Serdar NEPESOV, Sinem FIRTINA, Deniz AYGÜN, Begüm IŞIKGİL, Yıldız CAMCIOĞLU, Ayça KIYKIM, Esra ÖZEK, Yasemin KENDİR DEMİRKOL, Akif AYAZ

MİKOBAKTERİYEL HASTALIKLARA MENDEL DUYARLILIĞI HASTALARININ GENETİK VE KLİNİK PROFİLİ; TEK MERKEZ DENEYİMİ

Amaç: Mikobakteriyel hastalığa (MSMD) Mendel duyarlılığı, Bacille Calmette-Guérin (BCG) aşısı veya tüberküloz dışı mikobakteriyel enfeksiyonlarla gelişen primer immün yetmezliklerin bir alt grubudur. Klinik semptomlar, lokalize enfeksiyondan yayılmış enfeksiyona kadar geniş bir spektruma sahiptir. Gereç ve Yöntem: Bu çalışmada; MSMD fenotipli 13 hastada tüm ekzom dizileme (WES) yaptık. Tüm varyantlar Sanger dizileme ile doğrulandı. Bizim kohortumuzda ortalama yaş 8.41 yıl (en az 3 – en fazla 14 yıl) ve ortalama semptom başlangıç yaşı 4.6 idi. Bulgular: Dokuz hastada; IFNGR1 (n=2), IFNGR2 (n=1), TYK2 (n=1), IL12RB1 (n=1) ve CYBB (n=1) gen varyantları bulduk. Hastalarımızda en çok lenfadenit (%61,5), osteomiyelit (%38) ve miliyer tüberküloz (%31) mevcuttu. Biri hariç tüm hastalara BCG aşısı yapıldı. İki hastada aşılamadan sonra BCGitis gelişti. Üç hasta, yayılmış BCG enfeksiyonundan (BCGosis) muzdaripti. Sonuç: Bulgularımız, enfeksiyon hastalıklarının genetik temelinin anlaşılmasında ve tedavi seçeneklerine karar verilmesinde bir yaklaşım olarak ağır enfeksiyonlu hastalarda moleküler tanının önemini göstermektedir. IFN aracılı bağışıklık genlerinin eksikliği, MSMD’nin patogenezinde çok önemli bir rol oynar ve BCGitis’li pediatrik hastalarda düşünülmelidir.

Anahtar Kelimeler:

MSMD, BCGitis, tüm ekzom dizileme

GENETIC AND CLINICAL PROFILING OF MENDELIAN SUSCEPTIBILITY TO MYCOBACTERIAL DISEASE PATIENTS; SINGLECENTER EXPERIENCE

Objective: Mendelian susceptibility to mycobacterial disease (MSMD) is a subgroup of primary immunodeficiencies which develops with the Bacille Calmette–Guérin (BCG) vaccine or non-tuberculous mycobacterial infections. The clinical symptoms have a broad spectrum, from localized to disseminated infections. Materials and Methods: Herein, we performed whole-exome sequencing (WES) on 13 patients with MSMD phenotype. All variants were confirmed by Sanger sequencing. The mean age was 8.41 years (min 3 – max 14 years), and the mean age of symptom onset was 4.6 years in our cohort. Results: We found previously identified IFNGR1 (n=1), IFNGR2 (n=1), TYK2 (n=1), IL12RB1 (n=1), and CYBB (n=1) gene variants in nine patients. Our patients mostly suffered from lymphadenitis (61.5%), osteomyelitis (38%), and miliary tuberculosis (31%). All patients except one had had the BCG vaccination. Two patients developed BCGitis after vaccination. Three patients suffered from disseminated BCG infection (BCGosis). Conclusion: Our findings show the importance of molecular diagnosis in patients with severe infections as an approach for understanding the genetic basis of infectious diseases and deciding on treatment options. The deficiency of IFN-mediated immunity genes plays a crucial role in the pathogenesis of MSMD and must be considered in pediatric patients with BCGitis.

Keywords:

