Hypohidrotic Ectodermal Dysplasia Research Articles

Functional studies for a dominant mutation in the EDAR gene responsible for hypohidrotic ectodermal dysplasia.

Hypohidrotic ectodermal dysplasia (HED) is a rare genetic disorder characterized by hypotrichosis, hypohidrosis and hypodontia. The disease shows X-linked recessive, autosomal dominant or autosomal recessive inheritance traits. The X-linked form of HED is caused by mutations in the EDA gene, while autosomal forms result from mutations in either EDAR or EDARADD genes. Regarding recessive mutations in the EDAR gene, the pathomechanisms have been well characterized. However, it has remained largely unknown how dominant mutations in the EDAR cause HED. In this study, we performed in vitro analyses for a dominant EDAR gene mutation, p.F398*, as a representative. We showed that the p.F398* mutant EDAR completely lost its affinity to EDARADD, and suppressed the downstream nuclear factor-κB activation induced by wild-type EDAR in a dominant-negative manner. Furthermore, we demonstrated that the mutant EDAR was capable of binding with the wild-type EDAR, which led to reduced interaction between the wild-type EDAR and EDARADD. Our findings not only underscore an essential role of the interaction between EDAR and EDARADD in ectodermal development, but also disclose, in part, the molecular basis of autosomal dominant HED.

Novel and Private EDA Mutations and Clinical Phenotypes of Korean Patients with X-Linked Hypohidrotic Ectodermal Dysplasia

X-linked hypohidrotic ectodermal dysplasia (XLHED; OMIM 305100) is the most common form of ectodermal dysplasia, presenting with the triad of hypotrichosis, hypodontia, and hypohidrosis. This disorder is caused by mutations in EDA, which encodes ectodysplasin A, a member of the tumor necrosis factor superfamily. In this study, we describe clinical and genetic characteristics of 10 Korean XLHED patients (9 males, 1 female) from 9 families. Nine out of the 10 patients manifested the cardinal triad of symptoms. Six patients had a positive family history, while 2 patients were brothers. The most common initial presentation was hypotrichosis or hypodontia, while 1 patient presented with recurrent high fever in early infancy. Sanger sequencing of the EDA gene was performed and revealed 9 different mutations. Three had been reported previously, and 6 were novel mutations. One female patient, carrying a previously reported missense mutation, might be affected by skewed X-inactivation. This is the first observational study investigating genetically confirmed XLHED patients in Korea. To provide appropriate supportive care and genetic counseling, clinicians should consider the possibility of XLHED in the differential diagnosis of recurrent fever in infants, as well as recognize the typical triad of symptoms.

Zygomatic implants in dental rehabilitation of anhidrotic ectodermal dysplasia patients: report of two cases

Zygomatic implants in dental rehabilitation of anhidrotic ectodermal dysplasia patients: report of two cases

Prenatal Treatment of X-Linked Hypohidrotic Ectodermal Dysplasia using Recombinant Ectodysplasin in a Canine Model.

X-linked hypohidrotic ectodermal dysplasia (XLHED) is caused by defects in the EDA gene that inactivate the function of ectodysplasin A1 (EDA1). This leads to abnormal development of eccrine glands, hair follicles, and teeth, and to frequent respiratory infections. Previous studies in the naturally occurring dog model demonstrated partial prevention of the XLHED phenotype by postnatal administration of recombinant EDA1. The results suggested that a single or two temporally spaced injections of EDI200 prenatally might improve the clinical outcome in the dog model. Fetuses received ultrasound-guided EDI200 intra-amniotically at gestational days 32 and 45, or 45 or 55 alone (of a 65-day pregnancy). Growth rates, lacrimation, hair growth, meibomian glands, sweating, dentition, and mucociliary clearance were compared in treated and untreated XLHED-affected dogs, and in heterozygous and wild-type control dogs. Improved phenotypic outcomes were noted in the earlier and more frequently treated animals. All animals treated prenatally showed positive responses compared with untreated dogs with XLHED, most notably in the transfer of moisture through paw pads, suggesting improved onset of sweating ability and restored meibomian gland development. These results exemplify the feasibility of ultrasound-guided intra-amniotic injections for the treatment of developmental disorders, with improved formation of specific EDA1-dependent structures in dogs with XLHED.

