Hypohidrotic Ectodermal Dysplasia Research Articles

Activation of wnt/β-catenin signaling pathway down regulated osteogenic differentiation of bone marrow-derived stem cells in an anhidrotic ectodermal dysplasia patient with EDA/EDAR/EDARADD mutation

ObjectiveTo explore the mechanism by which the Wnt/β-catenin pathway induces osteogenic differentiation of bone marrow-derived stem cells (BMSCs) in anhidrotic ectodermal dysplasia (AED) with an Ectodysplasin A (EDA)/EDA receptor (EDAR)/EDARADD mutation. MethodsAn AED patient served as the AED group, whereas the other patients without AED were included in the normal group. Peripheral venous blood collected from the AED patient was subjected to whole-genome resequencing. BMSCs from the mandible of patients with AED and normal individuals were isolated and cultured in vitro. Cell proliferation assay was performed to compare the growth speed of BMSCs between the AED and normal groups. CHIR-99021, an activator of the Wnt/β-catenin pathway and XAV-939, an inhibitor, was used to manage BMSCs in an osteogenic environment in both groups. The expression of β-catenin was detected by quantitative polymerase chain reaction, while that of RUNX2 was detected by western blotting. Alizarin red was used for staining. ResultsA novel mutation (c.152T > A in EDA) and two known mutations (c.1109T > C in EDAR and c.27G > A in EDARADD) were identified. The growth rate in the normal group was higher than that in the AED group. In the normal group, the number and size of calcified nodes and the expression of RUNX-2 increased with CHIR-99021 treatment, which could be inhibited by XAV-939. In contrast, CHIR-99021 inhibited osteogenesis in the AED group and this effect was promoted by XAV-939. ConclusionActivation of the Wnt/β-catenin pathway downregulates osteogenesis of BMSCs in AED patients with EDA/EDAR/EDARADD gene mutations. Further investigation in more AED patients is required, given the wide range of mutations involved in AED.

The oligodontia phenotype in a X-linked hypohidrotic ectodermal dysplasia patient with a novel EVC2 variant

ObjectivesTo analyse the pathogenic genes in a patient with hypohidrotic ectodermal dysplasia (HED) and explore the relationship between pathogenic genes and the oligodontia phenotype. MethodsClinical data and peripheral blood were collected from a patient with HED. Pathogenic genes were analysed by whole-exon sequencing (WES) and verified by Singer sequencing. The secondary and tertiary structures of the variant proteins were predicted to analyse their toxicity. ResultsThe patient exhibited a severe oligodontia phenotype, wherein only two deciduous canines were left in the upper jaw. WES revealed a hemizygous EDA variant c.466C > T p.(Arg156Cys) and a novel heterozygous EVC2 variant c.1772T > C p.(Leu591Ser). Prediction of the secondary and tertiary structures of the EDA variant p.(Arg156Cys) and EVC2 variant p.(Leu591Ser) indicated impaired function of both molecules. ConclusionThe patient demonstrated a more severe oligodontia phenotype when compared with the other patients caused by the EDA variant c.466C > T. Since Evc2 is a positive regulator of the Sonic Hedgehog (Shh) signal pathway, we speculated that the EVC2 variant p.(Leu591Ser) may play a synergistic role in the oligodontia phenotype of HED, thereby exacerbating the oligodontia phenotype. Knowledge of oligodontia caused by multiple gene variants is of great significance for understanding individual differences in oligodontia phenotypes.

Oligodontia in the Clinical Spectrum of Syndromes: A Systematic Review.

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.

Prosthetic Treatment Strategies for Improving Denture Retention in Pediatric Patients with Hypohidrotic Ectodermal Dysplasia: a Report of Two Cases

This report presents two cases concerning strategies for improving denture retention in pediatric patients with oligodontia caused by hypohidrotic ectodermal dysplasia (HED). Both patients presented with multiple missing teeth, conical canines, alveolar bone atrophy, and a skeletal Class III tendency. In the first case, a modified form of conical-crown-retained denture was used to cover the canines. This approach was carried out without tooth extraction or coping. In the second case of severe alveolar bone resorption and a distally tilted lower left canine, the tooth was restored with a hybrid ceramic crown. It was subsequently converted into a clasp-retained removable partial denture, utilizing a suction mechanism. Both patients are currently receiving regular check-ups for the maintenance of their prosthetic appliances and the evaluation of their growth patterns. This study presents innovative prosthetic treatment methods for pediatric patients with HED who have inadequate denture retention.

