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Background Ectodermal dysplasia (ED) is a group of inherited disorders that affect ectodermally derived structures, including teeth, hair, sweat glands, and salivary glands. Variants in the EDAR gene, particularly within its intracellular death domain, disrupt EDA signaling and contribute to ED. Although EDAR -associated ED is well documented globally, clinical and molecular data from Southeast Asia remain limited. Objective To report two novel Thai cases with heterozygous EDAR variants and to systematically map the phenotypic and genotypic spectrum of previously reported EDAR -related disorders through a scoping review. Methods Two unrelated Thai patients with dental agenesis underwent detailed clinical, salivary, radiographic, ultrastructural, and genetic evaluations. A systematic scoping review was conducted following PRISMA-ScR guidelines to synthesize clinical phenotypes associated with EDAR variants across diverse populations. Eligibility criteria included original case reports, case series, and cohort studies reporting human subjects with EDAR variants; exclusion criteria were reviews, abstracts, and non-human studies. Sources of evidence included PubMed, Scopus, and Embase searched from January 1995 to April 2025. Results Both patients carried heterozygous EDAR variants within the death domain: a de novo frameshift (c.1087_1088insGA; p.Thr363Argfs*10) and a missense variant (c.1271T > G; p.Val424Gly). Both exhibited hypodontia and reduced salivary and sweat gland function, but clinically normal hair and nail morphology. The scoping review included nine studies across Europe, Asia, and the Middle East, highlighting common features like hypohidrosis and dental anomalies, while noting the infrequent assessment of salivary function. Conclusion These two EDAR variants broaden the mutational and phenotypic spectrum of EDAR- related ED and, to our knowledge, represent the first cases reported from Thailand, thereby expanding the geographic and ethnic understanding of EDAR -associated disorders. Beyond variant identification, this study emphasizes the diagnostic value of incorporating salivary flow and ultrastructural assessments into phenotyping, features rarely evaluated in prior reports.

Dental epithelial stem cells give rise to four types of dental epithelial cells: inner enamel epithelium (IEE), outer enamel epithelium (OEE), stratum intermedium (SI), and stellate reticulum (SR). IEE cells further differentiate into enamel-forming ameloblasts, which play distinct roles, and are essential for enamel formation. These are conventionally classified by their shape, although their transcriptome and biological roles are yet to be fully understood. Here, we aimed to use single-cell RNA sequencing to clarify the heterogeneity of dental epithelial cell types. Unbiased clustering of 6,260 single cells from incisors of postnatal day 7 mice classified them into two clusters of ameloblast, IEE/OEE, SI/SR, and two mesenchymal populations. Secretory-stage ameloblasts expressed and were divided into + and + ameloblasts. Pseudo-time analysis indicated + ameloblasts differentiate into + ameloblasts. Further, and could be stage-specific markers of ameloblasts. Gene ontology analysis of each cluster indicated potent roles of cell types: OEE in the regulation of tooth size and SR in the transport of nutrients. Subsequently, we identified novel dental epithelial cell marker genes, namely , , , and . The results not only provided a resource of transcriptome data in dental cells but also contributed to the molecular analyses of enamel formation.

Nature is a rich resource from which to learn how to engineer stem cells for the application of regenerative medicine, particularly for integumentary ectodermal organs. Reptile scales are formed as effective barriers to protect movement within their terrestrial environment. In mammals and birds, follicular structures are evolved. In feathers, further branching morphogenesis occurs. This chapter focuses on stem cells in feather follicles. It further discusses the stem cell activity in hair waves. Hair follicle stem cells within a specialized niche must be activated in order for the hair cycle to renew. Once activated, the stem cells proliferate to generate transient amplifying cells and a new progenitor cell. In this way, they can maintain their stem cell population throughout the life of the organism. During hair follicle evolution, epithelial stem cells undergo topological clustering where all stem cells within a cluster either remain quiescent or become activated relatively synchronously.

