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Erythrokeratodermia variabilis et progressiva 6(EKVP6)

MedGen UID:
1681026
•Concept ID:
C5193144
•
Disease or Syndrome
Synonyms: EKVP6; ERYTHROKERATODERMIA VARIABILIS ET PROGRESSIVA 6
 
Gene (location): TRPM4 (19q13.33)
 
Monarch Initiative: MONDO:0032801
OMIM®: 618531

Definition

EKVP6 is characterized by erythematous hyperkeratotic plaques that develop within the first year of life, beginning on distal extremities and progressing to involve the face, wrists, and ankles, with sparing of volar surfaces. Intrafamilial variation in severity has been observed, and most affected individuals experience slowly progressive spontaneous remission after puberty (Wang et al., 2019). For a general phenotypic description and discussion of genetic heterogeneity of EKVP, see EKVP1 (133200). [from OMIM]

Clinical features

From HPO
Cardiac arrhythmia
MedGen UID:
2039
•Concept ID:
C0003811
•
Finding
Any cardiac rhythm other than the normal sinus rhythm. Such a rhythm may be either of sinus or ectopic origin and either regular or irregular. An arrhythmia may be due to a disturbance in impulse formation or conduction or both.
See: Feature record | Search on this feature
Superficial dermal perivascular inflammatory infiltrate
MedGen UID:
1620848
•Concept ID:
C4531290
•
Anatomical Abnormality
Numerous lymphocytes surrounding blood vessels in the superfical part of the dermis.
See: Feature record | Search on this feature
Abnormal dental morphology
MedGen UID:
11849
•Concept ID:
C0040427
•
Anatomical Abnormality
An abnormality of the morphology of the tooth.
See: Feature record | Search on this feature
Parakeratosis
MedGen UID:
10572
•Concept ID:
C0030436
•
Disease or Syndrome
Abnormal formation of the keratinocytes of the epidermis characterized by persistence of nuclei, incomplete formation of keratin, and moistness and swelling of the keratinocytes.
See: Feature record | Search on this feature
Pruritus
MedGen UID:
19534
•Concept ID:
C0033774
•
Sign or Symptom
Pruritus is an itch or a sensation that makes a person want to scratch. This term refers to an abnormally increased disposition to experience pruritus.
See: Feature record | Search on this feature
Abnormal hair morphology
MedGen UID:
56381
•Concept ID:
C0157733
•
Finding
An abnormality of the hair.
See: Feature record | Search on this feature
Erythematous plaque
MedGen UID:
568360
•Concept ID:
C0332477
•
Finding
A plaque (a solid, raised, plateau-like (flat-topped) lesion greater than 1 cm in diameter) with a red or reddish color often associated with inflammation or irritation.
See: Feature record | Search on this feature
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Recent clinical studies

Etiology

Clinical variability of the GJB4:c.35G > A gene variant: a study of a large Brazilian erythrokeratodermia pedigree.
de Oliveira RTG, Christofolini DM, Criado PR, Lacaz Martins E, Kelsell D, Machado Filho CDS
Int J Dermatol 2020 Jun;59(6):722-725. Epub 2020 Apr 20 doi: 10.1111/ijd.14894. PMID: 32311086
A20 and ABIN1 Suppression of a Keratinocyte Inflammatory Program with a Shared Single-Cell Expression Signature in Diverse Human Rashes.
Harirchian P, Lee J, Hilz S, Sedgewick AJ, Perez White BE, Kesling MJ, Mully T, Golovato J, Gray M, Mauro TM, Purdom E, Kim EA, Sbitany H, Bhutani T, Vaske CJ, Benz SC, Cho RJ, Cheng JB
J Invest Dermatol 2019 Jun;139(6):1264-1273. Epub 2018 Dec 10 doi: 10.1016/j.jid.2018.10.046. PMID: 30543901Free PMC Article
Cx31 is assembled and trafficked to cell surface by ER-Golgi pathway and degraded by proteasomal or lysosomal pathways.
He LQ, Cai F, Liu Y, Liu MJ, Tan ZP, Pan Q, Fang FY, Liang DS, Wu LQ, Long ZG, Dai HP, Xia K, Xia JH, Zhang ZH
Cell Res 2005 Jun;15(6):455-64. doi: 10.1038/sj.cr.7290314. PMID: 15987604
Reticular erythrokeratoderma: a new disorder of cornification.
Itin PH, Moschopulos M, Richard G
Am J Med Genet A 2003 Jul 15;120A(2):237-40. doi: 10.1002/ajmg.a.20036. PMID: 12833406
Erythrokeratodermia variabilis in a patient followed through the first year of life.
Bond MJ, Donelan P, Fenske N
Cutis 1982 Nov;30(5):633-7. PMID: 7172743