Psychosocial and Behavioral Impact of Three Clinical Presentations of Oligodontia in a Tertiary Hospital.

To investigate the psychosocial and behavioral impact of oligodontia across three presentation types and determine if presentation type can infer impact. Thirty patients who had been diagnosed and treated for oligodontia between 2006 and 2021 were identified from hospital records. Patients received two questionnaires: (1) a modified version of a condition-specific questionnaire- the Cleft Research Questionnaire (CRQ), used to investigate demographic, life, and treatment details and impacts-and (2) the Oral Health Impact Profile (OHIP-14), used to investigate the oral health-related quality of life. Patients were assigned to three presentations (Types 1 to 3) of oligodontia, identified according to the edentulous space present and complexity of prosthodontic treatment required. The hypothesis that there is a relationship between oligodontia type and study variables was tested. Twenty-two questionnaires were completed and returned. There were 13 men and 9 women. The age range was from 16 to 32 years. In total, 18 patients had nonsyndromic oligodontia and 4 had oligodontia associated with anhidrotic ectodermal dysplasia (AED). The main areas of impact were patient-reported: life less satisfying (64.5%, n = 14; pretreatment), making friends (45%, n = 10), school participation (45%, n = 10), and public speaking (45%, n = 10). No relationship was discovered between the degree of physical effect of the presentation type and study variables, including the degree of psychosocial impact or life satisfaction. Oligodontia can have a negative functional and social impact on a patient prior to prosthodontic treatment. Prosthodontic treatment improved the life satisfaction for most patients. Psychosocial outcomes could not be inferred by the presentation type of oligodontia.

O02 A case for diagnosis: ectodermal dysplasia and severe myelodysplasia

Abstract A 13-year-old girl was referred to us by our paediatric colleagues due to vulval dermatitis. She had a history of congenital hypotrichosis, microcephaly, abnormal dentition, dyshidrosis manifest as recurrent febrile seizures in infancy, recurrent infections, neutropaenia and macrocytosis. Her father and younger brother have a similarly striking phenotype, with complete absence of scalp and body hair, abnormal teeth, abnormal sweating, but normal nails. In addition, the father has required a stem cell transplant for myelodysplastic syndrome. None of the family have keratoderma, cleft palate, ectrodactyly or cardiomyopathy. DNA from our index patient was sent to Cardiff for the ectodermal dysplasia (ED) plus 70 gene panel for next-generation sequencing, but no mutation was found. Our paediatric haematology colleagues sequentially arranged dyskeratosis congenita panel, myeloid panel, and whole-exome sequencing for the younger brother, which did not identify a causative mutation. Unusually, all three were found to have mosaic trisomy 18. The transmission of trisomy 18 from parent to child as a mosaic trait in both generations is extremely unusual, and mosaic trisomy 18 has not been previously reported to cause ED. We would appreciate any input on a genetic diagnosis for this family with a distinctive phenotype consistent with hypohidrotic ED associated with myelodysplasia, with extensive genetic testing revealing a potentially spurious or coincidental mosaic trisomy 18 in all three affected family members.

Rehabilitation with implant-supported overdentures in preteens patients with ectodermal dysplasia: A cohort study.

