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 persistent plaque-like or generalized hyperkeratosis and transient red patches of variable size, shape and location. Mutations in the GJB3 and GJB4 genes, encoding connexin 31 and 30.3 respectively, are responsible for the majority of EKV cases. However, no pathogenetic mutations in these genes could be identified in some EKV families, indicating further genetic heterogeneity.

Clinical Description

EKV is characterized by both hyperkeratosis (generalized or localized) and distinctive, sharply demarcated, migratory, red patches. The patches move over short periods of time (10 to 20 minutes) and may be precipitated by trauma or change in temperature. For patients with classic features, the diagnosis is clinically apparent; in others it can be elusive. These symptoms generally appear during the first year of life but onset sometimes occurs later in childhood.


The majority of EKV cases are due to specific mutations in the GJB3 and GJB4 genes encoding connexin 31 and 30.3, respectively. 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, and capillary dilatation. Marked papillomatosis and suprapapillary thinning may result in a "church spire" appearance of the epidermis. Identification of the causative mutations in the GJB3 (Cx31) and GJB4 (Cx30.3) genes allows affected families to receive molecular confirmation of their clinical diagnosis.


Treatment is based many on retinoid therapy, aiming to reduce hyperkeratosis and to minimise the discomfort. EKV does not affect other organs and life expectancy is normal.