X-Linked Hypohidrotic Ectodermal Dysplasia (XLHED): A Case Report and Overview of the Diagnosis and Multidisciplinary Modality Treatments.

Hypohidrotic ectodermal dysplasia (HED) is a rare genetic disorder caused by a mutation in either the ectodysplasin (EDA), ectodysplasin A receptor (EDAR), EDAR associated via death domain (EDARADD), or Wnt family member 10A (WNT10A) genes that result in impaired development of ectodermal-derived structures. The literature defines two types of ectodermal dysplasia, which are hypohidrotic and hidrotic. X-linked hypohidrotic ectodermal dysplasia (XLHED), also known as Christ-Siemens-Touraine syndrome, is the most common form and is a variant of ectodermal dysplasia characterized by a classical triad of hypo/adontia, hypohidrosis, and hypotrichosis; whereas, hidrotic type of ectodermal dysplasia, also known as Clouston syndrome, is characterized by a triad of onychodysplasia, hypotrichosis, and palmoplantar hyperkeratosis while sparing the sweat glands. Symptoms of XLHED can begin early in life between the ages of one month to 23 months. XLHED is more commonly seen in males due to the x-linked characteristics of the gene mutations. This disease can be diagnosed by physical exam alone, or in combination with molecular genetic testing. XLHED specifically has an estimated occurrence of one in every 20,000 newborns worldwide. Approximately 5,000 people in the United States have the disease.  In this case report, we present an adult patient diagnosed with XLHED. Our objective is to emphasize the significance of early diagnosis, advocate for a multidisciplinary management approach, and shed light on the potential of recombinant protein and targeted gene therapy for further research. By raising awareness of this condition, we aim to improve patient outcomes not only in newborns but also in adults who have already been diagnosed with XLHED.

A novel variant in the GJB6 gene in a large Chinese family with a unique phenotype of Clouston syndrome.

Clouston syndrome (OMIM #129500), also known as hidrotic ectodermal dysplasia type 2, is a rare autosomal dominant skin disorder. To date, four mutations in the GJB6 gene, G11R, V37E, A88V, and D50N, have been confirmed to cause this condition. In previous studies, the focus has been mainly on gene sequencing, and there has been a lack of research on clinical manifestations and pathogenesis. To confirm the diagnosis of this pedigree at the molecular level and summarize and analyse the clinical phenotype of patients and to provide a basis for further study of the pathogenesis of the disease, we performed whole-exome and Sanger sequencing on a large Chinese Clouston syndrome pedigree. Detailed clinical examination included histopathology, hair microscopy, and scanning electron microscopy. We found a novel heterozygous missense variant (c.134G>C:p.G45A) for Clouston syndrome. We identified a new clinical phenotype involving all nail needling pain in all patients and found a special honeycomb hole structure in the patients' hair under scanning electron microscopy. Our data reveal that a novel variant (c.134G>C:p.G45A) plays a likely pathogenic role in this pedigree and highlight that genetic testing is necessary for the diagnosis of Clouston syndrome.

A novel variant in the GJB6 gene in a large Chinese family with a unique phenotype of Clouston syndrome / 医学前沿

Clouston syndrome (OMIM #129500), also known as hidrotic ectodermal dysplasia type 2, is a rare autosomal dominant skin disorder. To date, four mutations in the GJB6 gene, G11R, V37E, A88V, and D50N, have been confirmed to cause this condition. In previous studies, the focus has been mainly on gene sequencing, and there has been a lack of research on clinical manifestations and pathogenesis. To confirm the diagnosis of this pedigree at the molecular level and summarize and analyse the clinical phenotype of patients and to provide a basis for further study of the pathogenesis of the disease, we performed whole-exome and Sanger sequencing on a large Chinese Clouston syndrome pedigree. Detailed clinical examination included histopathology, hair microscopy, and scanning electron microscopy. We found a novel heterozygous missense variant (c.134G>C:p.G45A) for Clouston syndrome. We identified a new clinical phenotype involving all nail needling pain in all patients and found a special honeycomb hole structure in the patients' hair under scanning electron microscopy. Our data reveal that a novel variant (c.134G>C:p.G45A) plays a likely pathogenic role in this pedigree and highlight that genetic testing is necessary for the diagnosis of Clouston syndrome.

The Clinical Manifestation of p.Asp50Asn Heterozygous Mutation of GJB2 Gene in 3 Members of a Family Is Similar to That of Clouston Syndrome.

