Erythrokeratoderma variabilis
Christopher M Hunzeker MD, Anthony C Soldano MD, William R Levis MD
Dermatology Online Journal 14 (5): 13

Department of Dermatology, New York University

Abstract

A 51-year-old woman presented with well-demarcated, erythematous patches and hyperkeratotic plaques that were arranged symmetrically on the upper extremities. Her skin lesions first appeared at age 17 and there was a family history of similar skin lesions in nine of her eleven siblings. Physical and emotional stress increased the number and intensity of her skin lesions as did chocolate. The distribution of lesions on her skin had changed over time; however, the lesions consistently appeared symmetrically and favored the extensor surfaces of her extremities. The physical examination, histopathologic findings, and family history were consistent with a diagnosis of erythrokeratoderma variabilis (EKV), a rare genodermatosis caused by various mutations in connexin genes. Connexin genes code for proteins that form intercellular channels called gap junctions that allow for transport and signaling between neighboring cells in the epidermis. Mutations in connexin-31 and connexin-30.3 are known to cause the EKV phenotype, which presents as erythematous patches and hyperkeratotic plaques. Studies to examine the effectiveness of treatment of EKV have not been performed although several case reports suggest the efficacy of oral retinoids. After 4 months of acitretin 25 mg per day, our patient experienced near complete clearance of her skin lesions.



Clinical synopsis

A healthy 51-year-old woman presented to Bellevue Hospital Center for evaluation and treatment of asymptomatic red and brown skin lesions on her upper extremities. She first noticed similar lesions on her thighs and legs at age 17. Within a few years both her upper and lower extremities were involved, but eventually her lower extremities cleared. For the past 20 years, the lesions have remained symmetrically distributed on her upper extremities; however, there has been variability with regard to the number and severity of lesions over time. Of her 11 siblings, 9 are affected with similar skin lesions of various degrees. Neither the patient's mother nor her father are affected. Her only daughter has skin involvement as do one niece and one nephew. The patient noted that she experienced increased numbers and severity of skin lesions with emotional stress and sleep deprivation. Through self-directed challenge and re-challenge techniques, she also associated chocolate as a trigger of her skin lesions. She denied sensitivity to temperature, ultraviolet light, or trauma, although she stated that wool caused pruritus and tended to exacerbate her condition. After receiving 4 months of acitretin 25 mg per day, she experienced improvement in her skin. There was complete clearance of erythematous patches and hyperkeratosis with only hyperpigmentation remaining. She has tolerated the acitretin well, with no appreciable side effects and is now recommending treatment to her affected siblings.


Physical examination

Co-existing, well-demarcated, erythematous patches and hyperpigmented, hyperkeratotic, thin plaques were arranged symmetrically on the upper extremities. The lesions favored the extensor surfaces and spared the palms and the antecubital fossae. Both the erythematous patches and hyperkeratotic plaques presented as geographic or figurate-shaped lesions. The hair, teeth, and nails were normal.


Figure 1 Figure 2

Laboratory data

None


Histopathology

The epidermis shows acanthosis with overlying hyperkeratosis. There are focal areas with a prominent granular layer interspersed with areas of loss of the granular layer above which are 2-3 layers of parakeratosis that transition into compact orthohyperkeratosis. Within the dermis there is a sparse, superficial, perivascular lymphocytic infiltrate that is associated with dilated blood vessels.


Comment

Erythrokeratoderma variabilis (EKV), which is also known as Mendes de Costa disease, is a rare genodermatosis with a characteristic phenotype that is associated with a number of different mutations in connexin genes that are clustered on chromosome 1p34-35. Erythrokeratoderma variabilis is usually inherited in an autosomal dominant fashion. However autosomal recessive transmission has been reported [1]. The most well known dominant mutations are of connexin genes GJB3 and GJB4, which code for connexin-31 and connexin-30.3, respectively. Connexin genes code for transmembrane proteins that assemble to form hexameric hemichannels (connexins) that pair in adjacent cell membranes to form dodecameric channels referred to as gap junctions [2]. Gap junctions, which are found in the skin, nervous tissue, heart, and muscle, allow for intercellular transport of water, ions, and small molecules and are necessary for the coordination and synchronization of cellular responses to internal and external stimuli [3, 4]. Mutations in connexin genes are believed to alter the structure and function of gap junctions, and thereby affect intercellular transport and signaling. Connexin-31 and connexin-30.3 are expressed in the stratum granulosum of the epidermis and are suggested to have a role in late keratinocyte differentiation [1]. The understanding of the interactions between connexins and the precise pathophysiology of gap junctions is in the beginning stages. The importance of connexin proteins is underscored by the number of additional syndromic skin disorders that are linked to connexin mutations. These include keratitis-ichthyosis deafness syndrome, Vohwinkel syndrome, and hidrotic ectodermal dysplasia (Clouston syndrome).

