Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pa; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pa.
Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pa; Division of Allergy and Immunology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pa.
J Allergy Clin Immunol Pract. 2021 Jul;9(7):2885-2893.e3. doi: 10.1016/j.jaip.2021.04.010. Epub 2021 Apr 21.
Mutations in ITCH, which encodes an E3 ubiquitin-protein ligase, can result in systemic autoimmunity and immunodeficiency. The clinical phenotype and mechanism of disease have not been fully characterized, resulting in a paucity of therapeutic options for this potentially fatal disease.
We aimed to (1) expand the understanding about the phenotype of human ITCH deficiency (2) further characterize the associated immune dysregulation, and (3) report the first successful hematopoietic cell transplant (HCT) in a patient with ITCH deficiency.
Disease profiling was performed in a patient with multisystem immune dysregulation. Whole exome sequencing with trio analysis and functional validation of candidate disease variants were performed, including mRNA and protein expression. Analyses to further delineate the immunophenotype included quantitative evaluation of lymphoid and myeloid subsets with flow cytometry and mass cytometry.
A patient with multisystem immune dysregulation presenting with growth failure, very-early-onset inflammatory bowel disease, arthritis, uveitis, psoriasis, and type 1 diabetes mellitus underwent whole exome sequencing, which identified novel compound heterozygous mutations in ITCH. Reduced expression of ITCH mRNA and absent ITCH protein were found. Abnormalities in both lymphoid and myeloid lineages were identified. The patient underwent HCT. He demonstrated excellent immune reconstitution and resolution of many manifestations of his systemic disease.
Here we report ITCH deficiency with unique clinical features of colonic very-early-onset inflammatory bowel disease, arthritis, and uveitis in the setting of immune dysregulation and further characterize the underlying immune dysregulation. We demonstrate that HCT can be an effective, and potentially curative, therapy for ITCH deficiency.
编码 E3 泛素蛋白连接酶的ITCH 基因突变可导致全身自身免疫和免疫缺陷。其临床表型和疾病机制尚未完全阐明，导致这种潜在致命疾病的治疗选择有限。
我们旨在（1）扩展对人类 ITCH 缺陷表型的认识，（2）进一步描述相关的免疫失调，（3）报告首例 ITCH 缺陷患者成功进行造血细胞移植（HCT）。
对一名多系统免疫失调患者进行疾病分析。对患者及其父母进行外显子组测序和三代分析，并对候选疾病变异进行功能验证，包括 mRNA 和蛋白表达。进一步分析免疫表型的分析包括使用流式细胞术和液质联用技术对淋巴细胞和髓系细胞亚群进行定量评估。
一名多系统免疫失调患者表现为生长发育不良、极早发性炎症性肠病、关节炎、葡萄膜炎、银屑病和 1 型糖尿病，进行了外显子组测序，发现了 ITCH 的新型复合杂合突变。发现 ITCH mRNA 表达降低且 ITCH 蛋白缺失。淋巴细胞和髓系细胞均存在异常。患者接受了 HCT。他表现出极好的免疫重建，并缓解了其全身疾病的许多表现。
我们在此报告了 ITCH 缺陷症，其独特的临床特征为伴有免疫失调的结肠极早发性炎症性肠病、关节炎和葡萄膜炎，并进一步描述了潜在的免疫失调。我们证明 HCT 可作为 ITCH 缺陷症的有效、潜在治愈性治疗方法。
