Search Results (35)

Background/Objectives: X-linked hypohidrotic ectodermal dysplasia (XLHED) is a rare monogenic disorder characterized by hypohidrosis, hypotrichosis, and hypodontia, caused primarily by pathogenic variants in the EDA gene. XLHED predominantly affects males due to its X-linked recessive inheritance, while female carriers may exhibit variable phenotypes due to random X-inactivation. Early diagnosis is critical for timely counseling and emerging therapeutic interventions. We report a rare prenatal diagnosis of XLHED in dizygotic dichorionic male twins during a dichorionic diamniotic pregnancy. At 24 weeks’ gestation, ultrasonographic anomalies—facial dysmorphisms, oligodontia, and hypoechogenic skin—raised suspicion for ectodermal dysplasia. Methods: Non-invasive prenatal test and targeted next-generation sequencing (NGS) of Cell-free DNA identified an hemizygous EDA deletion (c.612_629del; p.Ile205_Gly210del) with 52% variant allele frequency. Results: This in-frame deletion affects a highly conserved region in the TNF homology domain of ectodysplasin-A1, likely compromising protein function. The variant was confirmed in both fetuses via genetic analysis on amniotic fluid and in the heterozygous state in the mother, consistent with X-linked recessive inheritance. Family history revealed a maternal uncle with XLHED. Additional heterozygous variants were also identified in CPT2, GBA1, GJB2, and SMN1 genes. Following comprehensive genetic counseling, the mother opted for abortion. Conclusions: This case underscores the value of applying advanced genomic technologies—cfDNA-based NGS—for prenatal diagnosis of rare genetic disorders. The identification of apathogenic EDA variant expands the mutational spectrum of XLHED and supports early diagnosis for informed reproductive decisions and potential access to emerging prenatal therapies. Broader application of such technologies may improve outcomes in future pregnancies at risk for monogenic disorders. Full article

Background: Tooth development or odontogenesis is a complicated, multi-staged process, regulated by a plethora of genes. Disruptions during the early stages of odontogenesis may cause the complete absence of one or more teeth, known as tooth agenesis (TA). Except for PAX9, alterations in MSX1, AXIN2, WNT10A, and EDA/EDAR/EDARADD have gathered an increasing amount of interest. Objectives: This systematic review aims to investigate whether non-syndromic tooth agenesis (NSTA) is associated with MSX1, AXIN2, WNT10A, and EDA/EDAR/EDARADD mutations and to list the related phenotypic patterns of these alterations with regard to missing teeth. Methods: MEDLINE, Scopus, and Web of Science were the three selected databases. Duplicates were removed using Mendeley, and the records were assessed via the Rayyan platform. The Newcastle–Ottawa Scale was used to evaluate the quality of the evidence. Results: Fifteen case–control studies were eligible for this systematic review. The MSX1 gene was examined in most studies, whereas second premolars and lateral incisors were the most commonly missing teeth among TA cases. In total, 61.29% to 84.9% of the cases included one or two absent teeth. Conclusions: Due to the considerable heterogeneity in reporting results across the included studies, along with the high risk of bias present in most of them, it was not feasible to conduct a meta-analysis of the data. Nonetheless, the findings suggest that the NSTA phenotypes linked to the studied genes are similar to those associated with other forms of TA and share a common pattern of missing teeth. Future research should adopt a more standardized approach in presenting findings by adhering to established terminology and definitions and by utilizing common cut-off points to categorize results. Full article

