Hypohidrotic Ectodermal Dysplasia Research Articles

220 Two cases of hypohidrotic ectodermal dysplasia caused by novel mutations in the EDA gene

220 Two cases of hypohidrotic ectodermal dysplasia caused by novel mutations in the EDA gene

Mutation detection and prenatal diagnosis of XLHED pedigree.

BackgroundThe phenotypic characters of X -linked Hypohidrotic Ectodermal Dysplasia (XLHED) are the dysplasia of epithelial- and mesenchymal-derived organs. Ectodysplasin (EDA) is the causative gene of XLHED.MethodsThe current study reported a large Chinese XLHED pedigree. The genomic DNA of adult and fetus was extracted from peripheral blood and shed chorion cell respectively. The nucleotide variation in EDA gene was screened through direct sequencing the coding sequence. The methylation state of EDA gene’s promoter was evaluated by pyrosequencing.ResultsThis Chinese XLHED family had two male patients and three carriers. All of them were with a novel EDA frameshift mutation. The mutation, c.172-173insGG, which leads to an immediate premature stop codon in exon one caused severe structural changes of EDA. Prenatal diagnosis suggested that the fetus was a female carrier. The follow-up observation of this child indicated that she had mild hypodontia of deciduous teeth at age six. The methylation level of EDA gene’s promoter was not related to carriers’ phenotype changes in this family.DiscussionWe reported a new frameshift mutation of EDA gene in a Chinese family. Prenatal diagnosis can help to predict the disease status of the fetus.

Ectodysplasin A regulates epithelial barrier function through sonic hedgehog signalling pathway

Ectodysplasin A (Eda), a member of the tumour necrosis factor superfamily, plays an important role in ectodermal organ development. An EDA mutation underlies the most common of ectodermal dysplasias, that is X‐linked hypohidrotic ectodermal dysplasia (XLHED) in humans. Even though it lacks a developmental function, the role of Eda during the postnatal stage remains elusive. In this study, we found tight junctional proteins ZO‐1 and claudin‐1 expression is largely reduced in epidermal, corneal and lung epithelia in Eda mutant Tabby mice at different postnatal ages. These declines are associated with tail ulceration, corneal pannus formation and lung infection. Furthermore, topical application of recombinant Eda protein markedly mitigated corneal barrier dysfunction. Using cultures of a human corneal epithelial cell line and Tabby mouse skin tissue explants, Eda up‐regulated expression of ZO‐1 and claudin‐1 through activation of the sonic hedgehog signalling pathway. We conclude that EDA gene expression contributes to the maintenance of epithelial barrier function. Such insight may help efforts to identify novel strategies for improving management of XLHED disease manifestations in a clinical setting.

Oral rehabilitation with removable dental prosthesis in a six-year-old patient with hypohidrotic ectodermal dysplasia

Introduction: Ectodermal dysplasia is an abnormality of the ectoderm and its derivatives, phenotypically expressed in males and genetically inherited from mothers. Objective: To report the efficacy of the prosthetics treatment of severe ectodermal dysplasia in a 6-year-old boy with hypohidrotic ectodermal dysplasia (HED). Case report: The boy had difficulty in speaking and eating and the condition also affected his self-esteem. Prosthetic treatments included the construction of acrylic custom trays, determination of the vertical dimension of occlusion (VDO), construction of upper and lower dentures, and palatal expansion procedure. Conclusion: Significant improvements in the patient’s stomatognathic functionand self-esteem were evident.

Ectodysplasin A protein promotes corneal epithelial cell proliferation

The EDA gene encodes ectodysplasin A (Eda), which if mutated causes X-linked hypohidrotic ectodermal dysplasia (XLHED) disease in humans. Ocular surface changes occur in XLHED patients whereas its underlying mechanism remains elusive. In this study, we found Eda was highly expressed in meibomian glands, and it was detected in human tears but not serum. Corneal epithelial integrity was defective and the thickness was reduced in the early postnatal stage of Eda mutant Tabby mice. Corneal epithelial cell proliferation decreased and the epithelial wound healing was delayed in Tabby mice, whereas it was restored by exogenous Eda. Eda exposure promoted mouse corneal epithelial wound healing during organ culture, whereas scratch wound assay showed that it did not affect human corneal epithelial cell line migration. Epidermal growth factor receptor (EGFR), phosphorylated EGFR (p-EGFR), and phosphorylated ERK1/2 (p-ERK) were down-regulated in Tabby mice corneal epithelium. Eda treatment up-regulated the expression of Ki67, EGFR, p-EGFR, and p-ERK in human corneal epithelial cells in a dose-dependent manner. In conclusion, Eda protein can be secreted from meibomian glands and promotes corneal epithelial cell proliferation through regulation of the EGFR signaling pathway. Eda release into the tears plays an essential role in the maintenance of corneal epithelial homeostasis.

