PARTIAL INTERFERON-GAMMA RECEPTOR-1 DEFICIENCY IN A CHILD WITH TUBERCULOID BACILLUS-CALMETTE-GUERIN INFECTION AND A SIBLING WITH CLINICAL TUBERCULOSIS

Complete interferon-gamma receptor 1 (IFN gamma R1) deficiency has bee n identified previously as a cause of fatal bacillus Calmette-Guerin ( EGG) infection with lepromatoid granulomas, and of disseminated nontub erculous mycobacterial (NTM) infection in children who had not been in oculated with BCG, We report here a kindred with partial IFN gamma R1 deficiency: one child afflicted by disseminated BCG infection with tub erculoid granulomas, and a sibling, who had not been inoculated previo usly with BCG, with clinical tuberculosis. Both responded to antimicro bials and are currently well without prophylactic therapy, Impaired re sponse to IFN-gamma was documented in B cells by signal transducer and activator of transcription 1 nuclear translocation, in fibroblasts by cell surface HLA class II induction, and in monocytes by cell surface CD64 Induction and TNF-alpha secretion. Whereas cells from healthy ch ildren responded to even low IFN-gamma concentrations (10 IU/ml), and cells fi om a child with complete IFN gamma R1 deficiency did not resp ond to even high IFN-gamma concentrations (10,000 IU/ml), cells from t he two siblings did not respond to low or intermediate concentrations, yet responded to high IFN-gamma concentrations, A homozygous missense IFNgR1 mutation was identified, and its pathogenic role was ascertain ed by molecular complementation. Thus, whereas complete IFN gamma R1 d eficiency in previously identified kindreds caused fatal lepromatoid B CG infection and disseminated NTM infection, partial TFN gamma R1 defi ciency in this kindred caused curable tuberculoid BCG infection and cl inical tuberculosis.