Dermatology

Erythrokeratodermia variabilis (erythrokeratodermia figurate Variabilis, erythrokeratoderma congenitals progressiva symmetrica, erythrokeratoderma progressive)

Are You Confident of the Diagnosis?

Erythrokeratodermia variabilis (EKV) also called erthrokeratodermia figurate variabilis, erythrokeratoderma congenitals progressiva symmetrica, erythrokeratoderma progressive, is a rare genodermatosis characterized by variable migratory erythematous and relatively stable keratotic lesions.

What you should be alert for in the history

The patients initially present with lesions that are most prevalent during childhood and may become less frequent as the patient ages. After infancy and childhood, it seems to stabilize after puberty and slowly regresses when the patient is getting older. Improvement and periodic clearing of the skin are not unusual. Stress, sudden temperature changes, cold, mechanical friction and sun esposure can trigger skin lesions.

Characteristic findings on physical examination

EKV is characterized by distinctive lesions with two morphologic features. The erythematous component is manifested by bright red to brownish, sharply marginated patches, variable in intensity and shape, which may change their distribution patterns within minutes, hours, or days, and be aggravated by exposure to wind, cold, heat, or emotional disturbance.The other diagnostic feature is the independent occurrence of yellowish-brown, sharply marginated hyperkeratotic plaques with a “greasy” scale.

These hyperkeratotic lesions may develop on previously erythematous areas or normal skin. The erythematous and hyperkeratotic lesions may occur anywhere on the body, but the most common sites of involvement are the extensor surfaces of the limbs, face, buttocks, and axillae. One of the most striking characteristics of this disease is the variablility of the lesions in configuration and localization (Figure 1, Figure 2, Figure 3).

Figure 1.

Before treatment, red patches and plaques with scales on back and buttocks.

Figure 2.

Before treatment, red patches and plaques with scales on both upper extremities.

Figure 3.

Before treatment, red patches and plaques with scales on both lower extremities.

About 50% of EKV patients have palmoplantar keratoderma (PPK). There is no disturbance in the growth of hair or teeth. Nail dystrophy has been reported. Mucous membranes are not involved.

Expected results of diagnostic studies

The histologic features of EKV by light microscopy are not diagnostic, but may be supportive in the proper clinical setting. Marked orthohyperkeratosis and parakeratosis of epidermis, a granular zone of two or three cell layers, irregular acanthosis with suprapapillary thinning and papillomatosis may be seen. The dermis is slightly edematous and infiltrated with non-specific inflammatory cells. Electron microscopy shows deceased number of keratinosome.

The disorder has been mapped to chromosome 1 p35.1, but is genetically heterogeneous. EKV may be caused by pathogenic mutations in one of two neighbouring connexin genes, GJB3 and GJB4, encoding the gap junction proteins CX31 and CX30.3, respectively.

Diagnosis confirmation

EKV and progressive symmetric erythokeratodermia(PSEK) have overlapping features. Both are inherited as an autosomal dominant trait, both usually present within the first year of life, and both have well-defined erythema. But they have been regarded as distinct diseases in that the lesions of PSEK are fixed, slowly progressive, symmetric and well-defined hyperkeratotic plaques.

Netherton syndrome is a rare autosomal recessive genodermatosis characterized by congenital ichthyosiform erythroderma, trichorrhexis invaginata, and atopic diathesis. Genetic testing of SPINK5 helps distinguish Netherton syndrome from EKV.

Erythema annulare centrifugum (EAC) is charaterized by a trailing scale (or a deeper nonscaling form) but it tends to spread peripherally while clearing centrally, with no hyperkeratosis .

Who is at Risk for Developing this Disease?

EKV usually presents at birth or during infancy. It has been reported worldwild, especially in northen and middle Europe. The morbidity of EKV is equal between male and female.

What is the Cause of the Disease?

