Human Developmental Anomalies Research Articles

Agenesis of all premolars – the first reported case

Abstract The agenesis of teeth is the most common developmental anomaly in humans. Although third molars, mandibular second premolars, maxillary lateral incisors and maxillary second premolars are frequently found to be missing, the absence of all premolars has never been reported in the literature. This case report highlights the first-ever case of the complete agenesis of premolars in a 10-year-old male patient. It also discusses related definitions; commonly missing teeth and their prevalence; associated dental and skeletal features; genetic, drug-related and pathogenic etiological factors; and considerations for the future management of such cases.

The genetic basis of hypodontia in dental development.

Dental agenesis is one of the most common developmental anomalies in humans, characterised by the developmental absence of one or more teeth. It can present as an isolated condition (non-syndromic hypodontia) or associated with a syndrome (syndromic hypodontia). This paper aims to review the genetic basis of hypodontia with reference to aetiology, classification and the subsequent clinical features.Significant progress has been made to identify the developmental basis of tooth formation, though there is still a lack of knowledge within the literature of the aetiological basis of inherited tooth loss.Gene anomalies or mutations in WNT10A, MSX1, PAX9, AXIN2 and EDA appear to be most critical during tooth development, leading to various forms of tooth agenesis.

Patterns of nonsyndromic tooth agenesis and sexual dimorphism

BackgroundSex 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.MethodsOne 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.ResultsThe 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).ConclusionsWe 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.

Disease-associated inosine misincorporation into RNA hinders translation.

Failure to prevent accumulation of the non-canonical nucleotide inosine triphosphate (ITP) by inosine triphosphate pyrophosphatase (ITPase) during nucleotide synthesis results in misincorporation of inosine into RNA and can cause severe and fatal developmental anomalies in humans. While the biochemical activity of ITPase is well understood, the pathogenic basis of ITPase deficiency and the molecular and cellular consequences of ITP misincorporation into RNA remain cryptic. Here, we demonstrate that excess ITP in the nucleotide pool during in vitro transcription results in T7 polymerase-mediated inosine misincorporation in luciferase RNA. In vitro translation of inosine-containing luciferase RNA reduces resulting luciferase activity, which is only partly explained by reduced abundance of the luciferase protein produced. Using Oxford Nanopore Direct RNA sequencing, we reveal inosine misincorporation to be stochastic but biased largely towards misincorporation in place of guanosine, with evidence for misincorporation also in place of cytidine, adenosine and uridine. Inosine misincorporation into RNA is also detected in Itpa-null mouse embryonic heart tissue as an increase in relative variants compared with the wild type using Illumina RNA sequencing. By generating CRISPR/Cas9 rat H9c2 Itpa-null cardiomyoblast cells, we validate a translation defect in cells that accumulate inosine within endogenous RNA. Furthermore, we observe hindered cellular translation of transfected luciferase RNA containing misincorporated inosine in both wild-type and Itpa-null cells. We therefore conclude that inosine misincorporation into RNA perturbs translation, thus providing mechanistic insight linking ITPase deficiency, inosine accumulation and pathogenesis.

Molecular genetics of human developmental neurocranial anomalies: towards "precision surgery".

Recent trio-based whole-exome sequencing studies of congenital hydrocephalus and nonsyndromic craniosynostosis have identified multiple novel disease genes that have illuminated the pathogenesis of these disorders and shed new insight into the genetic regulation of human brain and skull development. Continued study of these and other historically understudied developmental anomalies has the potential to replace the current antiquated, anatomically based disease classification systems with a molecular nomenclature that may increase precision for genetic counseling, prognostication, and surgical treatment stratification-including when not to operate. Data will also inform future clinical trials, catalyze the development of targeted therapies, and generate infrastructure and publicly available data sets relevant for other related nonsurgical neurodevelopmental and neuropsychiatric diseases.

A UNIQUE DISORDER OF THE STERNUM : HONEYCOMB STERNA

This article describes an uncommon example of a human sternal developmental anomaly in an anatomical specimen from the Department of Anatomy at Shahid Nirmal Mahto Medical College Dhanbad. The non-fusion of lateral ossication centres in the sternebrae caused the uncommonly recognized developmental anomaly, which results in a honeycomb-like appearance of the mesosternum. Sternal deciencies are normally under diagnosed in the clinical literature due to the fact that many instances are asymptomatic. As a result, there is a gap in our modern understanding of the development and anatomical variations of the sternum. Although in the past, large-scale CT investigations have been conducted to explore the incidence of sternal developmental anomalies. A very rare work has been reported on sternal malformations. Most of the sternal abnormalities are clinically insignicant; a lack of awareness of these variants can lead to interpretation of radiological and pathological evidence. Hence, anatomical variants are asymptomatic which is vital in nature.

