AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Background

Erythrokeratodermia variabilis (EKV) is a rare genetic skin disorder listed in Online Mendelian Inheritance in Man (OMIM) # 133200. EKV belongs to the clinically and genetically heterogeneous group of erythrokeratodermias.

EKV is characterized by the coexistence of 2 distinct morphologic features: hyperkeratosis and transient erythema. de Buy Wenninger recognized and described the first cases of EKV in the Netherlands in 1907. In 1925, Mendes da Costa presented a detailed clinical description of the disease in a mother and daughter, reviewed 8 similar cases that were previously published, and coined the name "erythro- et keratodermia variabilis." During the next decades, multiple case reports emerged in the Northern European literature, including a study of 33 affected members of a Dutch family and 29 affected persons in 5 generations of a Swiss family. In 1964, Barsky and Bernstein reported the first case in the American literature.

Pathophysiology

EKV is a disorder of cornification associated with noninflammatory erythema. Marked hyperkeratosis is present, probably because of an increased proliferation and disturbed differentiation of keratinocytes.

Mutations have been identified in 2 connexin genes, GJB3 encoding connexin-31 and GJB4 encoding connexin-30.3. Connexins are a family of transmembrane proteins that assemble into hexameric hemichannels and form gated intercellular gap junction channels. The finding of mutations in GJB3 and GJB4 suggests that the clinical manifestations of EKV are caused by impaired gap junctional intercellular communication or hemichannel function due to a dominant effect of mutant gap junction proteins.

Frequency

United States

This skin disorder is rare, and its accurate prevalence is not known. More than 200 cases are reported in patients with diverse genetic backgrounds. Fifty-four affected individuals from 16 families were known to the author in the United States in 2004.

Mortality/Morbidity

EKV is a chronic skin disorder without other organ manifestations; patients have a normal life expectancy. Depending on the extent and severity of EKV, the skin lesions can be severely disfiguring and have a tremendous psychosocial effect on the patients. Generalized hyperkeratosis may be associated with heat intolerance.

Race

EKV has been reported worldwide. Most cases were whites of northern and middle European origin, but EKV also occurs in African Americans and Asians.

Sex

Both sexes are affected equally.

Age

More than 50% of patients present with symptoms at birth or in the neonatal period. Approximately 90% of patients present with EKV within the first year of life. In general, onset of disease is earlier in individuals with severe disease, including generalized hyperkeratosis.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

History

• Most 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 EKV 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.

Physical

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

• Erythema
• • The erythema in EKV manifests as well-demarcated patches of variable intensity, sometimes surrounded by an anemic halo.
  • They may coalesce into large figurate patches or have a circinate or targetlike appearance (see Images 1-2).
  • They can appear on healthy skin as well as 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 EKV 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 (see Image 3).
    • Rarely, thickened plates of gray-dark brown hyperkeratosis with a spiny, hystrixlike appearance are present on the lower extremities (see Image 4).
  • 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 over the limbs, buttocks, and trunk; often, the flexures, face, and scalp are spared (see Image 5).
    • Relatively fixed lesions over knees, elbows, Achilles tendons, dorsum of the feet, and belt area are common and can persist for months or years (see Image 6).
    • 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 Images 7-8).
• Hair, nails, teeth, and mucous membranes are not involved.

Causes

• EKV 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 band 1p34-p35.
• EKV is genetically heterogeneous and caused by mutations in different genes.
• • 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 22 unrelated EKV patients and families, including 8 distinct missense mutations in GJB3 and 6 missense mutations in GJB4.
  • Several cases of EKV without identifiable connexin gene mutations have been observed, suggesting that other disease genes exist.
• Both Cx31 and Cx30.3 belong to the group of b-type connexins and are preferentially expressed in the upper, differentiated keratinocytes of human epidermis, suggesting they play a crucial role during epidermal differentiation.
• In vitro expression studies suggest that EKV mutations disturb the intracellular processing and trafficking of gap junction proteins to the plasma membrane, alter gap junction communication, and induce cell death.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Other Problems to be Considered

Progressive symmetric erythrokeratodermia (PSEK): PSEK is considered an autosomal dominant genodermatosis with a less well-defined clinical presentation than EKV. The disease causes fixed, slowly progressive, symmetric, and well-defined hyperkeratotic plaques, which predominantly appear on the extensor surface of the extremities, trunk, and face.

In contrast to EKV, no independent, migrating red patches are present, the hyperkeratosis develops on an erythematous base, and the palms and soles are affected more often. The considerable phenotypic variability of PSEK and EKV and the observation of both phenotypes in one family raised the question of whether PSEK and EKV are distinct entities or entities within the spectrum of a single disorder. The reported family involved 2 affected children of unaffected parents; one child had the features of EKV, and the other had the features of PSEK, although the ultrastructural findings in both patients were similar.

Sequence analysis of the EKV genes GJB3 (encoding Cx31) and GJB4 (encoding Cx30.3) did not reveal any mutations in 2 families and 4 sporadic cases with the PSEK phenotype, indicating that PSEK and EKV are distinct clinical entities.

A frameshift mutation in the loricrin gene (ie, 709insC) on chromosome 1q was identified in a Japanese family with PSEK-like features and mutilating palmoplantar keratoderma (ie, pseudo-ainhum), which is usually not seen in PSEK. This observation is consistent with other loricrin gene mutations in mutilating palmoplantar keratoderma with ichthyosis (Camisa-type of palmoplantar keratoderma; Vohwinkel syndrome with ichthyosis, OMIM 603324) and these disorders are now classified as loricrin keratoderma, an entity distinct from PSEK. In 2006, PSEK has been mapped to a locus on 21q11.2-q21.2 (Cui, 2006).

