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    Erythrokeratodermia Variabilis et Progressiva

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    Definition

    Erythrokeratodermia variabilis et progressiva (EKVP) is a skin disorder that is present at birth or becomes apparent in infancy. Although its signs and symptoms vary, the condition is characterized by two major features.

    1. Introduction

    The first is hyperkeratosis, which is rough, thickened skin. These patches are usually reddish-brown and can either affect many parts of the body or occur in only a small area. They tend to be fixed, meaning they rarely spread or go away. However, the patches can vary in size and shape, and in some affected people they get larger over time. The areas of hyperkeratosis are generally symmetric, which means they occur in the same places on the right and left sides of the body.

    The second major feature of EKVP is patches of reddened skin called erythematous areas. Unlike the hyperkeratosis that occurs in this disorder, the erythematous areas are usually transient, which means they come and go. They vary in size, shape, and location, and can occur anywhere on the body. The redness is more common in childhood and can be triggered by sudden changes in temperature, emotional stress, or trauma or irritation to the area. It usually fades within hours to days.

    2. Frequency

    EKVP is a rare disorder; its prevalence is unknown. More than 200 cases have been reported in the medical literature.

    3. Causes

    EKVP can be caused by mutations in several genes, including GJB3, GJB4, and GJA1. These three genes provide instructions for making proteins called connexins 31, 30.3, and 43, respectively. These proteins are part of the connexin family, a group of proteins that form channels called gap junctions on the surface of cells. Gap junctions open and close to regulate the flow of nutrients, charged atoms (ions), and other signaling molecules from one cell to another. They are essential for direct communication between neighboring cells. Gap junctions formed with connexins 31, 30.3, and 43 are found in several tissues, including the outermost layer of skin (the epidermis).

    The GJB3, GJB4, and GJA1 gene mutations that lead to EKVP alter the structure or location of the connexins produced from these genes. Some GJB3 or GJB4 gene mutations lead to the production of abnormal connexins that can build up in a cell structure called the endoplasmic reticulum (ER), triggering a harmful process known as ER stress. Researchers suspect that ER stress damages cells in the epidermis and leads to their premature death. Other GJB3 or GJB4 gene mutations alter the flow of molecules through gap junctions, which may also lead to premature cell death in the epidermis. The mechanisms by which epidermal damage and cell death contribute to hyperkeratosis and erythematous areas are poorly understood.

    Mutations in the GJA1 gene lead to the production of an abnormal connexin 43 protein that is unable to reach the cell surface to become part of gap junctions. Instead, after it is produced, the abnormal protein becomes trapped in a cell structure called the Golgi apparatus. It is unclear how a shortage of connexin 43 at the cell surface affects the structure of gap junctions in the epidermis, or how these changes result in the skin abnormalities characteristic of EKVP.

    In some cases, people with EKVP do not have a known mutation in one of the three connexin genes described above. Mutations in at least one non-connexin gene have been reported in a very small number of affected people. Studies suggest that changes in other genes that have not been identified may also cause EKVP.

    4. Inheritance

    EKVP is most often inherited in an autosomal dominant pattern, which means one copy of an altered gene in each cell is sufficient to cause the disorder. In most cases, an affected person inherits the mutation from one affected parent. Other cases result from new gene mutations and occur in people with no history of the disorder in their family. Very rarely, the mutation is found in some of the body's cells but not others. In these individuals, the condition is described as mosaic EKVP or inflammatory linear verrucous epidermal nevus (ILVEN). In mosaic EKVP, the characteristic skin abnormalities affect a small region of the body and usually occur on just one side. They may follow a pattern on the skin known as the lines of Blaschko.

    A few studies have shown that EKVP can also have an autosomal recessive pattern of inheritance. However, this inheritance pattern has been reported in only a small number of affected families. Autosomal recessive inheritance means both copies of a gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

    5. Other Names for This Condition

    • EKV
    • EKV-P
    • EKVP
    • erythrokeratodermia variabilis
    • erythrokeratodermia variabilis of Mendes da Costa
    • erythrokeratodermia, progressive symmetric
    • progressive symmetrical erythrokeratoderma of Gottron

    This entry is adapted from https://medlineplus.gov/genetics/condition/erythrokeratodermia-variabilis-et-progressiva

