Erythrokeratoderma variabilis=تقرن الجلد الاحمراري المتباين |
atlas of dermatology - E |
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Erythrokeratodermia variabilis
Erythrokeratodermia variabilis (EKV) is a rare genetic skin disorder listed in Online Mendelian Inheritance in Man (OMIM) # 133200. Erythrokeratodermia variabilis belongs to the clinically and genetically heterogeneous group of erythrokeratodermas. Erythrokeratodermia variabilis is characterized by the coexistence of 2 distinct morphologic features: hyperkeratosis and transient erythema. de Buy Wenninger recognized and described the first cases of erythrokeratodermia variabilis in the Netherlands in 1907.1 In 1925, Mendes da Costa presented a detailed clinical description of the disease in a mother and daughter, reviewed 8 similar cases that were previously published, and coined the name "erythro- et keratodermia variabilis."2 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.3 In 1964, Barsky and Bernstein reported the first case in the American literature.4 PathophysiologyErythrokeratodermia variabilis 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. In approximately two thirds of erythrokeratodermia variabilis patients, mutations have been identified in 2 connexin genes, GJB3 encoding connexin-31 and GJB4 encoding connexin-30.3. 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 and GJB4 suggests that the clinical manifestations of erythrokeratodermia variabilis are caused by impaired gap junctional intercellular communication or hemichannel function due to a dominant effect of mutant gap junction proteins.
HistoryMost erythrokeratodermia variabilis patients initially present 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 yellow-brown, thickened, rough, hyperkeratotic plaques on the extremities and trunk. These hyperkeratotic plaques are relatively stable and last for months to years, but they can also clear completely. After erythrokeratodermia variabilis 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
The localized form is characterized by sharply demarcated, brownish, hyperkeratotic plaques with figurate outlined borders.
CausesErythrokeratodermia 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
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 ConsideredProgressive 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.
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 FindingsThe 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 CareThe 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
The use of topical agents in the management of erythrokeratodermia variabilis depends on the symptoms and focuses on hydration, lubrication, and keratolysis.
MedicationThe goals of pharmacotherapy are to reduce morbidity and prevent complications. RetinoidsSystemic 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. Adult25 or 50 mg/d PO initially; given as single dose with main meal; 25-50 mg/d maintenance; terminate therapy when lesions have resolved sufficiently PediatricNot established Interferes with contraceptive effect of microdosed minipill progestin contraceptives; not known whether other progestational contraceptives (eg, implants, injectables) are adequate methods of contraception during acitretin therapy; not established if pharmacokinetic interaction occurs between acitretin and other birth control pills Absolute: Pregnancy, likely to become pregnant, or intend to become pregnant within 3 y following cessation of treatment; females who cannot use reliable contraception while undergoing treatment and for at least 3 y after treatment; noncompliance with contraception; breastfeeding; concurrent use of methotrexate (increased liver toxicity) or tetracyclines (pseudotumor cerebri); documented hypersensitivity PregnancyX - Contraindicated; benefit does not outweigh risk PrecautionsMonitor ALT, AST, cholesterol, triglycerides, BUN/creat, and urine monthly for first 3 mo and q3mo thereafter; consider baseline ophthalmology examination and radiography; should be prescribed by physicians thoroughly familiar and experienced in its use Isotretinoin (Accutane)Decreases sebaceous gland size and sebum production. May inhibit sebaceous gland differentiation and abnormal keratinization. Adult40-60 mg/d PO for 4 mo PediatricNot established Toxicity may occur with vitamin A coadministration; pseudotumor cerebri or papilledema may occur; may reduce plasma levels of carbamazepine Absolute: Pregnancy or a woman who is likely to become pregnant or who intends to become pregnant; females who cannot use reliable contraception while undergoing treatment; noncompliance with contraception; nursing mothers; concurrent use of methotrexate (increased liver toxicity) or tetracyclines (pseudotumor cerebri); documented hypersensitivity PregnancyX - Contraindicated; benefit does not outweigh risk PrecautionsMay decrease night vision; inflammatory bowel disease may occur; may be associated with hepatitis; exaggerated healing response of acne lesions (excessive granulation with crusting) may occur; patients with diabetes may have problems controlling their blood sugar; avoid exposure to UV light or sunlight until tolerance is achieved; discontinue if rectal bleeding, abdominal pain, or severe diarrhea occur; should be prescribed by physicians thoroughly familiar and experienced in its use AntihistaminesThese 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. Adult25-50 mg PO q6-8h prn; not to exceed 400 mg/d Pediatric12.5-25 mg PO tid/qid, 5 mg/kg/d, or 150 mg/m2/d divided tid/qid; not to exceed 300 mg/d |
Last Updated on Saturday, 19 February 2011 08:44 |