The First Iranian Cohort of Pediatric Patients with Activated Phosphoinositide 3-Kinase-δ (PI3Kδ) Syndrome (APDS),Immunological Investigations

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The First Iranian Cohort of Pediatric Patients with Activated Phosphoinositide 3-Kinase-δ (PI3Kδ) Syndrome (APDS)
Immunological Investigations ( IF 2.9 ) Pub Date : 2021-01-06 , DOI: 10.1080/08820139.2020.1863982
Saba Fekrvand ₁ , Samaneh Delavari ₁ , Zahra Chavoshzadeh ₂ , Roya Sherkat ₃ , Seyed Alireza Mahdaviani ₄ , Mahnaz Sadeghi Shabestari ₅ , Gholamreza Azizi ₆ , Mohammad Taghi Arzanian ₇ , Bibi Shahin Shamsian ₇ , Shabnam Eskandarzadeh ₂ , Narges Eslami ₂ , William Rae _{8,

9} , Antonio Condino-Neto ₁₀ , Javad Mohammadi ₁₁ , Hassan Abolhassani _{12,

13} , Reza Yazdani _{1,

14} , Asghar Aghamohammadi ₁

Affiliation

Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Science, Tehran, Iran.
Pediatric Infections Research Center, Mofid Children's Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Acquired Immunodeficiency Research Center, lsfahan University of Medical Sciences, Isfahan, Iran.
Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Children Hospital of Tabriz, Immunology Research Center of Tabriz, TB and Lung Research Center of Tabriz, Tabriz University of Medical Science, Tabriz, Iran.
Non-communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran.
Pediatric Hematologist-Oncologist, Congenital Hematological Disorders Research Center, Mofid Children's Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, Cambridge, UK.
Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK.
Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
Department of Biomedical Engineering, Faculty of New Sciences and Technologies, University of Tehran, Tehran, Iran.
Research Center for Primary Immunodeficiencies, Iran University of Medical Science, Tehran, Iran.
Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden.
Primary Immunodeficiency Diseases Network (PIDNet), Universal Scientific Education and Research Network (USERN), Tehran, Iran.

ABSTRACT

Background

Activated phosphoinositide 3-kinase δ syndrome (APDS) is a recently defined combined primary immunodeficiency disease (PID) characterized by recurrent respiratory tract infections, lymphoproliferation, autoimmunity and lymphoma. Gain-of-function mutations in PIK3CD and loss-of-function of PIK3R1 genes lead to APDS1 and APDS2, respectively.

Methods

Demographic, clinical, immunological and genetic data were collected from medical records of 15 pediatric patients, who were genetically identified using the whole-exome sequencing method.

Results

Fifteen patients (6 APDS1 and 9 APDS2) were enrolled in this study. Recurrent respiratory tract infections followed by lymphoproliferation and autoimmunity were the most common manifestations (86.7%, 53.3% and 26.7%, respectively). Five patients (33.3%) had a Hyper-IgM-syndrome-like immunoglobulin profile. In the APDS1 group, splice site and missense mutations were found in half of the patients and the C-lobe domain of PIK3CD was the most affected region (50%). In the APDS2 group, splice site mutation was the most frequent mutation (77.8%) and the inter-SH2 domain was the most affected region of PIK3R1 (66.7%). Mortality rate was significantly higher in APDS2 group (P = .02) mainly due to chronic lung infections.

Conclusion

Respiratory tract infections and humoral immunodeficiency are commonly the most important complication in pediatric APDS patients, and they can be fatal by ultimately causing catastrophic damage to the structure of lungs. Hence, physicians should be aware of its significance and further work-up of patients with recurrent respiratory tract infections especially in patients with lymphoproliferation. Moreover, delineation of genotype-phenotype associations with disease severity could be helpful in the timely application of appropriate management and patients’ survival.

中文翻译：

伊朗首个活化磷酸肌醇 3-激酶-δ (PI3Kδ) 综合征 (APDS) 儿科患者队列

摘要

背景

活化的磷酸肌醇 3-激酶 δ 综合征 (APDS) 是一种最近定义的联合原发性免疫缺陷病 (PID)，其特征是反复呼吸道感染、淋巴组织增生、自身免疫和淋巴瘤。PIK3CD功能获得性突变和PIK3R1基因功能丧失分别导致 APDS1 和 APDS2。

方法

从 15 名儿科患者的医疗记录中收集人口统计学、临床、免疫学和遗传数据，这些患者使用全外显子组测序方法进行基因鉴定。

结果

15 名患者（6 名 APDS1 和 9 名 APDS2）参加了这项研究。复发性呼吸道感染，其次是淋巴组织增生和自身免疫是最常见的表现（分别为 86.7%、53.3% 和 26.7%）。5 名患者 (33.3%) 具有超 IgM 综合征样免疫球蛋白谱。在 APDS1 组中，一半的患者发现了剪接位点和错义突变，PIK3CD的 C 瓣结构域是受影响最大的区域（50%）。在APDS2组中，剪接位点突变是最常见的突变（77.8%），SH2间域是PIK3R1受影响最大的区域（66.7%）。APDS2 组的死亡率显着较高（P = .02），主要是由于慢性肺部感染。