Hypohidrotic ectodermal dysplasia (HED) patients suffering of oligo-anodontia require early dental treatment to improve oral functions and reduce social impairment. The aim of this study was to evaluate the skeletal growth, implant and prosthetic survival rate, success, and complications after the rehabilitation with a maxillary denture and an implant-supported overdenture provided by a sliding bar in case of severe hypodontia/anodontia related to HED. This retrospective cohort study began in 2009. Nine patients over 7 years old with HED and associated oligo-anodontia who presented at the University of Bologna for dental treatment were included in the study. They were first treated with conventional dentures and then with a maxillary denture and an implant-supported overdenture with a sliding bar connected to two implants placed in the anterior mandible. The subjects treated were followed for 3-12 years. In each case, orthopanoramic and lateral cephalometric radiographic exam were taken before implant placement and annually after prosthetic load. Vertical and transverse dimensions of the mandible in the symphysis area at implant sites were taken on the lateral cephalometric radiography at the time of implant placement and after 5 years from the prosthetic loading to assess the presence or absence of an anterior mandibular growth. Biologic and mechanical complications were also recorded at every visit. A mandibular vertical growth under the implant apex, at the implant neck, and a sagittal growth of the symphysis after 5 years from the prosthetic loading were observed and measured. Implant and prosthetic success and survival rates were 100% after 8.1 years (mean) follow-up period. No complications were reported except in one patient, where the repositioning of a retentive cap on the counter bar in the superstructure was necessary after 3 years from the prosthetic loading. The present study suggests that the growth of the mandible near implant sites continues even after their positioning. Implants can be successfully placed and provide support for prosthetic rehabilitation in preteens patients with HED.

A novel ectodysplasin-A receptor gene variant identified by whole-exome sequencing with hypohidrotic ectodermal dysplasia in a Chinese family

A novel ectodysplasin-A receptor gene variant identified by whole-exome sequencing with hypohidrotic ectodermal dysplasia in a Chinese family

A new variant of the ectodysplasin A receptor death domain gene associated with anhidrotic ectodermal dysplasia in a Turkish family and its simple diagnosis by restriction fragment length polymorphism.

Ectodermal dysplasia (ED), which exhibits a wide range of clinical symptoms, may be classified into three major types: hypohidrotic, anhidrotic, and hidrotic. A male child (proband) showing anhidrotic dysplasia was used as the subject of this study. The biopsy of the big toe revealed that the male child had no sweat glands. Genetic analysis of the patient revealed a mutation caused by a homozygous nucleotide substitution in the EDAR-associated death domain (EDARADD) (rs114632254) gene c.439G>A (p.Gly147Arg). Phenotypically, his teeth were sharp, but eight teeth were missing (oligodontia). The patient had normal nails with dry skin, sparse hair, everted lower lip vermilion, hyperpigmented eyelids, and abnormal nasal bridge morphology around the eyes. There is also a homozygous dominant (healthy) female and a heterozygous male in this family, who are cousins (aunt children) to the heterozygous parents. The daughter of the patient was also heterozygous. This mutation represents homozygous recessive inheritance, which we describe for the first time. Furthermore, we demonstrated that this genetic disorder can be readily diagnosed using the restriction fragment length polymorphism (RFLP) method after digestion with MnII restriction endonuclease.

HYPOHIDROTIC ECTODERMAL DYSPLASIA: A CASE REPORT

Our study presents a case of an 8-year-old Caucasian male patient, diagnosed with hypohidrotic ectodermal dysplasia, who sought out dental care for prosthetic rehabilitation. The patient presented dry periorbital and perilabial tissues, fine and sparse hair, eyebrows with sparse hair, and an everted lower lip. These characteristics are commonly present in hypohidrotic ectodermal dysplasia. Radiographic and tomographic examinations verified the presence of maxillary permanent canines in formation. The patient's treatment was divided into two stages. First, surgical treatment with labial and lingual frenectomies was performed. Second, the rehabilitation stage was implemented, consisting of two implants for the subsequent installation of an overdenture prosthesis and a removable prosthesis in the upper jaw. The patient is currently undergoing follow-up and is in the development stage. Our study presents a case of an 8-year-old Caucasian male patient, diagnosed with hypohidrotic ectodermal dysplasia, who sought out dental care for prosthetic rehabilitation. The patient presented dry periorbital and perilabial tissues, fine and sparse hair, eyebrows with sparse hair, and an everted lower lip. These characteristics are commonly present in hypohidrotic ectodermal dysplasia. Radiographic and tomographic examinations verified the presence of maxillary permanent canines in formation. The patient's treatment was divided into two stages. First, surgical treatment with labial and lingual frenectomies was performed. Second, the rehabilitation stage was implemented, consisting of two implants for the subsequent installation of an overdenture prosthesis and a removable prosthesis in the upper jaw. The patient is currently undergoing follow-up and is in the development stage.

