Erythrokeratodermia Variabilis Clinical Presentation

  • Author: Gabriele Richard, MD; Chief Editor: Dirk M Elston, MD   more...
 
Updated: Jan 24, 2012
 

History

Most erythrokeratodermia variabilis patients initially present 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. These hyperkeratotic plaques are relatively stable and last for months to years, but they can also clear completely.

After erythrokeratodermia variabilis 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

The hallmark of erythrokeratodermia variabilis 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 may constantly change their appearance and vary among patients.

  • Erythema
    • The erythema in erythrokeratodermia variabilis 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. CrawFigurate erythema. Courtesy of M. King and J. Crawford. Targetlike erythema. Courtesy of M. King and J. CrTargetlike 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, accentuatGeneralized 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 spineThick 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 plaquSharply 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 pFigurate 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. KPlantar 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.
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Causes

Erythrokeratodermia variabilis is usually inherited in an autosomal dominant pattern with nearly complete penetrance. A respectable number of sporadic cases and 2 families with autosomal recessive inheritance have been documented.

The disorder maps to a connexin gene cluster at band 1p34.3.

Erythrokeratodermia variabilis is genetically heterogeneous and caused by mutations in different genes.[7, 8, 9]

  • Two disease genes have been identified, GJB3 encoding connexin 31 (Cx31) and GJB4 encoding connexin 30.3 (Cx30.3). To date, pathogenic connexin gene mutations have been reported in 24 unrelated erythrokeratodermia variabilis patients and families, including 10 distinct missense mutations in GJB3 and 7 missense mutations in GJB4.[10, 11, 12, 13, 14, 15, 16, 17]
  • Several cases of erythrokeratodermia variabilis without identifiable connexin gene mutations have been observed, suggesting that other disease genes exist.[18, 19]

Both Cx31 and Cx30.3 belong to the group of beta-type connexins and are preferentially expressed in the upper, differentiated keratinocytes of human epidermis, suggesting they play a crucial role during epidermal differentiation.[20]

In vitro expression studies suggest that erythrokeratodermia variabilis mutations disturb the intracellular processing and trafficking of gap junction proteins to the plasma membrane, alter gap junction communication, and induce cell death.[21]

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Contributor Information and Disclosures
Author

Gabriele Richard, MD  Medical Director, GeneDx, Inc

Gabriele Richard, MD is a member of the following medical societies: American Society of Human Genetics and Society for Investigative Dermatology

Disclosure: BioReference Laboratories Salary Employment

Specialty Editor Board

Mark W Cobb, MD  Consulting Staff, WNC Dermatological Associates

Mark W Cobb, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, and American Society of Dermatopathology

Disclosure: Nothing to disclose.

Richard P Vinson, MD  Assistant Clinical Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine; Consulting Staff, Mountain View Dermatology, PA

Richard P Vinson, MD is a member of the following medical societies: American Academy of Dermatology, Association of Military Dermatologists, Texas Dermatological Society, and Texas Medical Association

Disclosure: Nothing to disclose.

Lester F Libow, MD  Dermatopathologist, South Texas Dermatopathology Laboratory

Lester F Libow, MD is a member of the following medical societies: American Academy of Dermatology, American Society of Dermatopathology, and Texas Medical Association

Disclosure: Nothing to disclose.

Catherine M Quirk, MD  Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania

Catherine M Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology

Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD  Director, Ackerman Academy of Dermatopathology, New York

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

References

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Figurate erythema. Courtesy of M. King and J. Crawford.
Targetlike erythema. Courtesy of M. King and J. Crawford.
Generalized hyperkeratosis with scaling, accentuated skin lines, and figurate erythema. Courtesy of M. King and J. Crawford.
Thick hyperkeratotic plates with hystrixlike spines. Courtesy of M. King and J. Crawford.
Sharply demarcated, figurate, hyperkeratotic plaques in a symmetric distribution. Courtesy of M. King and J. Crawford.
Figurate hyperkeratotic plaque with erythematous patches. Courtesy of M. King and J. Crawford.
Plantar keratoderma with peeling. Courtesy of M. King and J. Crawford.
Diffuse glovelike palmar keratoderma. Courtesy of M. King and J. Crawford.
 
 
 
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