LAUSR

To the Editor, X-linked lymphoproliferative disease (XLP1) was first described in the 1970s [1] and is a rare primary immunodeficiency (PID) caused by mutations in the SH2D1A gene. This gene encodes the SLAM-associated protein (SAP) which is a key regulator of immune function in T, NK, and NKT cells and defects in this protein may lead to the cellular and humoral immune defects characterized in patients [2]. Clinical manifestations vary and include hemophagocytic lymphohistiocytosis (HLH), lymphoma, and dysgammaglobulinemia [2, 3] but patients can experience a wide range of phenotypes associated with immune dysregulation, even independent of Epstein-Barr virus (EBV) infection [3, 4]. Although historically associated with EBV infection, a recent study showed 35% of patients with XLP1 had no evidence of previous EBV infection and patients are often diagnosed based on positive family history alone [4]. No clear genotypephenotype correlation has been identified [4]. Here, we report three siblings from a non-consanguineous family of Yemeni origin with hemizygous deletions of exon 2 of the SH2D1A gene who manifested different phenotypes at different ages (Table 1). Patient one was well until 21 months of age when he developed bilateral bronchopneumonia and pleural effusion requiring hospital admission. Further investigation confirmed severe hypogammaglobulinemia, marked lymphocytosis, and subsequently, hemizygous deletion of exon 2 of the SH2D1A gene. He commenced immunoglobulin replacement therapy and was monitored regularly. Lung function and chest imaging showed chronic changes. A donor search for hematopoietic stem cell transplant (HSCT) identified the best available donor was a haploidentical donor therefore HSCT was not undertaken at an early age. He first developed EBV viremia at six years old and received three courses of rituximab over the next five years. On depletion of B cells, EBV viremia persisted and further analysis confirmed the presence of EBV in T and NK cells. Recently, he developed fevers, weight loss, and increased cough. Investigations revealed autoimmune hemolytic anemia (AIHA) requiring rituximab and high-dose intravenous immunoglobulin (IVIG) alongside lower lobe lung collapse associated with Haemophilus influenza treated with a prolonged course of antibiotics. At this time, B cells had returned (CD19+ 660/μl) but were depleted upon rituximab administration. He remains on immunoglobulin therapy and prophylactic antibiotics awaiting HSCT. Patient two was diagnosed at birth based on the positive family history. He remained well until three years of age when he developed intermittent abdominal pain. This was not associated with fever, night sweats, or diarrhea/ constipation. Further investigation confirmed raised LDH, anemia, and negative EBV PCR. EBV is negative in 25% Capsule Summary XLP1 can present in many different ways with no genotype-phenotype correlation. Therefore, close monitoring is extremely important especially in those with a family history.