Published on 16/03/2015 by admin
Filed under Dermatology
Last modified 22/04/2025
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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
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.
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.
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Histopathology
Richard G. In: Richard G, ed. Molecular genetics in dermatology. Clinics in Dermatology 2005; 23: 23–32.
Summary of the clinical features and molecular genetics of EKV and other connexin disorders. The review discusses the spectrum and mechanism of disease-causing missense mutations in the connexin genes GJB3 and GJB4, which encode the gap junction proteins β-3 (connexin-31, Cx31) and β-4 (connexin-30.3, Cx30.3) associated with EKV. It also describes the mutation spectrum in other epidermal connexin genes, including GJB2 (Cx26), GJB6 (Cx30), and GJA1 (Cx43).
Van Steensel MAM, Oranje AP, van der Schroeff JG, Wagner A, van Geel M. Am J Med Genet Part A 2008; 149A: 657–61.
Mutation analysis in two patients with PSEK and three patients with EKV revealed the same G12D mutation in GJB4 (Cx30.3). All five Dutch patients shared the same haplotype over 2 Mb across the disease locus, indicating that G12D might be a Dutch founder mutation, which may manifest with features of either EKV or PSEK. Systemic treatment of an adult male patient with features of PSEK with 20–40 mg etretinate during the wintertime reportedly resulted in satisfactory symptomatic relief.
Wei S, Zhou Y, Zhang TD, Huang ZM, Zhang XB, Zhu HL, et al. Clin Exp Dermatol 2011; 36: 399–405.
None of 25 patients with PSEK were found to have a pathogenic mutation in the connexin genes GJB3 (Cx31) and GJB4 (Cx30.3), and the loricrin gene, suggesting that in the majority of cases PSEK is a disorder distinct from EKV and of currently unknown molecular cause.
Yoo S, Simzar S, Han K, Takahashi S, Cotliar R. Pediatr Dermatol 2006; 23: 382–5.
Topical short-contact (15 minutes) treatment with tazarotene (0.05% gel) once a day followed by the application of a topical corticosteroid (fluocinolone oil) on moist skin and hydrophilic ointments resulted in complete remission of hyperkeratotic plaques and erythematous patches in a 16-month-old child with EKV within 1 month. Emollients were continued during quiescent periods, and the above regimen during flares.
Tazarotene is a topical, receptor-selective retinoid.
Lacerda E, Costa MH, de Brito Caldeira J. Med Cutan Ibero Lat Am 1975; 3: 281–7.
Topical retinoic acid (0.1% cream) treatment of three patients with EKV substantially reduced hyperkeratosis. Discontinuation resulted in prompt relapse.
Ott H, Lehmann S, Poblete-Guitierrez P, Frank J. Hautarzt 2004; 10: 994–6.
A 5-year old boy with PSEK and severe palmoplantar keratoderma leading to flexural contractures on both hands was treated with topical steroids of various strength and urea without lasting improvement. Topical tretinoin 0.03% cream combined with hydrophilic ointments as well as physical therapy resulted in significant and lasting skin improvement and regression of contractures after a few weeks.
Knipe RC, Flowers FP, Johnson FR Jr, DeBusk FL, Ramos-Caro FA. Erythrokeratoderma variabilis: case report and review of the literature. Pediatr Dermatol. 1995 Mar; 12: 21–3.
Topical treatment with 0.025% triamcinolone cream and retinoic acid 0.05% cream, each for 4-6 weeks, was ineffective in a 5-month old boy with EKV.
Common JEA, O’Toole EA, Leigh IM, Thomas A, Griffiths WAD, Venning V, et al. J Invest Dermatol 2005; 125: 920–7.
Four of six EKV patients had a reportedly good to excellent response to oral acitretin when treated with 0.125–0.25 mg/kg/day. Two of these patients cleared completely, one on 20 mg acitretin daily. The remaining patients had residual hyperkeratosis, especially on the legs.
Fuchs-Telem D, Pessach Y, Mevorah B, Shirazi I, Sarig O, Sprecher E. Clin Exp Dermatol 2011; 36: 406–11.
Third report of a consanguineous family with EKV due to an autosomal recessive mutation in GJB3 (Cx31). A 14-year old boy with EKV showed dramatic improvement followed by complete resolution of hyperkeratosis with low-dose treatment (25 mg four times a week) with acitretin. The migratory erythematous patches, however, remained.
Hunzeker CM, Soldano AC, Levis WR. Dermatol Online J 2008; 14: 13.
A 51-year old woman with EKV was treated with acitretin, 25 mg/day. After 4 months, near complete clearance of hyperkeratotic plaques and erythematous patches was achieved except for hyperpigmentation, and no appreciable side effects were observed.
Singh N. Pediatr Dermatol 2010; 27: 111–13.
Low-dose treatment with oral isotretinoin at a dose of 0.5 mg/kg body weight per day along with topical emollients yielded remarkable improvement of hyperkeratotic plaques and erythema in a 2-year old boy with EKV. No significant side effects were observed during continued treatment over the next 6 months. The author concludes that low-dose therapy with isotretinoin is better tolerable, has fewer side effects and is cheaper compared to high-dose therapy.
Erbagci Z, Tuncel AA, Deniz H. J Dermatol Treat 2006; 17: 187–9.
An unusual case with onset of fixed erythrokeratoderma at 23 years of age. Topical steroids, topical PUVA for 3 months, and keratolytics (10% salicylic acid) did not yield satisfactory results. Subsequent systemic isotretinoin (0.7 mg/kg/day) combined with topical ointments containing 20% urea did not show improvement after 3 months. Acitretin (0.5 mg/kg/day) for 5 months also did not achieve a significant therapeutic response. However, sedating oral H1-antihistamines were beneficial for relief of pruritus.
Yüksek J, Sezer E, Köseoglu D, Marcoç F, Yildiz H. Jpn Dermatol Assoc J 2010; 725–7.
A female with EKV was first treated with 10 mg/day acitretin. After 1 week, PUVA therapy was added with 0.5 J/cm2 UVA twice weekly, with incremental increases by 0.5 J/cm2 UVA up to a cumulative dose of 129 J/cm2. A significant improvement of hyperkeratosis and erythema was achieved after 3 months; then PUVA was stopped, and acitretin was continued for up to 9 months. Dry lips were the only side effects observed. Follow-up after discontinued Re-PUVA was not reported.
Levi L, Beneggi M, Crippa D, Sala GP. Hautarzt 1982; 33: 605–8 (In German).
In one family with PSEK an adult patient was treated with an aromatic retinoid for 8 weeks, while her child received PUVA therapy for a total of 63 J/cm2 UVA. Both treatments were effective and reduced hyperkeratosis, but PUVA achieved superior results.
Papadavid E, Koumantaki E, Dawber RPR. J Eur Acad Dermatol Venereol 1998; 11: 180–3.
A good therapeutic response to systemic etretinate with initial dosage of 25 mg/day and maintenance dosage of 10 mg/day. Regular use of an oral H1-antihistamine was helpful in controlling the pruritus associated with the erythematous component of EKV.
Treatment of Skin Disease Comprehensive Therapeutic Strategies 4e
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Emollients
Topical keratolytics
Topical retinoids
Acitretin
Isotretinoin
PUVA
H1-antihistamines