Tooth agenesis (TA), the congenital absence of one or more teeth, is the most common manifestation of defective dental morphogenesis in humans. TA can occur as an isolated (non-syndromic) condition or as part of a broader syndromic presentation. In this review, we analyzed a total of 73 manuscripts to provide a comprehensive update on the genetic landscape of TA. To investigate the genes, variants, and associated phenotypes, we reviewed data from curated databases including Human Phenotype Ontology (HPO), OMIM, ClinVar and MalaCards. Based on the current evidence, the genes most frequently implicated in TA are MSX1, EDA, and PAX9. However, chromosomal abnormalities, such as those seen in Down syndrome and Williams syndrome, along with structural variations (e.g., deletions and duplications), also contribute significantly to TA etiology. The most involved pathways include TNF receptor binding, encompassing genes such as EDA, EDA2R, EDAR, and EDARADD, and the mTOR signaling pathway, which includes AXIN2, FGFR1, LRP6, WNT10A, and WNT10B. The aim of this review is to provide an critical synthesis of the genetic mechanisms underlying TA, highlighting the contribution of major signaling pathways, regulatory networks, and emerging molecular insights that may inform diagnostic and therapeutic advances. Full article

Background/Objectives: Hypohidrotic ectodermal dysplasia (HED) is a rare hereditary disorder affecting ectoderm-derived tissues including teeth, hair, and sweat glands. The dental abnormalities associated with HED, such as oligodontia and conical teeth, often result in significant functional, esthetic, and psychosocial challenges, particularly during childhood. Methods: A 10-year-old child presented with psychosocial concerns related to missing and malformed teeth. Clinical examination revealed oligodontia, conical anterior teeth, and a resorbed mandibular ridge. Based on clinical findings and a positive family history, a diagnosis of HED with significant dental involvement was confirmed. Results: A conservative prosthodontic approach was selected. A maxillary overdenture was fabricated over the retained primary teeth to enhance retention and preserve the alveolar bone, and a resin-bonded bridge was placed in the mandible due to poor ridge anatomy. The treatment restored oral function and esthetics and improved the child’s self-esteem. A recall visit after three months confirmed good prosthesis adaptation and a positive response from the patient and parents. Conclusions: This case highlights the importance of early, conservative, and developmentally appropriate prosthetic rehabilitation in pediatric patients with HED. Interim prostheses can significantly improve oral function, appearance, and psychosocial well-being while preserving future treatment options as the child matures. Full article

Background: Ectodermal dysplasia (ED) encompasses a heterogeneous group of genetic disorders affecting ectoderm-derived structures such as hair, teeth, nails, and sweat glands. Among these, variants in TSPEAR (Thrombospondin-type laminin G domain and epilepsy-associated repeats) have been implicated in autosomal recessive ED type 14 (OMIM 618180), predominantly manifesting with dental anomalies and hair dysplasia. However, the mutational spectrum of TSPEAR remains incompletely characterized. Methods: Two female siblings (ID#1 and ID#4) were clinically evaluated for ED. Genetic analysis, including next-generation sequencing (NGS) and Sanger validation, was conducted to identify TSPEAR variants. A segregation study confirmed inheritance patterns within the family. Results: Both affected siblings exhibited hallmark features of TSPEAR-related ED14, including oligodontia with dysmorphic, pointed maxillary central incisors. Hair thinning and cutaneous angiomas were predominant in ID#4. Genetic analysis identified two compound heterozygous variants in TSPEAR: c.543-1G>A, a splice-site variant likely to disrupt mRNA processing, and NM_144991.2:c.1251G>C(p.Gln417His), a missense variant with predicted deleterious effects. Segregation analysis confirmed maternal and paternal inheritance of the respective variants. A third sibling, ID#5, was identified as a heterozygous carrier without clinical manifestations. Conclusions: This study contributes to the expanding understanding of TSPEAR-related ED14 by providing novel genotype–phenotype correlations. Full article

