Academic Department of Pediatrics (DPUO), Immune and Infectious Diseases Division, Research Unit of Primary Immunodeficiencies, Bambino Gesù Children's Hospital, IRCCS, 00165, Rome, Italy.
Chair of Pediatrics, Department of Systems Medicine, University of Rome "Tor Vergata", via Montpellier, 1, 00133, Rome, Italy.
J Clin Immunol. 2022 Jan;42(1):130-145. doi: 10.1007/s10875-021-01130-3. Epub 2021 Oct 18.
We described clinical, immunological, and molecular characterization within a cohort of 22 RAG patients focused on the possible correlation between clinical and genetic data.
Immunological and genetic features were investigated by multiparametric flow cytometry and by Sanger or next generation sequencing (NGS) as appropriate.
Patients represented a broad spectrum of RAG deficiencies: SCID, OS, LS/AS, and CID. Three novel mutations in RAG1 gene and one in RAG2 were reported. The primary symptom at presentation was infections (81.8%). Infections and autoimmunity occurred together in the majority of cases (63.6%). Fifteen out of 22 (68.2%) patients presented autoimmune or inflammatory manifestations. Five patients experienced severe autoimmune cytopenia refractory to different lines of therapy. Total lymphocytes count was reduced or almost lacking in SCID group and higher in OS patients. B lymphocytes were variably detected in LS/AS and CID groups. Eighteen patients underwent HSCT permitting definitive control of autoimmune/hyperinflammatory manifestations in twelve of them (80%).
We reinforce the notion that different clinical phenotype can be found in patients with identical mutations even within the same family. Infections may influence genotype-phenotype correlation and function as trigger for immune dysregulation or autoimmune manifestations. Severe and early autoimmune refractory cytopenia is frequent and could be the first symptom of onset. Prompt recognition of RAG deficiency in patients with early onset of autoimmune/hyperinflammatory manifestations could contribute to the choice of a timely and specific treatment preventing the onset of other complications.
我们描述了 22 例 RAG 患者的临床、免疫和分子特征，重点关注临床和遗传数据之间的可能相关性。
通过多参数流式细胞术以及适当的 Sanger 或下一代测序（NGS）来研究免疫和遗传特征。
患者代表了 RAG 缺陷的广泛谱：SCID、OS、LS/AS 和 CID。报告了 RAG1 基因中的三个新突变和一个 RAG2 突变。首发症状为感染（81.8%）。大多数情况下，感染和自身免疫同时发生（63.6%）。22 例中有 15 例（68.2%）患者出现自身免疫或炎症表现。5 例患者发生严重自身免疫性血细胞减少症，对不同治疗方案均无反应。SCID 组的总淋巴细胞计数减少或几乎缺乏，而 OS 患者的总淋巴细胞计数较高。LS/AS 和 CID 组中可变地检测到 B 淋巴细胞。18 例患者接受了 HSCT，其中 12 例（80%）患者能够明确控制自身免疫/炎症表现。
我们强化了这样一种观念，即在同一家庭内，即使存在相同的突变，也可以发现不同的临床表型。感染可能影响基因型-表型相关性，并作为免疫失调或自身免疫表现的触发因素。严重且早期的自身免疫性难治性血细胞减少症较为常见，且可能是发病的首发症状。在自身免疫/炎症表现早期发病的患者中，及时识别 RAG 缺陷有助于选择及时且特异性的治疗方案，从而预防其他并发症的发生。
