Erythrokeratodermia Variabilis et Progressiva

Updated: May 30, 2017
  • Author: Gabriele Richard, MD, FACMG; Chief Editor: Dirk M Elston, MD  more...
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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) (OMIM # 133200), as well as autosomal dominant spinocerebellar ataxia with erythrokeratodermia (Giroux and Barbeau; 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 recently proposed to classify this disorder as erythrokeratodermia variabilis et progressiva (EKVP). [1] Nevertheless, PSEK and overlapping forms of erythrokeratoderma do exist as genetically distinct and heterogeneous entities from EKVP.

EKVP is characterized by the coexistence of two distinct morphologic features: hyperkeratosis and transient erythema, albeit one 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]



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 rare cases, 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 hemichannel function owing to a dominant effect of mutant gap junction proteins. [8, 9]



US frequency

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.


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.



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.


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.