Erythrokeratodermia Variabilis Research Articles

Expression and Characterization of Wildtype and Mutant Forms of Human Connexin31 using Xenopus Oocytes

Connexin31 is a gap junction protein encoded by the GJB3 gene in humans. Mutations in the gene lead to a rare skin disorder known as erythrokeratodermia variabilis (EKV) a disease characterized by figurate red patches and general hyperkeratosis. While a few mutations have also been linked to deafness and neuropathy, over twenty mutations, mostly point mutations within the coding region, have been associated with EKV. Oocytes from Xenopus laevis were used for expression and analysis of Cx31 and mutations. As far as we know this is the first time Cx31 has been expressed and characterized in oocytes. Wildtype Cx31 displayed gating properties similar to those reported after expression in mammalian cells but with some interesting differences. Several skin disease mutations induced leaky membranes associated with cell death, an effect that was both time- and concentration-dependent. It was hypothesized that aberrant hemichannel behavior was responsible for leaky membranes, which was supported by the observation that addition of calcium or cobalt to the extracellular media enhanced viability. Other mutations induced behavior ranging from failure to form functional channels to expression and gating similar to wtCx31. As well as providing insight into the mechanisms underlying skin disease, deafness and neuropathy, we will discuss the role of Cx31 mutants as tools to assess connexin interactions in skin.

Immunosuppressed cutaneous District: The finale of the fascinating farrago of confounding responses?

Immunosuppressed cutaneous District: The finale of the fascinating farrago of confounding responses?

Mutations in KDSR Cause Recessive Progressive Symmetric Erythrokeratoderma

Mutations in KDSR Cause Recessive Progressive Symmetric Erythrokeratoderma

A study on palmoplantar keratodermas in childhood in a district hospital

Introduction: Palmoplantar keratodermas (PPKs) are a group of disorders in which there is marked thickening of the skin of palms and soles. The keratodermas can be diffuse, focal, or punctuate type. Aims: The aim of this study was to study various types of PPKs, both hereditary and acquired in children up to 17 years of age. Methods: A randomized controlled prospective study of twenty patients of PPK was taken up for the study. A detailed history, general physical examination, cutaneous examination with special examination of the oral mucosa, teeth, and nails along with routine investigations were done in all the patients. Results: Most common causes of PPK were secondary to psoriasis and ichthyosis (25% each), followed by 15% cases secondary to pityriasis rubra pilaris. PPK due to pachyonychia congenita was seen in 5% patients and secondary to erythrokeratodermia variabilis in 5% patients. Monogenic PPKs including Vorners syndrome and Unna-Thost PPK were seen in 5% patients each and focal PPK seen in 15% patients. Conclusion: It is important to note the age of onset of the keratodermas, severity of disease process, and the histopathological findings before reaching a diagnosis of PPKs.

Erythrokeratodermia variabilis et progressiva.

Erythrokeratodermia variabilis et progressiva (EKVP) is a rare inherited skin disease characterized by fixed hyperkeratotic plaques and transient erythematous patches. EKVP is most often transmitted in an autosomal dominant manner. Causal mutations were found in the GJB3, GJB4 and GJA1 genes encoding connexins 31, 30.3 and 43, respectively. Approximately 50% of affected individuals develop palmoplantar keratoderma. Connexins are components of gap junctions, which are intercellular channels that are found in almost all tissues including the skin. Treatment of EKVP usually involves use of topical keratolytics and emollients resulting in some improvement in hyperkeratosis. Low-dose systemic retinoid may be beneficial. Novel therapies targeting connexin hemichannels and gap junctions may become available in the future.

