Screening for Genetic Mutations for the Early Diagnosis of Common Variable Immunodeficiency in Children With Refractory Immune Thrombocytopenia: A Retrospective Data Analysis From a Tertiary Children's Center.

Jingyao Ma,Lingling Fu,Zhenping Chen,Shasha Zhao,Huiqing Liu,Runhui Wu,Xiaojing Zhu,Jialu Zhang,Hao Gu

doi:10.3389/fped.2020.595135

Abstract

Aim: This study aimed to identify common variable immunodeficiency (CVID) by high-throughput next-generation sequencing (NGS) in children with refractory immune thrombocytopenia (RITP) to facilitate early diagnosis.Methods: CVID-related genetic mutations were explored in patients with RITP during 2016–2019. They were tested consecutively through NGS by the ITP team of the tertiary children hospital in China. An evaluation system was devised based on the phenotype, genetic rule, and serum immunoglobulins (Igs) of all patients with RITP. The patients were divided into highly suspicious, suspicious, and negative groups using the evaluation system.Results: Among 176 patients with RITP, 16 (9.1%) harbored CVID-related genetic mutations: 8 (4.5%) were highly suspicious of CVIDs. Five had mutations in tumor necrosis factor receptor superfamily 13B (TNFRSF13B), one in lipopolysaccharide responsive beige-like anchor protein (LRBA), one in nuclear factor kappa-B2 (NF-κB2), and one in caspase recruitment domain11 (CARD11). Others were classified into the suspicious group because the clinical phenotype and pedigree were suggestive, yet insufficient, for diagnosis. Repeated infection existed in all patients. Two had an allergic disease. Positive autoimmune serologies were noted in 62.5%. Five had a definite positive family history. The median serum immunoglobulin (Ig)A, IgG, and IgM levels were 0.3875, 6.14, and 0.522 g/L, respectively. Nearly 85.7% of patients had insufficient serum IgA levels, while 37.5% had low IgG and IgM levels.Conclusions: High-throughput NGS and a thorough review of the medical history are beneficial for the early diagnosis of patients without any significant clinical characteristics, distinguishing them from those with primary pediatric ITP. The cases suspicious of CVID need further investigation and follow-up to avoid deterioration.

Highlights

Immune thrombocytopenia (ITP) is the most commonly seen autoimmune thrombocytopenia manifested as different severity of bleeding
Children with RITP, age of onset ranging from 3 months to 15 years, were enrolled if their thrombocytopenia lasted >3 months, they did not respond to ≥2 therapies of ITP, and they were dependent on administrations of drugs such as steroids to avoid bleeding [19]
The clinical data were collected from admission and follow-ups, including demographics, present and past medical history, bleeding severity evaluated using the Adix– Buchanan bleeding score, family history, therapeutic response to intravenous immunoglobulin (IVIG)/corticosteroids and second-line therapy, concentrations of Igs, indicators of immune dysregulation/infection, and imaging results such as abdominal ultrasound and pulmonary computed tomography (CT) scan

Summary

Introduction

Immune thrombocytopenia (ITP) is the most commonly seen autoimmune thrombocytopenia manifested as different severity of bleeding. A majority of children with ITP have better outcomes compared with adult patients for their spontaneous remission and good response to standard treatments. Nearly 20–30% of children with ITP have a frequent relapse or no response to multiple treatments, leading to a chronic duration beyond 12 months and a lower quality of life. A disease interrupting the balance of the immune system, such as common variable immunodeficiency (CVID), is more likely to cause ITP. CVID is a primary immune deficiency disease (PID) associated with both immunodeficiency and autoimmune setting. It is one of the possible causes of chronic and refractory ITP (C/RITP) in children with poor prognosis [1], who need regular evaluation in follow-ups to exclude secondary causes

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