Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah-Hebrew University Hospital, POB 12000, 91200, Jerusalem, Israel.
Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg and Faculty of Medicine, University of Freiburg, Freiburg, Germany.
J Clin Immunol. 2018 May;38(4):527-536. doi: 10.1007/s10875-018-0514-y. Epub 2018 Jun 9.
All reported patients with hypomorphic X-linked severe combined immunodeficiency (X-SCID) due to c.664C>T (p.R222C) mutations in the gene (IL2RG) encoding the common γ chain (γc) have presented with opportunistic infections within the first year of life, despite the presence of nearly normal NK and T cell numbers. Reporting five children of one extended family with hemizygous mutations in IL2RG, we explore potential diagnostic clues and extend our comprehension of the functional impact of this mutation.
Whole exome sequencing (WES); detailed immune phenotyping; cytokine-induced STAT phosphorylation; B, T, and NK cell activation; and quantification of sjTRECs in five Arab children with c.664C>T (p.R222C) IL2RG mutation.
The mean age at clinical presentation with respiratory tract infection or diarrhea was 6.8 (range: 2-12) months. None of the children presented with opportunistic infections. Diagnostic clues were early onset in the first year of life, and a suggestive family history associated with reduced naïve CD4 T cells and absent switched memory B cells. Number and phenotype of NK cells and innate-like lymphocytes were normal. The diagnosis was made by WES and corroborated by absent STAT phosphorylation and reduced functional response after IL-2 and IL-21 stimulation. Four patients underwent successful hematopoietic stem cell transplantation.
As early diagnosis and treatment are important, a high index of suspicion in the diagnosis of c.664C>T (p.R222C) X-SCID is needed. This requires prompt genetic testing by next generation sequencing in order to avoid unnecessary delays in the definite diagnosis since immunological work up may not be discriminating. Assays directly testing cytokine signaling or cytokine-dependent functions are helpful in confirming the functional impact of the identified hypomorphic variants.
所有报道的由于基因（IL2RG）编码共同γ链（γc）的 c.664C>T（p.R222C）突变导致的低功能 X 连锁严重联合免疫缺陷（X-SCID）患者，尽管 NK 和 T 细胞数量几乎正常，但在生命的第一年都会出现机会性感染。报告一个扩展家族的五个孩子存在 IL2RG 半合子突变，我们探索了潜在的诊断线索，并扩展了对该突变的功能影响的理解。
全外显子组测序（WES）；详细的免疫表型分析；细胞因子诱导的 STAT 磷酸化；B、T 和 NK 细胞激活；以及 5 名具有 c.664C>T（p.R222C）IL2RG 突变的阿拉伯儿童的 sjTRECs 定量。
呼吸道感染或腹泻的临床发作的平均年龄为 6.8 个月（范围：2-12 个月）。没有儿童出现机会性感染。诊断线索是在生命的第一年早期发病，以及提示家族史，伴有幼稚 CD4 T 细胞减少和未转换的记忆 B 细胞缺失。NK 细胞和先天样淋巴细胞的数量和表型正常。通过 WES 做出诊断，并通过缺乏 STAT 磷酸化和 IL-2 和 IL-21 刺激后的功能反应降低得到证实。四名患者接受了成功的造血干细胞移植。
由于早期诊断和治疗很重要，因此需要高度怀疑 c.664C>T（p.R222C）X-SCID 的诊断。这需要通过下一代测序进行快速基因测试，以避免因免疫检查结果无特异性而导致的不必要的诊断延误。直接测试细胞因子信号或细胞因子依赖性功能的检测有助于确认鉴定的低功能变体的功能影响。
