident, it would add support to this theory, the relationship between this phenotype and craniofacial size remains largely unknown. The present case-control study shows that modern individuals with tooth agenesis have indeed smaller facial configurations. For example, a 15-year-old female with no, one, or ten missing teeth would have a facial centroid size of 511.83, 510.81, or 501.70 mm, respectively. No such effect was observable in the cranial base and the cranium. Our results suggest that common gene regulatory mechanisms that have evolved over time, continue to regulate the number of teeth and facial size of modern humans in a coordinated manner. We anticipate our findings to enrich our understanding of the evolution and development of the human head and kindle future developmental research on this field.

Three-dimensional geometric morphometric analysis of tooth shape in hypodontia: II size variation.

The study aimed to evaluate differences in tooth size between patients with hypodontia and those with normal complement of permanent teeth using three-dimensional geometric morphometric analysis. The number of anatomical landmarks was recorded on the clinical crown of the permanent teeth on three-dimensional scanned study models of hypodontia and in control subjects. The study sample comprised 120 patients with hypodontia (mild, moderate, severe) and 40 controls matched for age and sex. Tooth size differences were tested statistically using multivariate statistics. Size variation was for the most part found to be significant, especially when the control subjects were compared with the hypodontia groups. The explained variance among group membership was generally larger in the anterior and premolar region than in the molar region Sexual dimorphism was found less in the anterior region than in the posterior region; therefore, the sexes were pooled more often for teeth in the anterior region. Quantitative measurement of tooth size in patients with hypodontia may enhance the multidisciplinary management of these patients.

Biallelic variants in POLR3GL cause endosteal hyperostosis and oligodontia.

RNA polymerase III (Pol III) is an essential 17-subunit complex responsible for the transcription of small housekeeping RNAs such as transfer RNAs and 5S ribosomal RNA. Biallelic variants in four genes (POLR3A, POLR3B, and POLR1C and POLR3K) encoding Pol III subunits have previously been found in individuals with (neuro-) developmental disorders. In this report, we describe three individuals with biallelic variants in POLR3GL, a gene encoding a Pol III subunit that has not been associated with disease before. Using whole exome sequencing in a monozygotic twin and an unrelated individual, we detected homozygous and compound heterozygous POLR3GL splice acceptor site variants. RNA sequencing confirmed the loss of full-length POLR3GL RNA transcripts in blood samples of the individuals. The phenotypes of the described individuals are mainly characterized by axial endosteal hyperostosis, oligodontia, short stature, and mild facial dysmorphisms. These features largely fit within the spectrum of phenotypes caused by previously described biallelic variants in POLR3A, POLR3B, POLR1C, and POLR3K. These findings further expand the spectrum of POLR3-related disorders and implicate that POLR3GL should be included in genetic testing if such disorders are suspected.

A novel mutation of MSX1 inherited from maternal mosaicism causes a severely affected child with nonsyndromic oligodontia.

Mutations of MSX1 have been associated with nonsyndromic hypodontia. To seek the causal gene mutation sites in a family with nonsyndromic oligodontia, whole-exome sequencing (WES) was performed to seek the causative locus of the family. The candidate mutation was further identified by Sanger sequencing afterward. Two mutations of MSX1 were found both in the proband and her mother. One novel heterozygous missense mutation (c.C667G, p.R223G) of MSX1 inherited from the asymptomatic mother with mosaic mutation was located in the highly conserved fragment of exon 2. The other was a synonymous mutation (c.C348T, p.G116G) in exon 1, which had been reported. The novel maternal heterozygous missense mutation (c.C667G, p.R223G) was likely to be the major reason for nonsyndromic oligodontia in the family. This is the first mosaic variant that has been recorded of the MSX1 gene. Our study expands the phenotype-genotype correlation associated with MSX1 variants. Our study also suggests that the determination of the mosaicism is essential for precise genetic counseling if a disease appears to arise de novo.

Tooth agenesis patterns in Japanese orthodontic patients with nonsyndromic oligodontia.

INTRODUCTION: Tooth agenesis is the most common dental anomaly in humans and is often found in orthodontic patients. However, severe tooth agenesis (oligodontia) is rare and its characteristics are poorly understood. This study aimed to investigate tooth agenesis patterns of Japanese orthodontic patients with nonsyndromic oligodontia. METHODS: Panoramic radiographs of 228 orthodontic patients (141 females, 87 males) with nonsyndromic oligodontia were selected and permanent tooth agenesis excluding third molars was evaluated. Influence of cutoff age was tested, tooth agenesis patterns for each quadrant were calculated, and antagonistic maxillary and mandibular quadrants were merged as the occluding tooth agenesis pattern. Full-mouth tooth agenesis patterns were also evaluated. RESULTS: The highest prevalence of tooth agenesis was observed in maxillary and mandibular second premolars, followed by maxillary first premolars. Prevalence of a symmetric pattern between right and left quadrants was significantly higher than matched patterns between maxillary and mandibular antagonistic quadrants. Among 456 possible tooth agenesis patterns, 51 and 49 patterns were observed for the maxillary and mandibular quadrants, respectively, but 215 patterns for the occluding patterns were observed. In addition, 180 full-mouth tooth agenesis patterns were observed in the 228 patients. CONCLUSIONS: Distinct characteristics in highly ranked patterns were observed compared with studies from other geographic areas, especially in the maxillary arch. Occluding and full-mouth tooth agenesis patterns showed wide variation, suggesting difficulty in orthodontic diagnosis.

