X-linked lymphoproliferative syndrome in mainland China: review of clinical, genetic, and immunological characteristic

Tao Xu,Xiao Du,Lina Zhou,Xuemei Tang,Qin Zhao,Xi Yang,Xuemei Chen,Qian Zhao,Hirokazu Kanegane,Xiuhong Xue,Xiaoming Bai,Xiaodong Zhao,Wenyan Li,Zhi Chen

doi:10.1007/s00431-019-03512-7

Abstract

X-linked lymphoproliferative syndrome (XLP) is a rare primary immunodeficiency disease that can be divided into two types: SAP deficiency (XLP1) and XIAP deficiency (XLP2), caused by mutations in the SH2D1A and XIAP genes, respectively. Few cases of XLP (particularly XIAP deficiency) have been reported in mainland China; hence, little is known about the characteristics of Chinese patients with XLP. We identified 13 and 7 patients with SAP and XIAP deficiency, respectively, in our center. Of our 20 patients, 19/20 (95%) presented with disease symptoms at a very early age: six in infancy and 13 in childhood. One XIAP- and three SAP-deficient patients died, while 3/7(42.9%) and 4/13(30.8%), respectively, developed hemophagocytic lymphohistiocytosis (HLH). Epstein-Barr virus (EBV) infection was significantly more common in SAP-deficient 10/13 (76.9%) than XIAP-deficient 2/7 (28.6%) patients, as was hypogammaglobulinemia (10/13 (76.9%) vs. 1/7 (14.3%)). None of the seven XIAP-deficient patients had colitis or lymphoma. Nine SAP-deficient patients and five XIAP-deficient patients showed markedly deficient SAP and XIAP expression, respectively, in lymphocytes. Significantly reduced levels of switched memory B cells were observed in six SAP-deficient patients with persistent hypogammaglobulinemia. One of 13 (7.7%) SAP-deficient patients and 1 of 7 (12.3%) XIAP-deficient patients have received HSCT treatment and are now alive and well; the other alive patients were waiting for HSCT. We also summarized clinical, genetic, and immunological characteristics of all 55 patients (including our 20 patients) reported in the literature in mainland China today.Conclusion: The overall characteristics of SAP deficiency in mainland China were consistent with those in previous reports, whereas manifestations of XIAP deficiency varied significantly. None of inflammatory bowel disease (IBD) has been reported among XIAP-deficient patients in our center; however, whether Chinese XIAP-deficient patients will develop colitis in the future warrants further investigation. HSCT is the only curative therapy for XLP and this therapy should be urgently considered.What is Known:• SAP and XIAP deficiencies share common clinical feature, HLH, whereas they also have their own specific manifestations.• IBD affects 25–30% of XIAP-deficient patients, which has been reported in other countries especially in European country and Japan.What is New:• This is the largest patient cohort study of XLP in China.• We firstly summarized the clinical features and outcomes of Chinese XIAP-deficient patients and found only 1 in 22 patients developed IBD and diet background may contribute to it; Asian SAP-deficient patients carrying SH2D1A R55X mutation were more prone to HLH.

Highlights

Material and methodsX-linked lymphoproliferative syndrome (XLP) is a rare primary immunodeficiency disease characterized by extreme vulnerability to Epstein-Barr virus (EBV) infection, and with clinical features including hemophagocytic lymphohistiocytosis (HLH), lymphoproliferative disorder, and dysgammaglobulinemia
We firstly summarized the clinical features and outcomes of Chinese XIAP-deficient patients and found only 1 in 22 patients developed inflammatory bowel disease (IBD) and diet background may contribute to it; Asian SAP-deficient patients carrying SH2D1A R55X mutation were more prone to HLH
HLH relapses appear to be more common in patients with XIAP deficiency, since all patients with HLH and XIAP deficiency experienced relapse

Summary

Introduction

X-linked lymphoproliferative syndrome (XLP) is a rare primary immunodeficiency disease characterized by extreme vulnerability to Epstein-Barr virus (EBV) infection, and with clinical features including hemophagocytic lymphohistiocytosis (HLH), lymphoproliferative disorder, and dysgammaglobulinemia. XLP was initially described in the 1970s [30], while the first causative pathogenic gene, SH2D1A, which encodes signaling lymphocyte-activation molecule–associating protein (SLAM-associating protein, SAP) was discovered in 1998 [8]. In 2006, a second causative gene, XIAP, was found in some XLP-like patients without SH2D1A gene mutations [31]. SAP and XIAP deficiencies share some common clinical features, such as HLH and dysgammaglobulinemia, they have their own specific manifestations. XLP patients have high mortality rates, and hematopoietic stem cell transplantation (HSCT) is the only curative therapy

Results

Discussion

Conclusion