Turkish Ectodermal Dysplasia Cohort: From Phenotype to Genotype in 17 Families

Hypohidrotic or anhidrotic ectodermal dysplasia (HED/EDA) is characterized by impaired development of the hair, teeth, or sweat glands. HED/EDA is inherited in an X-linked, autosomal dominant, or autosomal recessive pattern and caused by the pathogenic variants in 4 genes: EDA, EDAR, EDARADD, and WNT10A. The aim of the present study was to perform molecular screening of these 4 genes in a cohort of Turkish individuals diagnosed with HED/EDA. We screened for pathogenic variants of WNT10A, EDA, EDAR, and EDARADD through Sanger sequencing. We further assessed the clinical profiles of the affected individuals in order to establish phenotype-genotype correlation. In 17 (63%) out of 27 families, 17 pathogenic variants, 8 being novel, were detected in the 4 well-known ectodermal dysplasia genes. EDAR and EDA variants were identified in 6 families each, WNT10A variants in 4, and an EDARADD variant in 1, accounting for 35.3, 35.3, 23.5, and 5.9% of mutation-positive families, respectively. The low mutation detection rate of the cohort and the number of the EDAR pathogenic variants being as high as the EDA ones were the most noteworthy findings which could be attributed to the high consanguinity rate.

Morphology of the Meibomian gland evaluated using meibography in patients with hypohidrotic ectodermal dysplasia

Abstract Introduction Hypohidrotic ectodermal dysplasia (HED) is a rare disease that results from the abnormal development of the ectodermal germ layer in early embryogenesis. In these patients, hypoplasia of Meibomian glands is one of the most frequent ophthalmological manifestations. The main aim of this study is to evaluate the usefulness of meibography for the morphology of Meibomian glands in a group of patients with HED, and to compare it with a control group. Methods A total of 14 eyes of 7 patients diagnosed with HED were included, and 32 eyes of 16 patients were included as a control group. The meibographic study was carried out using CA-800 Corneal Analyser (Topcon®). Grading of images was assessed by a meibomian gland atrophy score: grade 0, no alterations; grade 1, ≤25% gland atrophy; grade 2, 25% to 50% gland atrophy; grade 3, 51% to 75% gland atrophy; and grade 4 >75% gland atrophy. Both groups were compared using the Mann–Whitney U non-parametric test. Results All patients with HED showed some degree of gland atrophy, with 57% showing severe atrophy (>75% of gland atrophy), 35.8% with a grade 3, and 7.2% grade 2. The mean grade of glandular atrophy in HED was 3 (1–4). In the control group, 62.5% had no involvement (grade 0), with 28.1% showing grade 1 and 9.4% grade 2 gland atrophy. The mean glandular atrophy grade within the control group was 0 (0–2). There were statistically significant differences between both groups. Conclusions Meibography is a simple diagnostic tool that allows to differentiate between patients without disease and those with HED.

Role of ectodysplasin signalling in middle ear and nasal pathology in rat and mouse models of hypohidrotic ectodermal dysplasia.

ABSTRACTPatients with mutations in the ectodysplasin receptor signalling pathway genes – the X-linked ligand ectodysplasin-A (EDA), the receptor EDAR or the receptor adapter EDARADD – have hypohidrotic ectodermal dysplasia (HED). In addition to having impaired development of teeth, hair, eccrine sweat glands, and salivary and mammary glands, HED patients have ear, nose and throat disease. The mouse strains Tabby (EdaTa) and downless (Edardl-J/dl-J) have rhinitis and otitis media due to loss of submucosal glands in the upper airway. We report that prenatal correction of EDAR signalling in EdaTa mice with the agonist anti-EDAR antibody rescues the auditory-tube submucosal glands and prevents otitis media, rhinitis and nasopharyngitis. The sparse- and wavy-haired (swh) rat strain carries a mutation in the Edaradd gene and has similar cutaneous HED phenotypes to mouse models. We report that auditory-tube submucosal glands are smaller in the homozygous mutant Edaraddswh/swh than those in unaffected heterozygous Edaraddswh/+ rats, and that this predisposes them to otitis media. Furthermore, the pathogenesis of otitis media in the rat HED model differs from that in mice, as otitis media is the primary pathology, and rhinitis is a later-onset phenotype. These findings in rodent HED models imply that hypomorphic as well as null mutations in EDAR signalling pathway genes may predispose to otitis media in humans. In addition, this work suggests that the recent successful prenatal treatment of X-linked HED (XLHED) in humans may also prevent ear, nose and throat disease, and provides diagnostic criteria that distinguish HED-associated otitis media from chronic otitis media with effusion, which is common in children.

