Main Article Content
agammaglobulinemia, immunodeficiency, mutation, tyrosine kinase, X-linked agammaglobulinemia
Introduction and objectives: X-linked agammaglobulinemia (XLA), the first known primary immunodeficiency, is caused by rare mutations in Bruton’s tyrosine kinase (BTK) gene. Mutations in the BTK gene lead to a failure in the development and maturation of B-cell linage. A decreased number of B-cells results in agammaglobulinemia and increased susceptibility to a variety of infections. Therefore, patients with XLA usually manifest with repetitive bacterial infections, such as upper respiratory tract infections, septic arthritis, osteomyelitis, and urinary tract infections, since their infancy.
Patients: We report a 17-year-old Iranian boy with XLA, referred to us with a history of severe and recurrent episodes of bacterial infections for a period of six years.
Results: Genetic analysis using the whole Exome sequencing revealed a hemizygous missense mutation in the BTK gene (c.428 A > T, p.His143Leu).
Conclusion: To our knowledge, c.428 A > T has not been reported in the BTK gene.
2. Winkelstein JA, Marino MC, Johnston RB, Jr, Boyle J, Curnutte J, Gallin JI, et al. Chronic granulomatous disease: Report on a national registry of 368 patients. Medicine (Baltimore) 2000;79(3):155–69. https://doi.org/10.1097/00005792-200005000-00003
3. Vihinen M, Kwan SP, Lester T, Ochs HD, Resnick I, Väliaho J, et al. Mutations of the human BTK gene coding for bruton tyrosine kinase in X-linked agammaglobulinemia. Hum Mutat. 1999;13(4):280–5. https://doi.org/10.1002/(SICI)1098-1004(1999)13:4<280::AID-HUMU3>3.0.CO;2-L
4. Kanegane H, Futatani T, Wang Y, Nomura K, Shinozaki K, Matsukura H, et al. Clinical and mutational characteristics of X-linked agammaglobulinemia and its carrier identified by flow cytometric assessment combined with genetic analysis. J Allergy Clin Immunol. 2001;108(6):1012–20. https://doi. org/10.1067/mai.2001.120133
5. Hendriks RW, Bredius RG, Pike-Overzet K, Staal FJJ Eoott. Biology and novel treatment options for XLA, the most common monogenetic immunodeficiency in man. Expert Opin Ther Targets. 2011;15(8):1003–21. https://doi.org/10.1517/1472 8222.2011.585971
6. Lougaris V, Soresina A, Baronio M, Montin D, Martino S, Signa S, et al. Long term follow-up of 168 patients with X-linked agammaglobulinemia reveals increased morbidity and mortality. JAllergy Clin Immunol. 2020 Aug;146(2):429–437 2020. https:// doi.org/10.1016/j.jaci.2020.03.001
7. Shillitoe B, Gennery AJCI. X-linked agammaglobulinaemia: Outcomes in the modern era. Clin Immunol; 2017;183:54–62. https://doi.org/10.1016/j.clim.2017.07.008
8. Pyne D, Ehrenstein M, Morris VJR. The therapeutic uses of intravenous immunoglobulins in autoimmune rheumatic diseases. Rheumatology (Oxford) 2002;41(4):367–74. https://doi. org/10.1093/rheumatology/41.4.367
9. Mazhar M, Waseem M. Agammaglobulinemia. [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan.
10. Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alföldi J, Wang Q, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581(7809):434– 43. https://doi.org/10.1530/ey.17.14.3
11. Kircher M, Witten DM, Jain P, O’Roak BJ, Cooper GM, Shendure JJ Ng. A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet. 2014;46(3):310–5. https://doi.org/10.1038/ng.2892
12. Carrillo-Tapia E, García-García E, Herrera-González NE, Yamazaki-Nakashimada MA, Staines-Boone AT, Segura-Mendez NH, et al. Delayed diagnosis in X-linked agammaglobulinemia and its relationship to the occurrence of mutations in BTK non-kinase domains. Expert Rev Clin Immunol. 2018;14(1):83–93. https://doi.org/10.1080/17446 66X.2018.1413349
13. Lee J, Rhee M, Min TK, Bang HI, Jang M-A, Kang E-S, et al. A novel BTK gene mutation, c. 82delC (p. Arg28 Alafs* 5), in a Korean family with X-linked agammaglobulinemia. Korean J Pediatr. 2016;59(Suppl 1):S49. https://doi.org/10.3345/ kjp.2016.59.11.S49
14. Han S-P, Lin Y-F, Weng H-Y, Tsai S-F, Fu L-SJFii. A novel BTK gene mutation in a child with atypical X-linked agammaglobulinemia and recurrent hemophagocytosis: A case report. Front Immunol. 2019;10:1953. https://doi.org/10.3389/fimmu. 2019.01953
15. Abolhassani H, Vitali M, Lougaris V, Giliani S, Parvaneh N, Parvaneh L, et al. Cohort of Iranian patients with congenital agammaglobulinemia: Mutation analysis and novel gene defects. Expert Rev Clin Immunol. 2016;12(4):479–86. https:// doi.org/10.1586/1744666X.2016.1139451
16. El-Sayed ZA, Abramova I, Aldave JC, Al-Herz W, Bezrodnik L, Boukari R, et al. X-linked agammaglobulinemia (XLA): Phenotype, diagnosis, and therapeutic challenges around the world. World Allergy Organ J. 2019;12(3):100018. https://doi.org/10.1016/j. waojou.2019.100018