Human WNT10A mutations are associated with developmental tooth abnormalities and adolescent onset of a broad range of ectodermal defects. Here we show that β-catenin pathway activity and adult epithelial progenitor proliferation are reduced in the absence of WNT10A, and identify Wnt-active self-renewing stem cells in affected tissues including hair follicles, sebaceous glands, taste buds, nails and sweat ducts. Human and mouse WNT10A mutant palmoplantar and tongue epithelia also display specific differentiation defects that are mimicked by loss of the transcription factor KLF4. We find that β-catenin interacts directly with region-specific LEF/TCF factors, and with KLF4 in differentiating, but not proliferating, cells to promote expression of specialized keratins required for normal tissue structure and integrity. Our data identify WNT10A as a critical ligand controlling adult epithelial proliferation and region-specific differentiation, and suggest downstream β-catenin pathway activation as a potential approach to ameliorate regenerative defects in WNT10A patients. Human WNT10A mutations are associated with dental defects and adult onset ectodermal dysplasia. Xu et al . show that WNT10A-activated ß-catenin plays dual roles in adult epithelial progenitor proliferation and differentiation by complexing with KLF4 in differentiating, but not proliferating, cells.

The ectodermal dysplasias are a group of inherited autosomal dominant syndromes associated with heterozygous mutations in the Tumor Protein p63 (TRP63) gene. Here we show that, in addition to their epidermal pathology, a proportion of these patients have distinct levels of deafness. Accordingly, p63 null mouse embryos show marked cochlea abnormalities, and the transactivating isoform of p63 (TAp63) protein is normally found in the organ of Corti. TAp63 transactivates hairy and enhancer of split 5 (Hes5) and atonal homolog 1 (Atoh1), components of the Notch pathway, known to be involved in cochlear neuroepithelial development. Strikingly, p63 null mice show morphological defects of the organ of Corti, with supernumerary hair cells, as also reported for Hes5 null mice. This phenotype is related to loss of a differentiation property of TAp63 and not to loss of its proapoptotic function, because cochleas in mice lacking the critical Bcl-2 homology domain (BH-3) inducers of p53- and p63-mediated apoptosis—Puma, Noxa, or both—are normal. Collectively, these data demonstrate that TAp63, acting via the Notch pathway, is crucial for the development of the organ of Corti, providing a molecular explanation for the sensorineural deafness in ectodermal dysplasia patients with TRP63 mutations.

Germline heterozygous gain-of-function (GOF) mutations of NFKBIA , encoding IκBα, cause an autosomal dominant (AD) form of anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID). Fourteen unrelated patients have been reported since the identification of the first case in 2003. All mutations enhanced the inhibitory activity of IκBα, by preventing its phosphorylation on serine 32 or 36 and its subsequent degradation. The mutation certainly or probably occurred de novo in 13 patients, whereas it was inherited from a parent with somatic mosaicism in one patient. Eleven mutations, belonging to two groups, were identified: (i) missense mutations affecting S32, S36, or neighboring residues (8 mutations, 11 patients) and (ii) nonsense mutations upstream from S32 associated with the reinitiation of translation downstream from S36 (3 mutations, 3 patients). Thirteen patients had developmental features of EDA, the severity and nature of which differed between cases. All patient cells tested displayed impaired NF-κB-mediated responses to the stimulation of various surface receptors involved in cell-intrinsic (fibroblasts), innate (monocytes), and adaptive (B and T cells) immunity, including TLRs, IL-1Rs, TNFRs, TCR, and BCR. All patients had profound B-cell deficiency. Specific immunological features, found in some, but not all patients, included a lack of peripheral lymph nodes, lymphocytosis, dysfunctional α/β T cells, and a lack of circulating γ/δ T cells. The patients had various pyogenic, mycobacterial, fungal, and viral severe infections. Patients with a missense mutation tended to display more severe phenotypes, probably due to higher levels of GOF proteins. In the absence of hematopoietic stem cell transplantation (HSCT), this condition cause death before the age of 1 year (one child). Two survivors have been on prophylaxis (at 9 and 22 years). Six children died after HSCT. Five survived, four of whom have been on prophylaxis (3 to 21 years post HSCT), whereas one has been well with no prophylaxis. Heterozygous GOF mutations in IκBα underlie a severe and syndromic immunodeficiency, the interindividual variability of which might partly be ascribed to the dichotomy of missense and nonsense mutations, and the hematopoietic component of which can be rescued by HSCT.