Erythrokeratoderma variabilis is characterized by 2 distinct types of lesions: well-demarcated, transient, erythematous patches and hyperkeratotic plaques. The erythematous patches may be annular, polycyclic, or geographic in appearance and persist for hour to days. They may fade entirely or they may evolve into hyperkeratotic plaques. The hyperkeratotic plaques are similar in shape and distribution; however, they acquire a yellow or red-brown color and are more stable in terms of their duration, although they are not permanent. Lesions in EKV are classically symmetrical and favor the extensor surfaces of the extremities, the trunk, and the buttocks. Patchy or diffuse palmoplantar keratoderma is observed in approximately 50 percent of patients [4]. Although any area may be involved, the face, scalp, and flexures are typically spared [5]. Temperature, ultraviolet light, trauma, and emotional stress may be exacerbating factors. Although the lesions are usually asymptomatic, pruritus and a burning sensation have been described in association with erythematous patches [6, 7]. Erythrokeratoderma variabilis exhibits complete penetrance, with considerable inter- and intra-familial variability in expression [8]. Lesions are typically present at birth or appear within the first year of life. The intensity and distribution of the skin involvement can wax and wane. Periods of spontaneous remission can occur, but complete remission is not typically seen. Affected patients may suffer cosmetically and psychologically; however, EKV results in no functional or intellectual impairment and a normal life span should be anticipated. Controlled studies have not been performed for the treatment of EKV. Several authors report successful treatment with oral retinoids, which include etretinate, isotretinoin, and acitretin [9]. Low maintenance doses are usually sufficient because chronic treatment is necessary Therefore the potential risks side effects and monitoring requirements should be thoroughly reviewed with the patient prior to initiating therapy. One case report also claims successful treatment in a child with topical tretinoin cream [10]. Patients should avoid triggers, such as friction or trauma to the skin and sudden temperature changes, if these factors exacerbate their disease.

References

1. Common JEA, et al. Clinical and genetic heterogeneity of erythrokeratoderma variabilis. J Invest Dermatol 2005;125:920

2. Di WL, et al. Defective trafficking and cell death is characteristic of skin disease-associated connexin 31 mutations. Hum Mol Genet 2002;11:2005

3. Van Steensel MAM. Gap junction diseases of the skin. Am J Med Genet 2004;131C:12

4. Richard G, et al. Genetic heterogeneity in erythrokeratodermia variabilis: novel mutations in the connexin gene GJB4 (Cx30.3) and genotype-phenotype correlations. J Invest Dermatol 2003;120:601

5. Rogers M. Erythrokeratodermas: a classification in a state of flux? Australas J Dermatol 2005;46:127

6. Feldneyer L, et al. Novel mutation of connexin 31 causing erythrokeratoderma variabilis. Br J Dermatol 2005;152:1072

7. Papadavid E, et al. Erythrokeratoderma variabilis: case report and review of the literature. J Eur Acad Dermatol Venereol 1998;11:180

8. Richard G, et al. Mutations in the human connexin gene GJB3 cause erythrokeratoderma variabilis. Nat Genet 1998;20:366

9. Rappaport IP, et al. Erythrokeratodermia variabilis treated with isotretinoin. Arch Dermatol 1986;122:441

10. Luy JT, et al. A child with erythematous and hyperkeratotoic patches: erythrokeratodermia variabilis. Arch Dermatol 1988;124:1271

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Title:

Erythrokeratoderma variabilis

Journal Issue:

Dermatology Online Journal, 14(5)

Author:

Hunzeker, Christopher M;
Soldano, Anthony C;
Levis, William R

Publication Date:

2008

Publication Info:

Dermatology Online Journal, UC Davis

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