Erythrokeratodermia Variabilis et Progressiva

Updated: May 17, 2022

Author: Gabriele Richard, MD, FACMG; Chief Editor: Dirk M Elston, MD

Overview

Practice Essentials

The clinically and genetically heterogeneous group of erythrokeratodermas encompasses several rare genetic skin disorders, including autosomal dominant erythrokeratodermia variabilis (EKV) and progressive symmetric erythrokeratoderma (PSEK) (Online Mendelian Inheritance in Man [OMIM] # 133200), as well as autosomal dominant spinocerebellar ataxia with erythrokeratodermia (Giroux-Barbeau syndrome; spinocerebellar ataxia type 34 [SCA34]) (OMIM # 133190). The skin lesions of EKV and PSEK show many similarities, and a small subset of patients with features previously considered to be PSEK share the underlying cause of EKV. Therefore, it was proposed to classify this disorder as erythrokeratodermia variabilis et progressiva (EKVP).[1] Nevertheless, PSEK and overlapping forms of erythrokeratoderma do exist as genetically distinct entities from EKVP.

EKVP is characterized by the coexistence of 2 distinct morphologic features: hyperkeratosis and transient erythema, albeit 1 of these features may predominate. de Buy Wenninger recognized and described the first cases of erythrokeratodermia variabilis in the Netherlands in 1907.[2] In 1925, Mendes da Costa presented a detailed clinical description of the disease in a mother and daughter, reviewed eight similar cases that were previously published, and coined the name "erythro- et keratodermia variabilis."[3] 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.[4] In 1964, Barsky and Bernstein reported the first case in the American literature.[5] The first family in which affected members had features of either EKV or PSEK was reported in 1991.[6]

Causes

Erythrokeratodermia variabilis et progressiva (EKVP) is usually inherited in an autosomal dominant pattern with nearly complete penetrance. A respectable number of sporadic cases and a few families with autosomal recessive inheritance have been documented.

In large families, the disorder was mapped to a connexin gene cluster at band 1p34.3.

EKVP is genetically heterogeneous and caused by mutations in different genes.[7, 8, 9, 10]

Diagnostics

The diagnosis of erythrokeratodermia variabilis et progressiva (EKVP) is established on the basis of clinical features. Molecular genetic testing for sequence variants in the GJB3, GJB4, and GJA1 genes is available (also as next-generation sequencing panel) and expected to yield a positive result in at least two thirds of patients.

Treatment

Topical management with emollients and and keratolytic agents may be beneficial. Systemic retinoids are the treatment of choice in extensive erythrokeratodermia variabilis et progressiva (EKVP).[11, 12]

Prognosis

Erythrokeratodermia variabilis et progressiva (EKVP) is a chronic skin disorder without other organ manifestations; patients have a normal life expectancy. If properly treated, the skin manifestations of EKVP can be well controlled. Depending on the extent and severity of erythrokeratodermia variabilis, the skin lesions also can be severely disfiguring and have a tremendous psychosocial effect on the patients. In addition, the erythematous patches may diminish as the patient ages. Generalized hyperkeratosis may be associated with heat intolerance.

Complications

Complications are rare with erythrokeratodermia variabilis et progressiva (EKVP). Complications mainly involve the adverse effects of systemic retinoid therapy. Heat intolerance may occur in individuals with generalized hyperkeratosis.

Patient education

Patients of childbearing age should receive genetic counseling. Molecular diagnostic testing for mutations in the connexin genes GJB3, GJB4, and GJA1 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.

Pathophysiology

Erythrokeratodermia variabilis et progressiva (EKVP) is an inherited disorder of cornification associated with noninflammatory erythema. Marked hyperkeratosis is present, probably because of an increased proliferation and disturbed differentiation of keratinocytes.

