• H M Cornelissen, B Glanzmann, A Van Coller, C Engelbrecht, D R Abraham, K Reddy, M Möller, C Kinnear, R H Glashoff, and M Esser.
• Division of Haematopathology, National Health Laboratory Service and Faculty of Medicine and Health Sciences, Stellenbosch University and Tygerberg Hospital, Cape Town, South Africa. hcornelissen@sun.ac.za.
• S. Afr. Med. J. 2021 Oct 5; 111 (10): 998-1005.

BackgroundSevere infections in the absence of secondary immunodeficiency can alert clinicians to single-gene inborn errors of immunity/primary immunodeficiency disorders (PIDDs). Mendelian susceptibility to mycobacterial disease (MSMD) is characterised by selective susceptibility to mycobacterial infections due to inborn errors in the interleukin 12-interferon gamma pathway. The South African (SA) burden of hyperendemic tuberculosis (TB) infection provides an interesting context for the study of MSMD.Objectives To evaluate whether severe, persistent, unusual or recurrent (SPUR) definitions of TB can be applied in the context of MSMD in SA.MethodsThis study is a retrospective review of an SA PIDD cohort. Patients aged 0 - 15 years with SPUR TB infections, assessed between 2013 and 2018, were identified using a proposed algorithm. HIV infection or other secondary causes for immunodeficiency were excluded. Basic investigations, then focused immunophenotyping and next-generation sequencing, were performed.Results A total of 20 patients with a clinical diagnosis of MSMD were identified. A further two, forming part of a family cohort, had pathogenic variants but remain asymptomatic. Infection with Mycobacterium tuberculosis complex predominated (64%), while 27% had BCG infection or non-tuberculous mycobacteria (NTM) infection. Molecular analysis revealed pathogenic variants in 41% of patients with SPUR mycobacterial infection, mainly in those with BCG/NTM infection.Conclusions In the SA paediatric population, SPUR TB infections, particularly BCG/NTM, in the absence of secondary immunodeficiency, can alert to possible MSMD. The molecular diagnosis is pivotal, guiding disease classification and influencing clinical approach and management. The diagnosis is complex and requires a multidisciplinary approach with close collaboration between clinical immunologists, bioinformaticians, immunologists, clinical geneticists and genetic counsellors.

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