MSMD, BCGitis, whole exome sequencing,

PDF

___

1. Soyak Aytekin E, Keskin A, Tan C, Yalçın E , Dogru D, Ozcelik U, et al. Differential diagnosis of primary immunodeficiency in patients with BCGitis and BCGosis: A single-centre study. Scand J İmmunol 2021;94(4):e13084. doi: 10.1111/sji.13084. google scholar
2. Bustamante J. Mendelian susceptibility to mycobacterial disease: recent discoveries. Hum Genet 2020;139(6-7):993-1000. google scholar
3. Rosain J, Kong XF, Martinez-Barricarte R, Oleaga-Quintas C , Ramirez-Alejo N, Markle J, et al. Mendelian susceptibility to mycobacterial disease: 2014-2018 update. İmmunol Cell Biol 2019;97(4):360-7. google scholar
4. Das J, Banday AZ, Shandilya J, Sharma M, Vignesh P, Rawat A. An updated review on Mendelian susceptibility to mycobacterial diseases- a silver jubilee celebration of its first genetic diagnosis. Expert Rev Clin İmmunol 2021;17(10):1103-20. google scholar
5. Filipe-Santos O, Bustamante J, Chapgier A, Vogt G, Beaucoudrey L de, Feinberg J, et al. İnborn errors of İL-12/23- and İFN-gamma-mediated immunity: molecular, cellular, and clinical features. Semin İmmunol 2006;18(6):347-61. google scholar
6. Zhou X, Jia W, Ni Z, Wang A, Liu Z, Hou M, et al. Three novel compound heterozygous İL12RB1 mutations in Chinese patients with Mendelian susceptibility to mycobacterial disease. PLoS One 2019;14(4):e0215648. doi: 10.1371/journal.pone.0215648. google scholar
7. Tan C, Cagdas-Ayvaz D, Metin A, Keskin O, Tezcan İ, Sanal O. Clinical and genetic features of IL12Rb1 deficiency: Single center experience of 18 patients. Turk J Pediatr 2016;58(4):356-61. google scholar
8. Kerner G, Rosain J, Guerin A, Al-Khabaz A, Oleaga-Quintas C, Rapaport F, et al. Inherited human IFN-gamma deficiency underlies mycobacterial disease. J Clin Invest 2020;130(6):3158-71. google scholar
9. van de Vosse E, van Dissel JT. IFN-gammaR1 defects: Mutation update and description of the IFNGR1 variation database. Hum Mutat 2017;38(10):1286-96. google scholar
10. Indumathi CK, Bustamante J. Clinical and immunological profile of children with Mendelian Susceptibility to Mycobacterial Diseases (MSMD) from an Indian tertiary care hospital. Indian J Tuberc 2021;68(2):292-7. google scholar
11. Boisson-Dupuis S, Ramirez-Alejo N, Li Z, Rao G, Kerner G, Lim CK et al. Tuberculosis and impaired IL-23-dependent IFN-gamma immunity in humans homozygous for a common TYK2 missense variant. Sci Immunol 2018;3(30):eaau8714. doi: 10.1126/ sciimmunol.aau8714. google scholar
12. Wu P, Chen S, Wu B, Chen J, Lv G. A TYK2 Gene Mutation c. 2395G>A Leads to TYK2 Deficiency: A Case Report and Literature Review. Front Pediatr 2020;8:253. google scholar
13. Bustamante J, Arias AA, Vogt G, Galicia LB, Prando C, Grant AV, et al. Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked predisposition to tuberculous mycobacterial disease. Nat Immunol 2011;12(3):213-21. google scholar
14. Bustamante J, Picard C, Boisson-Dupuis S, Abel L, Casanova JL. Genetic lessons learned from X-linked Mendelian susceptibility to mycobacterial diseases. Ann N Y Acad Sci 2011;1246:92-101. google scholar
15. Chinn IK, Chan AY, Chen K, Chou J, Dorsey MJ, Hajjaret J, et al. Diagnostic interpretation of genetic studies in patients with primary immunodeficiency diseases: A working group report of the Primary Immunodeficiency Diseases Committee of the American Academy of Allergy, Asthma & Immunology. J Allergy Clin Immunol 2020;145(1):46-69. google scholar
16. Yang Y, Muzny DM, Xia F, Niu Z, Person R, Ding Y, et al. Molecular findings among patients referred for clinical whole-exome sequencing. JAMA 2014;312(18):1870-9. google scholar
17. van Coller A, Glanzmann B, Cornelissen H, Möller M, Kinnear C, Esseret M, et al. Phenotypic and immune functional profiling of patients with suspected Mendelian Susceptibility to Mycobacterial Disease in South Africa. BMC Immunol 2021;22(1):1-17. google scholar
18. Ahmed CM, Johnson HM. IFN-gamma and its receptor subunit IFNGR1 are recruited to the IFN-gamma-activated sequence element at the promoter site of IFN-gamma-activated genes: evidence of transactivational activity in IFNGR1. J Immunol 2006;177(1):315-21. google scholar
19. Marazzi MG, Chapgier A, Defilippi AC, Pistoia V, Mangini S, Savioli C, et al. Disseminated Mycobacterium scrofulaceum infection in a child with interferon-gamma receptor 1 deficiency. Int J Infect Dis 2010;14(2):e167-70. doi: 10.1016/j.ijid.2009.03.025. google scholar
20. Schroder K, Hertzog PJ, Ravasi T, Hume DA. Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol 2004;75(2):163-89. google scholar
21. Fieschi C, Bosticardo M, de Beaucoudrey L, Boisson-Dupuis S, Feinberg J, Santos OF, et al. A novel form of complete IL-12/IL-23 receptor beta1 deficiency with cell surface-expressed nonfunctional receptors. Blood 2004;104(7):2095-101. google scholar
22. Robinson RT. IL12Rbeta1: the cytokine receptor that we used to know. Cytokine 2015;71(2):348-59. google scholar
23. Kreins AY, Ciancanelli MJ, Okada S, KongX-F, Ramurez-Alejo Noe, Kilic SS, et al. Human TYK2 deficiency: Mycobacterial and viral infections without hyper-IgE syndrome. J Exp Med 2015;212(10):1641-62. google scholar
24. Guo W, Feng X, Yang M, Shangguan Y, Shi P, Wang S, et al. Mycobacterium Intracellulare Infection Associated with TYK2 Deficiency: A Case Report and Review of the Literature. Infect Drug Resist 2020;13:4347-53. google scholar