Erythrokeratodermia Variabilis 

  • Author: Gabriele Richard, MD; Chief Editor: Dirk M Elston, MD   more...
 
Updated: Jan 24, 2012
 

Background

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]

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Pathophysiology

Erythrokeratodermia 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.[5, 6]

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Epidemiology

Frequency

United States

Erythrokeratodermia variabilis 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.

Mortality/Morbidity

Erythrokeratodermia variabilis is a chronic skin disorder without other organ manifestations; patients have a normal life expectancy. Depending on the extent and severity of erythrokeratodermia variabilis, the skin lesions can be severely disfiguring and have a tremendous psychosocial effect on the patients. Generalized hyperkeratosis may be associated with heat intolerance.

Race

Erythrokeratodermia variabilis has been reported worldwide. Most cases were whites of northern and middle European origin, but erythrokeratodermia variabilis also occurs in African Americans and Asians.

Sex

Both sexes are affected equally.

Age

More than 50% of patients present with symptoms at birth or in the neonatal period. Approximately 90% of patients present with EKV within the first year of life. In general, onset of disease is earlier in individuals with severe disease, including generalized hyperkeratosis.

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Contributor Information and Disclosures
Author

Gabriele Richard, MD  Medical Director, GeneDx, Inc

Gabriele Richard, MD is a member of the following medical societies: American Society of Human Genetics and Society for Investigative Dermatology

Disclosure: BioReference Laboratories Salary Employment

Specialty Editor Board

Mark W Cobb, MD  Consulting Staff, WNC Dermatological Associates

Mark W Cobb, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, and American Society of Dermatopathology

Disclosure: Nothing to disclose.

Richard P Vinson, MD  Assistant Clinical Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine; Consulting Staff, Mountain View Dermatology, PA

Richard P Vinson, MD is a member of the following medical societies: American Academy of Dermatology, Association of Military Dermatologists, Texas Dermatological Society, and Texas Medical Association

Disclosure: Nothing to disclose.

Lester F Libow, MD  Dermatopathologist, South Texas Dermatopathology Laboratory

Lester F Libow, MD is a member of the following medical societies: American Academy of Dermatology, American Society of Dermatopathology, and Texas Medical Association

Disclosure: Nothing to disclose.

Catherine M Quirk, MD  Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania

Catherine M Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology

Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD  Director, Ackerman Academy of Dermatopathology, New York

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

References

  1. de Buy Wenninger LM. Erythrokeratodermie congenitale ichthyosiforme avec hyperepidermotrophie. Verslagen van vereeningingene. Nederl Tijdschr Geneesk. 1907;1A:510-5.

  2. Mendes da Costa S. Erythro et keratodermia variabilis in a mother and a daughter. Acta Derm Venerol. 1925;6:255-61.

  3. Noordhoek KJ. Over erythro-et keratodermia variabilis. In: Schiedam NV, ed. Drukkererije de Eendracht. Utrecht, The Netherlands: 1950.

  4. Barsky S, Bernstein G. Keratosis Rubra Figurata. Arch Dermatol. 1964;90:373-4.

  5. 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. Jun 2011;36(4):406-11. [Medline].

  6. Wei S, Zhou Y, Zhang TD, Huang ZM, Zhang XB, Zhu HL, et al. Evidence for the absence of mutations at GJB3, GJB4 and LOR in progressive symmetrical erythrokeratodermia. Clin Exp Dermatol. Jun 2011;36(4):399-405. [Medline].

  7. Common JE, O'Toole EA, Leigh IM, et al. Clinical and genetic heterogeneity of erythrokeratoderma variabilis. J Invest Dermatol. Nov 2005;125(5):920-7. [Medline].

  8. Richard G, Brown N, Smith LE, et al. The spectrum of mutations in erythrokeratodermias--novel and de novo mutations in GJB3. Hum Genet. Mar 2000;106(3):321-9. [Medline].

