Atypical X-linked lymphoproliferative syndrome type 2 presenting with polysaccharide antibody deficiency and infantile Langerhans cell histiocytosis

Introduction: X-linked lymphoproliferative syndrome type 2 (XLP-2) is caused by pathogenic variants in the X-linked inhibitor of apoptosis (XIAP) gene. XLP-2 classically presents with a triad of hemophagocytic lymphohistiocytosis triggered by Epstein-Barr virus infection, splenomegaly, and inflammatory bowel disease; however, a broad phenotypic spectrum has been reported. We present a case of an adult male with a history of infantile Langerhans cell histiocytosis, childhood splenectomy presumably for splenomegaly or cytopenias, a leukemoid reaction to COVID-19 vaccination and adult-onset recurrent pneumococcal infections with associated polysaccharide antibody deficiency, who carries a novel variant in XIAP with impaired XIAP expression. Methods: Data was collected by retrospective chart review of electronic medical records. Consent was obtained for presentation of the case. Results: Initial investigations showed undetectable IgM, nonprotective vaccine titres to diphtheria, measles and mumps, low CD19+ B cells, and high CD8+ T cells. Anti-pneumococcal IgG was low despite recent pneumococcal 23-valent polysaccharide vaccination. Genetic testing yielded a novel hemizygous c.693G>A (p.Leu231=) variant in XIAP not previously described in the literature and in-silico analysis predicted an acceptor site gain with high precision. Further functional testing demonstrated impaired XIAP expression, supporting the hypothesized abrogated protein expression. Conclusion: We describe a patient with a novel XIAP variant with impaired XIAP expression, demonstrating an atypical history not previously reported in XLP-2, comprising infantile LCH, leukemoid reaction to vaccination, and polysaccharide antibody deficiency. This case broadens the phenotypic spectrum of XLP-2 and highlights the necessity of immunological assessment in patients with an atypical symptom constellation.