Background/Objectives: The ectodysplasin A (EDA) gene, a member of the tumor necrosis factor ligand superfamily, is involved in the early epithelial–mesenchymal interaction that regulates ectoderm-derived appendage formation. Numerous studies have shown that mutations in the EDA gene can cause X-linked ectodermal dysplasia (ED) and non-syndromic oligodontia (NSO). Accordingly, this study aimed to identify the causative genetic mutations of the EDA gene. Methods: We investigated EDA gene mutations in two X-linked oligodontia families using candidate gene sequencing and whole-exome sequencing, with a single proband identified and studied for each family. The first family included a patient with NSO, while the second family had a patient exhibiting variable expression of ED. Results: Mutational analysis identified two missense mutations in the EDA gene (NM_001399.5): one novel mutation, c.787A>C p.(Lys263Gln), in family 2; and one previously reported mutation, c.457C>T p.(Arg153Cys), in family 1. All mutated residues are evolutionarily highly conserved amino acids. The p.(Arg153Cys) mutation would destroy the furin recognition site and affect the cleavage of EDA. The p.(Lys263Gln) mutation in a TNF homology domain would interfere with the binding of the EDA receptor. The p.(Lys263Gln) mutation was associated with NSO, while the other mutation demonstrated ED. Conclusions: This study helps to better understand the nature of EDA-related ED and NSO and their pathogenesis, and it expands the mutational spectrum of EDA mutations. Full article

Background/Objectives: There is a lack of evidence for the relationship between sweat pores and tooth agenesis. The aim of this study was to compare sweat pore density on fingertips between a group of patients with oligodontia and a control group without tooth agenesis. Methods: This parallel-group controlled clinical trial included 28 patients. Fourteen patients (f/m 9/5; mean age 13.5 ± 3.5 years) with ≥6 congenitally missing permanent teeth, excluding third molars (M3), were enrolled in the study group. The matched control group consisted of 14 patients (f/m 9/5; mean age 12.8 ± 1.8 years) without tooth agenesis. Impressions of 168 fingertips (left and right index, middle, and ring fingers) of the participating subjects were taken and examined using a scanning electron microscope with a 5.85 mm × 4.29 mm region of interest at the center of the fingertip. The primary outcome was the pore-to-pore distance (μm) on a dermal ridge, and the secondary outcome was the number of sweat pores per cm², while pore numbers were adjusted for individual body surface area (BSA). Results: There were no statistically significant differences in age, height, weight, and BSA between the groups. The study group had 11.07 ± 4.03 missing teeth, excluding M3. There was a statistically significant difference (p = 0.006) in the distance between adjacent pores on a dermal ridge between the study and control groups (354.89 $\pm$32.41 μm vs. 340.31 $\pm$39.04 μm). The unadjusted pore numbers showed a statistically significant difference between the groups, but after adjustment for BSA, this difference was no longer present. Conclusions: Patients with oligodontia differed from subjects without tooth agenesis in the distance between two adjacent sweat pores on a dermal ridge. However, the differences were small and of limited clinical significance. Increased pore distance appears to be a better predictor of oligodontia/ectodermal dysplasia than pore number. Full article

Background/Objectives: Oligodontia, the absence of six or more teeth excluding third molars, is a rare genetic condition, unlike hypodontia (missing one or more teeth), which is a relatively common human disease. Methods: To identify the genetic etiology of nonsyndromic oligodontia (NSO) families, we performed mutational analysis and investigated the functional effects of identified EDAR mutations. Whole-exome sequencing was conducted on recruited families with NSO. Bioinformatic analysis identified mutations in oligodontia-causing candidate genes, which were confirmed by Sanger sequencing and segregation within families. The impact of EDAR mutations on the EDA signaling pathway was assessed using luciferase activity analysis. Results: EDAR mutations were identified in three NSO families. A homozygous missense EDAR mutation (NM_022336.4: c.319A>G p.(Met107Val)) was found in the singleton proband of family 1. The proband of family 2 carried compound heterozygous EDAR mutations: a maternal missense mutation (c.319A>G p.(Met107Val)) and a paternal missense variant (c.1270G>A p.(Val424Met)). The proband of family 3 had heterozygous EDAR mutations: a maternal missense mutation (c.389T>A p.(Ile130Asn)) and paternal intronic variants in cis (c.[357-4G>A;440+50C>T]). Luciferase assays confirmed reduced transcriptional activity for all identified missense mutations, while splicing assays revealed altered splicing patterns. Conclusions: In conclusion, recessive EDAR mutations, including novel ones, were identified in NSO families, and their pathological mechanism was explored through transcriptional activity measurements. Full article

