Purpose

More than 50 different monogenic disorders causing inflammatory bowel disease (IBD) have been identified. Our goal was to characterize the clinical phenotype, genetic workup, and immunologic alterations in an Ashkenazi Jewish patient that presented during infancy with ulcerative colitis and unique clinical manifestations.

Methods

Immune workup and whole-exome sequencing were performed, along with Sanger sequencing for confirmation. Next-generation sequencing of the TCRB and IgH was conducted for immune repertoire analysis. Telomere length was evaluated by in-gel hybridization assay. Mass cytometry was performed on patient’s peripheral blood mononuclear cells, and compared with control subjects and patients with UC.

Results

The patient presented in infancy with failure to thrive and dysmorphic features, consistent with a diagnosis of dyskeratosis congenita and Hoyeraal-Hreidarsson syndrome. Severe ulcerative colitis manifested in the first year of life and proceeded to the development of a primary immunodeficiency, presenting as Pneumocystis jiroveci pneumonia and hypogammaglobulinemia. Genetic studies identified a deleterious homozygous C.3791G>A missense mutation in the helicase regulator of telomere elongation 1 (RTEL1), leading to short telomeres in the index patient. Immune repertoire studies showed polyclonal T and B cell receptor distribution, while mass cytometry analysis demonstrated marked immunological alterations, including a predominance of naïve T cells, paucity of B cells, and a decrease in various innate immune subsets.

Conclusions

RTEL1 mutations are associated with significant alterations in immune landscape and can manifest with infantile-onset IBD. A high index of suspicion is required in Ashkenazi Jewish families where the carriage rate of the C.3791G>A variant is high.

中文翻译：

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RTEL1 突变与婴儿型溃疡性结肠炎和严重免疫缺陷有关。

目的

已经确定了 50 多种导致炎症性肠病 (IBD) 的不同单基因疾病。我们的目标是表征一名在婴儿期患有溃疡性结肠炎和独特临床表现的德系犹太人患者的临床表型、基因检查和免疫学改变。

方法

进行了免疫检查和全外显子组测序，以及用于确认的 Sanger 测序。TCRB 和 IgH 的下一代测序用于免疫组库分析。端粒长度通过凝胶内杂交测定进行评估。对患者的外周血单个核细胞进行质谱流式细胞术，并与对照组和UC患者进行比较。

结果

患者在婴儿期出现发育迟缓和畸形特征，符合先天性角化不良和 Hoyeraal-Hreidarsson 综合征的诊断。严重的溃疡性结肠炎出现在出生后的第一年，并发展为原发性免疫缺陷，表现为肺孢子菌肺炎和低丙种球蛋白血症。遗传研究在端粒延长 1 ( RTEL1)，导致索引患者的端粒较短。免疫组库研究显示多克隆 T 和 B 细胞受体分布，而质谱流式细胞术分析显示显着的免疫学改变，包括幼稚 T 细胞占优势，B 细胞缺乏，以及各种先天免疫亚群减少。

结论

RTEL1突变与免疫景观的显着改变有关，并且可以表现为婴儿型 IBD。在德系犹太人家庭中，C.3791G>A 变体的携带率很高，因此需要高度怀疑。