Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Boston, Mass.
Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh Medical Center, Pittsburgh, Pa.
J Allergy Clin Immunol Pract. 2021 Feb;9(2):723-732.e3. doi: 10.1016/j.jaip.2020.08.008. Epub 2020 Aug 17.
The introduction of newborn screening for severe combined immunodeficiencies (NBS SCID) in 2010 was a significant public health milestone. Although SCID was the primary target, several other conditions associated with severe T-cell lymphopenia have subsequently been identified as secondary targets. The differential diagnosis in infants with an abnormal T-cell receptor excision circle result on NBS SCID who do not meet criteria for typical SCID is often broad, and often the evaluation of these conditions requires immunological and functional testing, in conjunction with genetic analysis, to obtain an accurate diagnosis and develop an appropriate management and treatment plan.
We describe here 3 infants identified by NBS SCID, who required additional workup as they did not have a typical SCID phenotype and meet the relevant diagnostic criteria. Genetic testing identified pathogenic variants in ATM in all 3 patients, and the pathogenicity of the variants was confirmed by a functional flow cytometry assay.
The patients underwent immunological and genetic workup to identify an underlying cause of their abnormal NBS SCID. Ataxia telangiectasia (AT) was suspected based on clinical and family history, and immunological analyses. The diagnosis was confirmed in all patients with a rapid functional flow cytometric assay and genetic testing.
A rapid functional flow cytometry assay was used as a diagnostic and confirmatory tool, in conjunction with genetic testing, to make a diagnosis of AT. Experimental validation of the causal relationship between genotype and phenotype allowed for expeditious diagnosis, which facilitated early discussions with families regarding prognosis, treatment, and management.
Even with increased rapidity and access to genetic results, functional testing is required for clinical diagnosis in infants identified by NBS SCID who do not fit into the classic categories or have novel genetic variants to confirm the diagnosis. Consideration should be given to the use of functional assays as an essential component of an integrated evaluation to characterize the genetics and mechanisms of inborn errors of immunity.
2010 年新生儿严重联合免疫缺陷病（NBS SCID）筛查的引入是一个重大的公共卫生里程碑。虽然 SCID 是主要目标，但随后发现与严重 T 细胞淋巴细胞减少症相关的其他几种疾病也作为次要目标。在 NBS SCID 中，T 细胞受体切除环结果异常但不符合典型 SCID 标准的婴儿的鉴别诊断通常很广泛，通常需要进行免疫和功能测试，同时结合遗传分析，以获得准确的诊断并制定适当的管理和治疗计划。
我们在这里描述了 3 名通过 NBS SCID 鉴定的婴儿，由于他们没有典型的 SCID 表型且不符合相关诊断标准，因此需要进一步检查。所有 3 名患者的基因检测均发现 ATM 中的致病性变异，通过功能流式细胞术检测证实了变异的致病性。
患者接受了免疫和遗传检查，以确定其异常 NBS SCID 的潜在原因。根据临床和家族史以及免疫分析，怀疑为共济失调毛细血管扩张症（AT）。所有患者均通过快速功能流式细胞术检测和基因检测确诊。
快速功能流式细胞术检测被用作诊断和确认工具，与基因检测相结合，用于诊断 AT。对基因型与表型之间因果关系的实验验证允许快速诊断，从而促进了与患者家属就预后、治疗和管理进行早期讨论。
即使快速获得遗传结果，对于不符合经典分类或具有新基因突变的通过 NBS SCID 鉴定的婴儿，仍需要进行功能测试以进行临床诊断。应考虑将功能检测作为综合评估的重要组成部分，以描述先天性免疫缺陷的遗传学和机制。