Signaling pathways involved in tooth development: why use zebrafish in dental research?

Zebrafish (Danio rerio, formerly named Brachydanio rerio) is an established model organism used in health research for a long time. In the past decades, some research groups have been using zebrafish model to understand the genes involved in tooth development. Objectives: To introduce zebrafish as an animal model for tooth development researchers and to highlight the advantages and limitations of this model. Literature review: Tooth development (also known as odontogenesis) is a complex process that relies on precise control of several critical regulatory pathways. Because of the complex development and morphogenesis of teeth, many human developmental dental anomalies arise due to disruptions during tooth development. The knowledge regarding signaling pathways and genes expressed during tooth development has mainly been discovered using mice (not modified and genetically modified) and other rodents. Zebrafish (Danio rerio, formerly named Brachydanio rerio) has also been used by some recent researchers. Results: Zebrafish as a model organism has several advantages, and for which a large and diverse set of genetic and molecular tools are already available. Zebrafish has an easy husbandry system and a relatively fast embryonic development. Conclusion: This review provides some insights for the use of zebrafish in understanding tooth development and developmental dental alterations for clinical and basic researchers alike.

Taurodontismo – Série de casos em pacientes jovens não sindrômicos e sindrômicos associado à hipodontia

Several human dentition developmental anomalies are reported in the literature. The etiology of these occurrences is related to genetic, environmental or sometimes idiopathic factors. Taurodontism is defined as apical displacement of the pulp floor and consequent enlargement of the pulp chamber in multiradicular teeth. It is a result of the failure to invaginate Hertwigs epithelial sheath horizontally and commonly expresses bilaterally. This morphological pattern of molars is observed in ruminant animals and was also found in ancient Neanderthals. Association of this condition to syndromes is not exclusive, it may be associated with genetic disorders such as Down Syndrome, Klinefelter Syndrome, among others. The diagnosis is exclusively radiographic, with no alterations in the dental element crown. Among the consequences is the complexity of endodontic treatment, greater fragility of taurodontic teeth submitted to endodontics and lower orthodontic anchorage of these elements. In this paper, three case reports of patients with taurodontism are described, two of them associated with hypodontia and one in a Down Syndrome patient. This paper also includes a literature review and discussion with the main clinical implications of this occurrence.

Genetic bases related to the development of non-syndromic dental agenesis: a literature review

Non-syndromic dental agenesis is characterized as the most common developmental anomaly in humans, causing the lack of one or more teeth, in deciduous or permanent dentition. Mutations in specific genes of dental development are pointed as etiological factors of this anomaly. To perform this work, two electronic databases were consulted to conduct a literature survey, including PubMed and BVS. The descriptor "Anodontia" was used in both. The articles were filtered from 2010 to 2020, including full texts, in english, portuguese and spanish. Dissertations, theses and book chapters were discarded. In PubMed, from 508 articles found, 13 were included for review. In the BVS, from 304 articles found, 07 were included for review, totaling 20 articles. Studies have shown that mutations by nucleotide subitusing and deletion were more present in genes that cause dental agenesis (PAX9, MSX1, AXIN2, WNT). In epidemiologic studies, women showed greater involvement than men, both in deciduous and permanent dentition, in a ratio of 3:2. In addition, leukoderms showed greater involvement than melanoderms. Knowledge of the genotype-phenotype correlation between mutations and dental agenesis is important for the dental surgeon, as it assists in diagnosis, genetic counseling, treatment and prognosis.

Approaches to studying the genomic architecture of complex birth defects.