  9. Richard G, Itin P, Bale SJ. Clinical heterogeneity in EKV. J Invest Dermatol. 1998;110:616A.

  10. Feldmeyer L, Plantard L, Mevorah B, Huber M, Hohl D. Novel mutation of connexin 31 causing erythrokeratoderma variabilis. Br J Dermatol. May 2005;152(5):1072-4. [Medline].

  11. Gottfried I, Landau M, Glaser F, et al. A mutation in GJB3 is associated with recessive erythrokeratodermia variabilis (EKV) and leads to defective trafficking of the connexin 31 protein. Hum Mol Genet. May 15 2002;11(11):1311-6. [Medline].

  12. Macari F, Landau M, Cousin P, et al. Mutation in the gene for connexin 30.3 in a family with erythrokeratodermia variabilis. Am J Hum Genet. Nov 2000;67(5):1296-301. [Medline].

  13. Plantard L, Huber M, Macari F, Meda P, Hohl D. Molecular interaction of connexin 30.3 and connexin 31 suggests a dominant-negative mechanism associated with erythrokeratodermia variabilis. Hum Mol Genet. Dec 15 2003;12(24):3287-94. [Medline].

  14. Renner R, Paasch U, Simon JC, Froster UG, Heinritz W. A new mutation in the GJB3 gene in a patient with erythrokeratodermia variabilis. J Eur Acad Dermatol Venereol. Jun 2008;22(6):750-1. [Medline].

  15. Richard G, Brown N, Rouan F, et al. Genetic heterogeneity in erythrokeratodermia variabilis: novel mutations in the connexin gene GJB4 (Cx30.3) and genotype-phenotype correlations. J Invest Dermatol. Apr 2003;120(4):601-9. [Medline].

  16. Richard G, Smith LE, Bailey RA, et al. Mutations in the human connexin gene GJB3 cause erythrokeratodermia variabilis. Nat Genet. Dec 1998;20(4):366-9. [Medline].

  17. Terrinoni A, Leta A, Pedicelli C, et al. A novel recessive connexin 31 (GJB3) mutation in a case of erythrokeratodermia variabilis. J Invest Dermatol. Mar 2004;122(3):837-9. [Medline].

  18. Arita K, Akiyama M, Tsuji Y, Onozuka T, Shimizu H. Erythrokeratoderma variabilis without connexin 31 or connexin 30.3 gene mutation: immunohistological, ultrastructural and genetic studies. Acta Derm Venereol. 2003;83(4):266-70. [Medline].

  19. Nakamura M. Erythrokeratoderma variabilis without GJB3 or GJB4 mutation: a review of Japanese patients. Br J Dermatol. Aug 2007;157(2):410-1. [Medline].

  20. Morley SM, White MI, Rogers M, et al. A new, recurrent mutation of GJB3 (Cx31) in erythrokeratodermia variabilis. Br J Dermatol. Jun 2005;152(6):1143-8. [Medline].

  21. Di WL, Monypenny J, Common JE, et al. Defective trafficking and cell death is characteristic of skin disease-associated connexin 31 mutations. Hum Mol Genet. Aug 15 2002;11(17):2005-14. [Medline].

  22. Korge BP, Ishida-Yamamoto A, Punter C, et al. Loricrin mutation in Vohwinkel's keratoderma is unique to the variant with ichthyosis. J Invest Dermatol. Oct 1997;109(4):604-10. [Medline].

  23. Maestrini E, Monaco AP, McGrath JA, et al. A molecular defect in loricrin, the major component of the cornified cell envelope, underlies Vohwinkel's syndrome. Nat Genet. May 1996;13(1):70-7. [Medline].

  24. Cui Y, Yang S, Gao M, et al. Identification of a novel locus for progressive symmetric erythrokeratodermia to a 19.02-cM interval at 21q11.2-21q21.2. J Invest Dermatol. Sep 2006;126(9):2136-9. [Medline].

  25. Montpetit A, Cote S, Brustein E, et al. Disruption of AP1S1, causing a novel neurocutaneous syndrome, perturbs development of the skin and spinal cord. PLoS Genet. Dec 2008;4(12):e1000296. [Medline].

