Background

Lymphoproliferation and autoimmune cytopenias characterise autoimmune lymphoproliferative syndrome. Other conditions sharing these manifestations have been termed autoimmune lymphoproliferative syndrome-like diseases, although they are frequently more severe. The aim of this study was to define the genetic, clinical, and immunological features of these disorders to improve their diagnostic classification.

Methods

In this prospective cohort study, patients were referred to the Center for Chronic Immunodeficiency in Freiburg, Germany, between Jan 1, 2008 and March 5, 2022. We enrolled patients younger than 18 years with lymphoproliferation and autoimmune cytopenia, lymphoproliferation and at least one additional sign of an inborn error of immunity (SoIEI), bilineage autoimmune cytopenia, or autoimmune cytopenia and at least one additional SoIEI. Autoimmune lymphoproliferative syndrome biomarkers were determined in all patients. Sanger sequencing followed by in-depth genetic studies were recommended for patients with biomarkers indicative of autoimmune lymphoproliferative syndrome, while IEI panels, exome sequencing, or genome sequencing were recommended for patients without such biomarkers. Genetic analyses were done as decided by the treating physician. The study was registered on the German Clinical Trials Register, DRKS00011383, and is ongoing.

Findings

We recruited 431 children referred for autoimmune lymphoproliferative syndrome evaluation, of whom 236 (55%) were included on the basis of lymphoproliferation and autoimmune cytopenia, 148 (34%) on the basis of lymphoproliferation and another SoIEI, 33 (8%) on the basis of autoimmune bicytopenia, and 14 (3%) on the basis of autoimmune cytopenia and another SoIEI. Median age at diagnostic evaluation was 9·8 years (IQR 5·5–13·8), and the cohort comprised 279 (65%) boys and 152 (35%) girls. After biomarker and genetic assessments, autoimmune lymphoproliferative syndrome was diagnosed in 71 (16%) patients. Among the remaining 360 patients, 54 (15%) had mostly autosomal-dominant autoimmune lymphoproliferative immunodeficiencies (AD-ALPID), most commonly affecting JAK-STAT (26 patients), CTLA4-LRBA (14), PI3K (six), RAS (five), or NFκB (three) signalling. 19 (5%) patients had other IEIs, 17 (5%) had non-IEI diagnoses, 79 (22%) were unresolved despite extended genetics (ALPID-U), and 191 (53%) had insufficient genetic workup for diagnosis. 16 (10%) of 161 patients with a final diagnosis had somatic mutations. Alternative classification of patients fulfilling common variable immunodeficiency or Evans syndrome criteria did not increase the proportion of genetic diagnoses.

Interpretation

The ALPID phenotype defined in this study is enriched for patients with genetic diseases treatable with targeted therapies. The term ALPID might be useful to focus diagnostic and therapeutic efforts by triggering extended genetic analysis and consideration of targeted therapies, including in some children currently classified as having common variable immunodeficiency or Evans syndrome.

Funding

Deutsche Forschungsgemeinschaft under Germany's Excellence Strategy.

Translation

For the German translation of the abstract see Supplementary Materials section.

中文翻译：

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儿科自身免疫性淋巴增殖性免疫缺陷 (ALPID) 的诊断评估：一项前瞻性队列研究

背景

淋巴细胞增殖和自身免疫性血细胞减少是自身免疫性淋巴细胞增殖综合征的特征。其他具有这些表现的疾病被称为自身免疫性淋巴增殖综合征样疾病，尽管它们通常更严重。本研究的目的是确定这些疾病的遗传、临床和免疫学特征，以改进其诊断分类。

方法

在这项前瞻性队列研究中，患者于 2008 年 1 月 1 日至 2022 年 3 月 5 日期间被转诊至德国弗莱堡慢性免疫缺陷中心。我们招募了年龄小于 18 岁、患有淋巴组织增生和自身免疫性血细胞减少症、淋巴组织增生以及至少一项其他疾病的患者。先天性免疫缺陷 (SoIEI)、双系自身免疫性血细胞减少症或自身免疫性血细胞减少症和至少一种其他 SoIEI 的迹象。对所有患者进行自身免疫性淋巴增殖综合征生物标志物测定。对于具有表明自身免疫性淋巴增殖综合征的生物标志物的患者，建议进行桑格测序，然后进行深入的遗传学研究，而对于没有此类生物标志物的患者，建议进行IEI panel、外显子组测序或基因组测序。遗传分析是根据治疗医生的决定进行的。该研究已在德国临床试验注册处注册，DRKS00011383，并且正在进行中。

发现

我们招募了 431 名转诊进行自身免疫性淋巴细胞增殖综合征评估的儿童，其中 236 名（55%）基于淋巴细胞增殖和自身免疫性血细胞减少纳入，148 名（34%）基于淋巴细胞增殖和另一项 SoIEI 纳入，33 名（8%）基于淋巴细胞增殖和自身免疫性血细胞减少纳入评估。自身免疫性双血细胞减少症的基础上，14 例（3%）基于自身免疫性血细胞减少症和另一种 SoIEI。诊断评估时的中位年龄为 9·8 岁（IQR 5·5–13·8），该队列由 279 名男孩（65%）和 152 名女孩（35%）组成。经过生物标志物和遗传评估后，71 名 (16%) 患者被诊断为自身免疫性淋巴增殖综合征。在其余 360 名患者中，54 名 (15%) 大多患有常染色体显性自身免疫性淋巴增殖性免疫缺陷 (AD-ALPID)，最常影响 JAK-STAT（26 名患者）、CTLA4-LRBA（14 名）、PI3K（6 名）、RAS（五) 或 NFκB (三) 信号传导。19 名 (5%) 患者有其他 IEI，17 名 (5%) 患者有非 IEI 诊断，79 名 (22%) 患者尽管进行了扩展遗传学 (ALPID-U) 仍未得到解决，191 名 (53%) 患者的基因检查不足以诊断。最终诊断的 161 名患者中有 16 名（10%）患有体细胞突变。满足常见变异免疫缺陷或埃文斯综合征标准的患者的替代分类并没有增加基因诊断的比例。

解释

本研究中定义的 ALPID 表型丰富了患有可通过靶向治疗治疗的遗传性疾病的患者。ALPID 一词可能有助于通过触发扩展的基因分析和考虑靶向治疗来集中诊断和治疗工作，包括目前被归类为患有常见变异性免疫缺陷或埃文斯综合征的一些儿童。

资金

德国卓越战略下的德国研究联盟。

翻译

有关摘要的德语翻译，请参阅补充材料部分。