Every year nearly 6 percent of children worldwide are born with a serious congenital malformation, resulting in death or lifelong disability. In the United States, birth defects remain one of the leading causes of infant mortality. Among the common structural congenital defects are conditions known as neural tube defects (NTDs). These are a class of malformation of the brain and spinal cord where the neural tube fails to close during the neurulation. Although NTDs remain among the most pervasive and debilitating of all human developmental anomalies, there is insufficient understanding of their etiology. Previous studies have proposed that complex birth defects like NTDs are likely omnigenic, involving interconnected gene regulatory networks with associated signals throughout the genome. Advances in technologies have allowed researchers to more critically investigate regulatory gene networks in ever increasing detail, informing our understanding of the genetic basis of NTDs. Employing a systematic analysis of these complex birth defects using massively parallel DNA sequencing with stringent bioinformatic algorithms, it is possible to approach a greater level of understanding of the genomic architecture underlying NTDs. Herein, we present a brief overview of different approaches undertaken in our laboratory to dissect out the genetics of susceptibility to NTDs. This involves the use of mouse models to identify candidate genes, as well as large scale whole genome/whole exome (WGS/WES) studies to interrogate the genomic landscape of NTDs. The goal of this research is to elucidate the gene-environment interactions contributing to NTDs, thus encouraging global research efforts in their prevention.

Discovering candidate imprinted genes and imprinting control regions in the human genome

BackgroundGenomic imprinting is a process thereby a subset of genes is expressed in a parent-of-origin specific manner. This evolutionary novelty is restricted to mammals and controlled by genomic DNA segments known as Imprinting Control Regions (ICRs) and germline Differentially Methylated Regions (gDMRs). Previously, I showed that in the mouse genome, the fully characterized ICRs/gDMRs often includes clusters of 2 or more of a set of composite-DNA-elements known as ZFBS-morph overlaps.ResultsBecause of the importance of the ICRs to regulating parent-of-origin specific gene expression, I developed a genome-wide strategy for predicting their positions in the human genome. My strategy consists of creating plots to display the density of ZFBS-morph overlaps along the entire chromosomal DNA sequences. In initial evaluations, I found that peaks in these plots pinpointed several of the known ICRs/gDMRs along the DNA in chromosomal bands. I deduced that in density-plots, robust peaks corresponded to actual or candidate ICRs in the DNA. By locating the genes in the vicinity of candidate ICRs, I could discover potential imprinting genes. Additionally, my assessments revealed a connection between several of the potential imprinted genes and human developmental anomalies. Examples include Leber congenital amaurosis 11, Coffin-Siris syndrome, progressive myoclonic epilepsy-10, microcephalic osteodysplastic primordial dwarfism type II, and microphthalmia, cleft lip and palate, and agenesis of the corpus callosum.ConclusionWith plots displaying the density of ZFBS-morph overlaps, researchers could locate candidate ICRs and imprinted genes. Since the datafiles are available for download and display at the UCSC genome browser, it is possible to examine the plots in the context of Single nucleotide polymorphisms (SNPs) to design experiments to discover novel ICRs and imprinted genes in the human genome.

Orthodontic management of patients with congenitally missing permanent teeth

Dental agenesis is one of the most common developmental anomalies in humans. It occurs as part of a genetic syndrome or as an isolated sporadic or familial finding. Third molars, second mandibular premolars and maxillary lateral incisors are the most frequently targeted teeth of the permanent dentition. Clinically, patients with congenitally missing permanent teeth seeking treatment present with unesthetic diastemas, midline deviation and tilting of adjacent teeth in the edentulous areas. The impact of tooth agenesis reflects on esthetics, function, psychological and social well-being of the individuals affected. Orthodontics can contribute to the treatment plan selected by rearranging the present teeth so as to open spaces for prosthetic restorations or close spaces by reshaping teeth if needed. Following orthodontic space opening/maintaining, the usual alternatives involve single implants, two-(cantilever) or full coverage(cantilever) prostheses. Less frequently, the treatment modality of autotransplantation is proposed with a good esthetic result but feasible only in young patients where the roots of the premolars are still developing. In orthodontic space closure, treatment is accomplished sooner without waiting for the completion of growth of the patient. Depending on various factors such as the malocclusion, the dento-skeletal profile, the smile line, the space requirements, the teeth missing, the periodontal issues, the age of the patient and any financial issues, the clinician will determine the most appropriate treatment approach. The final esthetic and functional result should resemble an intact natural dentition.

Genetic architecture of retinoic-acid signaling-associated ocular developmental defects.

