Erythrokeratodermas

Published on 16/03/2015 by admin

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Erythrokeratodermas

Gabriele Richard

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

image

Erythrokeratodermas are a clinically and genetically heterogeneous group of rare inherited disorders of cornification characterized by two distinct morphologic features: localized hyperkeratosis, and erythema. The hallmark of erythrokeratodermia variabilis (EKV) is the seemingly independent occurrence of transient, figurate erythema and hyperkeratosis, which can be localized or generalized. Progressive symmetric erythrokeratoderma (PSEK) is characterized by fixed, slowly progressive, symmetric and well-defined hyperkeratotic plaques with underlying erythema, predominantly on the extensor surface of the extremities, on the trunk, and on the face. EKV and PSEK have been observed within the same family, and the same disease-causing GJB4 (Connexin 30.3) mutation has been reported in patients with EKV and PSEK. These findings indicate that a subset of PSEK cases belong to the clinical spectrum of EKV. However, many other PSEK cases do not have identifiable connexin gene mutations and likely represent a heterogeneous group of other disorders that remain to be better defined on a clinical and molecular level.

Management strategy

Erythrokeratodermas are heritable, chronic disorders that often require lifelong treatment. Management depends on the severity and extent of hyperkeratosis, which may vary over time and from patient to patient. The spectrum may range from fixed hyperkeratotic plaques over the knees and elbows to generalized hyperkeratosis with accentuated skin markings and peeling, or thickened plates with a spiny, hystrix-like appearance.

The topical management of erythrokeratodermas remains a therapeutic cornerstone, albeit it can be disappointing in some cases. Topical treatment of patients with mild, localized hyperkeratosis is symptomatic and focuses on hydration, lubrication, and keratolysis. Whereas in some patients emollients such as petrolatum twice daily may suffice, most patients require topical treatment with keratolytic agents. Lactic acid (6–12%) and urea applied once or twice daily in combination with emollients are effective, although their use may be limited, especially in children, because of irritation. Other α-hydroxy acids, salicylic acid (3–6%), propylene glycol, glycolic acid (11%), topical vitamin D analogs, or combinations of these are alternative treatment options. Topical treatment with retinoids and derivatives has been successful in some patients (especially with EKV) but ineffective in others. Regimens with newer synthetic retinoids, such as short-contact topical tazarotene therapy combined with moisturizers, seems promising in EKV. In addition, avoidance of trauma to the skin, such as sudden temperature changes, friction, and mechanical irritation, may be beneficial.

Systemic retinoids are the treatment of choice in erythrokeratodermas with extensive or generalized skin involvement. Although they are highly effective in EKV, the therapeutic response in PSEK is less satisfactory. As is the case for other disorders of cornification, the effects of acitretin or etretinate are superior to those of systemic isotretinoin. It seems advantageous to start at low doses of acitretin for 3–6 weeks, and then to gradually increase the dose until the desired therapeutic effect is achieved. The minimal effective maintenance dose for patients with EKV is usually lower than for patients with PSEK. Both morphologic components respond well to retinoid treatment, resulting in rapid and dramatic improvement or clearing of the hyperkeratosis and significant moderation of the erythema. In some patients with EKV the erythematous component may be completely suppressed. Nevertheless, the use of retinoids should always be considered carefully, as chronic therapy is required to achieve continuing results, and long-term side effects, especially in children, may ensue. In some cases, intermittent cycles of systemic retinoid treatment may be considered to balance between beneficial therapeutic and adverse effects. Anecdotally, PUVA therapy alone or combined with acitretin (Re-PUVA) has been beneficial in the treatment of PSEK.

The variable erythema in EKV often results in cosmetic concerns, which can be limited by masking uncovered skin with make-up and camouflage. Serious discomfort due to burning and pruritus, which may accompany the variable erythema in some patients, can be therapeutically challenging. If systemic aromatic retinoid therapy alone fails to reduce or suppress erythema and the associated burning and itching sensations, symptomatic relief has been achieved in anecdotal cases with systemic therapy using sedating H1-antihistamines.

