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Erythrokeratodermia variabilis et progressiva 3(EKVP3)

MedGen UID:
1380593
•Concept ID:
C4479619
•
Disease or Syndrome
Synonym: EKVP3
 
Gene (location): GJA1 (6q22.31)
 
Monarch Initiative: MONDO:0033013
OMIM®: 617525

Definition

Erythrokeratodermia variabilis et progressiva is a rare skin disease. Patients with EKVP3 have normal skin at birth but develop hyperpigmentation and scaling at sites of friction in childhood, with progression to near-confluent corrugated hyperkeratosis, palmoplantar keratoderma, and transient figurate erythema (summary by Boyden et al., 2015). For a discussion of genetic heterogeneity of EKVP, see EKVP1 (133200). [from OMIM]

Clinical features

From HPO
Palmoplantar keratoderma
MedGen UID:
1635750
•Concept ID:
C4551675
•
Disease or Syndrome
Abnormal thickening of the skin of the palms of the hands and the soles of the feet.
See: Feature record | Search on this feature
Erythema
MedGen UID:
11999
•Concept ID:
C0041834
•
Disease or Syndrome
Redness of the skin, caused by hyperemia of the capillaries in the lower layers of the skin.
See: Feature record | Search on this feature
Epidermal acanthosis
MedGen UID:
65136
•Concept ID:
C0221270
•
Finding
Diffuse hypertrophy or thickening of the stratum spinosum of the epidermis (prickle cell layer of the skin).
See: Feature record | Search on this feature
Leukonychia
MedGen UID:
68698
•Concept ID:
C0240182
•
Finding
White discoloration of the nails.
See: Feature record | Search on this feature
Hyperkeratosis
MedGen UID:
209030
•Concept ID:
C0870082
•
Disease or Syndrome
Hyperkeratosis is thickening of the outer layer of the skin, the stratum corneum, which is composed of large, polyhedral, plate-like envelopes filled with keratin which are the dead cells that have migrated up from the stratum granulosum.
See: Feature record | Search on this feature
Orthokeratosis
MedGen UID:
375169
•Concept ID:
C1843359
•
Finding
Formation of an anuclear keratin layer
See: Feature record | Search on this feature
Hypergranulosis
MedGen UID:
481177
•Concept ID:
C3279547
•
Finding
Hypergranulosis is an increased thickness of the stratum granulosum.
See: Feature record | Search on this feature
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Professional guidelines

PubMed

Genetic heterogeneity in erythrokeratodermia variabilis: novel mutations in the connexin gene GJB4 (Cx30.3) and genotype-phenotype correlations.
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
J Invest Dermatol 2003 Apr;120(4):601-9. doi: 10.1046/j.1523-1747.2003.12080.x. PMID: 12648223

Recent clinical studies

Etiology

Erythrokeratodermia Variabilis-like Phenotype in Patients Carrying ABCA12 Mutations.
Hotz A, Fölster-Holst R, Oji V, Bourrat E, Frank J, Marrakchi S, Ennouri M, Wankner L, Komlosi K, Alter S, Fischer J
Genes (Basel) 2024 Feb 24;15(3) doi: 10.3390/genes15030288. PMID: 38540347Free PMC Article
The Role of Desmoglein 1 in Gap Junction Turnover Revealed through the Study of SAM Syndrome.
Cohen-Barak E, Godsel LM, Koetsier JL, Hegazy M, Kushnir-Grinbaum D, Hammad H, Danial-Farran N, Harmon R, Khayat M, Bochner R, Peled A, Rozenblat M, Krausz J, Sarig O, Johnson JL, Ziv M, Shalev SA, Sprecher E, Green KJ
J Invest Dermatol 2020 Mar;140(3):556-567.e9. Epub 2019 Aug 26 doi: 10.1016/j.jid.2019.08.433. PMID: 31465738Free PMC Article
Erythrokeratoderma variabilis caused by a recessive mutation in GJB3.
Fuchs-Telem D, Pessach Y, Mevorah B, Shirazi I, Sarig O, Sprecher E
Clin Exp Dermatol 2011 Jun;36(4):406-11. doi: 10.1111/j.1365-2230.2010.03986.x. PMID: 21564177
Familial erythrokeratodermia variabilis with pustular lesions: a new variant?
Zhang L, Huo W, Gao XH, Ma L, Xiu Y, Zheng S, Hong Y, Chen HD
Acta Derm Venereol 2010 May;90(3):274-8. doi: 10.2340/00015555-0821. PMID: 20526545
Erythrokeratodermia variabilis.
Maekawa Y, Yasaka S
J Dermatol 1977 Aug;4(4):147-50. doi: 10.1111/j.1346-8138.1977.tb01028.x. PMID: 15461342

