Department of Dermatology, Faculdade de Medicina do ABC, Santo André, SP, Brazil.
Department of Reproductive Health and Populational Genetics, Faculdade de Medicina do ABC, Santo André, SP, Brazil.
Int J Dermatol. 2020 Jun;59(6):722-725. doi: 10.1111/ijd.14894. Epub 2020 Apr 20.
Erythrokeratodermas are a heterogeneous group of keratinization disorders. They are inherited in both autosomal dominant and autosomal recessive pattern. Erythrokeratoderma variabilis et progressive (EKVP) is a disorder caused by variations in genes that codify connexins (GJA1, GJB3, GJB4). The distinction between different phenotypes is not always simple. Age of presentation varies from birth to adulthood; stationary or migratory erythematous plaques associated with nonmigratory hyperkeratosis are characteristic of this disorder. Nails, hair, and teeth are not affected.
In order to describe the clinical phenotypes and molecular findings in a large Brazilian pedigree affected by erythrokeratoderma, we performed a clinical evaluation of four patients with different presentations of erythrokeratoderma from the same family, in which there are 35 affected members distributed in six generations. Genomic DNA evaluation by Sanger sequencing of GJB3 and GJB4 was performed in two affected family members with different phenotypes.
Clinical heterogeneity in affected patients was remarkable. In patients investigated with genetic testing, a heterozygous pathogenic gene variant in the GJB4 (gap junction protein beta-4) gene was found positive for GJB4:c.35G>A (rsrs80358211). One patient also presented a synonymous variant in GJB3:c.357C>T (rs41310442).
Variants in GJB4 are classically associated with Erythrokeratodermia variabilis, but there is remarkable clinical heterogeneity. Our observation that the same variant caused different phenotypes within the same family corroborates clinical heterogeneity and suggests that other genes that compose the genetic background exert some influence on the disease phenotype.
红皮角化病是一组异质性的角化障碍。它们以常染色体显性和常染色体隐性方式遗传。红斑角化病可变和进行性（EKVP）是一种由连接蛋白（GJA1、GJB3、GJB4）编码基因变异引起的疾病。不同表型之间的区别并不总是简单的。发病年龄从出生到成年不等；与非迁移性过度角化相关的静止或迁移性红斑是该疾病的特征。指甲、毛发和牙齿不受影响。
为了描述一个受红斑角化病影响的大型巴西家系的临床表型和分子发现，我们对来自同一家庭的 4 名具有不同红斑角化病表现的患者进行了临床评估，其中有 35 名受影响的成员分布在 6 代中。对 2 名具有不同表型的受影响家族成员进行 GJB3 和 GJB4 的 Sanger 测序基因组 DNA 评估。
受影响患者的临床异质性非常显著。在接受基因检测的患者中，GJB4（间隙连接蛋白β-4 基因）基因中的杂合致病性基因突变 GJB4：c.35G>A（rsrs80358211）为阳性。一名患者还存在 GJB3：c.357C>T（rs41310442）同义变异。
GJB4 中的变异经典地与红斑角化病可变相关，但存在显著的临床异质性。我们的观察结果表明，同一变异在同一家庭中引起不同的表型，这证实了临床异质性，并表明构成遗传背景的其他基因对疾病表型有一定影响。