Diagnosis

A p.478I>T KRT1 mutation in a case of annular epidermolytic ichthyosis.
Zaki TD, Yoo KY, Kassardjian M, Choate KA
Pediatr Dermatol 2018 Nov;35(6):e414-e415. Epub 2018 Aug 28 doi: 10.1111/pde.13643. PMID: 30152556Free PMC Article
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
A Novel Mutation in ELOVL4 Leading to Spinocerebellar Ataxia (SCA) With the Hot Cross Bun Sign but Lacking Erythrokeratodermia: A Broadened Spectrum of SCA34.
Ozaki K, Doi H, Mitsui J, Sato N, Iikuni Y, Majima T, Yamane K, Irioka T, Ishiura H, Doi K, Morishita S, Higashi M, Sekiguchi T, Koyama K, Ueda N, Miura Y, Miyatake S, Matsumoto N, Yokota T, Tanaka F, Tsuji S, Mizusawa H, Ishikawa K
JAMA Neurol 2015 Jul;72(7):797-805. doi: 10.1001/jamaneurol.2015.0610. PMID: 26010696

Therapy

Both low-dose arotinoid ethylester and acitretin are effective in the treatment of familial erythrokeratodermia variabilis.
Zhang L, Hong Y, Zheng S, Huo W, Qi R, Geng L, Chen HD, Gao XH
Dermatol Ther 2014 Jul-Aug;27(4):240-3. Epub 2014 Apr 22 doi: 10.1111/dth.12127. PMID: 24754264
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
Acitretin for erythrokeratodermia variabilis in a 9-year-old girl.
Graham-Brown RA, Chave TA
Pediatr Dermatol 2002 Nov-Dec;19(6):510-2. doi: 10.1046/j.1525-1470.2002.00221.x. PMID: 12437552

Prognosis

Reticular erythrokeratoderma: a new disorder of cornification.
Itin PH, Moschopulos M, Richard G
Am J Med Genet A 2003 Jul 15;120A(2):237-40. doi: 10.1002/ajmg.a.20036. PMID: 12833406
The spectrum of mutations in erythrokeratodermias--novel and de novo mutations in GJB3.
Richard G, Brown N, Smith LE, Terrinoni A, Melino G, Mackie RM, Bale SJ, Uitto J
Hum Genet 2000 Mar;106(3):321-9. doi: 10.1007/s004390051045. PMID: 10798362
Mutations in the human connexin gene GJB3 cause erythrokeratodermia variabilis.
Richard G, Smith LE, Bailey RA, Itin P, Hohl D, Epstein EH Jr, DiGiovanna JJ, Compton JG, Bale SJ
Nat Genet 1998 Dec;20(4):366-9. doi: 10.1038/3840. PMID: 9843209
Erythrokeratodermia variabilis in a patient followed through the first year of life.
Bond MJ, Donelan P, Fenske N
Cutis 1982 Nov;30(5):633-7. PMID: 7172743

Clinical prediction guides

Clinical variability of the GJB4:c.35G > A gene variant: a study of a large Brazilian erythrokeratodermia pedigree.
de Oliveira RTG, Christofolini DM, Criado PR, Lacaz Martins E, Kelsell D, Machado Filho CDS
Int J Dermatol 2020 Jun;59(6):722-725. Epub 2020 Apr 20 doi: 10.1111/ijd.14894. PMID: 32311086
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
The spectrum of mutations in erythrokeratodermias--novel and de novo mutations in GJB3.
Richard G, Brown N, Smith LE, Terrinoni A, Melino G, Mackie RM, Bale SJ, Uitto J
Hum Genet 2000 Mar;106(3):321-9. doi: 10.1007/s004390051045. PMID: 10798362
Mutations in the human connexin gene GJB3 cause erythrokeratodermia variabilis.
Richard G, Smith LE, Bailey RA, Itin P, Hohl D, Epstein EH Jr, DiGiovanna JJ, Compton JG, Bale SJ
Nat Genet 1998 Dec;20(4):366-9. doi: 10.1038/3840. PMID: 9843209

Supplemental Content

Table of contents

    Clinical resources

    Reviews

    Related information

    • ClinVar
      Related medical variations
    • Gene
      Related information in NCBI Gene
    • GTR
      Related information in GTR
    • GTR(Clinical)
      Clinical tests in GTR
    • OMIM
      Related records in OMIM
    • OMIM(Genes)
      OMIM records containing genes associated with phenotypes registered in MedGen
    • PubMed (OMIM)
      Related literature resources in PubMed

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