Deciduous tooth agenesis is a severe craniofacial developmental defect because it affects masticatory function from infancy and may result in delayed growth and development. Here, we aimed to identify the crucial pathogenic genes and clinical features of patients with deciduous tooth agenesis. We recruited 84 patients with severe deciduous tooth agenesis. Whole-exome and Sanger sequencing were used to identify the causative variants. Phenotype–genotype correlation analysis was conducted. We identified 54 different variants in 8 genes in 84 patients, including EDA (73, 86.9%), PAX9 (2, 2.4%), LRP6 (2, 2.4%), MSX1 (2, 2.4%), BMP4 (1, 1.2%), WNT10A (1, 1.2%), PITX2 (1, 1.2%), and EDARADD (1, 1.2%). Variants in ectodysplasin A (EDA) accounted for 86.9% of patients with deciduous tooth agenesis. Patients with the EDA variants had an average of 15.4 missing deciduous teeth. Mandibular deciduous central incisors had the highest missing rate (100%), followed by maxillary deciduous lateral incisors (98.8%) and mandibular deciduous lateral incisors (97.7%). Our results indicated that EDA gene variants are major pathogenic factors for deciduous tooth agenesis, and EDA is specifically required for deciduous tooth development. The results provide guidance for clinical diagnosis and genetic counseling of deciduous tooth agenesis. Full article

Oligodontia can be isolated or syndromic, associated with other ectodermal abnormalities. The aim of the study was to perform hair examination in orthodontic patients diagnosed with oligodontia with a low clinical expression of symptoms of ectodermal origin. All available orthodontic patients diagnosed with oligodontia in the permanent dentition were enrolled. Hair examination included clinical evaluation of the patients’ hair, trichoscopy, trichogram and evaluation of the hair shafts under a polarized light microscope. In total, 25 patients, 18 males and 7 females, aged 6 to 24 years were evaluated for the presence of dental and hair abnormalities. The number of congenitally absent teeth ranged from 6 to 24 teeth and diastemas, microdontia, taurodontism and altered tooth shape were found in 23 patients. Hair disorders were found in 68% of the subjects. Hypotrichosis, the heterogeneity of shaft color and loss of pigment, androgenetic alopecia, telogen effluvium, trichoschisis, pili canaliculi, trichorrhexis nodosa and pseudomoniletrix were observed. Trichoscopy and trichogram are valid non-invasive diagnostic tests which could be used to differentiate between isolated and syndromic oligodontia in patients with a low clinical expression of ectodermal symptoms. Full article

Dental agenesis is one of the most common developmental anomalies in humans and it is frequently associated with several other oral abnormalities. The present case describes non-familial agenesis of permanent teeth in a twenty-one-year-old boy with no apparent systemic abnormalities. The treatment included a personalized and interdisciplinary approach involving endodontics, orthodontics, implant-supported restorations and prosthetic treatments. The treatment plan was thoroughly elaborated using photographic analysis, study models, orthopantomogram, CBCT and cephalograms. Virtual smile design, diagnostic waxing and mock-ups previsualized the treatment objectives. The edentulous spaces were reconstructed by inserting dental implants and monolithic zirconia implant-supported restorations. The final results showed a highly esthetic and functional rehabilitation. Periodic check-ups have shown that the stability of the result is well maintained and that the implant-supported restorations are an optimal solution for patients with multiple anodontia. Full article

Hypodontia, i.e., missing one or more teeth, is a relatively common human disease; however, oligodontia, i.e., missing six or more teeth, excluding the third molars, is a rare congenital disorder. Many genes have been shown to cause oligodontia in non-syndromic or syndromic conditions. In this study, we identified two novel PAX9 mutations in two non-syndromic oligodontia families. A mutational analysis identified a silent mutation (NM_006194.4: c.771G>A, p.(Gln257=)) in family 1 and a frameshift mutation caused by a single nucleotide duplication (c.637dup, p.(Asp213Glyfs*104)) in family 2. A minigene splicing assay revealed that the silent mutation resulted in aberrant pre-mRNA splicing instead of normal splicing. The altered splicing products are ones with an exon 4 deletion or using a cryptic 5’ splicing site in exon 4. Mutational effects were further investigated using protein expression, luciferase activity assay and immunolocalization. We believe this study will not only expand the mutational spectrum of PAX9 mutations in oligodontia but also strengthen the diagnostic power related to the identified silent mutation. Full article

