Introduction Patients with splenomegaly and lymphadenopathy are frequently referred to the hematologist. Although splenomegaly may be seen in primary immunodeficiency diseases, it is rarely the presenting symptom. Case Description A 21-year old male was admitted with severe pneumococcal pneumonia with respiratory failure. He was found to be agammaglobulinemic and treated with antibiotics and intravenous gamma globulin (IVIG). He had been followed by a hematologist, along with 2 siblings, for splenomegaly since birth, lymphadenopathy, and “polyclonal B cell activation,” but prior immunoglobulins were normal. T and B cell abnormalities included low CD3 and CD4 percentages, with elevated CD19 percentage/count. Past history included otitis media, warts, molluscum contagiosium, and Salmonella lymphadenitis. His sister died at age 17 of viral myocarditis. He recovered but then developed Hemophagocytic Lymphohistiocytosis. He received methylprednisolone, but succumbed to an intracranial bleed. Immune evaluation of his surviving brother revealed normal absolute lymphocyte count and immunoglobulins. T and B cell subsets showed low CD3 and CD4 percentages with elevated CD19 percentage/count. DNA testing showed a heterozygous variant in the CARD 11 gene (c.368G>T (p.Gly123Val), consistent with CARD 11 gain-of- function mutation, a newly described combined immunodeficiency disorder, also known as B-cell expansion with NF-κB and T-cell anergy (BENTA). Discussion Early onset splenomegaly may be a marker for CARD 11/BENTA, a condition in which patients with polyclonal B cell proliferation may show progressive immunodeficiency. This case highlights the benefits of genetic testing by an immunologist to establish a definitive diagnosis of primary immunodeficiency in an affected family.