Primary immune regulatory disorders (PIRDs) caused by interferon regulatory factor 8 (IRF8) gene defects are rare, with limited cases reported worldwide. IRF8 is essential for myeloid and lymphoid development, and its deficiency can lead to immune dysregulation manifested by infections, cytopenias, lymphoproliferation, and organ injury. The natural history of IRF8-associated disease remains poorly characterized.
A 25-year-old man presented for evaluation of immune deficiency and workup of an IRF variant of uncertain significance [c.1279dupT] in the context of liver failure. His disease course began in early childhood and was characterized by chronic lung disease, immune-mediated cytopenias with an autoimmune lymphoproliferative syndrome (ALPS)-like phenotype, and recurrent severe infections, including sepsis, pneumonias, and primary Epstein-Barr virus (EBV) lymphoproliferative disease controlled by periodic rituximab treatment. At age 4, he was diagnosed with combined immunodeficiency with lymphoproliferation and treated with immunoglobulin replacement therapy. At age 11, he underwent splenectomy for refractory thrombocytopenia. His subsequent course was complicated by portal vein thrombosis requiring emergent transjugular intrahepatic portosystemic shunt (TIPS) placement; the shunt later occluded, with progression to cavernous transformation and portal biliopathy. At age 20, his case was further complicated by progressive cholestatic liver dysfunction of unclear etiology. Post-splenectomy sequelae, chronic Cryptosporidium infection, and immune dysregulation were all considered as potential causes. At 25 years old, he developed end-stage liver disease characterized by severe hyperbilirubinemia. Biopsies revealed biliopathy consistent with sclerosing cholangitis, and his immune workup revealed combined immune defect with reduced natural killer (NK) cell cytotoxicity shown on 51Cr release assay. Deceased donor liver transplantation (DDLT) was performed with the goal of stabilizing hepatic function to permit subsequent curative hematopoietic stem cell transplantation (HSCT). His post-transplant course was complicated by persistent graft dysfunction and biliary disease, necessitating repeat liver transplantation with a living sibling donor six months later. After the second transplant, he experienced significant infectious burden, including ongoing chronic infection with norovirus and COVID-19, Cryptosporidium infection, vancomycin-resistant enterococci (VRE) bacteremia, and Candida glabrata fungemia. Two months later, he proceeded to HSCT. His clinical course rapidly deteriorated with severe colitis, progressive hepatic and renal failure, and septic shock. Despite transient improvement with escalation of antimicrobial therapy, he developed refractory shock and respiratory failure, failed to engraft, and died approximately one month after transplant at age 26.
Other reported IRF8 cases reveal similar infectious and lymphoproliferative manifestations, and several patients have been successfully treated with reduced-intensity HSCT. However, none of these patients have exhibited liver disease of comparable severity.
This case expands the phenotypic spectrum of IRF8-associated PIRDs to include progressive liver failure and highlights the need for improved understanding of immune-mediated organ dysfunction in rare PIRD conditions. It also aligns with existing reports of increased morbidity and mortality among patients with inborn errors of immunity who undergo splenectomy. Early recognition of non-hematologic complications and further study of disease natural history are critical to optimizing timing and sequencing of solid organ and hematopoietic transplantation in this population.
