X-linked lymphoproliferative disease type 1 (XLP-1) is a rare syndrome caused by an inactivating mutation in SH2D1A, which encodes for SLAM-Associated protein (SAP) on T and natural killer (NK) cells. The three classic manifestations of XLP-1 include Epstein–Barr virus (EBV)–induced hemophagocytic lymphohistiocytosis (HLH), B cell lymphoma, and dys-gammaglobulinemia. Genotype–phenotype correlation between patients with SH2D1A mutations is unknown. It is unclear how SAP protein levels are related to disease development. We describe a case of a family of 3 boys who had a pathogenic mutation in SH2D1A with different clinical phenotypes.
Brother 1 is a 2-year-old fully vaccinated male who initially presented to our immunology clinic for evaluation of recurrent ear infections. He was found to have low IgG (179 mg/dL), low IgM (<10 mg/dL), and failure to respond to multiple pediatric vaccines. Genetic testing showed a variant of unknown significance (VUS) in SH2D1A (hemizygous, c.95G>A p.Arg32Lys). Flow cytometry for SAP showed decreased expression of SAP in CD4 (28%), CD8 (23%), and NK cells (46%), suggesting a pathogenic VUS.
Brother 2 is a 4-year-old boy who was initially referred to the hospital for hypoxia in the setting of a multifocal pneumonia of unclear etiology. He quickly decompensated and required ECMO for respiratory support. Genetic testing showed the same mutation in SH2D1A as brother 1. Flow cytometry showed decreased expression of SAP in CD4 (8%), CD8 (4%), and NK cells (47%). He met 5 of 8 criteria for HLH. He passed away despite treatment with gamifant and anakinra.
Brother 3 is an 8-year-old fully vaccinated boy who also has the same pathogenic mutation in SH2D1A as both brothers. His immune workup was essentially normal except for a non-protective titer to tetanus toxoid. Flow cytometry for SAP showed slightly higher but low expression in CD4 (68%), CD8 (40%), and NK cells (86%).
Our case highlights the clinical variability of XLP-1 presentation in a family with the same pathogenic variant in SH2D1A. We conclude that the SH2D1A VUS is pathogenic and that SAP levels can correlate with severity of disease.