Approximately two thirds of cases of EKVP are caused by heterozygous missense variants in the connexin genes GJB3, encoding connexin-31 (Cx31), and GJB4, encoding connexin-30.3 (Cx30.3). In a small subset, pathogenic missense changes in the GJA1 gene encoding connexin-43 (Cx43) have been reported.[7] 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, GJB4, and GJA1 suggests that the clinical manifestations of EKVP are caused by impaired gap junctional intercellular communication or augmented hemichannel function owing to a dominant effect of mutant gap junction proteins.[13, 14]

Epidemiology

Erythrokeratodermia variabilis et progressiva (EKVP) 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.

EKVP has been reported worldwide. Most cases were whites of Northern and Middle European origin, but erythrokeratodermia variabilis also occurs in African Americans and Asians, particularly Chinese families of Han ethnicity.[15] Both sexes are affected equally.

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

Presentation

History

Most affected individuals with erythrokeratodermia variabilis et progressiva (EKVP) present initially 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 red or yellow-brown, thickened, rough, hyperkeratotic plaques on the extremities and trunk in a symmetrical distribution pattern. These hyperkeratotic plaques are relatively stable and last for months to years, but they can also clear completely. In some individuals, prominent hypertrichosis confined to the hyperkeratotic plaques may be present.[16] Rarely, generalized or spiny hyperkeratosis may occur. At least 50% of individuals with EKVP develop diffuse palmoplantar keratoderma, ranging from mild peeling to severe, glove-like hyperkeratosis.

After the disorder 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 Examination

The hallmark of erythrokeratodermia variabilis et progressiva (EKVP) 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 EKVP may constantly change their appearance and vary among patients.

Erythema

The erythema manifests as well-demarcated patches of variable intensity, sometimes surrounded by an anemic halo. They may coalesce into large figurate patches, as shown in the first image below, or have a circinate or targetlike appearance, as shown in the second image below.

Figurate erythema. Courtesy of M. King and J. Crawford.

Targetlike erythema. Courtesy of M. King and J. Crawford.

Predominance of circinate erythematous patches has been reported in patients with GJB4 (Cx30.3) mutations and has also been described as erythrokeratodermia variabilis with erythema gyratum repens–like lesions.

Erythema can appear on healthy skin and 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 erythrokeratodermia variabilis 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, as depicted below.

Generalized hyperkeratosis with scaling, accentuated skin lines, and figurate erythema. Courtesy of M. King and J. Crawford.

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

Thick hyperkeratotic plates with hystrixlike spines. Courtesy of M. King and J. Crawford.

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.

Sharply demarcated, figurate, hyperkeratotic plaques in a symmetric distribution. Courtesy of M. King and J. Crawford.

Relatively fixed lesions over knees, elbows, Achilles tendons, dorsum of the feet, and belt area, as depicted below, are common and can persist for months or years.

Figurate hyperkeratotic plaque with erythematous patches. Courtesy of M. King and J. Crawford.

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 the images below.

Plantar keratoderma with peeling. Courtesy of M. King and J. Crawford.

Diffuse glovelike palmar keratoderma. Courtesy of M. King and J. Crawford.

Hair, nails, teeth, and mucous membranes are not involved.

Mosaic EKVP

Rarely, a mosaic form of EKVP has been observed, clinically presenting as an inflammatory linear verrucous epidermal nevus (ILVEN). A postzygotic pathogenic variant in the GJA1 gene has been reported in 1 such case of somatic mosaicism.[17]

Causes

Three disease genes have been identified, GJB3 encoding connexin 31 (Cx31), GJB4 encoding connexin 30.3 (Cx30.3), and GJA1 encoding connexin 43 (Cx43). To date, pathogenic connexin gene mutations have been reported in at least 49 unrelated patients and families, including at least 17 distinct missense variants in GJB3, 12 missense variants in GJB4, and 4 in GJA1.[7, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 15]

Several cases of erythrokeratodermia variabilis without identifiable connexin gene mutations have been observed, suggesting that other disease genes may exist.[42, 43, 44]

Both Cx31 and Cx30.3 are beta-type connexins that are preferentially expressed in the upper, differentiated keratinocytes of human epidermis, suggesting they play a crucial role during epidermal differentiation.[45] Cx43 is an alpha-type connexin that is ubiquitously expressed, including throughout the epidermis, and plays a critical role during wound healing of the skin.

