Mendelian Susceptibility to Mycobacterial Disease (MSMD): Clinical and Genetic Features of 32 Iranian Patients

Abstract

Mendelian susceptibility to mycobacterial diseases (MSMD) is a rare congenital condition characterized by a selective predisposition to infections caused by weakly virulent mycobacteria and other types of intra-macrophagic pathogens. The 16 genes associated with MSMD display a considerable level of allelic heterogeneity, accounting for 31 distinct disorders with variable clinical presentations and prognosis. Most of MSMD deficiencies are isolated, referred to as selective susceptibility to mycobacterial diseases. However, other deficiencies are syndromic MSMD, defined by the combination of the mycobacterial infection with another, equally common, infectious, specific phenotypes. Herein, we described a series of 32 Iranian MSMD cases identified with seven distinct types of molecular defects, all of which are involved in the interferon gamma (IFNγ) immunity, including interleukin IL-12 receptor-β1 (IL-12Rβ1) deficiency (fifteen cases), IL-12p40 deficiency (ten cases), and IL-23R deficiency (three cases), as well as IFNγ receptor 1 (IFNγR1) deficiency, IFNγ receptor 2 (IFNγR2) deficiency, interferon-stimulated gene 15 (ISG15) deficiency, and tyrosine kinase 2 (TYK2) deficiency each in one case. Since the first report of two MSMD patients in our center, we identified 30 other affected patients with similar clinical manifestations. As the number of reported Iranian cases with MSMD diagnosis has increased in recent years and according to the national vaccination protocol, all Iranian newborns receive BCG vaccination at birth, early diagnosis, and therapeutic intervention which are required for a better outcome and also prevention of similar birth defects. Therefore, we investigated the clinical and molecular features of these 32 patients. The current report also defined novel classes of pathological mutations, further expanding our knowledge of the MSMD molecular basis and associated clinical manifestations.

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Acknowledgments

We thank patients and their families for participation in this study; Dr. Melanie Migaud for assistance with genetic analyses; and Dr. Sabereh Tashayoie-Nejad for the collection of patients’ blood samples.

Funding

The Laboratory of Human Genetics of Infectious Diseases is supported in part by institutional grants from INSERM, Paris Descartes University, St. Giles Foundation, The Rockefeller University Center for Clinical and Translational Science grant number 8UL1TR000043 from the National Center for Research Resources and the National Center for Advancing Sciences (NCATS), National Institutes of Health, the National Institute of Allergy and Infectious Diseases (5R01AI089970-02 and 5R37AI095983), and grants from the French National Research Agency (ANR) under the “Investments for the future” program (ANR-10-IAHU-01) and GENMSMD (ANR-16-CE17-0005-01 for JB) grants.

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Correspondence to Davood Mansouri.

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The present study was conducted according to the principles expressed in the Helsinki declaration and ethical standards of the National Research Institute of Tuberculosis and Lung Diseases (NRITLD) committee (IR.SBMU.NRITLD.REC.1397.510). The informed consent was obtained from all patients and/or their parents.

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Mahdaviani, S.A., Mansouri, D., Jamee, M. et al. Mendelian Susceptibility to Mycobacterial Disease (MSMD): Clinical and Genetic Features of 32 Iranian Patients. J Clin Immunol 40, 872–882 (2020). https://doi.org/10.1007/s10875-020-00813-7

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Keywords

  • Mendelian susceptibility to mycobacterial diseases
  • MSMD
  • primary immunodeficiency
  • mycobacteria
  • BCG
  • Salmonella