Childrens Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders (Chongqing), Chongqing, China; Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China; Chongqing Key Laboratory of Child Infection and Immunity, Children's Hospital of Chongqing Medical University, Chongqing, China.
Chongqing Key Laboratory of Child Infection and Immunity, Children's Hospital of Chongqing Medical University, Chongqing, China.
Clin Immunol. 2023 Dec;257:109844. doi: 10.1016/j.clim.2023.109844. Epub 2023 Nov 19.
Interferon-stimulated gene 15 (ISG15) deficiency, a rare human inborn error of immunity characterized by susceptibility to Bacillus Calmette-Guerin (BCG) diseases, neuropathic and dermatological manifestations.
The clinical and immunological features of two siblings with ISG15 deficiency combined with asymptomatic myeloperoxidase (MPO) mutations were analyzed, and their pathogenesis, as well as target therapeutic candidates, were explored.
The manifestation in patient 2 was skin lesions, while those in patient 1 were intracranial calcification and recurrent pneumonia. Whole-exome identified novel, dual mutations in ISG15 and MPO. PBMCs and B cell lines derived from the patients showed hyper-activated JAK/STAT signaling. Normal neutrophil function excluded pathogenicity caused by the MPO mutation. RNA sequencing identified baricitinib as therapeutic candidate.
We report two sibling patients harboring the same novel ISG15 mutation showing diverse clinical features, and one harbored a rare phenotype of pneumonia. These findings expand the clinical spectrum of ISG15 deficiency and identify baricitinib as therapeutic candidate.
干扰素刺激基因 15（ISG15）缺陷是一种罕见的人类先天性免疫缺陷，其特征是易患卡介苗（BCG）疾病、神经和皮肤表现。
分析了两名 ISG15 缺陷合并无症状髓过氧化物酶（MPO）突变的同胞的临床和免疫学特征，并探讨了其发病机制和靶向治疗候选物。
患者 2 的表现为皮肤损伤，而患者 1 的表现为颅内钙化和复发性肺炎。外显子组鉴定出 ISG15 和 MPO 的新型双重突变。来自患者的 PBMC 和 B 细胞系显示出过度激活的 JAK/STAT 信号。正常中性粒细胞功能排除了 MPO 突变引起的致病性。RNA 测序确定巴瑞替尼为治疗候选物。
我们报告了两名携带相同新型 ISG15 突变的同胞患者表现出不同的临床特征，其中一名患者表现出肺炎的罕见表型。这些发现扩展了 ISG15 缺陷的临床谱，并确定了巴瑞替尼为治疗候选物。