In vitro expression studies suggest that pathogenic sequence variants causing EKVP disturb the intracellular processing and trafficking of gap junction proteins to the plasma membrane and either alter gap junction communication between cells or augment connexin hemichannel function, which may induce cell death.[46] For example, the connexin-31 variant Cx31R42P has been associated with constitutively active hemichannels, resulting in cell death; understanding such pathophysiology may help in the discovery of novel therapeutic strategies in the future.[27]

DDx

Diagnostic Considerations

Also consider the following:

Progressive symmetric erythrokeratodermia (PSEK): PSEK is considered an autosomal dominant or recessive 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 EKV, no independent, migrating red patches are present, the hyperkeratosis develops on an erythematous base, and the palms and soles are affected more often. There is considerable phenotypic variability of PSEK and erythrokeratodermia variabilis. Moreover, EKV and PSEK have been observed within the same family ^[6], and the same disease-causing GJB4 (Connexin 30.3) mutation (p.Gly12Asp) has been reported in patients diagnosed with EKV or PSEK. ^[47]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 mutations in the connexin genes and likely represent a heterogeneous group of other disorders that remain to be better defined on a clinical and molecular level. ^{[42, 43, 44]}A frameshift mutation in the LOR gene encoding loricrin (ie, 709insC) on band 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 LOR 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. ^{[48, 49]}In 2006, a genetic locus for PSEK has been suggested on 21q11.2-q21.2. ^[50]An autosomal recessive form of PSEK has been reported in 4 affected members of a Pakistani family who had symmetric hyperkeratotic plaques without sharp borders, palmoplantar keratoderma, hyperkeratotic pads over interdigital joints, thick nails but normal hair, and all were homozygous for a frameshift variant in the KRT83 gene. This keratin gene is expressed mainly in hair but also in skin, and heterozygous missense variants typically cause monilethrix, an autosomal dominant hair shaft disorder. ^[51]
Spinocerebellar ataxia and erythrokeratoderma (type Giroux-Barbeau; OMIM 133190): This disorder was originally described in a large French-Canadian pedigree. Affected individuals manifested during childhood with symmetrical, well-demarcated, fleeting erythematous patches and scaling or hyperkeratotic plaques on the dorsum of the hands and feet and on limbs. While the skin lesions disappear in the third decade of life, progressive gait ataxia due to cerebellar atrophy manifests in the fourth and fifth decades. Linkage studies and exome sequencing uncovered a pathogenic missense variant (ie, L168F) in the ELOVL4 gene that completely co-segregates with the disorder. ELOVL4 encodes an enzyme of the elongase family responsible for the elongation of very long-chain fatty acids, which are crucial for peroxisome β-oxidation and formation of the skin barrier. ^{[1, 52]}
Greither disease (ie, keratosis palmoplantaris transgrediens et progrediens): This is now known to be a variant of epidermolytic ichthyosis (aka epidermolytic hyperkeratosis, EHK, 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 ichthyosis [epidermolytic hyperkeratosis, EHK, bullous ichthyosiform erythroderma])
NIPAL4-related autosomal recessive congenital ichthyosis (ARCI): A homozygous missense variant in the NIPAL4 gene was reported in 2 siblings from a consanguineous family, who had typical features for EKVP but no sequence variants in GJB3 or GJB4. ^[53]
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. ^[54]Originally, this syndrome was reported as "EKV 3 (Kamouraska type)," although that this syndromic disorder is obviously clinically and genetically distinct from erythrokeratodermia variabilis.
Severe dermatitis, multiple allergies, and metabolic wasting (SAM) syndrome: EKV-like skin features, such as erythematous to brown, circumscribed, well-demarcated plaques have been reported in several patients with SAM syndrome due to underlying bi-allelic desmoglein 1 ( DSG1) mutations. Other features included severe palmoplantar keratoderma and food allergies. Further studies revealed that desmoglein 1 plays a role in Cx43 stabilization and gap junction function in the epidermis, thus explaining the overlapping clinical phenotypes between EKVP and SAM syndrome. ^[55]

