The following is the summary of “Mendelian susceptibility to mycobacterial diseases: state of the art” published in the November 2022 issue of Clinical Microbiology and Infection by Noma, et al.

In individuals with Mendelian susceptibility to mycobacterial disease (MSMD), IFN- immunity is compromised, making them more susceptible to infections caused by intracellular organisms like mycobacteria. There are at least 18 distinct genes thought to be involved with MSMD. This article provides a 2020–2021 update on the latest findings in MSMD, including the identification of 3 novel genetic disorders—AR IFN-, T-bet, and ZNFX1 full deficiency—and the molecular pathways generating multifocal osteomyelitis in patients with this condition. Researchers looked for studies on MSMD that have been published after January 2020 in the PubMed collection of scholarly articles. Articles and their citations that might be relevant were checked.

 The history of MSMD is discussed, along with its classifications, symptoms, and therapies. Isolated MSMD and syndromic MSMD are the two broad categories into which MSMD falls. Among the 18 causal genes, 13 are responsible for isolated MSMD, which is characterized by a selective predisposition to one or more mycobacterial and related infections, and 8 are responsible for syndromic MSMD, which combines the infectious phenotype of mycobacterial disease with other clinical phenotypes. There are 3 genetic causes of MSMD; AR IFN- insufficiency is considered to be an independent form, while AR T-bet and ZNFX1 deficiencies are considered to be syndromic forms. Multifocal osteomyelitis is a hallmark of MSMD, and patients with impaired IFN-γ responses, such as those seen in individuals with acquired deficiency of interferon-gamma receptor 1 (IFN-γR1), (IFN-γR2), or activating transcription factor 1 (STAT1), report a high frequency of multifocal osteomyelitis. 

Multifocal osteomyelitis has been linked to impaired suppression of osteoclast development and bone resorption in MSMD, perhaps because of a suboptimal response to IFN-γ. Next-generation sequencing methods have been used to examine genes throughout the past decade, shedding light on the molecular foundations of the human immune response against mycobacteria. Unfortunately, genetic explanations are missing in 50% of MSMD cases. Research is needed to learn more about the causes of MSMD.