IRF4 p.T95R combined immunodeficiency: Clinical features and transplant outcomes

IRF4 is a transcription factor within the interferon regulatory factor family that controls key aspects of lymphocyte differentiation and adaptive immunity. The heterozygous IRF4 p.Thr95Arg (p.T95R) variant affecting the DNA-binding domain was recently identified to cause a new inborn error of immunity, but the longitudinal clinical course and therapeutic implications remain incompletely defined. We performed detailed clinical characterization and follow-up of all 10 known patients. Each presented with early-onset combined immunodeficiency characterized by hypo- or agammaglobulinemia and marked susceptibility to opportunistic infections. Pulmonary disease was universal, and gastrointestinal involvement was associated with a more severe clinical course. Four patients underwent hematopoietic stem cell transplantation; two survived, and two died. Notably, both deaths occurred in patients transplanted in the setting of active infection. These findings define IRF4 p.T95R as a profound combined immunodeficiency with high infectious burden and demonstrate that disease severity and intervention timing may contribute to transplant outcomes, supporting early diagnosis and timely transplantation before uncontrolled infection.