The aim of this systematic review was to describe the clinical and genetic features of syndromes showing oligodontia as a sign. The review was performed according to the PRISMA 2020 checklist guidelines, and the search was conducted using PubMed, Scopus, Lilacs, Web of science, Livivo, and EMBASE and supplemented by a gray literature search on Google Scholar and ProQuest, applying key terms relevant to the research questions. The systematic review identified 47 types of syndromes in 83 studies, and the most common was hypohidrotic ectodermal dysplasia, which was reported in 24 patients in 22 studies. Other common syndromes that reported oligodontia included Axenfeld–Rieger syndrome, Witkop’s syndrome, Ellis–van Creveld syndrome, blepharocheilodontic syndrome, and oculofaciocardiodental syndrome. The X-linked mode of inheritance was the most reported (n = 13 studies), followed by the autosomal dominant (n = 13 studies). The review describes the main syndromes that may have oligodontia as a clinical sign and reinforces the need for orodental–facial examining for adequate diagnosis and treatment of the affected patients. Molecular analysis in order to better understand the occurrence of oligodontia is imperative. Full article

Background: The risk of palatally displaced canines (PDCs) rises in patients with tooth agenesis. The orthodontic extrusion and alignment of PDCs require adequate anchorage to enable tooth movement and control the side effects. There is no paper presenting treatment in the case of severe oligodontia with simultaneous PDCs and the use of mini-implants (MIs) for their orthodontic extrusion. Case presentation: A 15-year-old patient presented with non-syndromic oligodontia and bilateral PDCs. Cone beam computed tomography revealed that both PDCs were in proximity to the upper incisors’ roots. There was no evident external root resorption of the incisors. The “canines first” approach was chosen. MIs were used both as direct and indirect anchorage. First, the extrusive forces of cantilevers were directed both occlusally and distally. Next, the buccal directions of forces were implemented. Finally, fixed appliances were used. PDCs were extruded, aligned, and torqued. Proper alignment and occlusion were achieved to enable further prosthodontic restorations. Conclusions: The use of MIs made it possible to avoid collateral effects, reduce the risk of complications, and treat the patient effectively. MIs provide adequate anchorage in demanding cases. The use of MIs for the extrusion of PDCs made it possible to offer this treatment option to patients with severe oligodontia. The presented protocol was effective and served to circumvent treatment limitations associated with an inadequate amount of dental anchorage and a high risk of root resorption. Full article

Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome is a rare autosomal dominant disorder. AEC is caused by mutations in the TP63 gene that encodes the tumor suppressor p63 protein, itself involved in the regulation of epidermal proliferation, development, and differentiation. We present here a typical AEC case of a four-year-old girl with extensive skin erosions and erythroderma of the scalp and the trunk, and to a lesser extent of the limbs, nail dystrophy on the fingers and toes, xerophthalmia, a high-arched palate, oligodontia, and hypohidrosis. Mutation analysis of the TP63 gene detected a de novo missense mutation in exon 14 (c.1799G>T; p.Gly600Val). We discuss the phenotype–genotype correlation by presenting the clinical features of AEC in the patient, and the effect of the detected mutation in p63 structure and function using protein structural modeling, in view of similar cases in the literature. We performed a molecular modeling study in order to link the effect on the protein structure level of the missense mutation G600V. We noted that the introduction of the bulkier Valine residue in place of the slim Glycine residue caused a significantly altered 3D conformational arrangement of that protein region, pushing away the adjacent antiparallel α helix. We propose that the introduced locally altered structure of the G600V mutant p63 has a significant functional effect on specific protein–protein interactions, thus affecting the clinical phenotype. Full article