Beyond Recurrent Infections: Immune Dysregulation Manifestations, Genotype–phenotype Heterogeneity, and Three Novel BTK Variants in X-linked Agammaglobulinemia
Immune Dysregulation and Genotype–Phenotype Heterogeneity in XLA
,
Abstract
X-linked agammaglobulinemia (XLA) is an inborn error of immunity caused by BTK gene mutations, characterized by hypogammaglobulinemia and recurrent infections. This study evaluates a long-term pediatric cohort to assess clinical spectrum, therapeutic outcomes, and molecular findings.
We retrospectively reviewed clinical, immunological, treatment, and genetic data for 11 male XLA patients followed over 20 years at our center.
Median age at symptom onset was 12.7 months (range: 3–60), while median age at diagnosis was 4.5 years (range: 1–10), revealing marked diagnostic delays in patients without family history. Severe complications included bronchiectasis, septic arthritis, and immune dysregulation (e.g., juvenile idiopathic arthritis, autoimmune hepatitis, pancytopenia, celiac disease). Immunoglobulin replacement and antibiotic prophylaxis significantly reduced median annual infections from 16.9 to 2.09. Six distinct BTK variants were identified, including three novel mutations: c.90del, c.1922_1924delGTC, and c.1589dup. Inter-sibling phenotypic heterogeneity was notable. In the absence of functional expression studies, pathogenic contributions of novel variants remain exploratory.
XLA extends beyond recurrent infections to encompass significant immune dysregulation and phenotypic variability. Early diagnosis, family screening, genetic testing, and tailored immunoglobulin therapy are vital to improve long-term outcomes. Larger multicenter cohorts with functional testing are needed to validate genotype–phenotype associations.
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2. Yeh Y-H, Hsieh M-Y, Lee W-I, Huang J-L, Chen L-C, Yeh K-W, et al. Distinct clinical features and novel mutations in Taiwanese patients with X-linked agammaglobulinemia. Front Immunol. 2020;11:2001.
3. Picard C, Bobby Gaspar H, Al-Herz W, Bousfiha A, Casanova J-L, Chatila T, et al. International union of immunological societies: 2017 primary immunodeficiency diseases committee report on inborn errors of immunity. J Allergy Clin Immunol. 2018;38(1):96-128.
4. 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.
5. Makkoukdji N, Pundit V, Wyke M, Giraldo J, Satnarine T, Kleiner GI, et al. Targeted treatments for immune dysregulation in inborn errors of immunity. Exp Immunol. 2024;4(2):218-37.
6. Hernandez-Trujillo VP, Scalchunes C, Cunningham-Rundles C, Ochs HD, Bonilla FA, Paris K, et al. Autoimmunity and inflammation in X-linked agammaglobulinemia. J Allergy Clin Immunol. 2014;34(6):627-32.
7. Lee PP, Chen T-X, Jiang L-P, Chan K-W, Yang W, Lee B-W, et al. Clinical characteristics and genotype-phenotype correlation in 62 patients with X-linked agammaglobulinemia. J Allergy Clin Immunol. 2010;30(1):121-31.
8. Holinski-Feder E, Weiss M, Brandau O, Jedele KB, Nore B, Bäckesjö CM, et al. Mutation screening of the BTK gene in 56 families with X-linked agammaglobulinemia (XLA): 47 unique mutations without correlation to clinical course. Pediatrics. 1998;101(2):276-84.
9. Shillitoe B, Bangs C, Guzman D, Gennery AR, Longhurst H, Slatter M, et al. The United Kingdom primary immune deficiency (UKPID) registry 2012 to 2017. Clin Exp Immunol. 2018;192(3):284-91.
10. Seidel MG, Kindle G, Gathmann B, Quinti I, Buckland M, van Montfrans J, et al. The European Society for Immunodeficiencies (ESID) registry working definitions for the clinical diagnosis of inborn errors of immunity. J Allergy Clin Immunol. 2019;7(6):1763-70.
11. Bakardjieva M. Immunophenotype and functional characteristics of lymphocytes in patients with primary immunodeficiency. 2024.
12. Kanegane H, Tanita K, Nishimura M, Tomomasa D, Inoue K, Kanamori T, et al. Revisiting X-linked agammaglobulinemia. Journal of Human Immunity. 2025;1(1):e20250020.
