Abstract：
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.
RESULTS: 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.
CONCLUSIONS: 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.
BACKGROUND: Deutsche Forschungsgemeinschaft under Germany\'s Excellence Strategy.
UNASSIGNED: For the German translation of the abstract see Supplementary Materials section.
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.
RESULTS: 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.
CONCLUSIONS: 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.
BACKGROUND: Deutsche Forschungsgemeinschaft under Germany\'s Excellence Strategy.
UNASSIGNED: For the German translation of the abstract see Supplementary Materials section.
摘要：
背景：淋巴增生和自身免疫性血细胞减少是自身免疫性淋巴增生综合征的特征。共有这些表现的其他病症被称为自身免疫性淋巴增生综合征样疾病。尽管它们通常更严重。这项研究的目的是定义遗传，临床,和这些疾病的免疫学特征，以提高其诊断分类。
方法：在这项前瞻性队列研究中，患者被转诊至弗莱堡慢性免疫缺陷中心，德国,2008年1月1日至2022年3月5日。我们招募了年龄小于18岁的淋巴增生和自身免疫性血细胞减少症患者，淋巴增殖和至少一个额外的迹象的一个先天的免疫错误（SoIEI），胆红素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个额外的SoIEI。在所有患者中确定了自身免疫性淋巴组织增生综合征的生物标志物。Sanger测序和深入的遗传学研究被推荐用于具有指示自身免疫性淋巴增生综合征的生物标志物的患者。而IEI面板，外显子组测序，或基因组测序被推荐用于没有此类生物标志物的患者.根据治疗医师的决定进行遗传分析。该研究已在德国临床试验登记册上注册，DRKS00011383，并且正在进行中。
结果：我们招募了431名接受自身免疫性淋巴增生综合征评估的儿童，其中236人（55％）是基于淋巴增生和自身免疫性血细胞减少症，148（34％）基于淋巴增生和另一个SoIEI，33（8％）的基础上的自身免疫性双环减少症，14（3％）基于自身免疫性血细胞减少症和另一个SoIEI。诊断评估时的中位年龄为9·8岁（IQR5·5-13·8），该队列包括279名(65%)男孩和152名(35%)女孩。经过生物标志物和遗传评估，在71例（16％）患者中诊断出自身免疫性淋巴增生综合征。在剩下的360名患者中，54（15％）主要是常染色体显性遗传的自身免疫淋巴增殖性免疫缺陷（AD-ALPID），最常见的影响JAK-STAT（26例患者），CTLA4-LRBA(14),PI3K(六),RAS（五），或NFκB（三）信号。19例(5%)患者有其他IEI，17人（5%）有非IEI诊断，79(22%)尽管有扩展遗传学(ALPID-U)，但仍未解决，191（53％）的基因检查不足以诊断。最终诊断为161例患者中有16例（10％）具有体细胞突变。符合常见可变免疫缺陷或Evans综合征标准的患者的替代分类并未增加遗传诊断的比例。
结论：本研究中定义的ALPID表型对于可通过靶向治疗治疗的遗传性疾病患者是丰富的。术语ALPID可能有助于通过触发扩展的遗传分析和考虑靶向治疗来集中诊断和治疗努力。包括一些目前被分类为常见可变免疫缺陷或Evans综合征的儿童。
背景：德国卓越战略下的德意志论坛。
■有关摘要的德语翻译，请参见补充材料部分。
方法：在这项前瞻性队列研究中，患者被转诊至弗莱堡慢性免疫缺陷中心，德国,2008年1月1日至2022年3月5日。我们招募了年龄小于18岁的淋巴增生和自身免疫性血细胞减少症患者，淋巴增殖和至少一个额外的迹象的一个先天的免疫错误（SoIEI），胆红素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个额外的SoIEI。在所有患者中确定了自身免疫性淋巴组织增生综合征的生物标志物。Sanger测序和深入的遗传学研究被推荐用于具有指示自身免疫性淋巴增生综合征的生物标志物的患者。而IEI面板，外显子组测序，或基因组测序被推荐用于没有此类生物标志物的患者.根据治疗医师的决定进行遗传分析。该研究已在德国临床试验登记册上注册，DRKS00011383，并且正在进行中。
结果：我们招募了431名接受自身免疫性淋巴增生综合征评估的儿童，其中236人（55％）是基于淋巴增生和自身免疫性血细胞减少症，148（34％）基于淋巴增生和另一个SoIEI，33（8％）的基础上的自身免疫性双环减少症，14（3％）基于自身免疫性血细胞减少症和另一个SoIEI。诊断评估时的中位年龄为9·8岁（IQR5·5-13·8），该队列包括279名(65%)男孩和152名(35%)女孩。经过生物标志物和遗传评估，在71例（16％）患者中诊断出自身免疫性淋巴增生综合征。在剩下的360名患者中，54（15％）主要是常染色体显性遗传的自身免疫淋巴增殖性免疫缺陷（AD-ALPID），最常见的影响JAK-STAT（26例患者），CTLA4-LRBA(14),PI3K(六),RAS（五），或NFκB（三）信号。19例(5%)患者有其他IEI，17人（5%）有非IEI诊断，79(22%)尽管有扩展遗传学(ALPID-U)，但仍未解决，191（53％）的基因检查不足以诊断。最终诊断为161例患者中有16例（10％）具有体细胞突变。符合常见可变免疫缺陷或Evans综合征标准的患者的替代分类并未增加遗传诊断的比例。
结论：本研究中定义的ALPID表型对于可通过靶向治疗治疗的遗传性疾病患者是丰富的。术语ALPID可能有助于通过触发扩展的遗传分析和考虑靶向治疗来集中诊断和治疗努力。包括一些目前被分类为常见可变免疫缺陷或Evans综合征的儿童。
背景：德国卓越战略下的德意志论坛。
■有关摘要的德语翻译，请参见补充材料部分。
