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

Area of Science:

• Immunology
• Genetics
• Virology

Background:

• X-linked lymphoproliferative disease (XLP) is a primary immunodeficiency characterized by impaired immune response to Epstein-Barr virus (EBV).
• Systemic EBV-positive T-cell and NK-cell lymphoproliferative diseases (LPDs), including chronic active EBV infection (CAEBV) and EBV-hemophagocytic lymphohistiocytosis (HLH), are distinct entities.
• Genetic predisposition, particularly in East Asian populations, is suggested for CAEBV, with distinct genetic underpinnings compared to classical XLP.

Observation:

• This study reports four cases of EBV-positive T/NK-cell LPDs with hypomorphic variants in XLP-related genes.
• A male patient with CAEBV had an SH2D1A mutation (c.7G > T, p.Ala3Ser).
• Two male and one female patient with CAEBV/EBV-HLH carried the XIAP hypomorphic variant (c.1045_1047delGAG, p.Glu349del).

Findings:

• The identified mutations in SH2D1A and XIAP genes represent the first documented cases in T/NK-cell type CAEBV/EBV-HLH.
• A female patient undergoing bone marrow transplantation for EBV-LPD, despite achieving donor chimerism, developed donor-derived CD4+ T-cell EBV-LPD, highlighting complex disease dynamics.
• These findings indicate that SH2D1A and XIAP are crucial for regulating EBV-positive T/NK-cell LPD.

Implications:

• The study implicates SH2D1A and XIAP genes in the pathogenesis of EBV-positive T/NK-cell LPD, expanding the known spectrum of XLP-related disorders.
• Understanding these genetic factors may lead to improved diagnostics and targeted therapies for EBV-associated lymphoproliferative diseases.
• The findings suggest potential ethnic variations in the genetic basis of EBV-associated LPDs.