Molecular, Immunological, and Clinical Features of 16 Iranian Patients with Mendelian Susceptibility to Mycobacterial Disease

  • Shokouh Azam Sarrafzadeh
  • Maryam Nourizadeh
  • Maryam Mahloojirad
  • Mohammad Reza Fazlollahi
  • Raheleh Shokouhi Shoormasti
  • Mohsen Badalzadeh
  • Caroline Deswarte
  • Jean-Laurent Casanova
  • Zahra Pourpak
  • Jacinta BustamanteEmail author
  • Mostafa MoinEmail author
Original Article



Mendelian susceptibility to mycobacterial disease (MSMD) is a rare primary immunodeficiency, triggered by non-tuberculous mycobacteria or Bacillus Calmette-Guérin (BCG) vaccines and characterized by severe diseases. All known genetic etiologies are inborn errors of IFN-γ-mediated immunity. Here, we report the molecular, cellular, and clinical features of patients from 15 Iranian families with disseminated disease without vaccination (2 patients) or following live BCG vaccination (14 patients).


We used whole blood samples from 16 patients and 12 age-matched healthy controls. To measure IL-12 and IFN-γ, samples were activated by BCG plus recombinant human IFN-γ or recombinant human IL-12. Immunological assessments and genetic analysis were also done for the patients.


Eight patients affected as a result of parental first-cousin marriages. Seven patients originated from multiplex kindred with positive history of death because of tuberculosis or finding the MSMD-related gene mutations. Two patients died due to mycobacterial disease at the ages of 8 months and 3.7 years. The remaining patients were alive at the last follow-up and were aged between 2 and 13 years. Patients suffered from infections including chronic mucocutaneous candidiasis (n = 10), salmonellosis (n = 2), and Leishmania (responsible for visceral form) (n = 2). Thirteen patients presented with autosomal recessive (AR) IL-12Rβ1 deficiency, meaning their cells produced low levels of IFN-γ. Bi-allelic IL12RB1 mutations were detected in nine of patients. Three patients with AR IL-12p40 deficiency (bi-allelic IL12B mutations) produced low levels of both IL-12 and IFN-γ. Overall, we found five mutations in the IL12RB1 gene and three mutations in the IL12B gene. Except one mutation in exon 5 (c.510C>A) of IL12B, all others were previously reported to be loss-of-function mutations.


We found low levels of IFN-γ production and failure to respond to IL12 in 13 Iranian MSMD patients. Due to complicated clinical manifestations in affected children, early cellular and molecular diagnostics is crucial in susceptible patients.


Immunodeficiency interleukin-12 interferon-gamma IL-12Rbeta1 



We would like to thank the patients and their families. We also thank Yelena Nemirovskaya, Cecile Patissier, and Céline Desvallées for their assistance. We would like to thank Nastaran Sabetkish and Fatemeh Talebian for English editing of the manuscript. This research was funded in part by a grant from the National Institute of Allergy and Infectious Diseases grant number 5R01AI089970, The Rockefeller University, the St. Giles Foundation, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris Descartes University, Laboratoire d’Excellence Integrative Biology of Emerging Infectious Diseases (ANR-10-LABX-62-IBEID), the French National Research Agency (ANR) under the “Investments for the future” (grant number ANR-10-IAHU-01) and ANR-GENMSMD (ANR-16-CE17-0005-01 for JB). This project has been granted and supported by Immunology, Asthma and Allergy Research Institute under the supervision of Tehran University of Medical Sciences (grant number: 89-33-1/253-1).

Financial Disclosure

The authors have no financial relationships relevant to this article to disclose.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Research Involving Human Participants

Informed consent for participation in this study was obtained in accordance with local regulations, with approval from ethics committee of Tehran University of Medical Sciences (TUMS). The experiments described here were performed in Iran and France, in accordance with local regulations, and with the approval of the TUMS for Immunology, Asthma and Allergy Research Institute (IAARI), Tehran-Iran; and for Necker Hospital for Sick Children, France.

Informed Consent

Written informed consent was obtained from the patients.


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Shokouh Azam Sarrafzadeh
    • 1
  • Maryam Nourizadeh
    • 1
  • Maryam Mahloojirad
    • 1
  • Mohammad Reza Fazlollahi
    • 1
  • Raheleh Shokouhi Shoormasti
    • 1
  • Mohsen Badalzadeh
    • 1
    • 2
  • Caroline Deswarte
    • 3
    • 4
  • Jean-Laurent Casanova
    • 3
    • 4
    • 5
    • 6
    • 7
  • Zahra Pourpak
    • 1
  • Jacinta Bustamante
    • 3
    • 4
    • 6
    • 8
    Email author
  • Mostafa Moin
    • 1
    Email author
  1. 1.Immunology, Asthma and Allergy Research InstituteTehran University of Medical SciencesTehranIran
  2. 2.Department of Cell and Molecular Biology, School of Biology, College of ScienceUniversity of TehranTehranIran
  3. 3.Laboratory of Human Genetics of Infectious Diseases, Necker BranchParisFrance
  4. 4.Imagine InstituteParis Descartes UniversityParisFrance
  5. 5.Howard Hughes Medical InstituteNew YorkUSA
  6. 6.St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller branchThe Rockefeller UniversityNew YorkUSA
  7. 7.Pediatric Hematology-Immunology UnitNecker Hospital for Sick Children, AP-HPParisFrance
  8. 8.Center for the Study of Primary ImmunodeficienciesNecker Hospital for Sick Children, AP-HPParisFrance

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