Case Report: Different faces of LRBA deficiency in five Moroccan families

Abstract

LPS-responsive beige-like anchor protein (LRBA) deficiency is a primary immunodeficiency belonging to the spectrum of common variable immunodeficiency disorders, frequently associated with immune dysregulation, autoimmunity, and lymphoproliferation. Its clinical presentation is highly heterogeneous, ranging from isolated autoimmune cytopenias to severe multisystem involvement. Here, we report five cases of LRBA deficiency from five Moroccan families, highlighting the broad clinical variability of this condition. The first patient presented with chronic immune thrombocytopenic purpura (ITP) as the initial and predominant manifestation, associated with hypogammaglobulinemia. The second patient developed ITP complicated by a hemorrhagic syndrome and significant lymphoproliferation, including splenomegaly and hepatomegaly. The third patient initially presented with autoimmune hemolytic anemia (AIHA), followed by splenomegaly. The fourth patient exhibited a complex clinical course, beginning with bicytopenia and progressing to enteropathy, arthritis, pneumopathy, and type 1 diabetes mellitus, associated with splenomegaly, hepatomegaly, and lymphadenopathy. Finally, the fifth patient initially presented with ITP and subsequently developed bilateral panuveitis, arthritis, and recurrent respiratory infections. Targeted next-generation sequencing identified homozygous pathogenic variants in the LRBA gene in all five patients, consistent with a loss-of-function mechanism. These included the nonsense variants c.3811C>T (p.Arg1271*) and c.5692G>T (p.Glu1898*), a large deletion encompassing exons 30 to 34, the frameshift variant c.5060_5067delACATACCA (p.Asn1687Serfs*21), and an extended deletion involving part of exon 4 (c.476_549 + 580del). All patients required immunosuppressive therapy and/or immunoglobulin replacement. LRBA deficiency should be considered in children presenting with autoimmune cytopenias, lymphoproliferation, and multisystem autoimmunity. The marked heterogeneity of clinical manifestations underscores the importance of early molecular diagnosis to guide therapeutic decision-making. In our experience, prompt recognition and the initiation of targeted therapies, such as abatacept or early hematopoietic stem cell transplantation, may improve patient outcomes.