Diagnosis

Erythrokeratodermia Variabilis-like Phenotype in Patients Carrying ABCA12 Mutations.
Hotz A, Fölster-Holst R, Oji V, Bourrat E, Frank J, Marrakchi S, Ennouri M, Wankner L, Komlosi K, Alter S, Fischer J
Genes (Basel) 2024 Feb 24;15(3) doi: 10.3390/genes15030288. PMID: 38540347Free PMC Article
Annular Epidermolytic Ichthyosis Mimicking Greither Disease: A Case Report and Literature Review.
Almuqarrab FJ, Alakloby OM, Alqahtani JM, Hennies HC
Am J Case Rep 2022 Feb 24;23:e935393. doi: 10.12659/AJCR.935393. PMID: 35202349Free PMC Article
Pluripotent stem cell-derived bile canaliculi-forming hepatocytes to study genetic liver diseases involving hepatocyte polarity.
Overeem AW, Klappe K, Parisi S, Klöters-Planchy P, Mataković L, du Teil Espina M, Drouin CA, Weiss KH, van IJzendoorn SCD
J Hepatol 2019 Aug;71(2):344-356. Epub 2019 Apr 6 doi: 10.1016/j.jhep.2019.03.031. PMID: 30965071
Pathogenic Cx31 is un/misfolded to cause skin abnormality via a Fos/JunB-mediated mechanism.
Tang C, Chen X, Chi J, Yang D, Liu S, Liu M, Pan Q, Fan J, Wang D, Zhang Z
Hum Mol Genet 2015 Nov 1;24(21):6054-65. Epub 2015 Aug 6 doi: 10.1093/hmg/ddv317. PMID: 26251042
Molecular genetics of hearing impairment due to mutations in gap junction genes encoding beta connexins.
Rabionet R, Gasparini P, Estivill X
Hum Mutat 2000 Sep;16(3):190-202. doi: 10.1002/1098-1004(200009)16:3<190::AID-HUMU2>3.0.CO;2-I. PMID: 10980526

Therapy

Erythrokeratodermia variabilis et progressiva.
Ishida-Yamamoto A
J Dermatol 2016 Mar;43(3):280-5. doi: 10.1111/1346-8138.13220. PMID: 26945536
Familial erythrokeratodermia variabilis with pustular lesions: a new variant?
Zhang L, Huo W, Gao XH, Ma L, Xiu Y, Zheng S, Hong Y, Chen HD
Acta Derm Venereol 2010 May;90(3):274-8. doi: 10.2340/00015555-0821. PMID: 20526545
Erythrokeratodermia variabilis with adult onset: report of a sporadic case unresponsive to systemic retinoids.
Erbagci Z, Tuncel AA, Deniz H
J Dermatolog Treat 2006;17(3):187-9. doi: 10.1080/09546630600696377. PMID: 16854764
A new, recurrent mutation of GJB3 (Cx31) in erythrokeratodermia variabilis.
Morley SM, White MI, Rogers M, Wasserman D, Ratajczak P, McLean WH, Richard G
Br J Dermatol 2005 Jun;152(6):1143-8. doi: 10.1111/j.1365-2133.2005.06610.x. PMID: 15948974
Is the use of Ro 10-9359 (Tigason) in children justified?
van der Rhee HJ, van Gelderen HH, Polano MK
Acta Derm Venereol 1980;60(3):274-5. PMID: 6158237

