Department of Pediatrics, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
Institute of Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Berlin Institute of Health, Humboldt-Universität zu Berlin, Berlin, Germany.
Front Immunol. 2022 May 16;13:878989. doi: 10.3389/fimmu.2022.878989. eCollection 2022.
Atopic dermatitis (AD) affects up to 25% of children and 10% of adults in Western countries. When severe or recurrent infections and exceedingly elevated serum IgE levels occur in AD patients, an inborn error of immunity (IEI) may be suspected. The International Union of Immunological Societies classification lists variants in different genes responsible for so-called Hyper-IgE syndromes. Diagnosing an underlying IEI may influence treatment strategies.
Clinical and diagnostic workup of family members are presented including a detailed immunological description and histology of the carcinoma. Functional testing of the novel variant in underlying 'CARD11-associated atopy with dominant interference of NF-kB signaling' (CADINS) was performed.
We report on an 18-year-old patient with a long-standing history of infections, accompanied by hypogammaglobulinemia, intermittent agranulocytosis, atopy, eosinophilia and colitis. The working diagnosis of common variable immunodeficiency was revised when a novel heterozygous variant [c.223C>T; p.(Arg75Trp)] was identified. Functional studies confirmed this variant to have a dominant negative (DN) effect, as previously described in patients with CADINS. Five other family members were affected by severe atopy associated with the above variant, but not hypogammaglobulinemia. Malignancies occurred in two generations: an HPV-positive squamous cell carcinoma and a cutaneous T-cell lymphoma. So far, one patient is under treatment with dupilumab, which has shown marked benefit in controlling severe eczema.
The phenotypic spectrum associated with heterozygous DN mutations is broad. Partial T-cell deficiency, diminished IFN-γ cytokine and increased IL-4 production, were identified as disease-causing mechanisms. Malignant disease associated with germline DN variants has only been reported sporadically. HPV vaccination in teenage years, and cytology screening analogous with routine cervical swabs may be recommended. Treatment with dupilumab, a monoclonal antibody blocking interleukin-4- and interleukin-13 signaling, may be of benefit in controlling severe and extended AD for some patients as reported for STAT3 loss-of-function.
特应性皮炎（AD）在西方国家影响高达 25%的儿童和 10%的成年人。当 AD 患者出现严重或复发性感染和极高的血清 IgE 水平时，可能怀疑存在先天性免疫缺陷（IEI）。国际免疫学联合会分类列出了不同基因中导致所谓的高 IgE 综合征的变异。诊断潜在的 IEI 可能会影响治疗策略。
呈现了对家族成员的临床和诊断评估，包括详细的免疫学描述和癌组织学。对潜在的“CARD11 相关特应性伴 NF-kB 信号的显性干扰”（CADINS）中的新型变异进行了功能测试。
我们报告了一名 18 岁患者，其病史悠久，伴有感染、间歇性粒细胞减少症、特应性、嗜酸性粒细胞增多症和结肠炎。当发现一种新型杂合变异[c.223C>T;p.(Arg75Trp)]时，对常见可变免疫缺陷的工作诊断进行了修订。功能研究证实该变异具有显性负（DN）效应，正如先前在 CADINS 患者中所描述的那样。其他 5 名家族成员也受到严重特应性的影响，伴上述变异，但无低丙种球蛋白血症。两代表亲发生恶性肿瘤：HPV 阳性鳞状细胞癌和皮肤 T 细胞淋巴瘤。迄今为止，一名患者正在接受度普利尤单抗治疗，该治疗在控制严重湿疹方面显示出显著益处。
与杂合 DN 突变相关的表型谱很广。部分 T 细胞缺陷、IFN-γ细胞因子减少和 IL-4 产生增加被确定为致病机制。与种系 DN 变异相关的恶性疾病仅零星报道。建议青少年时期接种 HPV 疫苗，并进行细胞学筛查，类似于常规宫颈涂片。已有报道称，阻断白细胞介素-4 和白细胞介素-13 信号的单克隆抗体度普利尤单抗可用于控制某些患者的严重和广泛特应性皮炎，这可能对一些患者有益。