13. 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.
14. 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. J Allergy Clin Immunol. 2020;146(2):429-37.
15. Rawat A, Jindal AK, Suri D, Vignesh P, Gupta A, Saikia B, et al. Clinical and genetic profile of X-linked agammaglobulinemia: a multicenter experience from India. Front Immunol. 2021;11:612323.
16. Conley ME, Howard V. Clinical findings leading to the diagnosis of X-linked agammaglobulinemia. The Journal of pediatrics. 2002;141(4):566-71.
17. Yıldırım İ, Topyıldız E, Bilgin RBG, Aykut A, Durmaz A, Karaca NE, et al. X-linked agammaglobulinemia: investigation of clinical and laboratory findings, novel gene mutations and prevention of infective complications in long-term follow-up. American Journal of Clinical and Experimental Immunology. 2021;10(2):63.
18. Plebani A, Fischer MB, Meini A, Duse M, Thon V, Eibl MM. T cell activity and cytokine production in X-linked agammaglobulinemia: implications for vaccination strategies. Int Arch Allergy Immunol. 1997;114(1):90-3.
19. Azizi G, Hesari MF, Sharifinejad N, Fayyaz F, Chavoshzadeh Z, Mahdaviani SA, et al. The autoimmune manifestations in patients with genetic defects in the B cell development and differentiation stages. J Allergy Clin Immunol. 2023;43(4):819-34.
20. Teocchi M, de Andrade Eugênio T, Furlaneto Marega L, Quinti I, dos Santos Vilela MM. Dysregulation of Toll-Like Receptor Signaling-Associated Gene Expression in X-Linked Agammaglobulinemia: implications for correlations genotype-phenotype and disease expression. J Innate Immun. 2024;16(1):425-39.
21. Xu K, Zhang B, Zhao S, Zhang Y, Wu N, Shen M, et al. RNA Sequencing Addresses a 5’UTR Variant Leading to X-Linked Agammaglobulinemia and Broader Immune Dysregulation. J Allergy Clin Immunol. 2026;46(1):7.
22. Agarwal S, Mayer L. Pathogenesis and treatment of gastrointestinal disease in antibody deficiency syndromes. J Allergy Clin Immunol. 2009;124(4):658-64.
23. Lehman H. Skin manifestations of primary immune deficiency. Clin Rev Allergy Immunol. 2014;46(2):112-9.
24. Kareva L, Mironska K, Stavric K. Joint disease in children with X-linked agammaglobulinemia. Journal of IMAB–Annual Proceeding Scientific Papers. 2013;19(3):457-60.
25. Lee AH, Levinson AI, Schumacher Jr HR, editors. Hypogammaglobulinemia and rheumatic disease. Seminars in arthritis and rheumatism; 1993: Elsevier.
26. Huq M, Bhatnagar NK, Hostoffer RW. Hypogammaglobulinemia. 2020.
27. Conley ME, Mathias D, Treadaway J, Minegishi Y, Rohrer J. Mutations in btk in patients with presumed X-linked agammaglobulinemia. Am J Hum Genet. 1998;62(5):1034-43.
28. 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.
29. Hu X-M, Yuan K, Chen H, Chen C, Fang Y-L, Zhu J-F, et al. Novel deletion mutation in Bruton’s tyrosine kinase results in X-linked agammaglobulinemia: A case report. World J Clin Cases. 2020;8(17):3859.
30. Wall LA, Wisner EL, Gipson KS, Sorensen RU. Bronchiectasis in primary antibody deficiencies: a multidisciplinary approach. Fron Immunol. 2020;11:522.
31. Pac MM, Bernatowska EA, Kierkuś J, Ryżko JP, Cielecka-Kuszyk J, Jackowska T, et al. Gastrointestinal disorders next to respiratory infections as leading symptoms of X-linked agammaglobulinemia in children–34-year experience of a single center. Arch Med Sci. 2017;13(2):412-7.
32. Quartier P, Debré M, De Blic J, De Sauverzac R, Sayegh N, Jabado N, et al. Early and prolonged intravenous immunoglobulin replacement therapy in childhood agammaglobulinemia: a retrospective survey of 31 patients. J Ped. 1999;134(5):589-96.