Treatment including orthognathic surgery of a patient with Hypohidrotic ectodermal dysplasia with cleft palate: A Clinical report

Ectodermal dysplasia is a genetic disorder in which various clinical manifestations involve two or more of the differentiated tissues of the ectoderm. Facial deformity, which is frequently associated with ectodermal dysplasia, appears in the form of cleft lip or cleft palate, especially in the middle facial area.Cleft and tooth defects result in decreased alveolar bone development.This leads to severe skeletal incongruity. Facial features include frontal protrusion, malar bone hypoplasia, flat nose, mandibular prominence and long lower facial height. This clinical report presents treatment including orthognathic surgery of a patient with Hypohidrotic Ectodermal dysplasia with cleft palate.

Hypohidrotic ectodermal dysplasia with autosomal inheritance: A rare entity

Hypohidrotic ectodermal dysplasia (HED) is a rare disorder which is characterized by the involvement of all ectodermal derivatives and marked deficiency of sweating. It has a prevalence of 1: 100,000. X-linked recessive fashion is the most common pattern of inheritance, and 90% of the individuals affected are males. Autosomal dominant and recessive forms of this disease are very rare. Here, a 24-year-old female presented with classical features of HED: sparse lusterless hair, everted lips, and artificial dentures with a history of hypodontia in childhood. Patient's niece had complaints of decreased hair growth and sweating since birth. The patient also gave a history of similar complaints in great grandmother. Hence, we present an uncommon scenario where three females of an extended family were affected with HED and had symptoms of varying severity.

A de Novo EDA-Variant in a Litter of Shorthaired Standard Dachshunds with X-Linked Hypohidrotic Ectodermal Dysplasia.

In this study, we present a detailed phenotype description and genetic elucidation of the first case of X-linked hypohidrotic ectodermal dysplasia in the shorthaired standard Dachshund. This condition is characterized by partial congenital hypotrichosis, missing and malformed teeth and a lack of eccrine sweat glands. Clinical signs including dental radiographs and histopathological findings were consistent with ectodermal dysplasia. Pedigree analysis supported an X-recessive mode of inheritance. Whole-genome sequencing of one affected puppy and his dam identified a 1-basepair deletion within the ectodysplasin-A (EDA) gene (CM000039.3:g.54509504delT, c.458delT). Sanger sequencing of further family members confirmed the EDA:c.458delT-variant. Validation in all available family members, 37 unrelated shorthaired standard Dachshunds, 128 further Dachshunds from all other coat and size varieties and samples from 34 dog breeds revealed the EDA:c.458delT-variant to be private for this family. Two heterozygous females showed very mild congenital hypotrichosis but normal dentition. Since the dam is demonstrably the only heterozygous animal in the ancestry of the affected animals, we assume that the EDA:c.458delT-variant arose in the germline of the granddam or in an early embryonic stage of the dam. In conclusion, we detected a very recent de-novo EDA mutation causing X-linked hypohidrotic ectodermal dysplasia in the shorthaired standard Dachshund.

Reliability of prenatal detection of X-linked hypohidrotic ectodermal dysplasia by tooth germ sonography.

