The term erythrokeratodemas is applied to a group of inherited disorders of keratinisation characterized by well demarcated erythematous lesions and hyperkeratotic plaques. Erythrokeratodermas have been divided into two major subtypes, erytrokeratoderma variabilis (EKV) (Mendes da Costa) [1] and progressive symmetric erythrokeratoderma (PSEK) (Gottron) [2], and several atypical variants [3]. EKV usually presents at birth or in early infancy and it is characterised by migratory irregularly shaped erythematous areas, that can be solid, annular or polycyclic, and vary in shape and position over hours or days, in association with hyperkeratotic, well-defined, more stable plaques, which may be associated with peeling or collarette-like scaling, and have a predilection for the extensor aspects of limbs, the lateral trunk and the buttocks, and tend to be symmetrical in distribution. Erythrokeratoderma en cocardes [4] and erythokeratoderma with erythema gyratum repens-like lesions [5] are considered to be clinical variants of EKV, characterized by figurate, polycyclic and concentric (cockade-like) lesions that vary in shape in the course of hours or days and tend to recur in the course of several weeks, in association with hyperkeratotic, well-defined reddish plaques [3,6]. PSEK differs from EKV in the absence of migratory erythematous lesions and a greater incidence of palmoplantar keratoderma [3], and a frameshift mutation of the loricrin gene has been identified in a patient with a diagnosis of PSEK [7]. Nevertheless, there is an opinion that socalled PSEK with loricrin mutation probably corresponds to variant form of Vohwinkel syndrome, or loricrin keratoderma [3], and recent evidence suggests that the same GJB4 mutation can cause either EKV [8] or a PSEK phenotype [9].

The pattern of inheritance of EKV is usually autosomal dominant, but cases consistent with autosomal recessive inherence, as well as sporadic cases have been reported [10]. The major gene map locus for EKV is 1p34- 1p35.1. Two disease related genes have been identified in the chromosomal region 1p34-35: GJB3 and GJB4, which encode for the gap junction proteins 3 and 4, also known as connexin 31 (Cx31) and connexin 30.3 (Cx30.3), respectively [11].

Connexins are gap junctions proteins that mediate the exchange of metabolites, ions and second messengers between cells, and mutations of their genes have been associated with EKV (GJB3, GJB4), KID syndrome (GJB2 encoding Cx26, and GJB6, encoding Cx30), palmoplantar keratoderma and Bart-Pumphrey syndrome (GJB2), and Clouston syndrome and pachyonychia congentita (GJB6) [12]; in addition, mutations in GJB2 and less frequently GJB6 are the main cause of nonsyndromic deafness worldwide [13]. Eryhtrokeratoderma with erythema gyratum repens-like lesions [5] has been described in a large kindred of Jewish and Kurdish origin; all affected members show fixed hyperkeratotic plaques, but in some members they coexist with variable erythematous plaques resembling erythema gyratum repens. A mutation in the Cx30.3 gene has been found in this family [14], and the corresponding phenotype, that has been reported in three other families and one sporadic case with standard EKV phenotypes [8] , appears to be rather specific for this mutation [3].

As regards erythrokeratoderma en cocardes there are no data reported concerning the genes that are mutated, except for one case in which mutations of GJB3 (or GJB2, encoding Cx26) were excluded. This patient was heterozygous for a non-disease associated polymorphism of GJB4 [15].

Herein we report the case of a patient with erythrokeratoderma en cocardes with no family history of the disease in whom a mutation in the GJB3 gene (R32W) was demonstrated.

A 31-year-old woman presented to our Dermatology Department with a 5-year history of erythematous plaques with scaly rims on the arms, trunk and flexures, that were fixed, with minimal variation for several months and disappeared spontaneously, recurring every summer. She had no associated diseases, including atopic dermatitis, and did not take any medication. She had no affected family members and there was no history of familial consaguinity.

Physical examination showed large erythematous and mildly hyperkeratotic patches, with figurate and occasionally cockade-like ('cocarde') areas resembling erythema annulare centrifugum. The patches had geographical circinate borders with an erythematous rim peripheral to a fine collarette of desquamation (Figure 1). They were symmetrically distributed on the upper trunk, upper arms, thighs and buttocks (Figure 2). There were no alterations on her palms and soles, and her hair, teeth, and nails were also normal. General physical examination showed no enlarged lymph nodes, neurologic or eye abnormalities. Audiometric analysis revealed no hearing alterations in the patient.

Figure 1: Hyperkeratotic plaques in axilla surrounded by erythematous rims.

Figure 2: Hyperkeratotic plaques with collarette-like scaling in buttocks.

Results of KOH preparations and mycologic and bacterial cultures of skin scrapings were repeatedly negative.

