Original Article

Clinical and Genetic Study of X-linked Agammaglobulinemia Patients (The Benefit of Early Diagnosis)


X-linked agammaglobulinemia (XLA) is a primary immunodeficiency caused by genetic defects in the Bruton tyrosine kinase (Btk) gene. XLA is characterized as an antibody deficiency by recurrent bacterial infections, the absence of peripheral B cells, and profound reductions in all immunoglobulin isotypes. This study aims to report the clinical and genetic features of five Iranian patients with XLA.
Five male cases with recurrent bacterial infection entered this study based on clinical evaluation and Immunological screening tests. The levels of T-cell receptor excision circle (TREC) and kappa-deleting recombination excision circle (KREC) were also measured in dried blood spot (DBS) samples. Sanger sequencing was applied to PCR products of DNA samples of the patients for genetic studies.
All patients were from unrelated families with a mean age of 6.7 years (2.5-11) at the time of diagnosis with 4.8 mean years of delay in diagnosis. The most frequent clinical manifestations were recurrent respiratory infections and arthritis. In these patients, five previously reported mutations were found including four mutations (p.Q496X, p.Q497X, p.R520X, and p.R641H) in the Kinase domain besides one mutation (p.L37P) in the pleckstrin homology (PH) domain. Evaluations of KREC and TREC level in patients’ DBS showed low-to-undetectable copies of KREC (0-2 copies/3.2mm DBS) with normal copies of TREC.
As patients with XLA have complete immunoglobulin defects and develop severe and recurrent infections, early diagnosis would be beneficial for the improvement of their quality of life. The study results may provide valuable information for the diagnosis, genetic counseling and prenatal diagnosis for the patients and their family members and emphasize performing KREC as an early diagnostic test in patients with XLA.

1. Weber ANR, Bittner Z, Liu X, Dang TM, Radsak MP, Brunner C. Bruton's Tyrosine Kinase: An Emerging Key Player in Innate Immunity. Front Immunol. 2017;8:1454.
2. Marron TU, Rohr K, Martinez-Gallo M, Yu J, Cunningham-Rundles C. TLR signaling and effector functions are intact in XLA neutrophils. Clin Immunol. 2010;137(1):74-80.
3. Winkelstein JA, Marino MC, Lederman HM, Jones SM, Sullivan K, Burks AW, et al. X-linked agammaglobulinemia: report on a United States registry of 201 patients. Medicine. 2006;85(4):193-202.
4. Plebani A, Soresina A, Rondelli R, Amato GM, Azzari C, Cardinale F, et al. Clinical, immunological, and molecular analysis in a large cohort of patients with X-linked agammaglobulinemia: an Italian multicenter study. Clin Immunol. 2002;104(3):221-30.
5. Borte S, von Dobeln U, Fasth A, Wang N, Janzi M, Winiarski J, et al. Neonatal screening for severe primary immunodeficiency diseases using high-throughput triplex real-time PCR. Blood. 2012;119(11):2552-5.
6. Nourizadeh M, Shakerian L, Borte S, Fazlollahi M, Badalzadeh M, Houshmand M, et al. Newborn screening using TREC/KREC assay for severe T and B cell lymphopenia in Iran. Scand J Immunol. 2018;88(2):e12699.
7. Aghamohammadi A, Fiorini M, Moin M, Parvaneh N, Teimourian S, Yeganeh M, et al. Clinical, immunological and molecular characteristics of 37 Iranian patients with X-linked agammaglobulinemia. Int Arch Allergy Immunol. 2006;141(4):408-14.
8. Singh S, Rawat A, Suri D, Gupta A, Garg R, Saikia B, et al. X-linked agammaglobulinemia: Twenty years of single-center experience from North West India. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, and Immunology. 2016;117(4):405-11.
9. Nakagawa N, Imai K, Kanegane H, Sato H, Yamada M, Kondoh K, et al. Quantification of kappa-deleting recombination excision circles in Guthrie cards for the identification of early B-cell maturation defects. J Allergy Clin Immunol. 2011;128(1):223-5.e2.
10. Esenboga S, Cagdas D, Ozgur TT, Gur Cetinkaya P, Turkdemir LM, Sanal O, et al. Clinical and genetic features of the patients with X-Linked agammaglobulinemia from Turkey: Single-centre experience. Scand J Immunol. 2018;87(3).
11. Valiaho J, Smith CI, Vihinen M. BTKbase: the mutation database for X-linked agammaglobulinemia. Hum Mutat. 2006;27(12):1209-17.
12. Lee PP, Chen TX, Jiang LP, Chan KW, Yang W, Lee BW, et al. Clinical characteristics and genotype-phenotype correlation in 62 patients with X-linked agammaglobulinemia. J Clin Immunol. 2010;30(1):121-31.
13. Hashimoto S, Tsukada S, Matsushita M, Miyawaki T, Niida Y, Yachie A, et al. Identification of Bruton's tyrosine kinase (Btk) gene mutations and characterization of the derived proteins in 35 X-linked agammaglobulinemia families: a nationwide study of Btk deficiency in Japan. Blood. 1996;88(2):561-73.
14. Hagemann TL, Chen Y, Rosen FS, Kwan SP. Genomic organization of the Btk gene and exon scanning for mutations in patients with X-linked agammaglobulinemia. Hum Mol Genet. 1994;3(10):1743-9.
15. Jin H, Webster AD, Vihinen M, Sideras P, Vorechovsky I, Hammarstrom L, et al. Identification of Btk mutations in 20 unrelated patients with X-linked agammaglobulinaemia (XLA). Hum Mol Genet. 1995;4(4):693-700.
IssueVol 19, No 3 (2020) QRcode
SectionOriginal Article(s)
DOI https://doi.org/10.18502/ijaai.v19i3.3458
Bruton tyrosine kinase Early diagnosis Mutation X-linked agammaglobulinemia

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
How to Cite
Alizadeh Z, Dashti P, Mazinani M, Nourizadeh M, Shakerian L, Tajik S, Movahedi M, Mamishi S, Pourpak Z, Fazlollahi MR. Clinical and Genetic Study of X-linked Agammaglobulinemia Patients (The Benefit of Early Diagnosis). Iran J Allergy Asthma Immunol. 2020;19(3):305-309.