In X-linked hypohidrotic ectodermal dysplasia (XLHED), dysfunction of ectodysplasin A1 (EDA1) due to EDA mutations results in malformation of hair, teeth, and sweat glands. Hypohidrosis, which can cause life-threatening hyperthermia, is amenable to intrauterine therapy with recombinant EDA1. This study aimed at evaluating tooth germ sonography as a noninvasive means to identify affected fetuses in pregnant carrier women. Sonography, performed at 10 study sites between gestational weeks 18 and 28, led to the diagnosis of XLHED if fewer than six tooth germs were detected in mandible or maxilla. The assessment was verified postnatally by EDA sequencing and/or clinical findings. Estimated fetal weights and postnatal weight gain of boys with XLHED were assessed using appropriate growth charts. In 19 of 38 sonographic examinations (23 male and 13 female fetuses), XLHED was detected prenatally. The prenatal diagnosis proved to be correct in 37 cases; one affected male fetus was missed. Specificity and positive predictive value were both 100%. Tooth counts obtained by clinical examination corresponded well with findings on panoramic radiographs. We observed no weight deficits of subjects with XLHED in utero but occasionally during infancy. Tooth germ sonography is highly specific and reliable in detecting XLHED prenatally.

Recurrent fever, bulging fontanelle and elevated white blood cell

This patient presented with fever, seizure and bulging fontanelle when he was 6-month-old.According to the investigations, white blood cell (WBC), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) increased significantly, and Streptococcus Pneumonia grew in both blood and cerebrospinal fluid (CSF). He responded to standard antibiotic treatment poorly even it lasted long enough.At the same time, the inflammation seemed to be over-activated, the WBC level was still elevated, high fever continued.Thus they thought of primary immunodeficiency and sent blood sample for gene panel testing (Sanger sequencing) but got negative result.At last, they added steroid together with anti-tuberculosis drug therapy, his temperature as well as the intracranial pressure became better ever since.At the age of 1 year and 1 month, he got another Streptococcus Pneumonia meningitis, while he was still on anti-tuberculosis drug therapy and tapering off steroid.At this time, he presented with coarse hair, hypohidrosis and delayed eruption of teeth, which strongly indicated Anhidrotic Ectodermal Dysplasia with Immunodeficiency (EDA-ID). NEMO is the most common gene responsible for EDA-ID and locates on X chromosome.It has a pseudogene named IKBKGP which locates downstream of NEMO. IKBKGP and NEMO share 3-10 exons with the homology of 99.8%, which makes it difficult to find out most real mutations within NEMO with Sanger sequencing.Then they performed PCR with the primer starting upstream of the shared exons.Finally, they found out the pathogenic mutation [c.505G>C(p.A169P)] of NEMO, which has been reported.This finding led us to make the right diagnosis as well as the proper treatment and the prognosis for this patient. Key words: Recurrent infection; Streptococcus Pneumonia meningitis; Primary immunodeficiency; Anhidrotic ectodermal dysplasia with immunodeficiency

Dental anomalies and lesions in Eastern Atlantic harbor seals, Phoca vitulina vitulina (Carnivora, Phocidae), from the German North Sea.

Skulls of 1,901 Eastern Atlantic harbor seals (Phoca vitulina vitulina) were systematically studied for externally visible dental anomalies and lesions. The sample comprised 927 males and 974 female individuals, with age at death ranging between 1 week and 25 years. Most of the skulls originated from animals collected in 1988, when the population suffered from a mass mortality event caused by the phocine distemper virus (PDV). Mean age (± SD) of females (6.7 ± 6.4 years) was higher (p = 0.002) than that of males (5.9 ± 5.2 years). In 264 individuals, one or more teeth were missing either congenitally (n = 26 animals, 1.4%) or due to intravital loss (n = 238 animals, 12.5%). One male exhibited congenital absence of all teeth (anodontia). As this animal had been reported to be almost hairless, the condition was tentatively diagnosed as a case of hypohidrotic ectodermal dysplasia. Males were more frequently (p = 0.002) affected by intravital tooth loss (15.0%) than females (10.2%). Supernumerary teeth were found in 3.4% of the skulls, with females (4.7%) showing hyperodontia more frequently (p < 0.001) than males (1.9%). Fifty-nine individuals (3.1%; 28 males, 31 females, p = 0.84) exhibited abnormal tooth morphology. Tooth fractures were noted in 40 seals (2.1%), with males being more frequently affected than females (p = 0.017). Periapical lesions were diagnosed in 143 skulls, with a tendency (p = 0.05) for males (8.7%) to be more frequently affected than females (6.4%). Enamel hypoplasia was not observed in the study sample. Analyzing the occurrence of dental anomalies and lesions in wild mammals can substantially contribute to an assessment of population health and thereby broaden the basis for effective species conservation and informed management decisions.

