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中国循证儿科杂志

中国循证儿科杂志 ›› 2024, Vol. 19 ›› Issue (3): 195-200.DOI: 10.3969/j.issn.1673-5501.2024.03.006

• 论著 • 上一篇    下一篇

雷帕霉素治疗PIK3CD基因突变致PI3Kδ过度活化综合征4例病例系列报告

钱凯1,2,卢美萍1,郭莉1,吴建强1   

  1. 1 浙江大学医学院附属儿童医院风湿免疫过敏科杭州，310052;2  湖州市中心医院儿科湖州，313000 


  • 收稿日期:2023-10-13 修回日期:2024-07-30 出版日期:2024-06-25 发布日期:2024-06-25
  • 通讯作者: 卢美萍

Therapy of rapamycin on children with PI3Kδ overactivation syndrome due to PIK3CD gene mutations: A case series of four cases

QIAN Kai1,2, LU Meiping1, GUO Li1, WU Jianqiang1   

  1. 1 Department of Rheumatology and Immunology, Children's Hospital of Zhejiang University,  Hangzhou 310011,China; 2 Department of Pediatrics, Huzhou Central Hospital, Huzhou 313000,China
  • Received:2023-10-13 Revised:2024-07-30 Online:2024-06-25 Published:2024-06-25
  • Contact: LU Meiping，email：meipinglu@zju.edu.cn

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摘要： 背景：PI3Kδ 过度活化综合征 (APDS) 采用传统治疗方案预防感染的疗效欠佳，近年来雷帕霉素被用于PIK3CD基因突变所致的APDS1患儿的临床治疗。 目的：探讨雷帕霉素治疗APDS1的疗效和安全性。 设计：病例系列报告。 方法：纳入2017年6月至2023年6月在浙江大学医学院附属儿童医院经基因检测确诊为APDS1且口服雷帕霉素治疗的连续病例。国内儿童雷帕霉素治疗APDS引起的非肿瘤性淋巴细胞增生，仍属于超说明书用药，用药前家长均充分了解用药风险并签署了知情同意书。雷帕霉素口服剂量为1 mg·m-2·d-1。 主要结局指标：①12个月内发生肺炎的次数；②B超评估肝、脾、淋巴结肿大情况。 结果：4例使用雷帕霉素治疗的APDS1患儿中，男3例、女1例，发病年龄为（35.5±17.9）月龄，确诊年龄（56.5±35.0)月龄；全外显子组测序均显示PIK3CD基因c.3061G>A（p.E1021K）新发杂合突变；均因“反复咳嗽”就诊，均有肝、脾、淋巴结肿大；均有肺炎，反复腮腺炎2例，伴特异性皮炎、炎症性肠病和韦格纳肉芽肿病各1例，生长迟缓2例；4例均行支气管镜检查，3例有支气管内膜鹅卵石样凸起；均有CD19+B细胞比例下降、CD4+/CD8+倒置，3例 IgM升高，1例 IgG下降。在雷帕霉素治疗前均予IVIG、抗感染、糖皮质激素等治疗，治疗后仍有反复呼吸道感染、肝脾肿大，且3例出现PLT减少，2例出现贫血。4例患儿确诊后1~44个月起口服雷帕霉素，疗程12~58个月。雷帕霉素治疗后12个月肺炎年均次数由5.3次降至1.0次，肝、脾和浅表淋巴结肿大均明显改善，Hb和PLT均恢复至正常水平，但免疫学指标在治疗前后比较差异均无统计学意义。随访期间未发现雷帕霉素相关不良反应，无发生肿瘤及死亡病例。 结论：雷帕霉素对APSD1有一定疗效且相对安全。

关键词: PIK3CD, PI3Kδ 过度活化综合征, 雷帕霉素, 临床症状, 治疗

Abstract: Background: The traditional treatment for activated phosphoinositide 3-kinase δ (PI3Kδ) syndrome (APDS) has shown limited efficacy in preventing infections. Recently, rapamycin has been used in the clinical treatment of children with APDS type1 (APDS1) caused by PIK3CD gene mutations. Objective: To investigate the efficacy and safety of rapamycin in the treatment of APDS1. Design: Case series report. Methods: This study included consecutive cases diagnosed with APDS1 via genetic testing and treated with oral rapamycin from June 2017 to June 2023 at the Children's Hospital of Zhejiang University School of Medicine. The use of rapamycin for treating non-tumorous lymphoproliferation due to APDS in children is off-label in China. Before treatment, parents were fully informed of the risks and signed informed consent. The oral dosage of rapamycin was 1 mg·m-2·d-1. Main outcome measures: The number of pneumonia episodes within 12 months and ultrasound assessment of liver, spleen, and lymph node enlargement. Results: Among the four children treated with rapamycin for APDS1, three were male and one was female. The average age of onset was 35.5±17.9 months, and the average age at diagnosis was 56.5±35.0 months. Whole-exome sequencing revealed a de novo heterozygous mutation in the PIK3CD gene (c.3061G>A, p.E1021K) in all cases. All presented with recurrent coughing and had hepatosplenomegaly and lymphadenopathy. All had pneumonia. There were 2 cases of recurrent mumps, 2 cases of growth retardation, and one case each of atopic dermatitis, inflammatory bowel disease, and Wegener's granulomatosis. Bronchoscopy showed cobblestone-like bulge in the bronchial mucosa in three cases. All had reduced CD19+ B cells and inverted CD4+/CD8+ ratios; three had elevated IgM levels, and one had decreased IgG. Prior to rapamycin, all received IVIG, anti-infective treatment and corticosteroids, yet continued to suffer from recurrent respiratory infections and hepatosplenomegaly. Additionally, three developed thrombocytopenia and two had anemia. Rapamycin was administered orally to all children from 1 to 44 months after diagnosis for 12 to 58 months. Following 12 months of rapamycin treatment, the average annual number of pneumonia episodes decreased from 5.3 to 1.0. There was significant improvement in hepatosplenomegaly and superficial lymphadenopathy, and Hb and PLT levels returned to normal. However, there were no statistically significant differences in immunological parameters before and after treatment. No rapamycin-related adverse effects, tumors, or deaths were observed during follow-up. Conclusion: Rapamycin is relatively safe and has some efficacy in treating APDS1.

Key words: PIK3CD, PI3Kδ overactivation syndrome, Rapamycin, Clinical symptoms, Treatment