Prosthetic Rehabilitation of a Child with Anhidrotic Ectodermal Dysplasia: A Case Report and a Review of Literature

Prosthetic Rehabilitation of a Child with Anhidrotic Ectodermal Dysplasia: A Case Report and a Review of Literature

Report of TSPEAR Variants, the Hypereosinophilic Syndrome, and Severe Atopy

BackgroundBiallelic loss-of-function variants in the thrombospondintype laminin G domain and epilepsy-associated repeats (TSPEAR) gene have been associated with ectodermal dysplasia (ED), phenotypes that affect ectodermal-derived structures, including hair, skin, nails and tooth involvement, as well as hearing loss, specifically, sensorineural hearing loss. Historically, TSPEAR related disorders have been autosomal recessive. Other forms of ectodermal dysplasia including anhidrotic ectodermal dysplasia with immune deficiency (EDA-ID) have been associated with immune dysregulation, primary immunodeficiency, and atopy, including EoE, atopic dermatitis (AD), food allergy (FA), asthma, and allergic rhinitis (AR). The abnormal skin barrier and transepidermal allergen absorption has been proposed as a mechanism. We report the first known case of Hypereosinophilic Syndrome (HES) and severe atopy including eosinophilic esophagitis (EoE) associated with TSPEAR mutations.Case presentation: 5-year-old male with a history of FA, asthma, and AR who later developed HES, severe AD, and EoE. HES presented age 2-years, resolving with a course and taper of high dose prednisolone. Remarkable findings on HES evaluation included an absolute eosinophil count of 10,480, IgE of 2,566 IUnits/mL, and EoE with up to 60 eos/HPF in esophagus on EGD. He was multiply sensitized to environmental allergens. FISH analysis was normal with no evidence of FIP1L1/PDGFRA. Bone marrow biopsy was significant for a normocellular bone marrow with multilineage hematopoiesis and markedly increase in eosinophils. Genetics evaluation noted hypodontia, pointed teeth, and coarse hair. He was found on whole exome sequencing to have 2 variants of unknown significance (VUS) in TSPEAR gene, one from each parent. His presentation was felt to be feasibly related to the VUS but more information about the VUS was needed to provide molecular confirmation. ConclusionWe report the first known case of association of two VUS in the TSPEAR gene with immune dysregulation including HES and severe atopy (FA, asthma, AR, AD, and EoE). Epidermal abnormalities with TSPEAR mutations may be similar to other ED syndromes with regards to development of severe atopy and immune dysregulation, with transepidermal sensitization playing a role.

Prevalence of Rare Variants Associated with Monogenic Diseases in Pre-contact Caribbean Communities

Genomic technologies in archaeology have been used to study migration patterns, origin of and genetic similarity between ancient populations. Researchers are, however, just beginning to employ these technologies to evaluate the genomic health of ancient communities. In this study we screen publicly available whole-genome sequencing data of pre-contact Caribbean individuals for the presence of pathogenic mutations causing monogenic diseases. Our results show that Caribbean communities from the Ceramic Age (3100–400 BP) had an unusually high frequency of pathogenic variants associated with three monogenic conditions, Classical Phenylketonuria, Hypohidrotic Ectodermal Dysplasia and LRRK2-Related Parkinson’s disease. The estimated frequency of these variants from the analyzed ancient samples is severalfold higher than that in contemporary populations. Three conditions classified today as rare diseases thus might have had much higher prevalence in the past. Studying the history of monogenic diseases from ancient communities will expand the list of rare diseases with larger prevalence in the past.

A Causal Treatment for X-Linked Hypohidrotic Ectodermal Dysplasia: Long-Term Results of Short-Term Perinatal Ectodysplasin A1 Replacement.