Giroux-Barbeau erythrokeratoderma and ataxia

Greither disease (ie, keratosis palmoplantaris transgrediens et progrediens)

Erythrokeratolysis hiemalis (ie, keratolytic winter erythema, Oudtshoorn skin)

Ichthyosis linearis circumflexa (a manifestation of Netherton syndrome)

Kamouraska erythrokeratoderma: Erythema and hyperkeratosis resembling EKV have been reported in a novel, autosomal recessive genetic syndrome observed in the Bas St-Laurent region of Quebec. Besides skin findings, patients have sensorineural hearing loss, peripheral neuropathy, psychomotor retardation, congenital chronic diarrhea, and an elevation of very long-chain fatty acids. This disorder was mapped to 7q22, and a splice site mutation in the AP1S1 gene encoding the small subunit of the AP1 complex has been identified (Saba, 2005). Originally, this syndrome was reported as "EKV 3 (Kamouraska type)," although that this syndromic disorder is obviously clinically and genetically distinct from EKV.

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Lab Studies

• The diagnosis is established on the basis of clinical features.

Histologic Findings

The histopathologic features in EKV include orthokeratotic hyperkeratosis, moderate-to-severe acanthosis, and papillomatosis. Although these features are nonspecific, the basket-weave hyperkeratosis may indicate EKV. In addition, dilated and elongated capillaries are present, with little perivascular inflammation in the papillary dermis. Severe papillomatosis with suprapapillary thinning may result in a church-spire configuration of the epidermis.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Medical Care

• The goals of the therapy are to diminish the hyperkeratosis and minimize the discomfort.
• Systemic retinoids are the treatment of choice in extensive EKV.
• • Systemic retinoid therapy with acitretin (Soriatane) or isotretinoin (Accutane) can induce dramatic improvement.
  • The use of retinoids should be considered carefully because long-term therapy is required to achieve continuing results.
  • The minimal effective dose for persons with EKV usually is low.
• The use of topical agents in the management of EKV depends on the symptoms and focuses on hydration, lubrication, and keratolysis.
• • Therapy may include the use of emollients and keratolytics, such as urea, alpha-hydroxy acids, propylene glycol, salicylic acid, and topical retinoid preparations.
  • Masking the erythematous lesions of uncovered skin with makeup and other forms of camouflage may provide a cosmetic benefit.
  • In case of pruritus and burning, mild sedative antihistamines are useful.
  • The avoidance of trauma to the skin may be also beneficial.

MEDICATION

Section 7 of 10  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Drug Category: Retinoids

Systemic retinoid therapy can induce dramatic improvement. Long-term therapy is required to achieve continuing results. The minimal effective dose for persons with EKV is usually low.

Drug Category: Antihistamines

These agents are used to prevent the histamine response in sensory nerve endings and blood vessels. They are more effective in preventing histamine response than in reversing it.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Further Outpatient Care

• Patients receiving systemic retinoid therapy should be followed up on a regular basis to monitor treatment effectiveness and adverse effects.
• Establishing a long-term relationship with patients is important in re-evaluating effectiveness of topical therapy and in directing the families to appropriate resources for social and family support.

Complications

• Complications are rare.
• Complications mainly involve the adverse effects of systemic retinoid therapy.

Prognosis

• Besides the skin, other organ systems generally are not involved.
• If properly treated, the skin manifestations of EKV can be well controlled.
• In addition, the erythematous patches may diminish as the patient ages.

Patient Education

• Patients of childbearing age should receive genetic counseling.
• Molecular diagnostic testing for mutations in the connexin genes GJB3 and GJB4 is available. The results of such analysis will allow for appropriate genetic counseling of the patient and family, particularly with respect to recurrence risk in future pregnancies.
• Triggering events, such as exposure to cold, drastic temperature changes, and mechanical irritation of the skin, should be avoided.
• Patients with generalized hyperkeratosis should be informed about the possibility of heat intolerance.
• The Foundation for Ichthyosis and Related Skin Types, F.I.R.S.T., is a patient advocacy group that offers information, educational materials, and support for patients and their families.

MULTIMEDIA

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Media file 1:  Figurate erythema. Courtesy of M. King and J. Crawford.
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Media file 2:  Targetlike erythema. Courtesy of M. King and J. Crawford.
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Media file 3:  Generalized hyperkeratosis with scaling, accentuated skin lines, and figurate erythema. Courtesy of M. King and J. Crawford.
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Media file 4:  Thick hyperkeratotic plates with hystrixlike spines. Courtesy of M. King and J. Crawford.
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Media file 5:  Sharply demarcated, figurate, hyperkeratotic plaques in a symmetric distribution. Courtesy of M. King and J. Crawford.
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Media file 6:  Figurate hyperkeratotic plaque with erythematous patches. Courtesy of M. King and J. Crawford.
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Media file 7:  Plantar keratoderma with peeling. Courtesy of M. King and J. Crawford.
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Media file 8:  Diffuse glovelike palmar keratoderma. Courtesy of M. King and J. Crawford.
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REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

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Article Last Updated: Feb 27, 2007