A frameshift variant in the EDA gene in Dachshunds with X-linked hypohidrotic ectodermal dysplasia.

X-linked hypohidrotic ectodermal dysplasia (XLHED) is a genetic disease characterized by hypoplasia or absence of hair, teeth and sweat glands. The EDA gene, located on the X chromosome, encodes the type II transmembrane protein ectodysplasin A. Variants in the EDA gene can lead to XLHED in humans, mice, cattle and dogs. In the present study, we investigated a litter of Dachshund puppies, of which four male puppies showed clinical signs of XLHED. We performed a candidate gene analysis in one affected puppy and several non-affected relatives. This analysis revealed a single base-pair deletion in the coding sequence of the EDA gene in the affected puppy (NM_001014770.2:c.842delT). The deletion is predicted to cause a frameshift, NP_001014770.1:p.(Leu281HisfsTer22), leading to a premature stop codon which truncates more than one quarter of the EDA protein. Sanger sequencing results confirmed that this variant was inherited from the dam. Based on knowledge about the functional impact of EDA variants in dogs and other species, c.842delT is a convincing candidate causative variant for the observed XLHED in the male puppies.

Prenatal Correction of X-Linked Hypohidrotic Ectodermal Dysplasia

(Abstracted from N Engl J Med 2018;378:1604–1610) Infants with a genetic deficiency of ectodysplasin A (EDA), resulting from a loss of function variant of the gene EDA, have a condition known as X-linked hypohidrotic ectodermal dysplasia (XLHED). This condition results in irreversible impairment of the sweat glands and can lead to life-threatening hyperthermia after birth.

Upper cervical spine and craniofacial morphology in hypohidrotic ectodermal dysplasia.

Morphological deviations in the upper cervical spine and craniofacial morphology in patients with X-linked hypohidrotic ectodermal dysplasia (XLHED) were compared to non-syndromic controls. All children and adolescents with genetically verified XLHED, registered at the Resource Centres for Oral Health in Rare Diseases, who met the inclusion criteria, were included. The group thus comprised 15 XLHED patients (3 girls and 12 boys, aged 8-16years, mean 11.2years). The control group comprised 22 non-syndromic pre-orthodontic children (14 girls and 8 boys aged 9-16years, mean 11.9years) with agenesis of one tooth, neutral occlusion and normal craniofacial morphology. The craniofacial and upper spine morphology was analysed on lateral cephalograms by standard methods. Differences between XLHED patients and controls were tested and adjusted for age and gender by multiple regression analyses. Morphological deviations in the upper spine occur significantly more often in XLHED patients compared to controls (60 vs. 9.1%; p < 0.01). The cranial base angle (n-s-ar, p < 0.05), sagittal jaw relationship (ss-n-pg, p < 0.001), maxillary inclination (NSL/NL, p < 0.001) and mandibular inclination (NSL/ML, p < 0.01) were significantly smaller in XLHED patients compared to controls. The mandibular prognathia (s-n-pg) was significantly larger in XLHED patients compared to controls (p < 0.05). The upper spine and the craniofacial morphology were different in XLHED patients compared to controls. The results of this study may contribute to a further understanding of the craniofacial and spinal phenotypic spectrum in patients with XLHED and thus have implications for diagnosis and treatment planning of these patients.