X-linked hypohidrotic ectodermal dysplasia (XLHED), caused by a genetic deficiency of ectodysplasin A1 (EDA1), is a rare developmental disorder of ectodermal derivatives such as hair, sweat glands, and teeth. The absence of sweat glands and perspiration can evoke life-threatening hyperthermia. As molecular genetic findings are not always conclusive, the concentrations of circulating EDA1 may help to distinguish between total and partial EDA1 deficiencies. We previously treated nine male patients with obvious signs of XLHED with a recombinant EDA1 replacement protein, Fc-EDA, either shortly after birth (n = 3) or by prenatal administration in gestational week 26 and beyond (n = 6). Here, we present the long-term follow-up for up to six years. In patients who had received Fc-EDA after birth, neither sweat glands nor sweating ability were detected at the age of 12-60 months. In contrast, prenatal EDA1 replacement resulted in ample sweat gland development and pilocarpine-inducible sweating in all treated subjects, who also attained more permanent teeth than their untreated affected relatives. Normal perspiration has persisted for six years in the two oldest boys treated repeatedly with Fc-EDA in utero. When they had a sauna, adequate thermoregulation was evidenced. Lower sweat production after single prenatal dosing may indicate a dose-response relationship. The absence of circulating EDA1 in five prenatally treated subjects proved that these children would have been unable to perspire if they had been left untreated. The sixth infant was shown to produce an EDA1 molecule that, albeit interacting with its cognate receptor, cannot activate EDA1 signaling. In conclusion, a causal treatment of XLHED before birth is feasible.

The EDA/EDAR/NF-κB pathway in non-syndromic tooth agenesis: A genetic perspective.

Non-syndromic tooth agenesis (NSTA) is one of the most common dental developmental malformations affected by genetic factors predominantly. Among all 36 candidate genes reported in NSTA individuals, EDA, EDAR, and EDARADD play essential roles in ectodermal organ development. As members of the EDA/EDAR/NF-κB signaling pathway, mutations in these genes have been implicated in the pathogenesis of NSTA, as well as hypohidrotic ectodermal dysplasia (HED), a rare genetic disorder that affects multiple ectodermal structures, including teeth. This review provides an overview of the current knowledge on the genetic basis of NSTA, with a focus on the pathogenic effects of the EDA/EDAR/NF-κB signaling pathway and the role of EDA, EDAR, and EDARADD mutations in developmental tooth defects. We also discuss the phenotypic overlap and genetic differences between NSTA and HED. Ultimately, this review highlights the importance of genetic analysis in diagnosing and managing NSTA and related ectodermal disorders, and the need for ongoing research to improve our understanding of these conditions.

A novel deletion of exon 4 in the Ectodysplasin A gene associated with X-linked hypohidrotic ectodermal dysplasia

ObjectiveIdentify the disease-causing mutation in a patient with features of X-linked hypohidrotic ectodermal dysplasia, which is a genetic disorder characterized by hypodontia, hypohidrosis and hypotrichosis. It is caused by mutations in Ectodysplasin A gene, which encodes ectodysplasin A, a member of the tumor necrosis factor superfamily. DesignGenetic analysis, was performed using chromosomal microarray analysis, whole exome sequencing and multiplex ligation-dependent probe amplification analysis in a 4-year-old boy with hypohidrotic ectodermal dysplasia features. Moreover, the boy’s parents were tested for clinically significant findings identified in order to elucidate the pattern of inheritance of the finding detected in the proband. ResultsA novel deletion of entire exon 4 in Ectodysplasin A gene identified in the 4-year-old patient. This deletion was found in heterozygous state in the mother of the proband and was not detected in his father. RNA analysis revealed an in-frame deletion r.527_706del, p.(176_236del) in exon 4 of the Ectodysplasin A gene. ConclusionWe identified a novel gross deletion in the Ectodysplasin A gene in a male patient with X-linked hypohidrotic ectodermal dysplasia. Clinical and molecular genetic analysis are crucial to set an accurate diagnosis in patients with hypohidrotic ectodermal dysplasia. These results highlight the importance of the collagen domain of Ectodysplasin A, encoded by exon 4, for its function in vivo.