Etiology

Pathophysiology

The pathogenesis of EKV is not entirely clear, but morphologic observations suggest EKV is a retention-type hyperkeratosis with abnormalities primarily involving the epidermis. A reduction in the number of keratinosomes might explain the decreased shedding of the stratum corneum.

In about two-thirds of EKV patients, mutation have been identified in two connexin genes, ie, GJB3 encoding connexin-31 and GJB4 encoding connexin-30.3. Connexins are a family of transmembrane proteins that form gated intercellular gap junction channels. The finding of mutitions in GJB3 and GJB4 suggests that the clinical manifestations of EKV are caused by impaired gap junctional intercellular communication or hemichannel function.

Systemic Implications and Complications

EKV can be complicated with neuropathies such as deafness, peripheral nerve disease, weakening of tendon reflex, ataxia of cerebellum.

Treatment Options

No specific therapy for EKV is currently available (Table I).

Table I.

Treatment options for erythrokeratodermia variabilis
Treatment Content
Topical  Emollients Keratolytics Retinoids
systemic Retinoic acidsAntihistamines
physical Psoralen plus ultraviolet A (PUVA)

Optimal Therapeutic Approach for this Disease

Mild, Localized Lesions

Treatment is focused on hydation, moisterization and keratolysis. Emollient with vaseline lanolin, stearyl-alcohol, cetyl-alcohol and isopropyl-palmitic twice a day is effective in some patients, but for most patients, keratolytics are necessory. A combination of lactic acid 5 or 12% and urea 10% emollient is effective, although is limtited by its irritation, especially for children. Other agents, such as hydroxy acid, salicylic acid, propylene glycol and glycolic acid or their combination are also effective.

Generalized Keratotic Lesions

Systemic retinoids are suitable for widespread or generalized keratotic lesions (Figure 6, Figure 7, Figure 8), although retinoids and its derivatives are effective in some patients but not all. The effect of isotretinoin or acitretin is achieved by sustained long-term use, although adverse reactions may occur, especially in children.

Figure 4.

Histology of EKV.

Figure 5.

Electron microscopy shows decreased number of keratinosomes.

Figure 6.

After oral Arotinoid ethylester 30mg daily for 6 weeks.

Figure 7.

After oral Arotinoid ethylester 30mg daily for 6 weeks.

Figure 8.

After oral Arotinoid ethylester 30mg daily for 6 weeks.

In comparison with the other retinoids available so far, acitretin is the first choice in the treatment of EKV. Usually acitretin 0.5mg-1mg /kg daily is initiated, given as a single dose with the main meal. Improvement will be observed after 2-4 weeks. The minimal effective dose is very variable, ranging from 50mg to 10mg daily. Almost all patients will experience rapid relapse when the therapy is discontinuted.

Antihistamines

Antihistamines should be used when the patient experiences pruritus. The sedating antihistamines diphenhydramine and hydroxizine are good first agents.

Psoralen plus Ultraviolet A (PUVA)

PUVA (total amount 63J/cm2 UVA) is effective as reported.

Patient Management

It is important to establish a long-term relationship with patients and their families to monitor progress and help secure appropriate resources for social and family support. Patients should avoid exposure to exposure to cold, drastic temperature changes, and mechanical irritation of skin. For patients on systemic retinoids, it is essential to monitor treatment effectiveness and adverse effects. Genetic counseling should be provided for patients of childbearing age.

Unusual Clinical Scenarios to Consider in Patient Management

Genetic determination is a clinical conundrum for these patients because genetic determination is not a routinely administered clinical test , and because not all patients with EKV have gene mutions. It is important to do the molecular diagnostic testing for mutations in the connexin gene GJB3 and GJB4.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.

Recently a familial form of EKV has been described without the GJB3 or GJB4 mutations. These patients had pustular lesions to go along with the other clinical findings.

What is the Evidence?

Common, JE, O'Toole, EA, Leigh, IM, Thomas, A, Griffiths, WA, Venning, V. "Clinical and genetic heterogeneity of erythrokeratoderma variabilis". J Invest Dermatol. vol. 125. 2005. pp. 920-7.