Analysis of the clinical and genetic characteristics of a progressive symmetric erythrokeratoderma

Objective To investigate the clinical and genetic characteristics of a progressive symmetric erythrokeratoderma (PSEK). Methods The clinical and genetic characteristics of a PSEK were compared and analyzed with clinical collection and review of 17 PSEK families reported in China since 1980. Results PSEK was consistent with autosomal dominant inheritance. PSEK had the feature with incomplete penetrance and variable expression. The clinical features included hyperkeratotic plaques with distinct border and strikingly symmetric distribution pattern on the extremities. Part of patients was extended to other areas of the body. The onset of the disease commonly started in infancy or childhood. The general health condition was not affected. PSEK might be associated with other clinical symptoms. The diseased potential increased in the family of consanguineous marriage. Conclusions PSEK has genetic heterogeneity. Its causative genes have not been determined. Further studies are needed. Key words: Erythema/GE; Keratosis/GE

Erythrokeratodermia variabilis and erythrokeratoderma en cocardes: Case series with review of literature

Erythrokeratodermia variabilis (EKV) are a rare heterogeneous group of inherited cornification disorders. They are characterized by two distinct morphological types of skin lesions: Fixed hyperkeratotic plaques and sharply marginated, pruritic, and migratory erythematous lesions. We report three cases of EKV along with a review of literature.

Progressive symmetric erythrokeratoderma: A rare case report

Erythrokeratodermas are a rare group of genetic disorders presenting early in childhood as erythematous, hyperkeratotic plaques on the skin. There may be associated neurological involvement. A 12-year-old boy presented with symmetric keratotic plaques on the body since infancy. Psoriasis and pityriasis rubra pilaris were ruled out after histopathological examination of the skin. We are reporting a case of progressive symmetric erythrokeratoderma with classical lesions but can be missed due to unawareness.

Pathogenic Cx31 is un/misfolded to cause skin abnormality via a Fos/JunB-mediated mechanism.

Mutations in connexin-31 (Cx31) are associated with multiple human diseases, including familial erythrokeratodermia variabilis (EKV). The pathogenic mechanism of EKV-associated Cx31 mutants remains largely elusive. Here, we show that EKV-pathogenic Cx31 mutants are un/misfolded and temperature sensitive. In Drosophila, expression of pathogenic Cx31, but not wild-type Cx31, causes depigmentation and degeneration of ommatidia that are rescued by expression of either dBip or dHsp70. Ectopic expression of Cx31 in mouse skin results in skin abnormalities resembling human EKV. The affected tissues show remarkable disrupted gap junction formation and significant upregulation of chaperones Bip and Hsp70 as well as AP-1 proteins c-Fos and JunB, in addition to molecular signatures of skin diseases. Consistently, c-Fos, JunB, Bip and Hsp70 are strikingly higher in keratinocytes of EKV patients than their matched control individuals. Furthermore, a druggable AP-1 inhibitory small molecule suppresses skin phenotype and pathological abnormalities of transgenic Cx31 mice. The study suggests that Cx31 mutant proteins are un/misfolded to cause EKV likely via an AP-1-mediated mechanism and identifies a small molecule with therapeutic potential of the disease.

A Novel Mutation in ELOVL4 Leading to Spinocerebellar Ataxia (SCA) With the Hot Cross Bun Sign but Lacking Erythrokeratodermia: A Broadened Spectrum of SCA34.

Although mutations in 26 causative genes have been identified in the spinocerebellar ataxias (SCAs), the causative genes in a substantial number of families with SCA remain unidentified. To identify the causative gene of SCA in 2 Japanese families with distinct neurological symptoms and radiological presentations. Clinical genetic study at a referral center of 11 members from 2 Japanese families, which started in 1997. Results of neurological examinations and radiological evaluations. The causative mutation was identified using genome-wide linkage analysis and next-generation sequencing. Affected members (9 of 11 members [81.8%]) showed slowly progressive cerebellar ataxia (all 9 members [100%]), ocular movement disturbance (all 9 members [100%]), and pyramidal tract signs (8 of 9 members [88.9%]) with an age at onset between the second and sixth decades of life. Besides cerebellar and pontine atrophy, magnetic resonance imaging of the brain revealed the hot cross bun sign (4 of 6 members [66.7%]), pontine midline linear hyperintensity (2 of 6 members [33.3%]), or high intensity in the middle cerebellar peduncle (1 of 6 members [16.7%]), which are all reminiscent of multiple system atrophy in tested patients. Using linkage analysis combined with exome and whole-genome sequencing, we identified a novel heterozygous mutation in the ELOVL fatty acid elongase 4 (ELOVL4) gene (c.736T>G, p.W246G) in both families. Haplotype analysis indicated that it was unlikely that these 2 Japanese families shared a common ancestor. Although a missense mutation in ELOVL4 (c.504G>C, p.L168F) was recently reported to be associated with SCA with erythrokeratodermia variabilis (SCA34) in a French-Canadian family, signs of erythrokeratodermia variabilis were absent in our families. Combined with the results of the family with SCA34 reported previously, this report confirms that mutations in ELOVL4 can cause dominantly inherited neurodegeneration severely affecting the cerebellum and brainstem. We should be aware that the presence of multiple system atrophy-like features on magnetic resonance imaging scans, together with cerebellar and brainstem atrophy, suggests SCA34, even when erythrokeratodermia variabilis is absent. The present study further broadened the spectrum of the clinical presentations of SCA34 associated with mutations in ELOVL4, which is involved in the biosynthesis of very long-chain fatty acids.