Keratitis-ichthyosis-deafness (KID) syndrome has genetic heterogeneity, and the clinical manifestations of some patients may overlap with Clouston syndrome. A 34-year-old female patient came to our department with a complain of "sparse hair, rough skin, photophobia and deafness for more than 30 years." We found that the proband and two other family members (57-year-old mother and 4-year-old daughter) had similar clinical manifestations: systemic hair loss, generalized skin hyperkeratosis, especially in the metacarpophalangeal area. Subungual hyperkeratosis, finger/toenail dystrophy, as well as photophobia and epiphora. According to the investigation, one of the family members also had similar clinical manifestations (grandfather of the proband) and he's died. The other three members of the family had no hearing impairment, and all patients had typical nail dystrophy, hair loss and palmoplantar hyperkeratosis, similar like as seen in Clouston syndrome, so we suspected to diagnose the case as Clouston syndrome. However, after genetic testing, it was found that the proband, his mother and daughter all had p.Asp50Asn heterozygous mutations in the GJB2 gene, and no mutation was detected in GJB6. The modified diagnosis was KID syndrome.

Hypohidrotic ectodermal dysplasia: a case report.

Hypohidrotic ectodermal dysplasia is a common variation of ectodermal dysplasia, characterized by hypohidrosis (or anhidrosis), hypotrichosis, hypodontia, and other distinct facial features. Furthermore, ocular tissues of ectodermal origin may also be affected in this disease. The most common ocular manifestations of hypohidrotic ectodermal dysplasia are dry eye, madarosis, alterations in the meibomian glands, abnormalities in the nasolacrimal duct, and infantile glaucoma. Herein, author reports a case of hypohidrotic ectodermal dysplasia in a 12-year-old Indian boy with dry eye and lacrimal sac mucocele.

Mutation-Proved Clouston Syndrome in a Large Indian Family with a Variant Phenotype.

Hereditary ectodermal dysplasias, a group of disorders affecting skin, hair, nails, and teeth, consist of two main clinical forms - hypohidrotic and hidrotic. Clouston syndrome is a hidrotic ectodermal dysplasia characterized by a triad of generalized hypotrichosis, palmoplantar hyperkeratosis, and nail dystrophy. This paper reports a large Indian family with Clouston syndrome but with the absence of palmoplantar keratoderma, one of the features of the typical triad, thus representing phenotypic heterogeneity, in spite of the presence of a common known mutation in GJB6 gene (p.Gly11Arg).

The connexin 30 A88V mutant reduces cochlear gap junction expression and confers long-term protection against hearing loss.

Mutations in the genes that encode the gap junction proteins connexin 26 (Cx26, encoded by GJB2) and Cx30 (GJB6) are the leading cause of hereditary hearing loss. That said, the Cx30 p.Ala88Val (A88V) mutant causes Clouston syndrome, but not hearing loss. Here, we report that the Cx30-A88V mutant, despite being toxic to inner ear-derived HEI-OC1 cells, conferred remarkable long-term protection against age-related high frequency hearing loss in Cx30A88V/A88V mice. During early development, there were no overt structural differences in the cochlea between genotypes, including a normal complement of hair cells; however, the supporting cell Cx30 gap junction plaques in mutant mice were reduced in size. In adulthood, Cx30A88V/A88V mutant mice had a reduction of cochlear Cx30 mRNA and protein, yet a full complement of hair cells. Conversely, the age-related high frequency hearing loss in Cx30+/+ and Cx30+/A88V mice was due to extensive loss of outer hair cells. Our data suggest that the Cx30-A88V mutant confers long-term hearing protection and prevention of hair cell death, possibly via a feedback mechanism that leads to the reduction of total Cx30 gap junction expression in the cochlea.

Mechanistic effect of the human GJB6 gene and its mutations in HaCaT cell proliferation and apoptosis

We constructed lentiviral vectors containing the human wild-type GJB6 gene and the mutant variants A88V and G11R. The three proteins were stably expressed by the Tet-on system in the HaCaT cell line and used to study the functional effect of the variants. The CCK-8 assay and flow cytometric analyses were used to determine the levels of cell proliferation and apoptosis. Western blot analyses were performed to analyze the relevant clinical indicators of hidrotic ectodermal dysplasia and markers of apoptosis in transfected HaCaT cells. The CCK8 assay and the flow cytometry results showed a significant increase (P<0.05) in the apoptosis of HaCaT cells expressing the A88V and G11R mutants. In addition, we demonstrated that the A88V and G11R mutants induced the apoptosis of transfected HaCaT cells via the activation of caspase-3, -8, -9, and PARA. No change was observed in the activity of BAX compared with the control. This study provides further clarification on the mechanisms underlying the effect of the mutant variants A88V and G11R of the GJB6 gene on the induction of HaCaT cell apoptosis.

