Genetic studies have led to identification of an increasing number of monogenic primary immunodeficiency disorders. Monoallelic pathogenic gain-of-function (GOF) variants in NFKBIA, the gene encoding IκBα, result in an immunodeficiency disorder, typically accompanied by anhidrotic ectodermal dysplasia (EDA). So far, 14 patients with immunodeficiency due to NFKBIA GOF mutations have been reported. In this study we report three patients from the same family with immunodeficiency, presenting with recurrent respiratory tract infections, bronchiectasis and viral skin conditions due to a novel pathogenic NFKBIA variant (c.106 T > G, p.Ser36Ala), which results in reduced IκBα degradation. Immunological investigations revealed inadequate antibody responses against vaccine antigens, despite hypergammaglobulinemia. Interestingly, none of the studied patients displayed features of EDA. Therefore, missense NFKBIA variants substituting serine 36 of IκBα, differ from the rest of pathogenic GOF NFKBIA variants in that they cause combined immunodeficiency, even in the absence of EDA.

中文翻译：

---

在没有外胚层发育异常的情况下，一种新的NFKBIA变体取代了IκBα的丝氨酸36导致了疣，支气管扩张和青少年类风湿性关节炎的免疫缺陷。

遗传研究已导致鉴定出越来越多的单基因原发性免疫缺陷疾病。编码IκBα的基因NFKBIA中的单等位基因致病性功能获得（GOF）变异会导致免疫缺陷症，通常伴有无角质外胚层发育不良（EDA）。迄今为止，已有14例因NFKBIA GOF突变而导致免疫缺陷的患者的报道。在这项研究中，我们报告了来自同一家族的三名免疫缺陷患者，由于新的致病性NFKBIA变异（c.106 T> G，p.Ser36Ala）而出现了反复呼吸道感染，支气管扩张和病毒性皮肤病，从而降低了病情。 IκBα降解。免疫学调查显示，尽管存在高球蛋白血症，但针对疫苗抗原的抗体反应不足。有趣的是，没有研究的患者表现出EDA的特征。因此，替代IκBα丝氨酸36的错义NFKBIA变体与其余的病原性GOF NFKBIA变体的不同之处在于，即使在没有EDA的情况下，它们也会引起联合免疫缺陷。