Consanguineous Siblings with a Novel Mutation in Lipopolysaccharide-Responsive Beige-like Anchor protein (LRBA)

LRBA deficiency is a primary immunodeficiency caused by absence or dysfunction of a protein involved in endosomal trafficking and CTLA-4 expression. LRBA deficiency can result in a variety of phenotypes, including hypogammaglobulinemia, autoimmunity, recurrent infections, and enteropathy. We present siblings with predominantly autoimmunity, minimal immunodeficiency, and a novel mutation in LRBA. Chart review. Case 1 is a 4-year-old Saudi Arabian boy of consanguineous parents who developed diarrhea and failure to thrive at 9 months, diagnosed with autoimmune enteropathy with minimal improvement on tacrolimus and cyclosporine. He developed cervical lymphadenopathy and tonsillar hypertrophy with EBV viral load of 1000 IU/ml. After discontinuation of therapy, viral load was undetectable over 18 months. Immunologic work-up revealed positive anti-goblet antibody, normal immunoglobulins, lymphocyte subsets, mitogenic responses, specific antibody response to tetanus, but inadequate Streptococcus pneumoniae responses. Whole exome sequencing revealed a homozygous c.240delGins17 mutation in LRBA. Case 2 is the 2-year-old female sibling with chronic EBV infection, persistent lymphadenopathy, splenomegaly, recurrent fevers, intermittent diarrhea, anemia, autoimmune neutropenia, and immune thrombocytopenia. Immune work-up revealed positive anti-platelet, anti-TPO, anti-neutrophil, and anti-enterocyte antibodies. EBV PCR remained positive without EBV-specific IgG or IgM. She had a normal albumin:protein ratio, normal IgM, low IgA, and normal specific antibody responses. Naïve CD4+ and CD8+ T-cells were decreased with increased CD8+ TEMRA cells. Genetic testing ultimately confirmed a homozygous c.240delGins17 mutation in LRBA. We present siblings with LRBA deficiency of varying presentations and novel mutation in LRBA. These cases highlight the variation in presentation among individuals with identical mutations in LRBA.