Vaccine-associated varicella and rubella infections in severe combined immunodeficiency with isolated CD4 lymphocytopenia and mutations in IL7R detected by tandem whole exome sequencing and chromosomal microarray
Vaccine-associated varicella and rubella infections in severe combined immunodeficiency with isolated CD4 lymphocytopenia and mutations in IL7R detected by tandem whole exome sequencing and chromosomal microarray
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DOI：
10.1111/cei.12421
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发表时间：
2014-12-01
影响因子：
4.6
通讯作者：
Stray-Pedersen, A.
中科院分区：
文献类型：
--
作者：
Bayer, D. K.;Martinez, C. A.;Stray-Pedersen, A.
在没有新生儿重症联合免疫缺陷（SCID）筛查的地区，疾病定义的感染可能导致诊断，在某些情况下，可能无法在生命的第一年之前确定。我们描述了一个女婴谁提出了传播疫苗获得性水痘（VZV）和疫苗获得性风疹感染在13个月大。免疫学评价显示中性粒细胞减少、孤立性CD 4淋巴细胞减少、存在CD 8（+）T细胞、淋巴细胞增殖不良、高丙种球蛋白血症和VZV感染和常规免疫的特异性抗体产生不良。全外显子组测序和定制设计的染色体微阵列与原发性免疫缺陷基因的外显子覆盖相结合，检测到IL 7 R基因内的复合杂合突变（一个单核苷酸变异和一个涉及一个外显子的基因内拷贝数变异）。在移植前血液和口腔DNA中检测到野生型等位基因的嵌合体（20-30%），并且在移植前血液DNA中证明了母体植入（5-10%）。与经典的白细胞介素（IL）-7R缺乏症相比，这可能是患者不寻常的免疫表型的原因。经抗病毒和免疫治疗，播散性VZV得到控制，脐带血干细胞移植获得成功。在新生儿古特里卡上完成的逆行性T细胞受体切除环（TREC）分析鉴定出TREC缺失。该病例强调了重症联合免疫缺陷（SCID）患者接种活病毒疫苗的危险性，以及新生儿筛查在高危暴露前识别患者的重要性。它还说明了侵袭性病原体识别和治疗的价值，新生儿筛查对发病率和死亡率的影响，以及更新的基因组诊断工具在识别SCID患者潜在遗传病因方面的重大影响。
In areas without newborn screening for severe combined immunodeficiency (SCID), disease-defining infections may lead to diagnosis, and in some cases, may not be identified prior to the first year of life. We describe a female infant who presented with disseminated vaccine-acquired varicella (VZV) and vaccine-acquired rubella infections at 13 months of age. Immunological evaluations demonstrated neutropenia, isolated CD4 lymphocytopenia, the presence of CD8(+) T cells, poor lymphocyte proliferation, hypergammaglobulinaemia and poor specific antibody production to VZV infection and routine immunizations. A combination of whole exome sequencing and custom-designed chromosomal microarray with exon coverage of primary immunodeficiency genes detected compound heterozygous mutations (one single nucleotide variant and one intragenic copy number variant involving one exon) within the IL7R gene. Mosaicism for wild-type allele (20-30%) was detected in pretransplant blood and buccal DNA and maternal engraftment (5-10%) demonstrated in pretransplant blood DNA. This may be responsible for the patient's unusual immunological phenotype compared to classical interleukin (IL)-7R deficiency. Disseminated VZV was controlled with anti-viral and immune-based therapy, and umbilical cord blood stem cell transplantation was successful. Retrospectively performed T cell receptor excision circle (TREC) analyses completed on neonatal Guthrie cards identified absent TREC. This case emphasizes the danger of live viral vaccination in severe combined immunodeficiency (SCID) patients and the importance of newborn screening to identify patients prior to high-risk exposures. It also illustrates the value of aggressive pathogen identification and treatment, the influence newborn screening can have on morbidity and mortality and the significant impact of newer genomic diagnostic tools in identifying the underlying genetic aetiology for SCID patients.