Specific investigations

First-line therapies

imageEmollients E
imageTopical keratolytics E
imageTopical retinoids E

Second-line therapies

imageAcitretin C
imageIsotretinoin E

Third-line therapies

imagePUVA E
imageH1-antihistamines E

[/level-membership-for-dermatology-category][not-level-membership-for-dermatology-category]

Erythrokeratodermas

Gabriele Richard

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

image

Erythrokeratodermas are a clinically and genetically heterogeneous group of rare inherited disorders of cornification characterized by two distinct morphologic features: localized hyperkeratosis, and erythema. The hallmark of erythrokeratodermia variabilis (EKV) is the seemingly independent occurrence of transient, figurate erythema and hyperkeratosis, which can be localized or generalized. Progressive symmetric erythrokeratoderma (PSEK) is characterized by fixed, slowly progressive, symmetric and well-defined hyperkeratotic plaques with underlying erythema, predominantly on the extensor surface of the extremities, on the trunk, and on the face. EKV and PSEK have been observed within the same family, and the same disease-causing GJB4 (Connexin 30.3) mutation has been reported in patients with EKV and PSEK. These findings indicate that a subset of PSEK cases belong to the clinical spectrum of EKV. However, many other PSEK cases do not have identifiable connexin gene mutations and likely represent a heterogeneous group of other disorders that remain to be better defined on a clinical and molecular level.

Management strategy

Erythrokeratodermas are heritable, chronic disorders that often require lifelong treatment. Management depends on the severity and extent of hyperkeratosis, which may vary over time and from patient to patient. The spectrum may range from fixed hyperkeratotic plaques over the knees and elbows to generalized hyperkeratosis with accentuated skin markings and peeling, or thickened plates with a spiny, hystrix-like appearance.

The topical management of erythrokeratodermas remains a therapeutic cornerstone, albeit it can be disappointing in some cases. Topical treatment of patients with mild, localized hyperkeratosis is symptomatic and focuses on hydration, lubrication, and keratolysis. Whereas in some patients emollients such as petrolatum twice daily may suffice, most patients require topical treatment with keratolytic agents. Lactic acid (6–12%) and urea applied once or twice daily in combination with emollients are effective, although their use may be limited, especially in children, because of irritation. Other α-hydroxy acids, salicylic acid (3–6%), propylene glycol, glycolic acid (11%), topical vitamin D analogs, or combinations of these are alternative treatment options. Topical treatment with retinoids and derivatives has been successful in some patients (especially with EKV) but ineffective in others. Regimens with newer synthetic retinoids, such as short-contact topical tazarotene therapy combined with moisturizers, seems promising in EKV. In addition, avoidance of trauma to the skin, such as sudden temperature changes, friction, and mechanical irritation, may be beneficial.

Systemic retinoids are the treatment of choice in erythrokeratodermas with extensive or generalized skin involvement. Although they are highly effective in EKV, the therapeutic response in PSEK is less satisfactory. As is the case for other disorders of cornification, the effects of acitretin or etretinate are superior to those of systemic isotretinoin. It seems advantageous to start at low doses of acitretin for 3–6 weeks, and then to gradually increase the dose until the desired therapeutic effect is achieved. The minimal effective maintenance dose for patients with EKV is usually lower than for patients with PSEK. Both morphologic components respond well to retinoid treatment, resulting in rapid and dramatic improvement or clearing of the hyperkeratosis and significant moderation of the erythema. In some patients with EKV the erythematous component may be completely suppressed. Nevertheless, the use of retinoids should always be considered carefully, as chronic therapy is required to achieve continuing results, and long-term side effects, especially in children, may ensue. In some cases, intermittent cycles of systemic retinoid treatment may be considered to balance between beneficial therapeutic and adverse effects. Anecdotally, PUVA therapy alone or combined with acitretin (Re-PUVA) has been beneficial in the treatment of PSEK.

The variable erythema in EKV often results in cosmetic concerns, which can be limited by masking uncovered skin with make-up and camouflage. Serious discomfort due to burning and pruritus, which may accompany the variable erythema in some patients, can be therapeutically challenging. If systemic aromatic retinoid therapy alone fails to reduce or suppress erythema and the associated burning and itching sensations, symptomatic relief has been achieved in anecdotal cases with systemic therapy using sedating H1-antihistamines.

Specific investigations

Connexin disorders of the skin.
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