Disease group Keratinization Disorder
Synonymous Erythrokeratodermia figurata, congenital familial, in plaques
Erythrokeratodermia variabilis with erythema gyratum repens
Estimated prevalence Very rare
OMIM 133200
Inheritance Autosomal Dominant
Gene (s) GJB3 (603324), GJB4 (605425)


Erythrokeratodermia variabilis (EKV) is a rare genetic skin disorder first described by the Dutch dermatologist Mendes da Costa in 1925. As reflected by this name, EKV is characterized by hyperkeratotic plaques and transient red patches of variable size, shape and location. Mutations in the GJB3 and GJB4 genes (rarely GJA1), encoding connexin 31 and 30.3 (43) respectively, are responsible for the majority of EKV cases. EKV is an autosomal dominant disease, however, autosomal recessive inheritance has been reported.1, 2


Clinical Description

EKV is characterized by both hyperkeratotic plaques (occasionally generalized hyperkeratosis) and well demarcated, sometimes migratory, erythematous patches with irregular borders that have a tendency to be confluent. First symptoms usually develop during the first year of life, rarely during late childhood or early adulthood. Lesions are usually not present at birth. The clinical presentation shows a great heterogeneity and often worsens during childhood/puberty with stabilization thereafter. A fine scaling may be present on the lesions that predominantly affect the extensor surfaces of extremities, buttocks and face in a quite symmetrical distribution. The red patches, which cause sometimes a burning sensation, migrate over time and last from hours to days. Changes may be precipitated by trauma, physical stressors like change in temperature, UV exposure or psychological influence. Palmoplantar keratoderma manifests in almost half of the patients. Although life expectancy is normal and no extracutaneous features are associated, the disease can cause significant negative psychosocial impact due to the disfiguring appearance. 1, 3



The majority of EKV cases are due to specific mutations in the GJB3 and GJB4 genes encoding connexin 31 and 30.3, respectively.4 Connexins are a family of proteins that form gap junctions, which are important channels for intercellular communication between keratinocytes in the epidermis. The resulting channels allow direct cell-to-cell communication, the transfer of physiologic signals, ions, and small nutrients, and coordination of cellular responses to internal and external stimuli. This intercellular signaling system is crucial for maintaining tissue homeostasis, growth control, development, and synchronized response of cells to stimuli.



Histopathologic features are non-specific and include hyperkeratosis, acanthosis, papillomatosis, epidermal hyperplasia and capillary dilatation. Marked papillomatosis and suprapapillary thinning may cause a "church spire" appearance of the epidermis. 5 Identification of the causative mutations in the GJB3 (Cx31), GJB4 (Cx30.3) and GJA1 (Cx43) genes may allow affected patients to receive molecular confirmation of their diagnosis.



There is no specific treatment for EKV. Treatment is based on (low-dose) systemic retinoid therapy, aiming at reducing hyperkeratosis and minimizing the discomfort. Further agents against hyperkeratosis include topical keratolytics, topical retinoids, tazarotene and alpha-hydroxy acid. Topical corticosteroids may be helpful against erythematous patches.