Phenotype in a patient with p.D50N mutation in GJB2 gene resemble both KID and Clouston syndromes.

Keratitis-ichthyosis-deafness (KID) syndrome (OMIM 148210) is a rare ectodermal dysplasia syndrome characterized by vascularizing keratitis, congenital profound sensorineural hearing loss, and progressive erythrokeratoderma. We have found a 148G-A transition in the GJB2 gene, resulting in an asp50-to-asn (D50N) substitution in a girl with congenital deafness. This finding allowed us to diagnose а KID syndrome. But clinical features were uncommon because of a mild skin manifestation, lack of keratitis and unusual appearance resembling Clouston syndrome. Molecular genetic tests showed that it was de novo mutation because parents have normal genotype. Several autosomal dominant mutations in the GJB2 gene (сonnexin 26) now established to underlie many of the affected cases, with the majority of patients harboring the p.D50N mutation. Skin disease-associated mutation of connexin proteins can cause functional disturbances in gap junction intercellular conductance. It is likely that multiple disease mechanisms are involved across the wide spectrum of hereditary diseases relating to connexin proteins. The clinical data may provide additional insights into the dysregulation mechanisms of mutations result in the disease.

The Clouston syndrome mutation connexin30 A88V leads to hyperproliferation of sebaceous glands and hearing impairments in mice.

Distinct mutations in the gap junction protein connexin30 (Cx30) can cause the ectodermal dysplasia Clouston syndrome in humans. We have generated a new mouse line expressing the Clouston syndrome mutation Cx30A88V under the control of the endogenous Cx30 promoter. Our results show that the mutated Cx30A88V protein is incorporated in gap junctional plaques of the epidermis. Homozygous Cx30A88V mice reveal hyperproliferative and enlarged sebaceous glands as well as a mild palmoplantar hyperkeratosis. Additionally, homozygous mutant mice show an altered hearing profile compared to control mice. We conclude that the Cx30A88V mutation triggers hyperproliferation in the skin and changes the cochlear homeostasis in mice.

Mutations in Cx30 that are linked to skin disease and non-syndromic hearing loss exhibit several distinct cellular pathologies.

Connexin 30 (Cx30), a member of the large gap-junction protein family, plays a role in the homeostasis of the epidermis and inner ear through gap junctional intercellular communication (GJIC). Here, we investigate the underlying mechanisms of four autosomal dominant Cx30 gene mutations that are linked to hearing loss and/or various skin diseases. First, the T5M mutant linked to non-syndromic hearing loss formed functional gap junction channels and hemichannels, similar to wild-type Cx30. The loss-of-function V37E mutant associated with Clouston syndrome or keratitis-ichthyosis-deafness syndrome was retained in the endoplasmic reticulum and significantly induced apoptosis. The G59R mutant linked to the Vohwinkel and Bart-Pumphrey syndromes was retained primarily in the Golgi apparatus and exhibited loss of gap junction channel and hemichannel function but did not cause cell death. Lastly, the A88V mutant, which is linked to the development of Clouston syndrome, also significantly induced apoptosis but through an endoplasmic-reticulum-independent mechanism. Collectively, we discovered that four unique Cx30 mutants might cause disease through different mechanisms that also likely include their selective trans-dominant effects on coexpressed connexins, highlighting the overall complexity of connexin-linked diseases and the importance of GJIC in disease prevention.

Clouston syndrome: gene diagnosis and pathogenic mechanism / 国际儿科学杂志

Clouston syndrome,also named hidrotic ectodermal dysplasia,is an autosomal dominant genetic disease.It is characterized by hypotrichosis,nail dystrophy and palmoplantar hyperkeratosis.It is caused by mutations in the GJB6 gene.Up to date,there are four GJB6 missense mutations that can cause Clouston syndrome:G1 1R,A88V,V37E and D50N.This article reviews the progress of gene diagnosis and pathogenic mechanism of Clouston syndrome,which can contribute to etiological diagnosis,genetic counseling,intervention as well as treatment.

Clouston syndrome: first case in Russia.

Hidrotic ectodermal dysplasia type 2 (HED2) or Clouston syndrome (OMIM #129500) is a rare autosomal dominant genetic disorder which affects skin and its derivatives, characterized by the major triad of features: nail dystrophy, generalized hypotrichosis, and palmoplantar hyperkeratosis. Here we describe the first case of Clouston syndrome in Russia and the molecular genetic analysis of this case.