Automatic recognition of the XLHED phenotype from facial images.

X-linked hypohidrotic ectodermal dysplasia (XLHED) is a genetic disorder that affects ectodermal structures and presents with a characteristic facial appearance. The ability of automated facial recognition technology to detect the phenotype from images was assessed . In Phase 1 of this study we examined if the age of male patients affected the technology's recognition. In Phase 2 we investigated how well the technology discriminated affected males cases from female carriers and from individuals with other ectodermal dysplasia syndromes. The system detected XLHED to be the most likely diagnosis in all genetically confirmed affected male patients of all ages, and in 55% of heterozygous females. Interestingly, patients with other ED syndromes were also detected by the XLHED-targeted analysis, consistent with shared developmental features. Thus the automated facial recognition system represents a promising non-invasive technology to screen patients at all ages for a possible diagnosis of ectodermal dysplasia, with greatest sensitivity and specificity for males affected with XLHED.

Mechanisms of genotype-phenotype correlation in autosomal dominant anhidrotic ectodermal dysplasia with immune deficiency

Autosomal dominant anhidrotic ectodermal dysplasia with immune deficiency (AD EDA-ID) is caused by heterozygous point mutations at or close to serine 32 and serine 36 or N-terminal truncations in IκBα that impair its phosphorylation and degradation and thus activation of the canonical nuclear factor κ light chain enhancer of activated B cells (NF-κB) pathway. The outcome of hematopoietic stem cell transplantation is poor in patients with AD EDA-ID despite achievement of chimerism. Mice heterozygous for the serine 32I mutation in IκBα have impaired noncanonical NF-κB activity and defective lymphorganogenesis. We sought to establish genotype-phenotype correlation in patients with AD EDA-ID. A disease severity scoring system was devised. Stability of IκBα mutants was examined in transfected cells. Immunologic, biochemical, and gene expression analyses were performed to evaluate canonical and noncanonical NF-κB signaling in skin-derived fibroblasts. Disease severity was greater in patients with IκBα point mutations than in those with truncation mutations. IκBα point mutants were expressed at significantly higher levels in transfectants compared with truncation mutants. Canonical NF-κB-dependent IL-6 secretion and upregulation of the NF-κB subunit 2/p100 and RELB proto-oncogene, NF-κB subunit (RelB) components of the noncanonical NF-κB pathway were diminished significantly more in patients with point mutations compared with those with truncations. Noncanonical NF-κB-driven generation of the transcriptionally active p100 cleavage product p52 and upregulation of CCL20, intercellular adhesion molecule 1 (ICAM1), and vascular cell adhesion molecule 1 (VCAM1), which are important for lymphorganogenesis, were diminished significantly more in LPS plus α-lymphotoxin β receptor-stimulated fibroblasts from patients with point mutations compared with those with truncations. IκBα point mutants accumulate at higher levels compared with truncation mutants and are associated with more severe disease and greater impairment of canonical andnoncanonical NF-κB activity in patients with AD EDA-ID.

Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency.

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 1year (one child). Two survivors have been on prophylaxis (at 9 and 22years). Six children died after HSCT. Five survived, four of whom have been on prophylaxis (3 to 21years 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.

Hematopoietic stem cell transplantation for RelB deficiency

Hematopoietic stem cell transplantation for RelB deficiency

Hypohidrotic Ectodermal Dysplasia: Breastfeeding Complications Due to Impaired Breast Development.

Background X-linked hypohidrotic ectodermal dysplasia (XLHED), the most common form of ectodermal dysplasia, is caused by mutations in the gene EDA. While only affected men develop the full-blown clinical picture, females who are heterozygous for an EDA mutation often also show symptoms such as hypodontia, hypotrichosis and hypohidrosis. These women may also suffer from malformations of the mammary gland which represent not just a cosmetic problem but can limit their breastfeeding capability. This paper summarizes the findings of the first systematic study on the impact of hypohidrotic ectodermal dysplasia on breastfeeding. Patients Thirty-eight adult female members of the German-Swiss-Austrian ectodermal dysplasia patient support group participated in a structured interview; most of them also agreed to a photodocumentation of their mammary region. Thirty-one women carried mutations in EDA (Group A) and seven were affected by other forms of hypohidrotic ectodermal dysplasia (Group B). Results 39 % of the women of Group A reported that their breasts were of different size or entirely absent on one side. In Group B, 86 % of the women reported differently sized or even absent breasts; two of these women lacked both breasts entirely. Most women described their nipples as exceptionally flat. 10 % of the women of Group A had more than two nipples. The high percentage of deviations from the norm was confirmed in the photodocumentation. Both groups had few or no sebaceous glands of Montgomery in the areolar region. Around 80 % of interviewed women had children and had attempted to breastfeed their first child. 67 % of the mothers in Group A had had difficulty in breastfeeding their infants and generally attributed this difficulty to their flat nipples. All of the mothers in Group B reported difficulties in breastfeeding; 60 % had not been able to breastfeed their first child. Conclusion Mothers with hypohidrotic ectodermal dysplasia very often have difficulty in breastfeeding because of their impaired breast development. This causal relationship needs to be taken into account in lactation counseling.