A call for implementing augmented intelligence in pediatric dermatology

Augmented intelligence (AI), the combination of artificial based intelligence with human intelligence from a practitioner, has become an increased focus of clinical interest in the field of dermatology. Technological advancements have led to the development of deep-learning based models to accurately diagnose complex dermatological diseases such as melanoma in adult datasets. Models for pediatric dermatology remain scarce, but recent studies have shown applications in the diagnoses of facial infantile hemangiomas and X-linked hypohidrotic ectodermal dysplasia; however, we see unmet needs in other complex clinical scenarios and rare diseases, such as diagnosing squamous cell carcinoma in patients with epidermolysis bullosa. Given the still limited number of pediatric dermatologists, especially in rural areas, AI has the potential to help overcome health disparities by helping primary care physicians treat or triage patients.

Next generation sequencing panel target genes: possible diagnostic tool for ectodermal dysplasia related diseases.

Ectodermal dysplasias (EDs) are a large and complex group of disorders affecting the ectoderm-derived organs; the clinical and genetic heterogeneity of these conditions renders an accurate diagnosis more challenging. The aim of this study is to demonstrate the clinical utility of a targeted resequencing panel through enhancing the molecular and clinical diagnosis of EDs. Given the recent developments in gene and protein-based therapies for X-linked hypohidrotic ectodermal dysplasia, there is a re-emerging interest in identifying the genetic basis of EDs and the respective phenotypic presentations, in an aim to facilitate potential treatments for affected families. We assessed seventeen individuals, from three unrelated families, who presented with diverse phenotypes suggestive of ED. An extensive multidisciplinary clinical evaluation was performed followed by a targeted exome resequencing panel (including genes that are known to cause EDs). MiSeqTM data software was used, variants with Qscore >30 were accepted. Three different previously reported hemizygous EDA mutations were found in the families. However, a complete genotype-phenotype correlation could not be established, neither in our patients nor in the previously reported patients. Targeted exome resequencing can provide a rapid and accurate diagnosis of EDs, while further contributing to the existing ED genetic data. Moreover, the identification of the disease-causing mutation in an affected family is crucial for proper genetic counseling and the establishment of a genotype-phenotype correlation which will subsequently provide the affected individuals with a more suitable treatment plan.

Ectodysplasin Signaling through XEDAR Is Required for Mammary Gland Morphogenesis

XEDAR is a member of the TNF receptor subfamily and a mediator of the ectodysplasin (EDA) pathway. EDA signaling plays evolutionarily conserved roles in the development of the ectodermal appendage organ class, which includes hair, eccrine sweat glands, and mammary glands. Loss-of-function sequence variants of EDA, which encodes the two major ligand isoforms, EDA-A1 and EDA-A2, result in X-linked hypohidrotic ectodermal dysplasia characterized by defects in two or more types of ectodermal appendages. EDA-A1 and EDA-A2 signal through the receptors EDAR and XEDAR, respectively. Although the contributions of the EDA-A1/EDAR signaling pathway to EDA-dependent ectodermal appendage phenotypes have been extensively characterized, the significance of the EDA-A2/XEDAR branch of the pathway has remained obscure. In this study, we report the phenotypic consequences of disrupting the EDA-A2/XEDAR pathway on mammary gland differentiation and growth. Using a mouse Xedar knockout model, we show that Xedar has a specific and temporally restricted role in promoting late pubertal growth and branching of the mammary epithelium that can be influenced by genetic background. Our findings implicate Xedar in ectodermal appendage development and suggest that the EDA-A2/XEDAR signaling axis contributes to the etiology of EDA-dependent mammary phenotypes.

Structural insights into pathogenic mechanism of hypohidrotic ectodermal dysplasia caused by ectodysplasin A variants

EDA is a tumor necrosis factor (TNF) family member, which functions together with its cognate receptor EDAR during ectodermal organ development. Mutations of EDA have long been known to cause X‐linked hypohidrotic dysplasia in humans characterized by primary defects in teeth, hair and sweat glands. However, the structural information of EDA interaction with EDAR is lacking and the pathogenic mechanism of EDA variants is poorly understood. Here, we report the crystal structure of EDA C-terminal TNF homology domain bound to the N-terminal cysteine-rich domains of EDAR. Together with biochemical, cellular and mouse genetic studies, we show that different EDA mutations lead to varying degrees of ectodermal developmental defects in mice, which is consistent with the clinical observations on human patients. Our work extends the understanding of the EDA signaling mechanism, and provides important insights into the molecular pathogenesis of disease-causing EDA variants.