PIK3CD基因突变致PI3Kδ过度活化综合征临床及免疫学特点分析

Clinical and immunological analysis of patients with activated phosphoinositide 3-kinase δ syndrome resulting from PIK3CD mutation

目的探讨中国PIK3CD基因增功能突变所致PI3Kδ过度活化综合征（APDS）的临床表现、免疫学表型、治疗及预后情况。方法回顾性分析重庆医科大学附属儿童医院、北京协和医院、深圳儿童医院2014年6月至2016年11月收治的15例APDS患儿的病例资料，实验室检查、治疗效果及预后等情况。结果（1）15例患儿中男11例，女4例，中位发病年龄1岁，中位诊断年龄4岁4月龄。均为PIK3CD基因E1021K位点杂合突变。（2）临床始发表现：以反复呼吸道感染为主，肺炎12例，支气管扩张5例。其他主要表现包括反复、慢性腹泻11例， EB病毒和（或）巨细胞病毒感染10例，肝脏及脾脏肿大13例，慢性淋巴结病10例。（3）免疫学检查：IgM水平升高（11例）、IgG缺乏（6例）；CD4^＋T淋巴细胞减少（7例），尤其是初始CD4^＋T细胞减少（9例）；终末分化的效应记忆CD8^＋T细胞增加（5例）；B 细胞减少（11例），其中初始 B 细胞减少（9例），而过渡 B 细胞增加（5例）。（4）经1-29个月随访，15例患儿现存活13例，其中5例接受规律静脉注射免疫球蛋白治疗，感染频率降低；3例接受雷帕霉素靶向治疗，肝脾肿大明显好转。结论 APDS发病年龄早，以反复呼吸道感染、肝脾淋巴结肿大、巨细胞病毒或EB病毒血症为主要临床表现，部分患儿有自身免疫现象及淋巴瘤。免疫表型为初始CD4^＋T细胞及初始B细胞减少，过渡B细胞及终末分化的效应记忆CD8^＋T细胞增加，IgM水平升高。E1021K杂合突变为热点突变。规律的静脉注射免疫球蛋白治疗可减少该类原发性免疫缺陷病患儿感染，雷帕霉素靶向治疗可改善肝脾肿大。

Objective To explore the clinical and immunological features , gene mutations , treatment and prognosis in patients with activated phosphoinositide 3-kinase δsyndrome （ APDS） caused by PIK3CD gene heterozygous germline mutation .Method The data of clinical , immunological phenotype , treatment, and prognosis of 15 patients with APDS, who visited Children′s Hospital of Chongqing Medical＆amp;nbsp;University, Peking Union Medical College Hospital , and Shenzhen Children′s Hospital from June 2014 to November 2016, were collected and analyzed.Result Of the 15 patients, 11 were males, remaining 4 patients were females.The median age of disease onset was 1 year, and median age at diagnosis was 4 years and 4 months.All patients had the de novo heterozygous germline mutation in PIK 3CD （ c.3061G＆gt;A, p.E1021K） .The common initial symptoms were respiratory infections , including pneumonia （12 cases ） , bronchiectasis （ 5 cases ） . Other common clinical manifestations were recurrent and chronic diarrhea （11 cases）, Epstein-Barr virus （EBV） and/or cytomegalovirus （CMV） viremia （10 cases）, hepatosplenomegaly （13 cases）, and lymphadenopathy （10 cases）.The main immunological features were increased IgM （ 11 cases ） , decreased IgG （ 6 cases ） , decreased numbers of CD 4^＋T cell （ 7 cases ） especially na？ve CD4^＋T cell （9 cases）, reduced numbers of B cells （11 cases） particularly na？ve B cells （9 cases）, increased numbers of transitional B cells （5 cases） and CD8^＋terminally differentiated effector memory T cells （5 cases）.After 1-29 months follow up, 13 of the 15 cases remain survived, of whom 5 cases received regular intravenous immunoglobulin （ IVIG） therapy, with reduced frequency of infections and improved severity of infections; of whom 3 cases received oral rapamycin therapy at the dosage of 1 mg/（m^2·d） and with a decrease in nonneoplastic lymphoproliferation .Conclusion E1021K is a hotspot for mutation in the PIK3CD gene in patients with APDS.Regular IVIG can improve their quality of life.Targetel treatment with rapamycin could mitigate hepatosplenomegaly .