Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study.
Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study.
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DOI：
10.1016/j.jaci.2016.06.021
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发表时间：
2017-02
期刊：
影响因子：
--
通讯作者：
Cant AJ
中科院分区：
文献类型：
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作者：
Coulter TI;Chandra A;Bacon CM;Babar J;Curtis J;Screaton N;Goodlad JR;Farmer G;Steele CL;Leahy TR;Doffinger R;Baxendale H;Bernatoniene J;Edgar JD;Longhurst HJ;Ehl S;Speckmann C;Grimbacher B;Sediva A;Milota T;Faust SN;Williams AP;Hayman G;Kucuk ZY;Hague R;French P;Brooker R;Forsyth P;Herriot R;Cancrini C;Palma P;Ariganello P;Conlon N;Feighery C;Gavin PJ;Jones A;Imai K;Ibrahim MA;Markelj G;Abinun M;Rieux-Laucat F;Latour S;Pellier I;Fischer A;Touzot F;Casanova JL;Durandy A;Burns SO;Savic S;Kumararatne DS;Moshous D;Kracker S;Vanhaesebroeck B;Okkenhaug K;Picard C;Nejentsev S;Condliffe AM;Cant AJ
活化型磷脂酰肌醇3-激酶δ综合征（APDS）是一种新近发现的联合免疫缺陷病，由编码磷脂酰肌醇3-激酶δ（PI 3 K δ）催化亚基的基因PIK 3CD功能获得性突变引起。我们试图在一个大型的基因定义的国际队列中回顾APDS的临床、免疫学、组织病理学和放射学特征。我们对53例APDS患者进行了临床问卷调查，并对病历、放射学、组织病理学和实验室检查进行了回顾。复发性鼻窦炎感染（98%）和非肿瘤性淋巴细胞增生（75%）是常见的，往往从童年。其他严重并发症包括疱疹病毒感染（49%）、自身炎症性疾病（34%）和淋巴瘤（13%）。出乎意料的是，在19%的队列中发生神经发育延迟，表明PI 3 K δ在中枢神经系统中的作用;与此一致，PI 3 K δ在发育中的小鼠中枢神经系统中广泛表达。胸部影像学显示马赛克衰减（90%）和支气管扩张（60%）的发生率很高。IgM升高（78%）、IgG缺乏（43%）和CD 4淋巴细胞减少（84%）是显著的免疫学特征。没有一种免疫学标志物能可靠地预测临床严重程度，其范围从无症状到儿童早期死亡。大部分患者接受免疫球蛋白替代和抗生素预防，5例患者接受造血干细胞移植。5例患者死于APDS并发症。APDS是一种具有多种临床表现的联合免疫缺陷病，许多表现为不完全性，另一些表现为可变性。一些患者并发症的严重程度支持考虑造血干细胞移植治疗严重的儿童疾病。选择性PI 3 K δ抑制剂的临床试验为APDS治疗提供了新的前景。
Activated phosphoinositide 3-kinase δ syndrome (APDS) is a recently described combined immunodeficiency resulting from gain-of-function mutations in PIK3CD, the gene encoding the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ). We sought to review the clinical, immunologic, histopathologic, and radiologic features of APDS in a large genetically defined international cohort. We applied a clinical questionnaire and performed review of medical notes, radiology, histopathology, and laboratory investigations of 53 patients with APDS. Recurrent sinopulmonary infections (98%) and nonneoplastic lymphoproliferation (75%) were common, often from childhood. Other significant complications included herpesvirus infections (49%), autoinflammatory disease (34%), and lymphoma (13%). Unexpectedly, neurodevelopmental delay occurred in 19% of the cohort, suggesting a role for PI3Kδ in the central nervous system; consistent with this, PI3Kδ is broadly expressed in the developing murine central nervous system. Thoracic imaging revealed high rates of mosaic attenuation (90%) and bronchiectasis (60%). Increased IgM levels (78%), IgG deficiency (43%), and CD4 lymphopenia (84%) were significant immunologic features. No immunologic marker reliably predicted clinical severity, which ranged from asymptomatic to death in early childhood. The majority of patients received immunoglobulin replacement and antibiotic prophylaxis, and 5 patients underwent hematopoietic stem cell transplantation. Five patients died from complications of APDS. APDS is a combined immunodeficiency with multiple clinical manifestations, many with incomplete penetrance and others with variable expressivity. The severity of complications in some patients supports consideration of hematopoietic stem cell transplantation for severe childhood disease. Clinical trials of selective PI3Kδ inhibitors offer new prospects for APDS treatment.