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Erythrokeratodermia Variabilis et Progressiva  Treatment & Management

  • Author: Gabriele Richard, MD, FACMG; Chief Editor: Dirk M Elston, MD  more...
Updated: Nov 04, 2015

Approach Considerations

The goals of the therapy are to diminish the hyperkeratosis and minimize the discomfort.


Medical Care

Systemic retinoids are the treatment of choice in extensive erythrokeratodermia variabilis et progressiva (EKVP).[41, 42] Systemic retinoid therapy with acitretin (Soriatane) or isotretinoin (Accutane) can induce dramatic improvement.[43] Systemic retinoids are the treatment of choice for extensive or generalized erythrokeratodermia variabilis. The effect of acitretin or etretinate is superior to that of isotretinoin. The use of retinoids should be considered carefully because long-term therapy is required to achieve continuing results. The minimal effective dose for persons with EKVP usually is very low.

The use of topical agents in the management depends on the symptoms and focuses on hydration, lubrication, and keratolysis. Therapy may include the use of emollients and keratolytics, such as urea, alpha-hydroxy acids, propylene glycol, salicylic acid, and topical vitamin D analogs and retinoid preparations. Newer synthetic retinoids, such as short-contact topical tazarotene, combined with moisturizers seem promising.[44] Masking the erythematous lesions of uncovered skin with makeup and other forms of camouflage may provide a cosmetic benefit. In case of pruritus and burning, mild sedative H1 antihistamines are useful.

The avoidance of trauma to the skin may be also beneficial.



Triggers for skin lesions, such as exposure to cold, drastic temperature changes, and mechanical irritation of the skin, should be avoided.


Long-Term Monitoring

Treatment with oral retinoids requires a long-term therapy and follow-up to achieve continuing results. Careful monitoring for adverse effects of retinoid therapy is necessary.

Contributor Information and Disclosures

Gabriele Richard, MD, FACMG Chief Medical Officer, GeneDx, Inc

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

Disclosure: Receive salary for employment from GeneDx, a wholly owned subsidiary of BioReference Labs, a wholly owned subsidiary of Opko Health.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Harry Dao, Jr, MD Assistant Professor, Department of Dermatology, Baylor College of Medicine

Harry Dao, Jr, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

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

Disclosure: Nothing to disclose.

Additional Contributors

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, American Society of Dermatopathology

Disclosure: Nothing to disclose.

  1. Cadieux-Dion M, Turcotte-Gauthier M, Noreau A, Martin C, Meloche C, Gravel M, et al. Expanding the clinical phenotype associated with ELOVL4 mutation: study of a large French-Canadian family with autosomal dominant spinocerebellar ataxia and erythrokeratodermia. JAMA Neurol. 2014 Apr. 71 (4):470-5. [Medline].

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

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

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

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

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

  7. Boyden LM, Craiglow BG, Zhou J, Hu R, Loring EC, Morel KD, et al. Dominant De Novo Mutations in GJA1 Cause Erythrokeratodermia Variabilis et Progressiva, without Features of Oculodentodigital Dysplasia. J Invest Dermatol. 2015 Jun. 135 (6):1540-7. [Medline].

  8. 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. [Medline].

  9. 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. 2011 Jun. 36(4):399-405. [Medline].

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

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

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

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

  14. 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. 2002 May 15. 11(11):1311-6. [Medline].

  15. 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. 2000 Nov. 67(5):1296-301. [Medline].

  16. 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. 2003 Dec 15. 12(24):3287-94. [Medline].

  17. 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. 2008 Jun. 22(6):750-1. [Medline].

  18. 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. 2003 Apr. 120(4):601-9. [Medline].

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

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

  21. 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. 1999 Dec. 113(6):1119-22. [Medline].

  22. Wang ZX, Lu WS, Li H, Lin D, Zhou FS, Sun LD, et al. A novel GJB3 (Cx31) missense mutation in a Chinese patient with erythrokeratodermia variabilis. J Eur Acad Dermatol Venereol. 2011 Jan. 25(1):113-5. [Medline].

  23. Scott CA, O'Toole EA, Mohungoo MJ, Messenger A, Kelsell DP. Novel and recurrent connexin 30.3 and connexin 31 mutations associated with erythrokeratoderma variabilis. Clin Exp Dermatol. 2011 Jan. 36(1):88-90. [Medline].

  24. Glatz M, van Steensel MA, van Geel M, Steijlen PM, Wolf P. An unusual missense mutation in the GJB3 gene resulting in severe erythrokeratodermia variabilis. Acta Derm Venereol. 2011 Oct. 91(6):714-5. [Medline].

  25. Sugiura K, Arima M, Matsunaga K, Akiyama M. The novel GJB3 mutation p.Thr202Asn in the M4 transmembrane domain underlies erythrokeratodermia variabilis. Br J Dermatol. 2015 Jul. 173 (1):309-11. [Medline].

  26. Ikeya S, Urano S, Sakabe J, Ito T, Tokura Y. Erythrokeratodermia variabilis: first Japanese case documenting GJB3 mutation. J Dermatol. 2013 May. 40 (5):402-3. [Medline].

  27. Liu H, Liu H, Fu XA, Yu YX, Zhou GZ, Lu XM, et al. Mutation analysis of GJB3 and GJB4 in Chinese patients with erythrokeratodermia variabilis. J Dermatol. 2012 Apr. 39 (4):400-1. [Medline].

  28. Torres T, Velho G, Sanches M, Selores M. A case of erythrokeratodermia variabilis with connexin 31 gene mutation (Cx31F137L). Int J Dermatol. 2012 Apr. 51 (4):494-6. [Medline].

  29. Wang W, Liu LH, Chen G, Gao M, Zhu J, Zhou FS, et al. A missense mutation in the GJB3 gene responsible for erythrokeratodermia variabilis in a Chinese family. Clin Exp Dermatol. 2012 Dec. 37 (8):919-21. [Medline].

  30. 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].

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

  32. Zhou F, Fu H, Liu L, Cui Y, Zhang Z, Chang R, et al. No exonic mutations at GJB2, GJB3, GJB4, GJB6, ARS (Component B), and LOR genes responsible for a Chinese patient affected by progressive symmetric erythrokeratodermia with pseudoainhum. Int J Dermatol. 2014 Sep. 53 (9):1111-3. [Medline].

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

  34. 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. 2002 Aug 15. 11(17):2005-14. [Medline].

  35. 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. [Medline].

  36. 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. 1997 Oct. 109(4):604-10. [Medline].

  37. 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. 1996 May. 13(1):70-7. [Medline].

  38. 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. 2006 Sep. 126(9):2136-9. [Medline].

  39. Bourassa CV, Raskin S, Serafini S, Teive HA, Dion PA, Rouleau GA. A New ELOVL4 Mutation in a Case of Spinocerebellar Ataxia With Erythrokeratodermia. JAMA Neurol. 2015 Aug. 72 (8):942-3. [Medline].

  40. 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. 2008 Dec. 4(12):e1000296. [Medline].

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

  42. 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].

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

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

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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