JL Casanova

Abstract

Selective susceptibility to weakly pathogenic mycobacteria, such as bacille Calmette-Guérin (BCG) vaccine and environmental non-tuberculous mycobacteria (NTM), has long been suspected to be a Mendelian disorder but its molecular basis remained elusive. Recently, mutations in the interferon γ receptor ligand-binding chain (IFNγR1), interferon γ receptor signalling chain (IFNγR2), interleukin 12 p40 subunit (IL-12 p40), and interleukin 12 receptor β1 chain (IL-12Rβ1) genes have been identified in a number of children with severe BCG or NTM infection. Dominant or recessive alleles causing complete or partial cellular defects have been found to define eight different inheritable disorders. Although genetically distinct, these conditions are immunologically related and highlight the essential role of interferon γ-mediated immunity in the control of mycobacteria in man. The genetic and immunologic heterogeneity of this syndrome makes accurate diagnosis challenging but vital as decisions about the most appropriate treatment are best taken based on an accurate molecular diagnosis.