Prognosis

Expanding the clinical phenotype associated with NIPAL4 mutation: Study of a Tunisian consanguineous family with erythrokeratodermia variabilis-Like Autosomal Recessive Congenital Ichthyosis.
Charfeddine C, Laroussi N, Mkaouar R, Jouini R, Khayat O, Redissi A, Mosbah A, Dallali H, Chedly Debbiche A, Zaouak A, Fenniche S, Abdelhak S, Hammami-Ghorbel H
PLoS One 2021;16(10):e0258777. Epub 2021 Oct 20 doi: 10.1371/journal.pone.0258777. PMID: 34669720Free PMC Article
The Role of Desmoglein 1 in Gap Junction Turnover Revealed through the Study of SAM Syndrome.
Cohen-Barak E, Godsel LM, Koetsier JL, Hegazy M, Kushnir-Grinbaum D, Hammad H, Danial-Farran N, Harmon R, Khayat M, Bochner R, Peled A, Rozenblat M, Krausz J, Sarig O, Johnson JL, Ziv M, Shalev SA, Sprecher E, Green KJ
J Invest Dermatol 2020 Mar;140(3):556-567.e9. Epub 2019 Aug 26 doi: 10.1016/j.jid.2019.08.433. PMID: 31465738Free PMC Article
Erythrokeratodermia variabilis: report of two cases and a novel missense variant in GJB4 encoding connexin 30.3.
Kokotas H, Papagiannaki K, Grigoriadou M, Petersen MB, Katsarou A
Eur J Dermatol 2012 Mar-Apr;22(2):182-6. doi: 10.1684/ejd.2011.1617. PMID: 22266302
Familial erythrokeratodermia variabilis with pustular lesions: a new variant?
Zhang L, Huo W, Gao XH, Ma L, Xiu Y, Zheng S, Hong Y, Chen HD
Acta Derm Venereol 2010 May;90(3):274-8. doi: 10.2340/00015555-0821. PMID: 20526545
Genetic heterogeneity in erythrokeratodermia variabilis: novel mutations in the connexin gene GJB4 (Cx30.3) and genotype-phenotype correlations.
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
J Invest Dermatol 2003 Apr;120(4):601-9. doi: 10.1046/j.1523-1747.2003.12080.x. PMID: 12648223

Clinical prediction guides

Expanding the clinical phenotype associated with NIPAL4 mutation: Study of a Tunisian consanguineous family with erythrokeratodermia variabilis-Like Autosomal Recessive Congenital Ichthyosis.
Charfeddine C, Laroussi N, Mkaouar R, Jouini R, Khayat O, Redissi A, Mosbah A, Dallali H, Chedly Debbiche A, Zaouak A, Fenniche S, Abdelhak S, Hammami-Ghorbel H
PLoS One 2021;16(10):e0258777. Epub 2021 Oct 20 doi: 10.1371/journal.pone.0258777. PMID: 34669720Free PMC Article
Sphingolipid dysregulation due to lack of functional KDSR impairs proplatelet formation causing thrombocytopenia.
Bariana TK, Labarque V, Heremans J, Thys C, De Reys M, Greene D, Jenkins B, Grassi L, Seyres D, Burden F, Whitehorn D, Shamardina O, Papadia S, Gomez K, BioResource N, Van Geet C, Koulman A, Ouwehand WH, Ghevaert C, Frontini M, Turro E, Freson K
Haematologica 2019 May;104(5):1036-1045. Epub 2018 Nov 22 doi: 10.3324/haematol.2018.204784. PMID: 30467204Free PMC Article
Erythrokeratodermia variabilis: report of two cases and a novel missense variant in GJB4 encoding connexin 30.3.
Kokotas H, Papagiannaki K, Grigoriadou M, Petersen MB, Katsarou A
Eur J Dermatol 2012 Mar-Apr;22(2):182-6. doi: 10.1684/ejd.2011.1617. PMID: 22266302
An atypical form of erythrokeratodermia variabilis maps to chromosome 7q22.
Saba TG, Montpetit A, Verner A, Rioux P, Hudson TJ, Drouin R, Drouin CA
Hum Genet 2005 Feb;116(3):167-71. Epub 2004 Nov 25 doi: 10.1007/s00439-004-1193-8. PMID: 15668823
Genetic heterogeneity in erythrokeratodermia variabilis: novel mutations in the connexin gene GJB4 (Cx30.3) and genotype-phenotype correlations.
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
J Invest Dermatol 2003 Apr;120(4):601-9. doi: 10.1046/j.1523-1747.2003.12080.x. PMID: 12648223

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