Differential Diagnoses

Annular epidermolytic ichthyosis
Ichthyosis linearis circumflexa (Netherton syndrome)
Plaque Psoriasis
Progressive symmetric erythrokeratoderma (PSEK)
Severe dermatitis, multiple allergies, and metabolic wasting (SAM) syndrome
Spinocerebellar ataxia and erythrokeratoderma
Trichorrhexis Invaginata (Netherton Syndrome or Bamboo Hair)

Workup

Histologic Findings

The histopathologic features in erythrokeratodermia variabilis et progressiva (EKVP) 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.

Treatment

Medical Care

Systemic retinoid therapy with acitretin (Soriatane) or isotretinoin (Accutane) can induce dramatic improvement.[56] 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 EKVP usually is very low.

The use of topical agents in the management 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.[57] 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 H1 antihistamines are useful. Anecdotally, narrowband ultraviolet B has been beneficial in the treatment of EKVP.

The avoidance of trauma to the skin may be also beneficial.

Long-Term Monitoring

Erythrokeratodermia variabilis et progressiva (EKVP) 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. Careful monitoring for adverse effects of retinoid therapy is necessary.

Medication

Retinoid-like Agents

Class Summary

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

Acitretin (Soriatane)

Acitretin is a 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. For EKVP, the effect of acitretin or etretinate is superior to that of isotretinoin. The minimal effective dose for persons with EKVP usually is very low. Treatment may be started at a very low dose (10 mg/day or less) and adjusted based on the therapeutic effect, which begins 1-2 weeks after initiating systemic retinoid therapy. The use of retinoids should be considered carefully because long-term therapy is required to achieve continuing results.

Isotretinoin (Amnesteem, Claravis, Sotret)

Isotretinoin decreases sebaceous gland size and sebum production. It 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. For EKVP, the effect of acitretin or etretinate is superior to that of isotretinoin.

The minimal effective dose for persons with EKVP usually is very low. Treatment may be started at low dose (0.5 mg/kg/day) and adjusted based on therapeutic effect, which begins 1-2 weeks after initiating systemic retinoid therapy. The use of retinoids should be considered carefully because long-term therapy is required to achieve continuing results.

Antihistamines, 1st Generation

Class Summary

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, Aler-Dryl, Diphen, AllerMax)

Diphenhydramine is used for symptomatic relief of pruritus and burning caused by the release of histamine.

Cyproheptadine

Cyproheptadine is used for the symptomatic relief of allergic symptoms caused by histamine released in response to allergens and skin manifestations.

Hydroxyzine (Vistaril)

Hydroxyzine antagonizes H1 receptors in the periphery. It may suppress histamine activity in the subcortical region of the CNS.

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Erythrokeratodermia Variabilis et Progressiva

Overview

Practice Essentials

Causes

Diagnostics

Treatment

Prognosis

Complications

Patient education

Pathophysiology

Epidemiology

Presentation

History

Physical Examination

Erythema

Hyperkeratosis

Mosaic EKVP

Causes

DDx

Diagnostic Considerations

Differential Diagnoses

Workup

Histologic Findings

Treatment

Medical Care

Long-Term Monitoring

Medication

Retinoid-like Agents

Class Summary

Acitretin (Soriatane)

Isotretinoin (Amnesteem, Claravis, Sotret)

Antihistamines, 1st Generation

Class Summary

Diphenhydramine (Benadryl, Aler-Dryl, Diphen, AllerMax)

Cyproheptadine

Hydroxyzine (Vistaril)

Contributor Information and Disclosures

References