Chinese patients with defective IL-12/23-interferon-γ circuit in Taiwan: Partial dominant interferon-γ receptor 1 mutation presenting as cutaneous granuloma and IL-12 receptor β1 mutation as pneumatocele

Background: IL-12/23-interferon-γ circuit enhances reactive oxygen species (ROS) synthesis in macrophage to attack intracellular pathogens such as mycobacteria and salmonella. Defective ROS in patients with chronic granulomatous disease (CGD) have increased susceptibility to these pathogens. However, patients with defective IL-12/23-interferon-γ circuit rather than CGD are not recognized in Taiwan, endemic for tuberculosis and salmonella. Aim: The purpose of this study was to identify Taiwanese patients with defective IL-12/23-IFN-γ circuit. Patients and Methods: In a long-term molecular study of primary immunodeficiency diseases (PIDD), the tentative CGD patients presenting with Bacille Calmette-Guerin (BCG)-induced infection, refractory atypical mycobacterial cutaneous granuloma and osteomyelitis, recurrent salmonella sepsis, and pneumatocele were studied for the IL-12/23-IFN-γ circuit. ROS was first measured to exclude CGD. Candidate genes of IL12RB1, IFNRG1, IL12p40, IFNRG2, signal transducer and activator of transcription-1, and NF-κB essential modulator and their encoding protein expressions were analyzed. Results: Of the 175 Taiwanese PIDD patients during a 28-year period, three patients from two unrelated families were identified with the hotspot INFRG1 deletion mutation (818del4) and had CGD features, presenting as cutaneous granuloma, and multiple osteomyelitis infected by non-tuberculosis mycobacteria, Mycobacteria avium complex and Mycobacterium scrofulaceum. Another with mis-sense IL12RB1 mutation (Arg211Pro) was noted as recurrent Salmonella enteritidis D sepsis and pneumatocele. Conclusion: Patients with defective IL-12/23-IFN-γ circuit may resemble or overlap CGD manifestations of refractory cutaneous atypical mycobacterial granuloma and salmonella pneumatocele.