  26. Magyarlaki M, Drobnitsch I, Zombai E, Schneider I. [A case of erythrokeratodermia figurata variabilis successfully treated with tigason]. Z Hautkr. Oct 15 1989;64(10):881-2, 885-7. [Medline].

  27. van de Kerkhof PC, Steijlen PM, van Dooren-Greebe RJ, Happle R. Acitretin in the treatment of erythrokeratodermia variabilis. Dermatologica. 1990;181(4):330-3. [Medline].

  28. Singh N, Thappa DM. Erythrokeratoderma variabilis responding to low-dose isotretinoin. Pediatr Dermatol. Jan-Feb 2010;27(1):111-3. [Medline].

  29. Yoo S, Simzar S, Han K, Takahashi S, Cotliar R. Erythrokeratoderma variabilis successfully treated with topical tazarotene. Pediatr Dermatol. Jul-Aug 2006;23(4):382-5. [Medline].

  30. Brown J, Kierland RR. Erythrokeratodermia variabilis. Report of three cases and review of the literature. Arch Dermatol. Feb 1966;93(2):194-201. [Medline].

  31. Itin P, Levy CA, Sommacal-Schopf D, Schnyder UW. [Family study of erythrokeratodermia figurata variabilis]. Hautarzt. Aug 1992;43(8):500-4. [Medline].

  32. Lee JS, Sung YH, Lee JH, et al. Erythrokeratodermia variabilis with alopecia universalis. Ann Dermatol. 1990;2:17-20.

  33. Macfarlane AW, Chapman SJ, Verbov JL. Is erythrokeratoderma one disorder? A clinical and ultrastructural study of two siblings. Br J Dermatol. May 1991;124(5):487-91. [Medline].

  34. McFadden N, Oppedal BR, Ree K, Brandtzaeg P. Erythrokeratodermia variabilis: immunohistochemical and ultrastructural studies of the epidermis. Acta Derm Venereol. 1987;67(4):284-8. [Medline].

  35. Micali G, Musumeci ML, Montalvo A, et al. Erythrokeratodermia variabilis: a case report. Eur J Dermatol. 1996;6:479-81.

  36. van der Schroeff JG, Nijenhuis LE, Meera Khan P, et al. Genetic linkage between erythrokeratodermia variabilis and Rh locus. Hum Genet. 1984;68(2):165-8. [Medline].

  37. van der Schroeff JG, van Leeuwen-Cornelisse I, van Haeringen A, Went LN. Further evidence for localization of the gene of erythrokeratodermia variabilis. Hum Genet. Sep 1988;80(1):97-8. [Medline].

  38. Vandersteen PR, Muller SA. Erythrokeratodermia variabilis. An enzyme histochemical and ultrastructural study. Arch Dermatol. Apr 1971;103(4):362-70. [Medline].

  39. Wilgoss A, Leigh IM, Barnes MR, et al. Identification of a novel mutation R42P in the gap junction protein beta-3 associated with autosomal dominant erythrokeratoderma variabilis. J Invest Dermatol. Dec 1999;113(6):1119-22. [Medline].

 
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Figurate erythema. Courtesy of M. King and J. Crawford.
Targetlike erythema. Courtesy of M. King and J. Crawford.
Generalized hyperkeratosis with scaling, accentuated skin lines, and figurate erythema. Courtesy of M. King and J. Crawford.
Thick hyperkeratotic plates with hystrixlike spines. Courtesy of M. King and J. Crawford.
Sharply demarcated, figurate, hyperkeratotic plaques in a symmetric distribution. Courtesy of M. King and J. Crawford.
Figurate hyperkeratotic plaque with erythematous patches. Courtesy of M. King and J. Crawford.
Plantar keratoderma with peeling. Courtesy of M. King and J. Crawford.
Diffuse glovelike palmar keratoderma. Courtesy of M. King and J. Crawford.
 
 
 
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