Characterization of the clinical and immunologic phenotype and management of 157 individuals with 56 distinct heterozygous NFKB1 mutations.
Characterization of the clinical and immunologic phenotype and management of 157 individuals with 56 distinct heterozygous NFKB1 mutations.
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DOI：
10.1016/j.jaci.2019.11.051
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发表时间：
2020-10
期刊：
影响因子：
--
通讯作者：
NIHR BioResource
中科院分区：
文献类型：
--
作者：
Lorenzini T;Fliegauf M;Klammer N;Frede N;Proietti M;Bulashevska A;Camacho-Ordonez N;Varjosalo M;Kinnunen M;de Vries E;van der Meer JWM;Ameratunga R;Roifman CM;Schejter YD;Kobbe R;Hautala T;Atschekzei F;Schmidt RE;Schröder C;Stepensky P;Shadur B;Pedroza LA;van der Flier M;Martínez-Gallo M;Gonzalez-Granado LI;Allende LM;Shcherbina A;Kuzmenko N;Zakharova V;Neves JF;Svec P;Fischer U;Ip W;Bartsch O;Barış S;Klein C;Geha R;Chou J;Alosaimi M;Weintraub L;Boztug K;Hirschmugl T;Dos Santos Vilela MM;Holzinger D;Seidl M;Lougaris V;Plebani A;Alsina L;Piquer-Gibert M;Deyà-Martínez A;Slade CA;Aghamohammadi A;Abolhassani H;Hammarström L;Kuismin O;Helminen M;Allen HL;Thaventhiran JE;Freeman AF;Cook M;Bakhtiar S;Christiansen M;Cunningham-Rundles C;Patel NC;Rae W;Niehues T;Brauer N;Syrjänen J;Seppänen MRJ;Burns SO;Tuijnenburg P;Kuijpers TW;NIHR BioResource;Warnatz K;Grimbacher B;NIHR BioResource
越来越多的NFKB1变异在异质免疫表型的患者中被发现。表征临床和细胞表型以及管理患者杂合NFKB1突变。在一项全球合作研究中，我们评估了231个携带105种不同杂合NFKB1变异的个体。为了提供致病性证据，每个变异都进行了计算机评估；此外，通过B细胞kappa轻多肽基因增强子核因子（NF-κB）信号传导的体外功能测试，对32个变异进行了评估。我们将来自68个不相关家族的157个个体的105个不同的NFKB1变异中的56个分类为致病性。观察到不完全临床外显率（70%）和nfkb1相关表型的年龄依赖性严重程度。表型包括低γ -球蛋白血症（88.9%），开关记忆B细胞减少（60.3%），呼吸（83%）和胃肠道（28.6%）感染，因此将该疾病表征为原发性免疫缺陷。然而，自身免疫（57.4%）、淋巴细胞增生（52.4%）、非感染性肠病（23.1%）、机会性感染（15.7%）、自身炎症（29.6%）和恶性肿瘤（16.8%）的高频率表明，NF-κ b1相关疾病是一种先天性免疫错误和免疫失调，而不仅仅是原发性免疫缺陷。目前的治疗包括免疫球蛋白替代和免疫抑制剂。我们对NF-κ b1相关表型进行了全面的临床综述，包括免疫缺陷、自身免疫、自身炎症和癌症。由于其涉及多系统，每个医学学科的临床医生都需要了解这种常染色体显性疾病。未来应考虑造血干细胞移植和NF-κB1通路靶向治疗策略。
An increasing number of NFKB1 variants are being identified in patients with heterogeneous immunologic phenotypes. To characterize the clinical and cellular phenotype as well as the management of patients with heterozygous NFKB1 mutations. In a worldwide collaborative effort, we evaluated 231 individuals harboring 105 distinct heterozygous NFKB1 variants. To provide evidence for pathogenicity, each variant was assessed in silico; in addition, 32 variants were assessed by functional in vitro testing of nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-κB) signaling. We classified 56 of the 105 distinct NFKB1 variants in 157 individuals from 68 unrelated families as pathogenic. Incomplete clinical penetrance (70%) and age-dependent severity of NFKB1-related phenotypes were observed. The phenotype included hypogammaglobulinemia (88.9%), reduced switched memory B cells (60.3%), and respiratory (83%) and gastrointestinal (28.6%) infections, thus characterizing the disorder as primary immunodeficiency. However, the high frequency of autoimmunity (57.4%), lymphoproliferation (52.4%), noninfectious enteropathy (23.1%), opportunistic infections (15.7%), autoinflammation (29.6%), and malignancy (16.8%) identified NF-κB1–related disease as an inborn error of immunity with immune dysregulation, rather than a mere primary immunodeficiency. Current treatment includes immunoglobulin replacement and immunosuppressive agents. We present a comprehensive clinical overview of the NF-κB1–related phenotype, which includes immunodeficiency, autoimmunity, autoinflammation, and cancer. Because of its multisystem involvement, clinicians from each and every medical discipline need to be made aware of this autosomal-dominant disease. Hematopoietic stem cell transplantation and NF-κB1 pathway–targeted therapeutic strategies should be considered in the future.
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影响因子：
7.3
作者：
Hoeger B;Serwas NK;Boztug K
通讯作者：
Boztug K
DOI：
10.1016/j.biocel.2007.05.004
发表时间：
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影响因子：
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14.2
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Warnatz, Klaus
影响因子：
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作者：
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通讯作者：
Plebani, Alessandro