Atypical epidermolytic palmoplantar keratoderma presentation associated with a mutation in the keratin 1 gene
Atypical epidermolytic palmoplantar keratoderma presentation associated with a mutation in the keratin 1 gene
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DOI：
10.1111/j.1365-2133.2004.05967.x
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发表时间：
2004-06-01
影响因子：
10.3
通讯作者：
McLean, WHI
中科院分区：
文献类型：
--
作者：
Terron-Kwiatkowski, A;Terrinoni, A;McLean, WHI
背景：表皮松解性掌跖角化病(EPPK)是一种常染色体显性遗传性皮肤病，其特征是严格局限于手掌和足底的表皮松解性角化过度，通常与角蛋白K9基因(KRT9)的突变有关。角蛋白K1基因(KRT1)突变是泛发性表皮松解性角化过度症的多种表型的基础，但在某些情况下，表型可能更具地域性限制。目的确定两个最初表现为EPPK的无关家系的遗传缺陷，但仔细检查发现角化过度症延伸至腕屈曲近端。方法连锁分析和DNA测序。结果发现该表型是由K1基因杂合错义突变引起的，编号为1479T。这种突变存在于高度保守的K1螺旋末端基序中，此前已证明K1对角蛋白组装和细丝形成具有重要作用。一般来说，角蛋白这一区域的突变与更严重的疾病表型有关。然而，该区域的K1突变，特别是1479T突变，以前曾与重度和轻度大疱性先天性鱼鳞状红皮病表型相关。当进一步的临床询问时，在本研究的家系中发现几个受影响的个体在新生儿期有一过性屈曲脱皮和角化过度。结论K1突变可能是一种与EPPK非常相似的表型。儿童时期有一过性屈曲剥离和角化过度的病史，以及延伸到掌底边缘以外的掌跖角化病，可能提示K1突变，而不是K9缺陷。由于K1突变也与严重的广泛性表型有关，对预后和遗传咨询具有重要意义，建议对出现EPPK的患者进行全身检查。
Background Epidermolytic palmoplantar keratoderma (EPPK) is an autosomal dominant genodermatosis characterized by epidermolytic hyperkeratosis strictly confined to the palms and soles, and usually associated with mutations in the keratin K9 gene (KRT9). Mutations in the keratin K1 gene (KRT1) have been shown to underlie a variety of phenotypes typically involving generalized epidermolytic hyperkeratosis, but in some cases the phenotype can be more regionally restricted.Objectives To identify the genetic defect in two unrelated families initially presenting with EPPK but where careful examination revealed hyperkeratosis extending on to the proximal wrist flexure.Methods Linkage analysis and DNA sequencing.Results We found that this phenotype is caused by a heterozygous missense mutation in the K1 gene, designated 1479T. This mutation lies in the highly conserved helix termination motif of K1, previously shown to be important for keratin assembly and filament formation. In general, mutations in this region of keratins are associated with more severe disease phenotypes. However, K1 mutations in this region and the 1479T mutation in particular have previously been associated with both severe and mild bullous congenital ichthyosiform erythroderma phenotypes. When further clinical enquiries were made, several affected individuals in the families studied here were found to have had transient flexural peeling and hyperkeratosis in the neonatal period.Conclusions K1 mutations may underlie a phenotype closely resembling EPPK. A history of transient flexural peeling and hyperkeratosis in childhood and palmoplantar keratoderma which extends beyond the boundary of the palmoplantar margins may indicate a K1 mutation rather than a K9 defect. As K1 mutations are also associated with severe widespread phenotypes, with important implications for prognostic and genetic counselling, whole body examination is recommended for patients presenting with EPPK.