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Genetics Home Reference: your guide to understanding genetic conditions
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Erythrokeratodermia variabilis et progressiva

(often shortened to EKVP)
Reviewed January 2014

What is EKVP?

Erythrokeratodermia variabilis et progressiva (EKVP) is a skin disorder that is present at birth or becomes apparent in infancy. Although its signs and symptoms vary, the condition is characterized by two major features. The first is areas of hyperkeratosis, which is rough, thickened skin. These thickened patches are usually reddish-brown and can either be widespread over many parts of the body or occur only in a small area. They tend to be fixed, meaning they do not spread or go away. However, the patches can vary in size and shape, and in some affected people they get larger over time. The areas of thickened skin are generally symmetric, which means they occur in the same places on the right and left sides of the body.

The second major feature of EKVP is patches of reddened skin called erythematous areas. Unlike the hyperkeratosis that occurs in this disorder, the erythematous areas are usually transient, which means they come and go. They vary in size, shape, and location, and can occur anywhere on the body. The redness can be triggered by sudden changes in temperature, emotional stress, or trauma or irritation to the area. It usually fades within hours to days.

How common is EKVP?

EKVP is a rare disorder; its prevalence is unknown.

What genes are related to EKVP?

EKVP can be caused by mutations in the GJB3 or GJB4 gene. These genes provide instructions for making proteins called connexin 31 and connexin 30.3, respectively. These proteins are part of the connexin family, a group of proteins that form channels called gap junctions on the surface of cells. Gap junctions open and close to regulate the flow of nutrients, charged atoms (ions), and other signaling molecules from one cell to another. They are essential for direct communication between neighboring cells. Gap junctions formed with connexin 31 and connexin 30.3 are found in several tissues, including the outermost layer of skin (the epidermis).

The GJB3 and GJB4 gene mutations that cause EKVP alter the structure of the connexins produced from these genes. Studies suggest that the abnormal proteins can build up in a cell structure called the endoplasmic reticulum (ER), triggering a harmful process known as ER stress. Researchers suspect that ER stress damages and leads to the premature death of cells in the epidermis. This cell death leads to skin inflammation, which appears to underlie the development of erythematous areas. The mechanism by which epidermal damage and cell death contributes to hyperkeratosis is poorly understood.

In some cases, affected individuals have no identified mutation in the GJB3 or GJB4 gene. In these individuals, the cause of the disorder is unknown. Researchers suspect that changes in other, unidentified genes may also be associated with EKVP.

Related Gene(s)

Changes in these genes are associated with erythrokeratodermia variabilis et progressiva.

  • GJB3
  • GJB4

How do people inherit EKVP?

EKVP is most often inherited in an autosomal dominant pattern, which means one copy of an altered gene in each cell is sufficient to cause the disorder. In most cases, an affected person inherits the mutation from one affected parent. Other cases result from new gene mutations and occur in people with no history of the disorder in their family.

A few studies have suggested that EKVP can also have an autosomal recessive pattern of inheritance. However, this inheritance pattern has only been reported in a small number of affected families, and not all researchers agree that it is truly autosomal recessive. Autosomal recessive inheritance means both copies of a gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Where can I find information about diagnosis or management of EKVP?

These resources address the diagnosis or management of EKVP and may include treatment providers.

  • Genetic Testing Registry: Erythrokeratodermia variabilis (http://www.ncbi.nlm.nih.gov/gtr/conditions/C0265961)

You might also find information on the diagnosis or management of EKVP in Educational resources (http://www.ghr.nlm.nih.gov/condition/erythrokeratodermia-variabilis-et-progressiva/show/Educational+resources) and Patient support (http://www.ghr.nlm.nih.gov/condition/erythrokeratodermia-variabilis-et-progressiva/show/Patient+support).

General information about the diagnosis (http://ghr.nlm.nih.gov/handbook/consult/diagnosis) and management (http://ghr.nlm.nih.gov/handbook/consult/treatment) of genetic conditions is available in the Handbook. Read more about genetic testing (http://ghr.nlm.nih.gov/handbook/testing), particularly the difference between clinical tests and research tests (http://ghr.nlm.nih.gov/handbook/testing/researchtesting).

To locate a healthcare provider, see How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

Where can I find additional information about EKVP?

You may find the following resources about EKVP helpful. These materials are written for the general public.

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

What other names do people use for EKVP?

