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.

Both low-dose arotinoid ethylester and acitretin are effective in the treatment of familial erythrokeratodermia variabilis.

We previously reported a large Chinese pedigree of erythrokeratodermia variabilis (EKV). A unique feature was that some of the affected members experienced transitory pustules on the border of classic lesions. Here we prescribed oral arotinoid ethylester and acitretin to two of the affected members in the pedigree, at starting dosage of 0.03 mg/day for arotinoid ethylester and 30 mg/day for acitretin, maintenance dosage of 0.03 mg every other day and 20 mg/day, respectively. Both patients reached complete clearance of the lesions during the treatment period. Side effect was negligible for the case on arotinoid ethylester. The patient on acitretin experienced elevated level of serum triglyceride and alanine aminotransferase that restrained further use.

Progressive symmetrical erythrokeratodermia -- case report.

Progressive symmetrical erythrokeratodermia is a rare autosomal dominant genodermatosis with variable penetrance described by Darier in 1911. It is characterized by erythematous and keratotic plaques, sharply defined and symmetrically distributed along the extremities, buttocks and, more rarely, on the face. We report a case of a 55-year-old patient with lesions on the dorsum of the hands, interphalangeal pads, wrists, groin and back feet. This case demonstrates a rare and late diagnosis, clinical profusion and presence of familiar involvement.

[Erythrokeratodermia variabilis]. / Érythrokératodermie variable.

BACKGROUND: Erythrokeratodermia variabilis (EKV) is a rare genodermatosis associated with keratinisation disorders. Mutations are found in genes encoding connexin 31 and 30.3 mapped to chromosome 1 p34-35. We report two cases of EKV, one of which presented dramatic improvement with oral retinoids. PATIENTS AND METHODS: A 15-month-old boy was referred to us with reddish-brown hyperkeratotic and well-demarcated plaques on the extremities, axillary space and face. The lesions started when he was 6months of age. Cutaneous histopathology showed acanthosis and papillomatosis associated with orthokeratotic hyperkeratosis. Anatomoclinical comparison confirmed the diagnosis of EKV. A second child aged 10years was referred to us with fixed, well-demarcated hyperkeratotic plaques associated with transient red patches. The lesions began when she was 1month old. Anatomoclinical comparison confirmed the diagnosis of EKV and the patient showed dramatic improvement after 2weeks on acitretin. DISCUSSION: EKV is characterized by the association of fixed well-demarcated plaques and transient erythematous patches. Although cutaneous histopathology is not specific, a typical physical examination and a compatible cutaneous histopathology can aid the diagnosis. Oral retinoids are often very rapidly effective.

Erythrokeratoderma variabilis responding to low-dose isotretinoin.

A 2-year-old male child was diagnosed with erythrokeratoderma variabilis, and showed an excellent response to low-dose isotretinoin, with remarkable improvement in all the affected areas within just 2 weeks of treatment.