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Mendelian Susceptibility to Mycobacterial Disease (MSMD): Clinical, Immunological, and Genetic Features of 22 Patients from 15 Moroccan Kindreds

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Abstract

Purpose

The first molecular evidence of a monogenic predisposition to mycobacteria came from the study of Mendelian susceptibility to mycobacterial disease (MSMD). We aimed to study this Mendelian susceptibility to mycobacterial diseases in Moroccan kindreds through clinical, immunological, and genetic analysis.

Methods

Patients presented with clinical features of MSMD were recruited into this study. We used whole blood samples from patients and age-matched healthy controls. To measure IL-12 and IFN-γ production, samples were activated by BCG plus recombinant human IFN-γ or recombinant human IL-12. Immunological assessments and genetic analysis were also done for patients and their relatives.

Results

Our study involved 22 cases from 15 unrelated Moroccan kindreds. The average age at diagnosis is 4 years. Fourteen patients (64%) were born to consanguineous parents. All patients were vaccinated with the BCG vaccine, and twelve of them (55%) developed locoregional or disseminated BCG infections. The other symptomatic patients had severe tuberculosis and/or recurrent salmonellosis. Genetic mutations were identified on the following genes: IL12RB1 in 8 patients, STAT1 in 7 patients; SPPL2A, IFNGR1, and TYK2 in two patients each; and TBX21 in one patient, with different modes of inheritance. All identified mutations/variants altered production or response to IFN-γ or both.

Conclusion

Severe forms of tuberculosis and complications of BCG vaccination may imply a genetic predisposition present in the Moroccan population. In the presence of these infections, systematic genetic studies became necessary. BCG vaccination is contraindicated in MSMD patients and should be delayed in newborn siblings until the exclusion of a genetic predisposition to mycobacteria.

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Data Availability

All data are included in the manuscript.

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Acknowledgements

We thank the patients and their families for their collaboration.

Funding

The HGMI laboratory is funded in part by the National Institute of Allergy and Infectious Diseases (grant numbers 5R01AI089970 and 5R37AI095983); the National Center for Research Resources and the National Center for Advancing Sciences of the National Institutes of Health (grant number 8UL1TR000043 for JLC and U19AI142737 to SBD), the Rockefeller University, the St. Giles Foundation, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris Cité University, and the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID); and the French National Research Agency (ANR) under the “Investments for the future” program (grant number ANR-10-IAHU-01), ANR-GENMSMD/ANR-16-CE17-0005–01 (for JB), ANRS project ECTZ170784-ANRS0073 to SBD, and the SCOR Corporate Foundation for Science.

Author information

Authors and Affiliations

  1. Laboratory of Clinical Immunology, Inflammation, and Allergy (LICIA), Faculty of Medicine and Pharmacy, Hassan II University, 19, Rue Tarik Ibnou Ziad, B.P. 9154, Casablanca, Morocco

    Abderrahmane Errami, Fatima Ailal, Ibtihal Benhsaien, Jalila El Bakkouri, Noureddine Rada, Noufissa Benajiba, Khaoula Mokhantar, Kaoutar Ouazahrou, Sanae Zaidi & Ahmed Aziz Bousfiha

  2. Department of Pediatric Infectious and Immunological Diseases, Abderrahim El Harouchi Children Hospital, University Hospital Center Ibn Rochd, Casablanca, Morocco

    Abderrahmane Errami, Fatima Ailal, Ibtihal Benhsaien & Ahmed Aziz Bousfiha

  3. Genetics Unit, Military Hospital Mohammed V, Rabat, Morocco

    Abderrahmane Errami & Jamila El Baghdadi

  4. Immunology Laboratory, IBN Rochd University Hospital, Casablanca, Morocco

    Jalila El Bakkouri

  5. National Reference Laboratory, Mohamed VI University of Health Sciences (UM6SS), Casablanca, Morocco

    Leila Jeddane

  6. Pediatric Department, University Hospital Med VI, Marrakesh, Morocco

    Noureddine Rada

  7. Department of Pediatrics, Mohammed VI University Hospital, Oujda, Morocco

    Noufissa Benajiba

  8. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA

    Laurent Abel, Jean-Laurent Casanova, Stéphanie Boisson-Dupuis & Jacinta Bustamante

  9. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Necker Hospital for Sick Children, INSERM U1163, Paris, France

    Laurent Abel, Jean-Laurent Casanova, Stéphanie Boisson-Dupuis & Jacinta Bustamante

  10. Imagine Institute, Paris Cité University, Paris, France

    Laurent Abel, Jean-Laurent Casanova, Stéphanie Boisson-Dupuis & Jacinta Bustamante

  11. Department of Pediatrics, Necker Hospital for Sick Children, AP-HP, Paris, France

    Jean-Laurent Casanova

  12. Howard Hughes Medical Institute, New York, NY, USA

    Jean-Laurent Casanova

  13. Study Center for Primary Immunodeficiencies, Necker Hospital for Sick Children, AP-HP, Paris, France

    Jacinta Bustamante

Authors
  1. Abderrahmane Errami
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  2. Jamila El Baghdadi
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  3. Fatima Ailal
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  4. Ibtihal Benhsaien
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  5. Jalila El Bakkouri
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  6. Leila Jeddane
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  7. Noureddine Rada
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  8. Noufissa Benajiba
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  9. Khaoula Mokhantar
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  10. Kaoutar Ouazahrou
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  11. Sanae Zaidi
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  12. Laurent Abel
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  13. Jean-Laurent Casanova
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  14. Stéphanie Boisson-Dupuis
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  15. Jacinta Bustamante
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  16. Ahmed Aziz Bousfiha
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Contributions

AER, JE, JB, and AAB contributed to the study conception and design and drafted the manuscript. AER, JE, SBD, and JB performed experimental work and genetic analysis. JLC, LA, SBD, and JB gave academic feedback and revised and corrected the manuscript. AAB, FA, IB, NR, and NB were involved in clinical care. All authors have reviewed the final manuscript and agreed to be accountable for the work. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Abderrahmane Errami.

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Ethics Approval

The study was approved by the ethics committee of the Faculty of Medicine and Pharmacy Casablanca of Hassan II University.

Consent to Participate

Written informed consent was obtained from the guardians of the pediatric patients or directly from adult relatives and controls.

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The subject has given consent for findings based on his samples and history to be published.

Competing Interests

The authors declare no competing interests.

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Errami, A., Baghdadi, J.E., Ailal, F. et al. Mendelian Susceptibility to Mycobacterial Disease (MSMD): Clinical, Immunological, and Genetic Features of 22 Patients from 15 Moroccan Kindreds. J Clin Immunol 43, 728–740 (2023). https://doi.org/10.1007/s10875-022-01419-x

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