Reabilitação temporária com mini-implantes em criança com displasia ectodérmica

Objetivo: apresentar a versatilidade de mini-implantes para reabilitação temporária de pacientes com displasia ectodérmica hipoidrótica (DEH). Relato de Caso: descreve a reabilitação iniciada em abril / 2015 em um menino de oito anos de idade com DMC e histórico familiar da doença. Tendo em vista o grande número de casos relatando a difícil adaptação de próteses removíveis em crianças, a reabilitação oral desse paciente foi planejada com base na fabricação de próteses apoiadas em mini-implantes ortodônticos. Conclusão: esta abordagem alternativa facilita o uso e adaptação de próteses, promove a preservação do osso alveolar e melhora as condições funcionais, estéticas e psicossociais do paciente. Deve haver acompanhamento clínico anual radiográfico e trimestral até o final do estirão de crescimento, para reavaliação e renovação das próteses sempre que necessário, de acordo com a crista alveolar.

Treatment of syndromic hypodontia in ectodermal dysplasia(s)

Ectodermal dysplasia (ED) is a diverse set of syndromic conditions that are derived from mutations. It affects developmental pathways including communication between the overlaying ectoderm and the underlying mesoderm in embryonic development. The most common form of ED syndromes is referred to as X-linked hypohidrotic ectodermal dysplasia or HED. The HED phenotype includes: (1) hypodontia (missing < 5 teeth); (2) oligodontia (missing six or more teeth); (3) anodontia (missing all teeth); (4) conical- shaped teeth; (5) altered hair growth, distribution, and amount (trichodysplasia); (6) reduced sweating (dyshidrosis); (7) altered mucosal sebaceous function (asteatosis); (8) altered keratin nail formation (onychodysplasia).

Rare health conditions 14: glucagonoma, porphyria and hypohidrotic ectodermal dysplasia

The purpose of this series is to briefly highlight a range of rare health conditions. Rare health conditions are those that affect no more and usually less than 1 person in every 2000 and many HCAs and nurses will encounter some of these conditions, given the high number of them. This fourteenth article will explore three of these conditions: glucagonoma, porphyria and hypohidrotic ectodermal dysplasia.

Defective NaCl Reabsorption in Salivary Glands of Eda-Null X-LHED Mice

Mutations in the ectodysplasin A gene (EDA) cause X-LHED (X-linked hypohidrotic ectodermal dysplasia), the most common human form of ectodermal dysplasia. Defective EDA signaling is linked to hypoplastic development of epithelial tissues, resulting in hypotrichosis, hypodontia, hypohidrosis, and xerostomia. The primary objective of the present study was to better understand the salivary gland dysfunction associated with ectodermal dysplasia using the analogous murine disorder. The salivary flow rate and ion composition of the 3 major salivary glands were determined in adult Eda-deficient Tabby hemizygous male (Ta/Y) and heterozygous female (Ta/X) mice. Submandibular and sublingual glands of Eda-mutant mice were smaller than wild-type littermates, while parotid gland weight was not significantly altered. Fluid secretion by the 3 major salivary glands was essentially unchanged, but the decrease in submandibular gland size was associated with a dramatic loss of ducts in Ta/Y and Ta/X mice. Reabsorption of Na+ and Cl–, previously linked in salivary glands to Scnn1 Na+ channels and Cftr Cl- channels, respectively, was markedly reduced at high flow rates in the ex vivo submandibular glands of Ta/Y mice (~60%) and, to a lesser extent, Ta/X mice (Na+ by 14%). Consistent with decreased Na+ reabsorption in Ta/Y mice, quantitative polymerase chain reaction analysis detected decreased mRNA expression for Scnn1b and Scnn1g, genes encoding the β and γ subunits, respectively. Moreover, the Na+ channel blocker amiloride significantly inhibited Na+ and Cl– reabsorption by wild-type male submandibular glands to levels comparable to those observed in Ta/Y mice. In summary, fluid secretion was intact in the salivary glands of Eda-deficient mice but displayed marked Na+ and Cl– reabsorption defects that correlated with the loss of duct cells and decreased Scnn1 Na+ channel expression. These results provide a likely mechanism for the elevated NaCl concentration observed in the saliva of affected male and female patients with X-LHED.