Signal transducer and activator of transcription 3 (STAT-3) gain-of-function (GOF) syndrome is an early-onset monogenic inborn error of immunity characterized by multi-organ autoimmune disorders, growth failure and lymphoproliferation. We describe that STAT-3 GOF syndrome may be presented with hypogammaglobulinemia and recurrent severe upper and lower respiratory tract infections. In addition, the patient had lymphoproliferation, short stature and interstitial lung disease. Chest computerized tomography examinations showed mild bronchiectasis with areas of non-fibrosing alveolar-interstitial disease and maldevelopment of bilateral first ribs. Using Sanger sequencing, we revealed a novel c.508G>C, p.D170H STAT-3 variant affecting the coiled coil domain of STAT-3. Functional studies confirmed that p.D170H was a GOF variant, as shown by increased phosphorylated STAT-3 (pSTAT-3) and STAT-3 transcriptional activity. Our observation suggests that STAT-3 GOF syndrome can manifest in early childhood with hypogammaglobulinemia and recurrent severe respiratory tract infections. We suggest that patients with lymphoproliferation, hypogammaglobulinemia and severe recurrent infections should be screened for STAT-3 variants, even if autoimmune manifestations are missing.

中文翻译：

---

具有低丙种球蛋白血症和复发性感染表型的新型 STAT-3 功能获得性变异

信号转导和转录激活因子 3 (STAT-3) 功能获得 (GOF) 综合征是一种早发性单基因先天性免疫错误，其特征是多器官自身免疫性疾病、生长障碍和淋巴细胞增殖。我们描述了 STAT-3 GOF 综合征可能表现为低丙种球蛋白血症和复发性严重的上呼吸道和下呼吸道感染。此外，患者还有淋巴增生、身材矮小和间质性肺病。胸部计算机断层扫描检查显示轻度支气管扩张伴非纤维化肺泡间质疾病区域和双侧第一肋骨发育不良。使用 Sanger 测序，我们揭示了一种新的 c.508G>C、p.D170H STAT-3 变体，它影响了 STAT-3 的卷曲螺旋结构域。功能研究证实 p.D170H 是 GOF 变体，如磷酸化 STAT-3 (pSTAT-3) 和 STAT-3 转录活性增加所示。我们的观察表明 STAT-3 GOF 综合征可在儿童早期表现为低丙种球蛋白血症和反复出现的严重呼吸道感染。我们建议淋巴增生、低丙种球蛋白血症和严重反复感染的患者应筛查 STAT-3 变异，即使自身免疫表现缺失。