Early Prosthetic Treatment of Children with Hypohidrotic Ectodermal Dysplasia: Six Case Reports

Early Prosthetic Treatment of Children with Hypohidrotic Ectodermal Dysplasia: Six Case Reports

Displasia ectodérmica hipohidrótica: Reporte de casos

La Displasia Ectodérmica Hipohidrótica (DEH) es una genodermatosis que se caracteriza por presentar alteraciones en las estructuras derivadas del ectodermo, frecuentemente se da la triada: hipohidrosis, hipotricosis e hipodoncia. El síndrome puede manifestarse como herencia autosómica dominante o recesiva y también como herencia ligada al sexo, la forma más frecuente es la de herencia recesiva relacionada al cromosoma X con sujetos de sexo masculino afectados y de sexo femenino portadores. Puede ocurrir a través de mutaciones autosómicas, de las cuales las del gen EDA1 son responsables del 58% de los casos. La DEH presenta tasa de mortalidad infantil entre 2% y 20%, dependiendo de la precocidad del diagnóstico y de los protocolos de tratamiento. Este artículo presenta un paciente de 23 meses de edad quien había sido hospitalizado por otrapatología y se refirió al Instituto Hondureño de Seguridad Social (IHSS), por observar cabello hipopigmentado, escaso, fino, ausencia de pestañas y cejas, dientes cónicos e hipohidrosis: por lo que se diagnostica displasia ectodérmica hipohidrótica, quedando pendiente la realización de biopsia de piel y exámenes genéticos debido a que no se cuenta con el equipo médico necesario. Por tal motivo, no se conoció el patrón de segregación. Palabras clave Displasia Ectodérmica Hipohidrótica Autosómica Recesiva, Anodoncia, Hipotricosis

Oral rehabilitation with removable dental prosthesis in a six-year-old patient with hypohidrotic ectodermal dysplasia

Ectodermal dysplasia is an abnormality of the ectoderm and its derivatives, phenotypically expressed in males and genetically inherited from mothers. Objective: To report the efficacy of the prosthetics treatment of severe ectodermal dysplasia in a 6-year-old boy with hypohidrotic ectodermal dysplasia (HED). Case report: The boy had difficulty in speaking and eating and the condition also affected his self-esteem. Prosthetic treatments included the construction of acrylic custom trays, determination of the vertical dimension of occlusion (VDO), construction of upper and lower dentures, and palatal expansion procedure. Conclusion: Significant improvements in the patient’s stomatognathic function and self-esteem were evident.

Novel EDA gene splicing mutation in a X-linked hypohidrotic ectodermal dysplasia family

Novel EDA gene splicing mutation in a X-linked hypohidrotic ectodermal dysplasia family

Evaluation of Masticatory Stimulation Effect on the Maxillary Transversal Growth in Ectodermal Dysplasia Children.

AimsSevere oligodontia is one of the most important symptoms in children with hypohidrotic ectodermal dysplasia (HED). The growth of the maxilla is a key consideration in restoring their mouth. The aim of this study was to evaluate the transversal maxillary sutural growth, after passive masticatory stimulation, in HED children. We also thought to assess the efficiency and functional outcome of the proposed propriocep-tive passive expansion (PPE) prosthetic device.Materials and methodsWe studied 13 children (age 6-11 years) suffering from HED with severe oligodontia. Their maxilla was restored by a PPE device formed from two parts and joined by a passive slide system. Distance between the two parts was noted at the anterior and posterior regions at each control visit over an average of 23 months. We also conducted and filled a satisfaction questionnaire over the same period.We tested the hypothesis that the posterior expansion is greater than the anterior expansion (one-tailed Student’s t-test with p-value <0.05). Best-fit linear and quadratic models were used to explore the relationship between age, duration of observation, and the rate of growth.ResultsThe average opening of the device was 2.27 mm in the anterior region and 2.96 mm in the posterior region. The questionnaire response was positive for all children. There are no significant linear or quadratic relationships between the data at the 5% significance level. The posterior expansion is greater than the anterior expansion at the 5% significance level (p-value 0.000394).LimitationsFurther studies are mandatory to assess the reliability of our particular intervention and treatment modalities for these cases.ConclusionThe PPE device, we propose, assures function and esthetics in the long- term. It enhances stimulation by a passive way that leads to physiological growth of the palatal suture.Clinical significanceUsing this PPE device to restore the maxilla in children with HED promotes physiological growth. The passive nature of this prosthesis helps by eliminating the need for any changes or replacement over time.How to cite this articleSfeir E, Nahass MG, Mourad A. Evaluation of Masticatory Stimulation Effect on the Maxillary Transversal Growth in Ectodermal Dysplasia Children. Int J Clin Pediatr Dent 2017;10(1):55-61.