Erythrokeratodermia Variabilis et Progressiva Allelic to Oculo-Dento-Digital Dysplasia

Erythrokeratodermia variabilis et progressiva (EKVP) is a genodermatosis with clinical and genetic heterogeneity, most often transmitted in an autosomal dominant manner, caused by mutations in GJB3 and GJB4 genes encoding connexins (Cx)31 and 30.3, respectively. In this issue, Boyden et al. (2015) report for the first time de novo dominant mutations in GJA1 encoding the ubiquitous Cx43 in patients with EKVP. These results expand the genetic heterogeneity of EKVP and the human disease phenotypes associated with GJA1 mutations. They disclose that EKVP is allelic to oculo-dento-digital dysplasia, a rare syndrome previously known to be caused by dominant GJA1 mutations.

Dominant De Novo Mutations in GJA1 Cause Erythrokeratodermia Variabilis et Progressiva, without Features of Oculodentodigital Dysplasia

Genetic investigation of inherited skin disorders has informed understanding of skin self-renewal, differentiation, and barrier function. Erythrokeratodermia variabilis et progressiva (EKVP) is a rare, inherited skin disease characterized by transient figurate patches of erythema, localized or generalized scaling, and frequent palmoplantar keratoderma. By employing exome sequencing, we show that de novo missense mutations in GJA1 (gap junction protein alpha 1) cause EKVP. The severe, progressive skin disease in EKVP subjects with GJA1 mutations is distinct from limited cutaneous findings rarely found in the systemic disorder oculodentodigital dysplasia, also caused by dominant GJA1 mutations. GJA1 encodes connexin 43 (Cx43), the most widely expressed gap junction protein. We show that the GJA1 mutations in EKVP subjects lead to disruption of Cx43 membrane localization, and aggregation within the Golgi. These findings reveal a critical role for Cx43 in epidermal homeostasis, and provide evidence of organ-specific pathobiology resulting from different mutations within GJA1.

A Japanese case of erythrokeratodermia variabilis caused by connexin-30.3 (GJB4) mutation

A Japanese case of erythrokeratodermia variabilis caused by connexin-30.3 (GJB4) mutation

Progressive symmetric erythrokeratoderma having overlapping features with erythrokeratoderma variabilis and lesional hypertrichosis: Is nomenclature "erythrokeratoderma variabilis progressiva" more appropriate?

Progressive symmetric erythrokeratoderma having overlapping features with erythrokeratoderma variabilis and lesional hypertrichosis: Is nomenclature "erythrokeratoderma variabilis progressiva" more appropriate?

Symmetrical progressive erythrokeratoderma in siblings

Progressive symmetric erythrokeratoderma or Gottron's syndrome is a rare autosomal dominantly inherited disorder with <100 cases reported worldwide, of which <10 are from India. It is characterized by erythematous, well-defined, hyperkeratotic plaques distributed mainly on the knees, elbows, buttocks, scalp, and dorsal surfaces of the hands and feet. In general, the trunk is spared. The condition has a progressive course during early childhood, and then is usually stable. We report a case of symmetric progressive erythrokeratoderma in two male siblings, aged 11 years and 7 years born out of second degree consanguineous marriage who presented with erythematous, scaly plaques over the extensor aspect of both extremities.