(Although EKV has been shown to be associated with connexin 30.3 or 31 gene mutations, this study demonstrates the heterogeneous natuere of the disease.)

Erbagci, Z, Tuncel, AA, Deniz, H. "Erythrokeratodermia variabilis with adult onset: report of a sporadic case unresponsive to systemic retinoid". J Dermatol Treat. vol. 17. 2006. pp. 187-9.

(EKV begins mostly at birth or within the first year of life. This article present a sporadic case with adult onset which was unusually resistant to both isotretinoin and acitretin.)

Rapparport, P, Goldes, J, Goltz, RW. "Erythrokeratodermia treated with isotretinoin: a clinical,histological and ultra-structural study". Arch Dermatol. vol. 122. 1986. pp. 441-5.

(This article described the clinical, histological and ultra-structural features of a 30-year-old woman with EKV treated with isotretinoin.)

Vandersteen, PR, Muller, SA. "Erythrokeratodermia variabilis. An enzyme, histochemical and ultrastructural study". Arch Dermatol. vol. 105. 1971. pp. 562-70.

(A study on enzyme, histochemical and ultra-structural features of EKV.)

Jurecka, W. "Erythrokeratoderma variabilis". Arch Dermatol. vol. 122. 1986. pp. 1356.

(This article reviewed the epidemiologic character and summarized the clinical and histologic features of EKV.)

Niemi, KM, Kanerva, L. "Histological and ultrastructural study of a family with erythrokeratoderma progressiva symmetrica". J Cutan Pathol. vol. 20. 1993. pp. 242-9.

(This work examined a family with four members in three succeeding generations suffering from severe erthrokeratodermia progressiva symmetrica, and described the histological and ultra-structural features of the disease.)

Plantard, L, Huber, M, Macari, F, Meda, P, Hohl, D. "Molecular interation of connexin 30.3 and connexin 31 suggests a dominant-negative mechanism associated with erythrokeratodermia variabilis". Hum Mol Genet. vol. 12. 2003. pp. 3287-94.

(This research focuses on molecular interaction of connexin 30.3 and connexin 31. The interaction provides new insights into epidermal connexin synthesis and polymerization, also allows a novel molecular explanation for the similarity of EKV phenotypes.)

Arita, K, Akiyama, M, Tsuji, Y, Onozuka, T, Onozuka, T, Shimizu, H. "Erythrokeratoderma variabilis without connexin 31 or connexin 30.3 gene mutations: immunohistological, ultrastructural and genetic studies". Acta Derm Venereol. vol. 83. 2003. pp. 266-70.

(EKV is a rare congenital disoeder which has recently been connected with connexin 30.3 or 31 gene mutations. This work presents a 9-month-old Japanese girl who exhibited the typical clinical features of the disease but carried no gene mutations.)

Rogers, M. "Erythrokeratodermas: A classification in a state of flux". Australasian J Dermatol. vol. 46. 2005. pp. 127-43.

(The classification of progressive symmetric erythrokeratoderma has becomeunclear, since the existence of the diseaseas a distinct entity is under question.)

Laudau, M, Cohen-Bar-Dayan, M, Hohl, D, Ophir, J, Wolf, CR, Gat, A. "Erythrokeratodermia variabilis with erythema gyratum repens-like lesions". Pediatric Dermatol. vol. 19. 2002. pp. 285-92.

(This paper described the clinical, laboratory and histologic findings of a large pedigree with EKV and erythema gyratum repens-like lesions.)

Li, Zhang, Wei, Huo, Xing-hua, Gao, Lei, Ma, Yuhong, Xiu, Song, Zheng. "Familial erythrokeratodermia variabilis with pustular lesions:A new variant". Acta Derm Venereol. vol. 90. 2010. pp. 274-78.

(This article reported a Chinese family with EKV. Five out of 30 patients noted episodes of pustule-like lesions during their disease course. These unusual presentations may suggest a new phenotype of EKV.)

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