Department of Dermatology, Liverpool Hospital, Sydney, New South Wales, Australia.
University of New South Wales, Sydney, New South Wales, Australia.
Br J Dermatol. 2017 Oct;177(4):987-998. doi: 10.1111/bjd.15441. Epub 2017 Sep 20.
Hidradenitis suppurativa (HS) is a severe chronic inflammatory disorder characterized by recurrent painful deep-seated nodules with a predilection to the apocrine-bearing areas of skin. A minority of cases of HS are due to mutations in the γ-secretase complex. Contention exists surrounding the pathogenicity of sequence variants and their effects upon Notch signalling. This systematic review was registered with PROSPERO (CRD42016041425) and was conducted in line with the PRISMA statement. Eligibility criteria for this review included published case reports, case series and reviews that identified sequence variants or protein or functional studies from patients with HS. Sixty-two articles were identified reporting a total of 41 sequence variants - heterozygous missense (nine), splice site (nine), insertion resulting in frameshift (one), premature termination codon (19) and promoter region PSTPIP1 (three) - with 18 associated protein or functional studies. The American College of Medical Genetics and Genomics standards and guidelines on the interpretation of sequence variants were applied to each identified variant to assess evidence for pathogenicity. Twenty-three variants were assessed as likely pathogenic, 17 of uncertain significance and one benign. The large number of variants of 'uncertain significance' is largely due to the variable number of functional studies. Four studies used Notch as a proxy for γ-secretase function, with conclusions of nonpathogenicity based on the assumption of Notch signalling as the sole pathogenic process. The role of Notch-independent signalling mechanisms requires further research. Limitations to this study include identification of variants of Mendelian inheritance and not complex polygenic traits.
化脓性汗腺炎（HS）是一种严重的慢性炎症性疾病，其特征是反复发作的疼痛性深部结节，偏爱顶泌汗腺分布的皮肤区域。少数 HS 病例是由于 γ-分泌酶复合物的突变引起的。关于序列变异的致病性及其对 Notch 信号的影响存在争议。这项系统评价已在 PROSPERO（CRD42016041425）上注册，并按照 PRISMA 声明进行。本综述的纳入标准包括发表的病例报告、病例系列和综述，这些报告确定了 HS 患者的序列变异、蛋白质或功能研究。确定了 62 篇文章，共报道了 41 个序列变异 - 杂合错义（9 个）、剪接位点（9 个）、插入导致移码（1 个）、提前终止密码子（19 个）和启动子区域 PSTPIP1（3 个）- 其中 18 个与蛋白质或功能研究相关。应用美国医学遗传学和基因组学学院关于序列变异解释的标准和指南，对每个确定的变异进行评估，以评估其致病性证据。23 个变异被评估为可能致病性，17 个为意义不明，1 个为良性。大量的“意义不明”变异主要是由于功能研究的数量不同。有四项研究使用 Notch 作为 γ-分泌酶功能的替代物，基于 Notch 信号作为唯一致病过程的假设得出非致病性结论。 Notch 非依赖性信号机制的作用需要进一步研究。本研究的局限性包括确定孟德尔遗传变异和复杂多基因特征的识别。