Ocular developmental anomalies are among the most common causes of severe visual impairment in newborns (combined incidence 1-2:10,000). They comprise a wide range of inborn errors of eye development with a spectrum of overlapping phenotypes and they are frequently associated with extraocular malformations, neuropsychomotor developmental delay and/or intellectual disabilities. Many studies from model organisms have demonstrated the role of retinoic acid (RA) during organogenesis, including eye development, and have revealed the wide spectrum of malformations that can arise from defective RA signaling. However, genes coding for homeobox proteins and morphogenetic factors were implicated in anomalies of ocular development long before genes coding for RA-signaling proteins. The purpose of this review is to discuss current knowledge about the highly complex genetic architecture of RA-signaling-associated ocular developmental anomalies in humans. Despite less than a dozen genes identified thus far, all steps of RA-signaling, from vitamin A transport to target cells to transcriptional activation of RA targets, have been implicated. Furthermore, the majority of these genetic disorders are associated with both dominant and recessive inheritance patterns and a wide spectrum of ocular malformations, which can dominate the phenotype or represent one of many features. Although some genotype-phenotype correlations are described, in many cases, the variability of clinical expression cannot be accounted for by the genotype alone. This observation and the large number of unsolved cases suggest that the relationship between RA signaling and eye development deserves further investigation.

Craniofacial, orofacial and dental disorders: the role of the RAS/ERK pathway.

Deviations from the precisely coordinated programme of human head development can lead to craniofacial and orofacial malformations often including a variety of dental abnormalities too. Although the aetiology is still unknown in many cases, during the last decades different intracellular signalling pathways have been genetically linked to specific disorders. Among these pathways, the RAS/extracellular signal-regulated kinase (ERK) signalling cascade is the focus of this review since it encompasses a large group of genes that when mutated cause some of the most common and severe developmental anomalies in humans. We present the components of the RAS/ERK pathway implicated in craniofacial and orodental disorders through a series of human and animal studies. We attempt to unravel the specific molecular targets downstream of ERK that act on particular cell types and regulate key steps in the associated developmental processes. Finally we point to ambiguities in our current knowledge that need to be clarified before RAS/ERK-targeting therapeutic approaches can be implemented.

Mesenchymal Wnt/β-catenin signaling limits tooth number.

Tooth agenesis is one of the predominant developmental anomalies in humans, usually affecting the permanent dentition generated by sequential tooth formation and, in most cases, caused by mutations perturbing epithelial Wnt/β-catenin signaling. In addition, loss-of-function mutations in the Wnt feedback inhibitor AXIN2 lead to human tooth agenesis. We have investigated the functions of Wnt/β-catenin signaling during sequential formation of molar teeth using mouse models. Continuous initiation of new teeth, which is observed after genetic activation of Wnt/β-catenin signaling in the oral epithelium, was accompanied by enhanced expression of Wnt antagonists and a downregulation of Wnt/β-catenin signaling in the dental mesenchyme. Genetic and pharmacological activation of mesenchymal Wnt/β-catenin signaling negatively regulated sequential tooth formation, an effect partly mediated by Bmp4. Runx2, a gene whose loss-of-function mutations result in sequential formation of supernumerary teeth in the human cleidocranial dysplasia syndrome, suppressed the expression of Wnt inhibitors Axin2 and Drapc1 in dental mesenchyme. Our data indicate that increased mesenchymal Wnt signaling inhibits the sequential formation of teeth, and suggest that Axin2/Runx2 antagonistic interactions modulate the level of mesenchymal Wnt/β-catenin signaling, underlying the contrasting dental phenotypes caused by human AXIN2 and RUNX2 mutations.

Genetic study of non-syndromic tooth agenesis through the screening of paired box 9, msh homeobox 1, axin 2, and Wnt family member 10A genes: a case-series.

Non-syndromic tooth agenesis (NSTA) is the most common developmental anomaly in humans. Several studies have been conducted on dental agenesis and numerous genes have been identified. However, the pathogenic mechanisms responsible for NSTA are not clearly understood. We studied a group of 28 patients with sporadic NSTA and nine patients with a family history of tooth agenesis. We focused on four genes - paired box 9 (PAX9), Wnt family member 10A (WNT10A), msh homeobox 1 (MSX1), and axin 2 (AXIN2) - using direct Sanger sequencing of the exons and intron-exon boundaries. The most prevalent variants identified in PAX9 and AXIN2 genes were analyzed using the chi-square test. The sequencing results revealed a number of variants in the AXIN2 gene, including one novel missense mutation in one patient with agenesis of a single second premolar. We also identified one variant in the AXIN2 gene as being a putative risk factor for tooth agenesis. Only one missense mutation was identified in the WNT10A gene and this mutation was found in two patients. Interestingly, WNT10A is reported as the most prevalent gene mutated in the European population with NSTA.