Oral Health-Related Quality of Life in Dutch Children Diagnosed with Oligodontia. A Cross-Sectional Study.

There is need to get insight into condition-specific oral health-related quality of life in Dutch children with oligodontia. Between October 2014 and March 2017, 11-17-year-old oligodontia patients were approached to join a study assessing the impact of oligodontia on condition-specific oral health-related quality of life (OHrQoL). The patients received a condition-specific OHrQoL questionnaire prior to the start of orthodontic treatment. Non-oligodontia children in the same age group, but also requiring orthodontic treatment, were approached to serve as a control. The Fisher's Exact Test was used for comparison purposes with the control group because of the small group sizes. Furthermore, subgroup analyses were performed for gender, age, number of congenitally missing teeth, tooth agenesis in the aesthetic region, orthodontic classification and microdontia via independent t-tests. p-values of <0.05 were considered statistically significant. Twenty-eight oligodontia patients and 23 controls agreed to participate. The oligodontia patients' scores were comparable to the controls except for the items about dental appearance and treatment complexity. The impact of oligodontia on OHrQoL in youngsters is limited and mainly concerns dental appearance and the complexity of the treatment.

Concurrent manifestation of oligodontia and thrombocytopenia caused by a contiguous gene deletion in 12p13.2: A three-generation clinical report.

BACKGROUND: Wnt and Wnt-associated pathways play an important role in the genetic etiology of oligodontia, a severe form of tooth agenesis. Loss-of-function mutations in LRP6 , encoding a transmembrane cell-surface protein that functions as a coreceptor in the canonical Wnt/b-catenin signaling cascade, also contribute to genetic oligodontia. METHODS AND RESULTS: We describe a three-generation family with hereditary thrombocytopenia and oligodontia. Genome wide array analysis was performed. The array results from the index patient revealed an interstitial loss of 150 kb in 8p23.1 (chr8:6,270,299-6,422,558; hg19) encompassing MCPH1 and ANGPT2 and an interstitial loss of 290 kb in 12p13.2 (chr12:12,005,720-12,295,290; hg19) encompassing ETV6, BCL2L14 and LRP6. CONCLUSION: This case report shows a three-generation family with hereditary thrombocytopenia and oligodontia with a heterozygous 290 kb novel contiguous gene deletion in band p13.2 of chromosome 12, encompassing LRP6 and ETV6. In this report we discuss the clinical relevance of the deletion of both genes and illustrate the importance of thorough examination of oligodontia patients. Comprising not only the oral status but also the medical history of the patients and their relatives.

The solitary median maxillary central incisor (SMMCI) syndrome: Associations, prenatal diagnosis, and outcomes.

Solitary median maxillary central incisor (SMMCI) syndrome is a complex disorder consisting of multiple, developmental defects involving midline structures of the head, which includes the cranial bones, the maxilla, and its container dentition (specifically the central incisor tooth germ), together with other midline structures of the body. SMMCI may appear as an isolated trait or in association with other midline developmental anomalies. We describe the case of a patient with SMMCI. He presented with a solitary median maxillary incisor, short stature, corpus callosum anomalies and a microform of holoprosencephaly (HPE), diabetes insipidus, and neurodevelopmental delay. The diagnosis was performed postnatally based on clinical features, radiological imaging, and a comprehensive genetic study. SMMCI can be diagnosed during the prenatal or neonatal periods or during infancy. Evaluation of the superior maxillary bone is important for prenatal diagnosis. Direct evaluation through bidimensional ultrasound or the use of multiplanar ultrasound or tridimensional reconstruction should be performed in cases of brain or face malformations. Early diagnosis can contribute to improved prenatal assessment and postnatal management.

[Study of skeletal features in congenital hypodontia]. / Veleszületett csírahiánnyal társuló skeletalis eltérések vizsgálata.

INTRODUCTION: The incidence of congenital hypodontia is increasing in daily practice. Early diagnosis of this dental disorder and the associated skeletal malocclusions is crucial for successful and stable final rehabilitation. AIM: Comparison of cephalometric findings of patients with hypodontia of 1-4 teeth with the measurement results of the control group without teeth agenesis. MATERIAL AND METHOD: We evaluated the lateral X-ray of 41 patients with 1-4 teeth agenesis selected from patients referred for orthodontic treatment to the Orthodontic Department of the University of Medicine and Pharmacy from Târgu Mures within a two-year period. The results were compared with the values of the age and sex matched control group. RESULTS: Bilateral upper incisor and lower bicuspid were missing in most of the hypodontia cases. When looking at the NSGn angle predicting the growth direction of the mandible, statistically significant differences were found between the male (p = 0.012), the front (p = 0.010) and the hypodontia group (p = 0.024) and the control group. Regarding the ANB angle, which shows the sagittal position of the maxilla to the mandible, statistically significant differences were found between the subgroups (women, men, anterior or posterior hypodontia) and the control group. CONCLUSION: Larger number of skeletal class 3 and vertical hypodivergent tendency were observed in the hypodontia group. Orv Hetil. 2019; 160(6): 214-219.