    References

    1. Boyden LM, Craiglow BG, Zhou J, Hu R, Loring EC, Morel KD, Lauren CT, LiftonRP, Bilguvar K, Paller AS, Choate KA. Dominant De Novo Mutations in GJA1 CauseErythrokeratodermia Variabilis et Progressiva, without Features ofOculodentodigital Dysplasia. J Invest Dermatol. 2015 Jun;135(6):1540-1547. doi:10.1038/jid.2014.485.
    2. Boyden LM, Vincent NG, Zhou J, Hu R, Craiglow BG, Bayliss SJ, Rosman IS, LuckyAW, Diaz LA, Goldsmith LA, Paller AS, Lifton RP, Baserga SJ, Choate KA. Mutationsin KDSR Cause Recessive Progressive Symmetric Erythrokeratoderma. Am J Hum Genet.2017 Jun 1;100(6):978-984. doi: 10.1016/j.ajhg.2017.05.003.
    3. Chi J, Li L, Liu M, Tan J, Tang C, Pan Q, Wang D, Zhang Z. Pathogenicconnexin-31 forms constitutively active hemichannels to promote necrotic celldeath. PLoS One. 2012;7(2):e32531. doi: 10.1371/journal.pone.0032531.
    4. Deng Y, Wang H, Mou Y, Zeng Q, Xiong X. Exome sequencing identifies novelcompound heterozygous mutations in GJB3 gene that cause erythrokeratodermiavariabilis et progressiva. Australas J Dermatol. 2019 Feb;60(1):e87-e89. doi:10.1111/ajd.12887.
    5. Duchatelet S, Hovnanian A. Erythrokeratodermia variabilis et progressivaallelic to oculo-dento-digital dysplasia. J Invest Dermatol. 2015Jun;135(6):1475-1478. doi: 10.1038/jid.2014.535.
    6. Fuchs-Telem D, Pessach Y, Mevorah B, Shirazi I, Sarig O, Sprecher E.Erythrokeratoderma variabilis caused by a recessive mutation in GJB3. Clin ExpDermatol. 2011 Jun;36(4):406-11. doi: 10.1111/j.1365-2230.2010.03986.x.
    7. Gottfried I, Landau M, Glaser F, Di WL, Ophir J, Mevorah B, Ben-Tal N, KelsellDP, Avraham KB. A mutation in GJB3 is associated with recessiveerythrokeratodermia variabilis (EKV) and leads to defective trafficking of theconnexin 31 protein. Hum Mol Genet. 2002 May 15;11(11):1311-6.
    8. Ishida-Yamamoto A. Erythrokeratodermia variabilis et progressiva. J Dermatol. 2016 Mar;43(3):280-5. doi: 10.1111/1346-8138.13220. Review.
    9. Macari F, Landau M, Cousin P, Mevorah B, Brenner S, Panizzon R, Schorderet DF,Hohl D, Huber M. Mutation in the gene for connexin 30.3 in a family witherythrokeratodermia variabilis. Am J Hum Genet. 2000 Nov;67(5):1296-301.
    10. 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. Genetic heterogeneity in erythrokeratodermia variabilis: novel mutationsin the connexin gene GJB4 (Cx30.3) and genotype-phenotype correlations. J Invest Dermatol. 2003 Apr;120(4):601-9.
    11. Richard G, Smith LE, Bailey RA, Itin P, Hohl D, Epstein EH Jr, DiGiovanna JJ, Compton JG, Bale SJ. Mutations in the human connexin gene GJB3 causeerythrokeratodermia variabilis. Nat Genet. 1998 Dec;20(4):366-9.
    12. Umegaki-Arao N, Sasaki T, Fujita H, Aoki S, Kameyama K, Amagai M, Seishima M, Kubo A. Inflammatory Linear Verrucous Epidermal Nevus with a Postzygotic GJA1Mutation Is a Mosaic Erythrokeratodermia Variabilis et Progressiva. J InvestDermatol. 2017 Apr;137(4):967-970. doi: 10.1016/j.jid.2016.11.016.
    13. van Steensel MA, Oranje AP, van der Schroeff JG, Wagner A, van Geel M. Themissense mutation G12D in connexin30.3 can cause both erythrokeratodermiavariabilis of Mendes da Costa and progressive symmetric erythrokeratodermia ofGottron. Am J Med Genet A. 2009 Feb 15;149A(4):657-61. doi: 10.1002/ajmg.a.32744.
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