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

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.

• 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.

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.^5,6,7

• 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.^{8,9,10,11,12,13,14,15}
• Several cases of erythrokeratodermia variabilis without identifiable connexin gene mutations have been observed, suggesting that other disease genes exist.^16,17

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.¹⁸

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

Other Problems to Be Considered

Progressive symmetric erythrokeratodermia (PSEK): PSEK is considered an autosomal dominant genodermatosis with a less well-defined clinical presentation than erythrokeratodermia variabilis (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 erythrokeratodermia variabilis, 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 erythrokeratodermia variabilis and the observation of both phenotypes in one family raised the question of whether PSEK and erythrokeratodermia variabilis 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 erythrokeratodermia variabilis, and the other had the features of PSEK, although the ultrastructural findings in both patients were similar.
• Sequence analysis of the erythrokeratodermia variabilis 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 erythrokeratodermia variabilis 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.^20,21 In 2006, a genetic locus for PSEK has been suggested on 21q11.2-q21.2.²²

Giroux-Barbeau erythrokeratoderma and ataxia (OMIM 133190)

Greither disease (ie, keratosis palmoplantaris transgrediens et progrediens): This is now known to be a variant of epidermolytic hyperkeratosis (bullous congenital ichthyosiform erythroderma). Two unrelated families have been described with mutations in the keratin 1 (KRT1) gene.

Erythrokeratolysis hiemalis (OMIM 148370, keratolytic winter erythema, Oudtshoorn skin)

Ichthyosis linearis circumflexa (a manifestation of Netherton syndrome)

Annular epidermolytic ichthyosis (as subtype of epidermolytic hyperkeratosis [EHK, bullous ichthyosiform erythroderma])

MEDNIK (mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratodermia) syndrome: Erythema and hyperkeratosis resembling erythrokeratodermia variabilis 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.²³ Originally, this syndrome was reported as "EKV 3 (Kamouraska type)," although that this syndromic disorder is obviously clinically and genetically distinct from erythrokeratodermia variabilis.

Histologic Findings

The histopathologic features in erythrokeratodermia variabilis include orthokeratotic hyperkeratosis, moderate-to-severe acanthosis, and papillomatosis. Although these features are nonspecific, the basket-weave hyperkeratosis may indicate erythrokeratodermia variabilis. 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

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 erythrokeratodermia variabilis (EKV).^24,25

• Systemic retinoid therapy with acitretin (Soriatane) or isotretinoin (Accutane) can induce dramatic improvement.
• Systemic retinoids are the treatment of choice for extensive or generalized erythrokeratodermia variabilis.
• The effect of acitretin or etretinate is superior to that of isotretinoin.
• 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 erythrokeratodermia variabilis usually is very low.

The use of topical agents in the management of erythrokeratodermia variabilis 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 vitamin D analogs and retinoid preparations.
• Newer synthetic retinoids, such as short-contact topical tazarotene, combined with moisturizers seem promising.²⁶
• 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

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

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 very low.

Acitretin (Soriatane)

Retinoic acid analog similar to etretinate and isotretinoin. Etretinate is the main metabolite; it has demonstrated clinical effects similar to those of etretinate. The mechanism of action is unknown.

Isotretinoin (Accutane)

Decreases sebaceous gland size and sebum production. May inhibit sebaceous gland differentiation and abnormal keratinization.
A US Food and Drug Administration–mandated registry is now in place for all individuals prescribing, dispensing, or taking isotretinoin. For more information on this registry, see iPLEDGE. This registry aims to further decrease the risk of pregnancy and other unwanted and potentially dangerous adverse effects during a course of isotretinoin therapy.

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.

Diphenhydramine (Benadryl, Benylin, Diphen, AllerMax)

For symptomatic relief of pruritus and burning caused by the release of histamine.