Esthetic Rehabilitation of Familial Hypodontia: A Case Report

Dental agenesis is the most common developmental anomaly in humans and is frequently associated with several other oral abnormalities. In the literature, some terms are used to describe missing teeth like oligodontia, anodontia and hypodontia. Hypodontia is the developmental absence of one or more teeth. It can be isolated or as a part of a syndrome such as in ectodermal dysplasia. The consequences of missing teeth include abnormal occlusion or altered facial appearance which can cause psychological distress in some patients. The present case report describes case of familial hypodontia in 14 years female patient with no apparent systemic abnormalities.Birat Journal of Health Sciences 2016 1(1): 71-74

Comprehensive genetic exploration of selective tooth agenesis of mandibular incisors by exome sequencing

Tooth agenesis is described as the absence of one or more teeth. It is caused by a failure in tooth development and is one of the most common human developmental anomalies. We herein report genomic analyses of selective mandibular incisor agenesis (SMIA) using exome sequencing. Two Japanese families with SMIA were subjected to exome sequencing, and family with sequence similarity 65 member A (FAM65), nuclear factor of activated T-cells 3 (NFATC3) and cadherin-related 23 gene (CDH23) were detected. In the follow-up study, 51 Japanese and 32 Korean sporadic patients with SMIA were subjected to exome analyses, and 18 reported variants in PAX9, AXIN2, EDA, EDAR, WNT10A, BMP2 and GREM2 and 27 variants of FAM65, NFATC3 and CDH23 were found in 38 patients. Our comprehensive genetic study of SMIA will pave the way for a full understanding of the genetic etiology of SMIA and provide targets for treatment.

Genetic interactions between the hedgehog co-receptors Gas1 and Boc regulate cell proliferation during murine palatogenesis.

Abnormal regulation of Sonic hedgehog (Shh) signaling has been described in a variety of human cancers and developmental anomalies, which highlights the essential role of this signaling molecule in cell cycle regulation and embryonic development. Gas1 and Boc are membrane co-receptors for Shh, which demonstrate overlapping domains of expression in the early face. This study aims to investigate potential interactions between these co-receptors during formation of the secondary palate. Mice with targeted mutation in Gas1 and Boc were used to generate Gas1; Boc compound mutants. The expression of key Hedgehog signaling family members was examined in detail during palatogenesis via radioactive in situ hybridization. Morphometric analysis involved computational quantification of BrdU-labeling and cell packing; whilst TUNEL staining was used to assay cell death. Ablation of Boc in a Gas1 mutant background leads to reduced Shh activity in the palatal shelves and an increase in the penetrance and severity of cleft palate, associated with failed elevation, increased proliferation and reduced cell death. Our findings suggest a dual requirement for Boc and Gas1 during early development of the palate, mediating cell cycle regulation during growth and subsequent fusion of the palatal shelves.

Mutations in WNT10B Are Identified in Individuals with Oligodontia

Tooth agenesis is one of the most common developmental anomalies in humans. Oligodontia, a severe form of tooth agenesis, is genetically and phenotypically a heterogeneous condition. Although significant efforts have been made, the genetic etiology of dental agenesis remains largely unknown. In the present study, we performed whole-exome sequencing to identify the causative mutations in Chinese families in whom oligodontia segregates with dominant inheritance. We detected a heterozygous missense mutation (c.632G>A [p.Arg211Gln]) in WNT10B in all affected family members. By Sanger sequencing a cohort of 145 unrelated individuals with non-syndromic oligodontia, we identified three additional mutations (c.569C>G [p.Pro190Arg], c.786G>A [p.Trp262(∗)], and c.851T>G [p.Phe284Cys]). Interestingly, analysis of genotype-phenotype correlations revealed that mutations in WNT10B affect the development of permanent dentition, particularly the lateral incisors. Furthermore, a functional assay demonstrated that each of these mutants could not normally enhance the canonical Wnt signaling in HEPG2 epithelial cells, in which activity of the TOPFlash luciferase reporter was measured. Notably, these mutant WNT10B ligands could not efficiently induce endothelial differentiation of dental pulp stem cells. Our findings provide the identification of autosomal-dominant WNT10B mutations in individuals with oligodontia, which increases the spectrum of congenital tooth agenesis and suggests attenuated Wnt signaling in endothelial differentiation of dental pulp stem cells.