33. Lim L-M, Chang J-M, Wang I-F, Chang W-C, Hwang D-Y, Chen H-C. Atypical X-linked agammaglobulinaemia caused by a novel BTK mutation in a selective immunoglobulin M deficiency patient. BMC pediatrics. 2013;13(1):150.
34. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Geneti Med. 2015;17(5):405-23.
35. Biesecker LG, Byrne AB, Harrison SM, Pesaran T, Schäffer AA, Shirts BH, et al. ClinGen guidance for use of the PP1/BS4 co-segregation and PP4 phenotype specificity criteria for sequence variant pathogenicity classification. Am J Hum Genet. 2024;111(1):24-38.
2. Yeh Y-H, Hsieh M-Y, Lee W-I, Huang J-L, Chen L-C, Yeh K-W, et al. Distinct clinical features and novel mutations in Taiwanese patients with X-linked agammaglobulinemia. Front Immunol. 2020;11:2001.
3. Picard C, Bobby Gaspar H, Al-Herz W, Bousfiha A, Casanova J-L, Chatila T, et al. International union of immunological societies: 2017 primary immunodeficiency diseases committee report on inborn errors of immunity. J Allergy Clin Immunol. 2018;38(1):96-128.
4. 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.
5. Makkoukdji N, Pundit V, Wyke M, Giraldo J, Satnarine T, Kleiner GI, et al. Targeted treatments for immune dysregulation in inborn errors of immunity. Exp Immunol. 2024;4(2):218-37.
6. Hernandez-Trujillo VP, Scalchunes C, Cunningham-Rundles C, Ochs HD, Bonilla FA, Paris K, et al. Autoimmunity and inflammation in X-linked agammaglobulinemia. J Allergy Clin Immunol. 2014;34(6):627-32.
7. Lee PP, Chen T-X, Jiang L-P, Chan K-W, Yang W, Lee B-W, et al. Clinical characteristics and genotype-phenotype correlation in 62 patients with X-linked agammaglobulinemia. J Allergy Clin Immunol. 2010;30(1):121-31.
8. Holinski-Feder E, Weiss M, Brandau O, Jedele KB, Nore B, Bäckesjö CM, et al. Mutation screening of the BTK gene in 56 families with X-linked agammaglobulinemia (XLA): 47 unique mutations without correlation to clinical course. Pediatrics. 1998;101(2):276-84.
9. Shillitoe B, Bangs C, Guzman D, Gennery AR, Longhurst H, Slatter M, et al. The United Kingdom primary immune deficiency (UKPID) registry 2012 to 2017. Clin Exp Immunol. 2018;192(3):284-91.
10. Seidel MG, Kindle G, Gathmann B, Quinti I, Buckland M, van Montfrans J, et al. The European Society for Immunodeficiencies (ESID) registry working definitions for the clinical diagnosis of inborn errors of immunity. J Allergy Clin Immunol. 2019;7(6):1763-70.
11. Bakardjieva M. Immunophenotype and functional characteristics of lymphocytes in patients with primary immunodeficiency. 2024.
12. Kanegane H, Tanita K, Nishimura M, Tomomasa D, Inoue K, Kanamori T, et al. Revisiting X-linked agammaglobulinemia. Journal of Human Immunity. 2025;1(1):e20250020.
13. 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.
14. 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. J Allergy Clin Immunol. 2020;146(2):429-37.
15. Rawat A, Jindal AK, Suri D, Vignesh P, Gupta A, Saikia B, et al. Clinical and genetic profile of X-linked agammaglobulinemia: a multicenter experience from India. Front Immunol. 2021;11:612323.
16. Conley ME, Howard V. Clinical findings leading to the diagnosis of X-linked agammaglobulinemia. The Journal of pediatrics. 2002;141(4):566-71.
17. Yıldırım İ, Topyıldız E, Bilgin RBG, Aykut A, Durmaz A, Karaca NE, et al. X-linked agammaglobulinemia: investigation of clinical and laboratory findings, novel gene mutations and prevention of infective complications in long-term follow-up. American Journal of Clinical and Experimental Immunology. 2021;10(2):63.
18. Plebani A, Fischer MB, Meini A, Duse M, Thon V, Eibl MM. T cell activity and cytokine production in X-linked agammaglobulinemia: implications for vaccination strategies. Int Arch Allergy Immunol. 1997;114(1):90-3.