Hypohidrotic Ectodermal Dysplasia (HED)

Hypohidrotic ectodermal dysplasia is a rare genetic disorder presenting with features of faulty development of ectodermal structures. A boy with hypohidrosis hypotrichosis and hypodontia is reported.

Nasal Crust in a Case of Hypohidrotic Ectodermal Dysplasia

Hypohidrotic ectodermal dysplasia is a hereditary syndrome characterized mainly by the triad of less hair, less sweat and less teeth. It is associated with hypoplasia of the ectoderm caused by a genetic abnormality, and treatment remains mainly symptomatic. I encountered a case in a boy who presented with rhinostenosis at one month after birth. There were no anatomic abnormalities of the nasal cavity, however, the entire nasal cavity was filled with crust associated with atrophic nasal inflammation. Nose breathing was disturbed because of the pervasive crust and the child developed recurrent episodes of upper respiratory tract infection with a bad odor of the nasal mucus. Provision of care to prevent nasal crust formation for 4 years 6 months at the outpatient department led to improvement of the nose breathing and the bad odor of the nasal mucus. Herein, I report the method and the outcome.

Despite the hair failing, nails thrive…

Ectodermal dysplasias are defined as a group of congenital, nonprogressive, developmental syndromes with primary disorders in at least two ectoderm-derived structures namely eccrine glands, hair, nail and teeth. Pure hair and nail affecting ectodemal dysplasias are exceedingly rare in occurance and have been known to be associated with multiple abnormalities, such as keratoderma or ichthyosis, skeletal and hematological abnormalities, cardiac irregularities, mental or psychomotor retardation and cataracts. We herein report a case of hypotrichosis with trichorrhexis nodosa and twenty nail dystrophy- a hypohidrotic ectodermal dysplasia variant.

KDF1, encoding keratinocyte differentiation factor 1, is mutated in a multigenerational family with ectodermal dysplasia.

Ectodermal dysplasia is a highly heterogeneous group of disorders that variably affect the derivatives of the ectoderm, primarily skin, hair, nails and teeth. TP63, itself mutated in ectodermal dysplasia, links many other ectodermal dysplasia disease genes through a regulatory network that maintains the balance between proliferation and differentiation of the epidermis and other ectodermal derivatives. The ectodermal knockout phenotype of five mouse genes that regulate and/or are regulated by TP63 (Irf6, Ikkα, Ripk4, Stratifin, and Kdf1) is strikingly similar and involves abnormal balance towards proliferation at the expense of differentiation, but only the first three have corresponding ectodermal phenotypes in humans. We describe a multigenerational Saudi family with an autosomal dominant form of hypohidrotic ectodermal dysplasia in which positional mapping and exome sequencing identified a novel variant in KDF1 that fully segregates with the phenotype. The recapitulation of the phenotype we observe in this family by the Kdf1-/- mouse suggests a causal role played by the KDF1 variant.

Case Report: X-linked recessive anhidrotic ectodermal dysplasia with immunodeficiency and an unusual Aspergillus infection

NEMO (NF-kB essential modulator) is a regulatory factor involved in signaling pathways of the innate and adaptative immune systems. Hypomorphic mutation of the NEMO gene (also called IKBKG gene) on the X chromosome leads to X-linked recessive anhidrotic ectodermal dysplasia with immunodeficiency. Affected male children present a developmental phenotype with hypotrichosis, hypohydrosis, and hypodontia with conical incisors and susceptibility to pyogenic bacteria, mycobacteria and viruses. Most also have impaired antibody response to polysaccharide antigens. Here we present the case of a 7-year-old boy with disseminated BCGitis and unusual Aspergillus infection who was later diagnosed with a homozygous mutation of the NEMO gene. Appropriate long term anti-mycobacterial medications, prophylactic anti-fungal therapy and current monthly intravenous immunoglobulin (IVIG) stabilized the patient’s condition and has significantly improved his general health. High incidence of atypical mycobacterial infection in such cases emphasize the need for prophylaxis. In conclusion, attention to gender, pattern of infections, and precise physical exam helped us to diagnose and appropriately manage this case. We propose prophylactic therapy for mycobacterial and opportunistic infections after the confirmation of homozygous NEMO gene mutation.