IRF4 p.T95R Combined Immunodeficiency: Clinical Features and Transplant Outcomes

Introduction Inborn errors of interferon response factors (IRFs) are a subset of monogenic inborn errors of immunity, occurring as a result of damaging variants in the IRF genes. Of these diseases, IRF4 deficiencies are associated with the broadest range of phenotypes, each of which is highly genotype dependent. In 2023, our consortium characterized seven patients carrying the IRF4 p.T95R variant, which was demonstrated to be damaging through various models. The clinical profile of these patients has not been described in detail. Methods This study summarizes our understanding of IRF4 p.T95R in all nine known patients, including two patients new to this report. Key features were extracted from clinical records, publications, and follow-up with clinicians, with a focus on pretransplant infectious susceptibility and treatment outcomes, particularly following hematopoietic stem cell transplant (HSCT). Results 7/9 patients are male, with ages ranging from 6.5 to 31 years at last update. All had opportunistic infections before 1.5 years of age. Notable pretransplant opportunistic infections included Pneumocystis jirovecii (8/9), cytomegalovirus (CMV) (3/9), onychomycosis (3/9), and weakly virulent mycobacteria (2/9). 5/9 patients also had gastrointenstinal (GI) manifestations, including colitis, proctocolitis, and mucosal eosinophilia. All had combined immunodeficiency with notable defects in B cell development and antibody production (9/9 hypo/agammaglobulinemia). All patients received immunoglobulin replacement therapy and antimicrobial prophylaxis. 4/9 patients received HSCT. Of those transplanted, one had good outcomes (i.e., resolution of enteropathy and protection from infections), 2/4 died (pretransplant CMV and cryptosporidium), and 1/4 lost their graft. In those managed without transplant, 2/9 have reached adulthood (20 and 31 years at last update). Conclusion This cohort of 9 patients with combined immunodeficiency due to heterozygosity for IRF4 p.T95R experienced a spectrum of outcomes. IRF4 p.T95R patients all have profound combined immunodeficiency, characterized by classic opportunistic infections early in life. HSCT is potentially curative (n = 1). Active infection at the time of transplant was associated with poor outcomes, further emphasizing the value of early recognition and intervention. The phenotype of IRF4 p.T95R is uniquely severe when compared to the growing list of IEIs affecting IRF4, emphasizing the critical need to consider IRF4 genotype-specific effects in IEI patients. Figure 1. Clinical features and transplant outcomes of IRF4 p.T95R patients. (A) IRF4 p.T95R cohort. *Awaiting first transplant. (B) Phenotypes of IRF4 p.T95R patients. (C) Survival timelines for IRF4 p.T95R patients. (D) Transplant outcomes for IRF4 p.T95R patients. (E) HSCT donor types. MUD, matched unrelated donor. **Patient received multiple grafts, including grafts from haploidentical and MUD.