Systemic Epstein–Barr Virus-Positive T/NK Lymphoproliferative Diseases With SH2D1A/XIAP Hypomorphic Gene Variants

Abstract

X-linked lymphoproliferative disease (XLP) is one of the X-linked primary immunodeficiency diseases (PIDs) with defective immune response to Epstein–Barr virus (EBV) infection. Chronic active EBV infection (CAEBV) and EBV-hemophagocytic lymphohistiocytosis (HLH) are recognized as systemic EBV-positive T-cell and natural killer (NK)-cell lymphoproliferative diseases (LPDs) arising from the clonal proliferations of EBV-infected T cells and NK cells. A high incidence of CAEBV in East Asia implies the unknown genetic predisposition. In patients with XLP, EBV-infected cells are generally B cells. No mutation of SH2D1A / XIAP genes has ever been identified in patients with systemic EBV-positive T-cell and NK-cell LPD. We report herewith a male case of NK-cell type CAEBV with SH2D1A hypomorphic mutation (c.7G > T, p.Ala3Ser), two male cases of CAEBV/EBV-HLH with XIAP hypomorphic variant (c.1045_1047delGAG, p.Glu349del), and another female case of CD4 + CAEBV with the same XIAP variant. The female underwent bone marrow transplantation from an HLA-matched sister with the XIAP variant and obtained a complete donor chimerism and a cure of laryngeal LPD lesion, but then suffered from donor-derived CD4 + T cell EBV-LPD. These observations demonstrated that SH2D1A and XIAP genes are critical for the complete regulation of EBV-positive T/NK cell LPD. X-linked lymphoproliferative disease (XLP) is one of the X-linked primary immunodeficiency diseases (PIDs) reported to have a defective immune response to Epstein–Barr virus (EBV) infection. Mutations in SH2D1A and XIAP genes cause XLP. Systemic EBV-positive T-cell and natural killer (NK)-cell lymphoproliferative diseases (LPDs) consist of three major types: EBV-positive hemophagocytic lymphohistiocytosis (HLH), chronic active EBV infection (CAEBV), and EBV-positive T-cell/NK-cell lymphoma. CAEBV is recognized as a poor prognostic disease of EBV-associated T-cell and NK-cell LPD arising from the clonal proliferation of EBV-infected T cells (CD4 + , CD8 + , and TCRγδ + ) and/or NK cells. The majority of cases with CAEBV were reported from East Asia and South America. In Caucasian patients with CAEBV disease, the target of infection is exclusively B cells. These imply a genetic predisposition to EBV-positive T/NK cell LPD according to ethnicity. In reported cases with XLP, EBV-infected cells are B cells. On the other hand, no mutation of SH2D1A / XIAP genes have been determined in patients with T/NK-cell-type (Asian type) CAEBV. We here describe, for the first time, four case series of CAEBV/EBV-HLH patients who carried the hypomorphic variants of XLP-related genes. These cases included a male ...

Epstein–Barr virus-related hemophagocytic lymphohistiocytosis complicated with coronary artery dilation and acute renal injury in a boy with a novel X-linked inhibitor of apoptosis protein (XIAP) variant: a case report

“…In cases of XLP-related EBV-HLH, EBV-infected cells are predominantly B cells [3]. Therefore, in our case, combination therapy of rituximab and ganciclovir was administered, which cleared the EBV DNA titers and relieved symptoms.…”

“…Other viral infections, such as human herpes virus 6, cytomegalovirus, have also been reported in association with XLP, although cases without an identifiable infectious agent have also been described [7,8]. The life-threatening manifestations of XLP triggered by EBV include EBV-positive hemophagocytic lymphohistiocytosis (EBV-HLH), chronic active EBV infection (CAEBV) and EBV-positive lymphoma [3].…”

“…XIAP is located close to SH2D1A on the X-chromosome and contains six exons that encode the X-linked inhibitor of apoptosis (XIAP) protein [1]. Both of these variants are associated with defective immune responses to Epstein-Barr virus (EBV) infection [3]. Here, we report the case of a young boy with cardiovascular and renal lesions who was diagnosed with EBV-positive hemophagocytic lymphohistiocytosis (EBV-HLH) secondary to an underlying XIAP gene variant [c.116G > C(p.G39A)].…”

Hydroa vacciniforme-like lymphoproliferative disorder: A study of clinicopathology and whole-exome sequencing in Chinese patients

“…In recent years, many scholars have made important contributions to research in EBV-related lymphoproliferative diseases, leading to breakthroughs in genomic exploration. Nonetheless, relevant studies have mostly focused on EBV T/natural killer (NK) cell lymphoproliferative diseases or chronic active EBV (CAEBV) infection [7][8][9][10], and sequencing for HVLPD has rarely been performed. HVLPD shares many common features with EBV T/NK cell lymphoproliferative diseases or CAEBV without HVLPD, including high levels of EBV DNA in the blood (primarily inTor NK cells) and a high frequency of clonal T cells.…”

Clinical Warning of Hemophagocytic Syndrome Caused by Epstein-barr Virus

“…The majority of EBV-IM cases are selflimited and mild with a good prognosis. In contrast, most cases of EBV-HLH are severe, involve multiple organs, and are life-threatening [7] . Therefore, the early identi cation of EBV-HLH by a simple laboratory examination is of great signi cance.…”