Radiotherapy for breast cancer and erythrokeratodermia variabilis

We report the first case report indicating that locoregional radiotherapy provide acceptable early and late toxicities in patient with erythrokeratodermia variabilis after 2years of follow-up. However, preclinical data showing radiation-induced tumor genesis in case of deficiency of some connexins point out the need of a careful surveillance of these patients.

Expanding the Clinical Phenotype Associated WithELOVL4Mutation

The autosomal dominant spinocerebellar ataxias (SCAs) are a complex group of neurodegenerative disorders with significant genetic heterogeneity. Despite the identification of 20 SCA genes, the cause of the disorder in a significant proportion of families with SCA remains unexplained. In 1972, a French-Canadian family segregating a combination of SCA and erythrokeratodermia variabilis (EKV) in an autosomal dominant fashion was described. To map and identify the causative gene in this large family with SCA and EKV using a combination of linkage analysis and whole-exome sequencing. A total of 32 individuals from the family have undergone complete neurologic and dermatologic examinations. Mutations in ELOVL4 have been reported in families with macular degeneration. Recently, homozygous mutations were found in patients with ichthyosis, spastic paraplegia, and severe neurodevelopmental defects. In the present study, we report on a heterozygote mutation in ELOVL4 in affected individuals from the family with SCA and EKV. The mutation segregates with a milder phenotype consisting of early-onset patches of erythema and hyperkeratosis, as well as SCA manifesting in the fourth or fifth decade of life. We describe the mapping and the identification of a c.504G>C transversion in ELOVL4 resulting in the p.L168F substitution. We also provide clinical characterization of the phenotypes in 19 mutation carriers. We report, to our knowledge, the first mutation in ELOVL4 that is associated with SCA and EKV. This gene encodes a member of the elongase family, which is responsible for the elongation of very long-chain fatty acids (at least 26 carbons). These fatty acids participate in a wide variety of physiological functions, including skin barrier formation and peroxisome β-oxidation. Overall, these results provide additional insight into the pathogenesis of these complex neurodegenerative disorders.

Erythrokeratodermia variabilis: A case report

A case of erythrokeratodermia variabilis (EKV) in a 9-year-old black girl is presented. The skin lesions first appeared at three months of age as an erythematous patch on the upper inner thigh. Later, scaling hyperkeratotic plaques on erythematous bases with well-demarcated and hyperpigmented borders appeared on her trunk, face, and upper abdomen. According to the child's parents and to the child herself the lesions changed their shape and distribution over minutes, hours and days and were exacerbated by external factors and emotional stress. Palmar and plantar keratoderma was present. The patient was otherwise normal and was the only child of apparently healthy parents. A punch biopsy showed basket-weave hyperkeratosis, with papillomatosis and acanthosis and these findings were consistent with the diagnosis of EKV. The patient was treated with isotretinoin 10 mg/day and topically with 2.5% hydrocortisone cream and 12% lactic acid lotion. There was some improvement at a three-month follow-up. In the majority of cases, EKV is inherited as an autosomal dominant trait. Because of the apparent absence of clinical symptoms in the patient's relatives, the disease in our case could be sporadic, or, alternatively, due to incomplete gene penetrance.

Progressive symmetric erythrokeratoderma: report of an Indian family

Progressive symmetric erythrokeratoderma: report of an Indian family

Progressive Symmetric Erythrokeratoderma. First case reported in the Dominican Republic

Progressive symmetric erythrokeratoderma (PSEK) is an autosomal dominant genodermatosis with incomplete penetrance and variable expressivity. It belongs to the group of erythrokeratodermas where it can be differentiated from erythrokeratoderma variabilis in the absence of migratory erythematous lesions and in a greater incidence of palmoplantar keratoderma. Molecular basis of PSEK has not yet been established although there are reports of mutations in the loricrin gene. We report a 13-year-old boy with symmetrically distributed hyperkeratotic plaques over the dorsum of the hands and the extensor aspect of the forearms, elbows and knees. As far as we are aware, we report the first case of PSEK in the Dominican Republic.