Severe combined immunodeficiency (SCID) disorders compromise lymphocyte numbers and/or function. One subset of SCID typically affects T cell and Natural Killer (NK) cell development in tandem (T-B+NK-) due to mutations arising in the genes encoding the common γ chain or Janus Kinase 3 (JAK3). In rare circumstances, mutations in the JAK3 gene have been reported to cause atypical SCID that selectively affects T cells (T-B+NK+). Here we describe a case involving a female infant who was referred to our institution on day nine of life following an abnormal newborn screen result for T-SCID. Immunological assessments revealed a T-B+NK+ phenotype and molecular analyses, including whole exome sequencing, identified compound heterozygous JAK3 variants (R117C and E658K). Pre-transplant phosflow analyses revealed a persistent IL-7 signaling defect, based on phospho-STAT5 measurements, only in CD8 but not CD4 T cells. Intriguingly, phospho-STAT5 signals in response to IL-2 stimulation were not affected in either CD4 or CD8 T cells. The pre-transplant clinical course was unremarkable, and the patient received a cord-blood stem cell transplant on day 716 of life. Post-transplant monitoring revealed that despite normalization of lymphocyte counts, the CD8 T cell-restricted IL-7 signaling defect was still evident at day 627 post-transplant (phospho-STAT5 signal in CD8 T cells was > 60% reduced compared with CD4 T cells). The post-transplant clinical course has also been complicated by identification of autoimmune responses and likely GVHD-induced ichthyosis. To the best of our knowledge, this report represents the third case of JAK3-associated atypical SCID reported in the literature.

中文翻译：

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一例带有Janus激酶3缺陷相关的非典型严重联合免疫缺陷的CD8 T细胞限制性IL-7信号异常的病例。

严重的联合免疫缺陷（SCID）疾病会损害淋巴细胞数量和/或功能。SCID的一个子集通常会由于编码共同γ链或Janus Kinase 3（JAK3）的基因中发生突变而串联（T-B + NK-）影响T细胞和自然杀伤（NK）细胞的发育。在极少数情况下，据报道，JAK3基因的突变会导致非典型SCID，选择性地影响T细胞（T-B + NK +）。在这里，我们描述了一名婴儿，该婴儿在T-SCID的新生儿筛查结果异常后的生命的第9天被转诊到我们的机构。免疫学评估显示T-B + NK +表型和分子分析，包括整个外显子组测序，鉴定出复合杂合JAK3变体（R117C和E658K）。移植前的光流分析表明存在持续的IL-7信号缺陷，根据磷酸STAT5测量结果，仅在CD8 T细胞中存在，而在CD4 T细胞中没有。有趣的是，响应IL-2刺激的磷酸STAT5信号在CD4或CD8 T细胞中均不受影响。移植前的临床过程并不明显，患者在生命的第716天接受了脐血干细胞移植。移植后监测表明，尽管淋巴细胞计数正常化，但在移植后第627天，CD8 T细胞限制性IL-7信号缺陷仍然明显（与CD4 T相比，CD8 T细胞中的磷酸STAT5信号降低了60％以上）细胞）。鉴定自身免疫反应和可能的GVHD诱导的鱼鳞病也使移植后的临床过程复杂化。据我们所知，本报告代表文献中报道的第三例与JAK3相关的非典型SCID。