Saito Koji, Fujimoto Minoru, Funajima Eiji, Serada Satoshi, Ohkawara Tomoharu, Ishihara Masayuki, Yamada Mamiko, Suzuki Hisato, Miya Fuyuki, Kosaki Kenjiro, Fujieda Mikiya, Naka Tetsuji
Department of Pediatrics, Kochi Medical School, Kochi University, Nankoku, Japan.
Department of Pediatrics, National Hospital Organization Kochi National Hospital, Kochi, Japan.
J Allergy Clin Immunol Glob. 2024 Jul 26;3(4):100312. doi: 10.1016/j.jacig.2024.100312. eCollection 2024 Nov.
In recent years, germline gain-of-function (GOF) mutations in signal transducer and activator of transcription 3 () have been identified as a cause of early-onset multiorgan autoimmune diseases with the widespread use of next-generation sequencing, and targeted therapies such as tocilizumab have been reported to be effective.
We sought to assess whether a novel mutation detected by whole-exome sequencing is pathogenic and examine the efficacy of targeted therapy.
A pediatric patient with idiopathic pulmonary hemosiderosis, autoimmune thyroiditis, inflammatory bowel disease unclassified, leukocytosis, thrombocytosis, and severe growth failure was examined.
This 7-year-old boy had idiopathic pulmonary hemosiderosis at the age of 6 months. Despite high-dose steroid therapy, pulmonary fibrosis progressed. Furthermore, he presented with severe growth failure, autoimmune thyroiditis, leukocytosis, thrombocytosis, and inflammation bowel disease unclassified. Given the presence of multiple autoimmune diseases, whole-exome sequencing was performed, which detected germline heterozygous mutation (NM_139276.2; c.2144C>A, p.(P715Q)). Dual-luciferase reporter assay revealed this novel STAT3 mutation as GOF. After starting tocilizumab therapy at the age of 6, hospital stays decreased, and the progression of pulmonary fibrosis was decelerated without increasing the steroid dose. New autoimmune diseases did not develop, and no apparent adverse effects on growth have been observed.
Tocilizumab may be effective for patients with STAT3 GOF mutation, including those requiring long-term management of idiopathic pulmonary hemosiderosis. Diagnosis of patients with early-onset multiorgan autoimmune diseases in which STAT3 GOF is suspected should be confirmed by genetic testing and functional analysis to consider the introduction of targeted therapies.
近年来，随着新一代测序技术的广泛应用，已确定信号转导和转录激活因子3（STAT3）的种系功能获得性（GOF）突变是早发性多器官自身免疫性疾病的一个病因，并且据报道，托珠单抗等靶向治疗有效。
我们试图评估通过全外显子组测序检测到的一种新的STAT3突变是否具有致病性，并检验靶向治疗的疗效。
对一名患有特发性肺含铁血黄素沉着症、自身免疫性甲状腺炎、未分类的炎症性肠病、白细胞增多、血小板增多和严重生长发育迟缓的儿科患者进行了检查。
这名7岁男孩在6个月大时患有特发性肺含铁血黄素沉着症。尽管接受了高剂量类固醇治疗，但肺纤维化仍在进展。此外，他还出现了严重的生长发育迟缓、自身免疫性甲状腺炎、白细胞增多、血小板增多和未分类的炎症性肠病。鉴于存在多种自身免疫性疾病，进行了全外显子组测序，检测到种系STAT3杂合错义突变（NM_139276.2；c.2144C>A，p.(P715Q)）。双荧光素酶报告基因检测显示这种新的STAT3突变为功能获得性突变。在6岁开始使用托珠单抗治疗后，住院次数减少，肺纤维化进展减缓，且未增加类固醇剂量。未出现新的自身免疫性疾病，也未观察到对生长有明显不良影响。
托珠单抗可能对STAT3 GOF突变患者有效，包括那些需要长期治疗特发性肺含铁血黄素沉着症的患者。对于怀疑有STAT3 GOF的早发性多器官自身免疫性疾病患者，应通过基因检测和功能分析来确诊，以考虑引入靶向治疗。