Impaired ectodysplasin A (EDA) receptor (EDAR) signaling affects ectodermally derived structures including teeth, hair follicles, and cutaneous glands. The X-linked hypohidrotic ectodermal dysplasia (XLHED), resulting from EDA deficiency, can be rescued with lifelong benefits in animal models by stimulation of ectodermal appendage development with EDAR agonists. Treatments initiated later in the developmental period restore progressively fewer of the affected structures. It is unknown whether EDAR stimulation in adults with XLHED might have beneficial effects. In adult Eda mutant mice treated for several weeks with agonist anti-EDAR antibodies, we find that sebaceous gland size and function can be restored to wild-type levels. This effect is maintained upon chronic treatment but reverses slowly upon cessation of treatment. Sebaceous glands in all skin regions respond to treatment, although to varying degrees, and this is accompanied in both Eda mutant and wild-type mice by sebum secretion to levels higher than those observed in untreated controls. Edar is expressed at the periphery of the glands, suggesting a direct homeostatic effect of Edar stimulation on the sebaceous gland. Sebaceous gland size and sebum production may serve as biomarkers for EDAR stimulation, and EDAR agonists may improve skin dryness and eczema frequently observed in XLHED.

Mutations in the p63 gene (TP63) underlie several monogenic malformation syndromes manifesting cleft lip with or without cleft palate (CL/P). We investigated whether p63 mutations also result in non-syndromic CL/P. Specifically, we performed mutation analysis of the 16 exons of the p63 gene for 100 Thai patients with non-syndromic CL/P. In total, 21 variant sites were identified. All were single nucleotide changes, with six in coding regions, including three novel non-synonymous changes: S90L, R313G, and D564H. The R313G was concluded to be pathogenic on the basis of its amino acid change, evolutionary conservation, its occurrence in a functionally important domain, its predicted damaging function, its de novo occurrence, and its absence in 500 control individuals. Our data strongly suggest, for the first time, a causative role of a heterozygous mutation in the p63 gene in non-syndromic CL/P, highlighting the wide phenotypic spectrum of p63 gene mutations.

Ectodermal dysplasias (EDs) are a heterogeneous rare group of disorders with an incidence at 1/100,000 live births. Currently, there are limited case reports of patients requiring lung transplantation. Here, we report two brothers who present with a constellation of features including alopecia, nail dystrophy, ophthalmic complications, thyroid disease, hypohidrosis, ephelides, enteropathy and recurrent respiratory tract infections, known as ANOTHER syndrome, a rare autosomal recessive variant of ED. Both presented in early childhood with progressive respiratory decline and eventual failure. Chronic respiratory decline was refractory to standard therapy. Both patients required lung transplantation for sequelae of end‐stage lung disease. Pathology demonstrated multifocal bronchiectasis with areas of fibrosis and small airway obstruction. ANOTHER syndrome is rare with a paucity of data in the literature. Given the limited therapeutic options available with natural progression towards respiratory failure, lung transplantation may be considered. We report two brothers who presented with a constellation of features including alopecia, nail dystrophy, ophthalmic complications, thyroid disease, hypohidrosis, ephelides, enteropathy and recurrent respiratory tract infections, known as ANOTHER syndrome, a rare autosomal recessive variant of ectodermal dysplasia (ED). Both received lung transplantation, and we report their clinical course to highlight the sequelae of end‐stage lung disease of hypohidrotic EDs.

Background Epithelial invagination is important for initiation of ectodermal organogenesis. Although many factors regulate ectodermal organogenesis, there is not any report about their functions in real-time study. Electric cell-substrate impedance sensing (ECIS), a non-invasive, real-time surveillance system, had been used to detect changes in organ cell layer thickness through quantitative monitoring of the impedance of a cell-to-microelectrode interface over time. It was shown to be a good method for identifying significant real-time changes of cells. The purpose of this study is to establish a combined bioengineered organ-ECIS model for investigating the real time effects of fibroblast growth factor-9 (FGF-9) on epithelial invagination in bioengineered ectodermal organs. We dissected epithelial and mesenchymal cells from stage E14.5 murine molar tooth germs and identified the real-time effects of FGF-9 on epithelial-mesenchymal interactions using this combined bioengineered organ-ECIS model. Results Measurement of bioengineered ectodermal organ thickness showed that Fibroblast growth factor-9 (FGF-9) accelerates epithelial invagination in reaggregated mesenchymal cell layer within 3 days. Gene expression analysis revealed that FGF-9 stimulates and sustains early Ameloblastin and Amelogenin expression during odontogenesis. Conclusions This is the first real-time study to show that, FGF-9 plays an important role in epithelial invagination and initiates ectodermal organogenesis. Based on these findings, we suggest FGF-9 can be applied for further study in ectodermal organ regeneration, and we also proposed that the ‘FGF-BMP balancing system’ is important for manipulating the morphogenesis of ectodermal organs. The combined bioengineered organ-ECIS model is a promising method for ectodermal organ engineering and regeneration research.