  • EKV
  • EKV-P
  • erythrokeratodermia, progressive symmetric
  • erythrokeratodermia variabilis
  • erythrokeratodermia variabilis of Mendes da Costa
  • progressive symmetrical erythrokeratoderma of Gottron

For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines (http://ghr.nlm.nih.gov/ConditionNameGuide) and How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.

What if I still have specific questions about EKVP?

Ask the Genetic and Rare Diseases Information Center (http://rarediseases.info.nih.gov/GARD/).

What glossary definitions help with understanding EKVP?

autosomal ; autosomal dominant ; autosomal recessive ; cell ; connexin ; endoplasmic reticulum ; epidermis ; ER ; gap junctions ; gene ; inflammation ; inheritance ; inheritance pattern ; inherited ; ions ; mutation ; oxygen ; pattern of inheritance ; prevalence ; reactive oxygen species ; recessive ; stress ; transient ; trauma

You may find definitions for these and many other terms in the Genetics Home Reference Glossary (http://www.ghr.nlm.nih.gov/glossary).

References

  • Chi J, Li L, Liu M, Tan J, Tang C, Pan Q, Wang D, Zhang Z. Pathogenic connexin-31 forms constitutively active hemichannels to promote necrotic cell death. PLoS One. 2012;7(2):e32531. doi: 10.1371/journal.pone.0032531. Epub 2012 Feb 29. (http://www.ncbi.nlm.nih.gov/pubmed/22393412?dopt=Abstract)
  • Fuchs-Telem D, Pessach Y, Mevorah B, Shirazi I, Sarig O, Sprecher E. Erythrokeratoderma variabilis caused by a recessive mutation in GJB3. Clin Exp Dermatol. 2011 Jun;36(4):406-11. doi: 10.1111/j.1365-2230.2010.03986.x. (http://www.ncbi.nlm.nih.gov/pubmed/21564177?dopt=Abstract)
  • Gottfried I, Landau M, Glaser F, Di WL, Ophir J, Mevorah B, Ben-Tal N, Kelsell DP, Avraham KB. A mutation in GJB3 is associated with recessive erythrokeratodermia variabilis (EKV) and leads to defective trafficking of the connexin 31 protein. Hum Mol Genet. 2002 May 15;11(11):1311-6. (http://www.ncbi.nlm.nih.gov/pubmed/12019212?dopt=Abstract)
  • Macari F, Landau M, Cousin P, Mevorah B, Brenner S, Panizzon R, Schorderet DF, Hohl D, Huber M. Mutation in the gene for connexin 30.3 in a family with erythrokeratodermia variabilis. Am J Hum Genet. 2000 Nov;67(5):1296-301. Epub 2000 Oct 3. (http://www.ncbi.nlm.nih.gov/pubmed/11017804?dopt=Abstract)
  • Richard G, Brown N, Rouan F, Van der Schroeff JG, Bijlsma E, Eichenfield LF, Sybert VP, Greer KE, Hogan P, Campanelli C, Compton JG, Bale SJ, DiGiovanna JJ, Uitto J. Genetic heterogeneity in erythrokeratodermia variabilis: novel mutations in the connexin gene GJB4 (Cx30.3) and genotype-phenotype correlations. J Invest Dermatol. 2003 Apr;120(4):601-9. (http://www.ncbi.nlm.nih.gov/pubmed/12648223?dopt=Abstract)
  • Richard G, Smith LE, Bailey RA, Itin P, Hohl D, Epstein EH Jr, DiGiovanna JJ, Compton JG, Bale SJ. Mutations in the human connexin gene GJB3 cause erythrokeratodermia variabilis. Nat Genet. 1998 Dec;20(4):366-9. (http://www.ncbi.nlm.nih.gov/pubmed/9843209?dopt=Abstract)
  • van Steensel MA, Oranje AP, van der Schroeff JG, Wagner A, van Geel M. The missense mutation G12D in connexin30.3 can cause both erythrokeratodermia variabilis of Mendes da Costa and progressive symmetric erythrokeratodermia of Gottron. Am J Med Genet A. 2009 Feb 15;149A(4):657-61. doi: 10.1002/ajmg.a.32744. (http://www.ncbi.nlm.nih.gov/pubmed/19291775?dopt=Abstract)

 

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

 
Reviewed: January 2014
Published: August 25, 2014