19. Azizi G, Hesari MF, Sharifinejad N, Fayyaz F, Chavoshzadeh Z, Mahdaviani SA, et al. The autoimmune manifestations in patients with genetic defects in the B cell development and differentiation stages. J Allergy Clin Immunol. 2023;43(4):819-34.
20. Teocchi M, de Andrade Eugênio T, Furlaneto Marega L, Quinti I, dos Santos Vilela MM. Dysregulation of Toll-Like Receptor Signaling-Associated Gene Expression in X-Linked Agammaglobulinemia: implications for correlations genotype-phenotype and disease expression. J Innate Immun. 2024;16(1):425-39.
21. Xu K, Zhang B, Zhao S, Zhang Y, Wu N, Shen M, et al. RNA Sequencing Addresses a 5’UTR Variant Leading to X-Linked Agammaglobulinemia and Broader Immune Dysregulation. J Allergy Clin Immunol. 2026;46(1):7.
22. Agarwal S, Mayer L. Pathogenesis and treatment of gastrointestinal disease in antibody deficiency syndromes. J Allergy Clin Immunol. 2009;124(4):658-64.
23. Lehman H. Skin manifestations of primary immune deficiency. Clin Rev Allergy Immunol. 2014;46(2):112-9.
24. Kareva L, Mironska K, Stavric K. Joint disease in children with X-linked agammaglobulinemia. Journal of IMAB–Annual Proceeding Scientific Papers. 2013;19(3):457-60.
25. Lee AH, Levinson AI, Schumacher Jr HR, editors. Hypogammaglobulinemia and rheumatic disease. Seminars in arthritis and rheumatism; 1993: Elsevier.
26. Huq M, Bhatnagar NK, Hostoffer RW. Hypogammaglobulinemia. 2020.
27. Conley ME, Mathias D, Treadaway J, Minegishi Y, Rohrer J. Mutations in btk in patients with presumed X-linked agammaglobulinemia. Am J Hum Genet. 1998;62(5):1034-43.
28. 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.
29. Hu X-M, Yuan K, Chen H, Chen C, Fang Y-L, Zhu J-F, et al. Novel deletion mutation in Bruton’s tyrosine kinase results in X-linked agammaglobulinemia: A case report. World J Clin Cases. 2020;8(17):3859.
30. Wall LA, Wisner EL, Gipson KS, Sorensen RU. Bronchiectasis in primary antibody deficiencies: a multidisciplinary approach. Fron Immunol. 2020;11:522.
31. Pac MM, Bernatowska EA, Kierkuś J, Ryżko JP, Cielecka-Kuszyk J, Jackowska T, et al. Gastrointestinal disorders next to respiratory infections as leading symptoms of X-linked agammaglobulinemia in children–34-year experience of a single center. Arch Med Sci. 2017;13(2):412-7.
32. Quartier P, Debré M, De Blic J, De Sauverzac R, Sayegh N, Jabado N, et al. Early and prolonged intravenous immunoglobulin replacement therapy in childhood agammaglobulinemia: a retrospective survey of 31 patients. J Ped. 1999;134(5):589-96.
33. Lim L-M, Chang J-M, Wang I-F, Chang W-C, Hwang D-Y, Chen H-C. Atypical X-linked agammaglobulinaemia caused by a novel BTK mutation in a selective immunoglobulin M deficiency patient. BMC pediatrics. 2013;13(1):150.
34. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Geneti Med. 2015;17(5):405-23.
35. Biesecker LG, Byrne AB, Harrison SM, Pesaran T, Schäffer AA, Shirts BH, et al. ClinGen guidance for use of the PP1/BS4 co-segregation and PP4 phenotype specificity criteria for sequence variant pathogenicity classification. Am J Hum Genet. 2024;111(1):24-38.
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| BTK gene mutations Genotype–phenotype correlation Immune dysregulation Inborn error of immunity X-linked agammaglobulinemia | ||
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How to Cite
1.
Kapçay O, Şen A, Demir Şahin F, Kılıç M. Beyond Recurrent Infections: Immune Dysregulation Manifestations, Genotype–phenotype Heterogeneity, and Three Novel BTK Variants in X-linked Agammaglobulinemia. Iran J Allergy Asthma Immunol. 2026;:1-14.
