Erythrokeratodermia Variabilis et Progressiva  Clinical Presentation

Updated: May 30, 2017
  • Author: Gabriele Richard, MD, FACMG; Chief Editor: Dirk M Elston, MD  more...
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Presentation

History

Most affected individuals with erythrokeratodermia variabilis et progressiva (EKVP) present initially with transient, circumscribed, figurate erythematous patches that may involve any part of the integument. These lesions are most prevalent during childhood and may become less frequent as the patient ages.

Concurrently or over time, a thickening of the skin (hyperkeratosis) develops, which may be generalized or localized with yellow-brown, thickened, rough, hyperkeratotic plaques on the extremities and trunk in a symmetrical distribution pattern. These hyperkeratotic plaques are relatively stable and last for months to years, but they can also clear completely.

After the disorder progresses throughout the patient's infancy and childhood, it seems to stabilize after puberty and slowly regresses when the patient is older. Improvement and periodic clearing of the skin are not unusual.

Skin lesions may be triggered by internal and/or external factors. These factors include stress, sudden temperature changes, cold, mechanical friction, and, rarely, sun exposure.

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Physical Examination

The hallmark of erythrokeratodermia variabilis et progressiva (EKVP) is the seemingly independent occurrence of transient, figurate erythema and hyperkeratosis. Frequently, one of these features predominates; occasionally, one may be absent. Skin lesions in erythrokeratodermia variabilis et progressiva may constantly change their appearance and vary among patients.

Erythema

The erythema manifests as well-demarcated patches of variable intensity, sometimes surrounded by an anemic halo. They may coalesce into large figurate patches, as shown in the first image below, or have a circinate or targetlike appearance, as shown in the second image below.

Figurate erythema. Courtesy of M. King and J. Craw Figurate erythema. Courtesy of M. King and J. Crawford.
Targetlike erythema. Courtesy of M. King and J. Cr Targetlike erythema. Courtesy of M. King and J. Crawford.

Predominance of circinate erythematous patches has been reported in patients with GJB4 (Cx30.3) mutations and has also been described as erythrokeratodermia variabilis with erythema gyratum repens–like lesions.

Erythema can appear on healthy skin and within hyperkeratotic plaques. The individual erythematous lesions are transient, usually persisting only for minutes to hours, although they may last for days. In about 35% of patients, erythema may be preceded or accompanied by a burning sensation, which may cause serious discomfort for patients.

The remarkable variability of the erythematous patches in number, size, shape, location, and duration is a typical feature of erythrokeratodermia variabilis that is reflected by the name of the disease.

Hyperkeratosis

Hyperkeratosis may be localized or generalized, but tends to be consistent within a family. The generalized form of hyperkeratosis manifests as persistent, yellow-brown-gray thickening of the skin with accentuated skin markings. Fine scaling or peeling may also be present, as depicted below.

Generalized hyperkeratosis with scaling, accentuat Generalized hyperkeratosis with scaling, accentuated skin lines, and figurate erythema. Courtesy of M. King and J. Crawford.

Rarely, thickened plates of gray-dark brown hyperkeratosis with a spiny, hystrixlike appearance, as in the image below, are present on the lower extremities.

Thick hyperkeratotic plates with hystrixlike spine Thick hyperkeratotic plates with hystrixlike spines. Courtesy of M. King and J. Crawford.

The localized form is characterized by sharply demarcated, brownish, hyperkeratotic plaques with figurate outlined borders. Their surface may be ridged and verrucous or show a collarettelike peeling or fine scaling. The plaques are almost symmetrically distributed, as shown below, over the limbs, buttocks, and trunk; often, the flexures, face, and scalp are spared.

Sharply demarcated, figurate, hyperkeratotic plaqu Sharply demarcated, figurate, hyperkeratotic plaques in a symmetric distribution. Courtesy of M. King and J. Crawford.

Relatively fixed lesions over knees, elbows, Achilles tendons, dorsum of the feet, and belt area, as depicted below, are common and can persist for months or years.

Figurate hyperkeratotic plaque with erythematous p Figurate hyperkeratotic plaque with erythematous patches. Courtesy of M. King and J. Crawford.

Nevertheless, individual plaques may change size and shape; they may also regress, leaving healthy skin in their place. Sometimes, hyperkeratotic plaques have hyperpigmented borders or are associated with hypertrichosis. Over the distal joints, the surface of these plaques may become velvety or have a cobblestone pattern.

In about half the affected families, hyperkeratosis involves the palms and soles of the feet as a patchy or diffuse palmoplantar keratoderma. Often, this palmoplantar hyperkeratosis is associated with peeling. See the images below.

Plantar keratoderma with peeling. Courtesy of M. K Plantar keratoderma with peeling. Courtesy of M. King and J. Crawford.
Diffuse glovelike palmar keratoderma. Courtesy of Diffuse glovelike palmar keratoderma. Courtesy of M. King and J. Crawford.

Hair, nails, teeth, and mucous membranes are not involved.

Mosaic EKVP

Rarely, a mosaic form of EKVP has been observed, clinically presenting as an inflammatory linear verrucous epidermal nevus (ILVEN). A postzygotic pathogenic variant in the GJA1 gene has been reported in one such case of somatic mosaicism. [10]

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Causes

Erythrokeratodermia variabilis et progressiva (EKVP) is usually inherited in an autosomal dominant pattern with nearly complete penetrance. A respectable number of sporadic cases and a few families with autosomal recessive inheritance have been documented.

In large families, the disorder was mapped to a connexin gene cluster at band 1p34.3.

EKVP is genetically heterogeneous and caused by mutations in different genes. [7, 11, 12, 13]

Three disease genes have been identified, GJB3 encoding connexin 31 (Cx31), GJB4 encoding connexin 30.3 (Cx30.3), and GJA1 encoding connexin 43 (Cx43). To date, pathogenic connexin gene mutations have been reported in at least 45 unrelated patients and families, including 15 distinct missense variants in GJB3, 9 missense variants in GJB4, and 2 in GJA1. [7, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33]

Several cases of erythrokeratodermia variabilis without identifiable connexin gene mutations have been observed, suggesting that other disease genes may exist. [34, 35, 36]

Both Cx31 and Cx30.3 are beta-type connexins that are preferentially expressed in the upper, differentiated keratinocytes of human epidermis, suggesting they play a crucial role during epidermal differentiation. [37] Cx43 is an alpha-type connexin that is ubiquitously expressed, including throughout the epidermis, and plays a critical role during wound healing of the skin.

In vitro expression studies suggest that pathogenic sequence variants causing EKVP disturb the intracellular processing and trafficking of gap junction proteins to the plasma membrane either alter gap junction communication or hemichannel function and may induce cell death. [38]

A connexin-31 mutant Cx31R42P has been associated with constitutively active hemichannels, resulting in cell death; understanding such pathophysiology may help in the discovery of novel therapeutic strategies in the future. [23]

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