Laboratory analysis results were normal, including blood cell counts, liver and kidney function tests and antinuclear antibody, anti- Ro and anti-La determinations. Histopathologic study of a cutaneous punch biopsy showed irregular acanthosis with slight papillomatosis and ortokeratotic hyperkeratosis with preservation of a normal granular layer. No dyskeratotic cells were observed. On the upper dermis there was a mild perivascular lymphocytic infiltrate (Figure 3). These findings were non-specific but consistent with the diagnosis of erythrokeratoderma.

Figure 3: Histological examination of the skin showed acanthosis with slight papillomatosis and ortokeratotic hyperkeratosis with a mild perivascular lymphocytic infiltrate on the upper dermis.

The topical administration of tacrolimus 0.1%, calcipotriol and adapalen was partially efficacious for the eruption. During followup the patient presented several periods of remission followed by periods with affected skin.

To study connexin gene mutations, genome DNA was extracted from peripheral blood samples [10]. PCR amplification and direct sequencing of the GJB3 and GJB4 genes revealed a missense mutation c.94C>T (R32W) in the GJB3 gene encoding Cx31 (Figure 4), whereas no alterations in the GJB4 gene were detected.

Figure 4: Identification of the 94C>T (R32W) mutation of the GJB3 gene.

Erythrokeratodermas are a group of genodermatoses that share clinical features but are heterogeneous at the genetic level [16]. The diagnosis of erythrokeratodermas is usually made according to typical clinical features. In our case, the patient presented with symmetrical erythematous, mildly desquamative patches with geographic configuration and circinate borders with peripheral collarette and occasional concentric and rosette-like appearance. The lesions tended to be fixed for 5-6 months and disappeared spontaneously, reappearing again after several months of remission, and there was no palmoplantar involvement. Tinea corporis, ichthyosis linearis circunflexa, subacute lupus erythematosus, erythema gyratum repens and other conditions included in the differential diagnosis of EKV were ruled out. According to clinical criteria and histopathologic correlation, the diagnosis of (sporadic) erythrokeratoderma en cocardes was established in this patient.

EKV is usually characterized by fixed hyperkeratotic plaques, but several authors have described periods of remission in certain patients [16], that suggest the diagnosis of the subtype erythrokeratoderma en cocardes.

In our case, the patient was asymptomatic during childhood and the first signs of disease appeared in adulthood. This is not consistent with the typical cases of EKV described in the literature, because clinical lesions usually appear during the first year of life [3,16]. Nevertheless, EKV lesions can seldom be observed for the first time in teenagers [6] and adult patients [17].

One of the typical signs referred by our patient was the aggravation of the lesions in summer. This is consistent with previous cases reported in the literature corresponding to erythrokeratoderma en cocardes [6,18], whereas the cases with classical EKV present aggravation in winter [19].

As regards genetic studies, several mutations of GJB3 and GJB4 (coding for connexin 31 and connexin 30.3, respectively) have been reported in both familial and sporadic cases of EKV [8,9,11,19,20], suggesting a genetic heterogeneity in EKV. Lesions in patients with EKV due to Cx30.3 tend to be more annular in appearance [8,14] than EKV of the Mendes da Costa type (Cx31) [11]. In the family with erythrokeratoderma with erythema gyratum repens-like lesions reported by Landau et al. [5] a mutation in the GJB4 gene have been reported [11], and other families with GJB4 mutations also show marked annular lesions [5]. Interestingly enough, all the four Japanese patients with EKV reviewed by Nakamura et al. [10] were female and without family history, as in our case and no mutations in GJB3 and GJB4 could be demonstrated in them.

In a Japanese girl with erythrokeratoderma en cocardes no mutations of GJB3 (or GJB2, encoding Cx26) were detected, and the patient was found to be heterozygous for a non-disease associated polymorphism of GJB4 [15].

In our patient we found a missense mutation 94C>T (R32W) in the GJB3 gene that has been previously found in patients with palmoplantar keratoderma and profound deafness [21]. The arginine residue is present in the first transmembrane domain of the protein and is conserved in all connexin species. In palmoplantar keratoderma with deafness, the R32W mutation in the GJB3 gene is associated with mutations in the GJB2 gene, correlating with the severity of hearing impairment [21]. Nevertheless, according to López-Bigas et al. [22], R32W is a rather common polymorphism (7.5%) in the Spanish population, having been detected in 17% of control subjects in the population they analysed.

Further studies are required to clarify the genetic and phenotypic variability of the erythrokeratodermas. The R32W mutation of GJB3 might be related to the erythrokeratoderma en cocardes subtype, but this missense mutation has been considered to be a functionally inconsequential polymorphism [23,24], and other as yet unidentified (connexin?) genes might be etiologically involved in EKV, as previously suggested [10].