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X-linked Agammaglobulinemia

The Indian Journal of Pediatrics volume 83, pages 331–337 (2016)Cite this article

Abstract

X-linked agammaglobulinemia (XLA) is one of the commonest primary immune deficiencies encountered in pediatric clinical practice. In adults, common variable immunodeficiency (CVID) is the most common primary immunodeficiency disease (PID). It is an X-linked disorder characterized by increased susceptibility to encapsulated bacteria, severe hypergammaglobulinemia and absent circulating B cells in the peripheral blood. Replacement immunoglobulin therapy is the main cornerstone of treatment. Aggressive management of intercurrent infections and prophylactic antimicrobials are needed. This review attempts to highlight varied clinical manifestations and management of XLA, especially in the context of developing country.

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References

  1. Bruton OC. Agammaglobulinemia. Pediatrics. 1952;9:722–8.

    CAS  PubMed  Google Scholar 

  2. Tsukada S, Saffran DC, Rawlings DJ, et al. Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia. 1993. J Immunol. 2012;188:2936–47.

    CAS  PubMed  Google Scholar 

  3. Vetrie D, Vorechovský I, Sideras P, et al. The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases. Nature. 1993;361:226–33.

    CAS  Article  PubMed  Google Scholar 

  4. Winkelstein JA, Marino MC, Lederman HM, et al. X-linked agammaglobulinemia: report on a United States registry of 201 patients. Medicine (Baltimore). 2006;85:193–202.

    Article  Google Scholar 

  5. Conley ME, Rohrer J, Rapalus L, Boylin EC, Minegishi Y. Defects in early B-cell development: comparing the consequences of abnormalities in pre-BCR signaling in the human and the mouse. Immunol Rev. 2000;178:75–90.

    CAS  Article  PubMed  Google Scholar 

  6. Ochs HD, Smith CI. X-linked agammaglobulinemia. A clinical and molecular analysis. Medicine (Baltimore). 1996;75(6):287–99.

  7. Takada H, Kanegane H, Nomura A, et al. Female agammaglobulinemia due to the Bruton tyrosine kinase deficiency caused by extremely skewed X-chromosome inactivation. Blood. 2004;103:185–7.

    CAS  Article  PubMed  Google Scholar 

  8. Plebani A, Soresina A, Rondelli R, et al; Italian Pediatric Group for XLA-AIEOP. Clinical, immunological, and molecular analysis in a large cohort of patients with X-linked agammaglobulinemia: an Italian multicenter study. Clin Immunol. 2002;104:221–30.

  9. Conley ME, Rohrer J, Minegishi Y. X-linked agammaglobulinemia. Clin Rev Allergy Immunol. 2000;19:183–204.

    CAS  Article  PubMed  Google Scholar 

  10. Conley ME, Howard V. Clinical findings leading to the diagnosis of X-linked agammaglobulinemia. J Pediatr. 2002;141:566–71.

    Article  PubMed  Google Scholar 

  11. Lederman HM, Winkelstein JA. X-linked agammaglobulinemia: an analysis of 96 patients. Medicine (Baltimore). 1985;64:145–56.

    CAS  Article  Google Scholar 

  12. Roifman CM, Rao CP, Lederman HM, Lavi S, Quinn P, Gelfand EW. Increased susceptibility to mycoplasma infection in patients with hypogammaglobulinemia. Am J Med. 1986;80:590–4.

    CAS  Article  PubMed  Google Scholar 

  13. Chusid MJ, Coleman CM, Dunne WM. Chronic asymptomatic Campylobacter bacteremia in a boy with X-linked hypogammaglobulinemia. Pediatr Infect Dis J. 1987;6:943–4.

    CAS  Article  PubMed  Google Scholar 

  14. Kerstens PJ, Endtz HP, Meis JF, et al. Erysipelas-like skin lesions associated with Campylobacter jejuni septicemia in patients with hypogammaglobulinemia. Eur J Clin Microbiol Infect Dis. 1992;11:842–7.

    CAS  Article  PubMed  Google Scholar 

  15. Sarpong S, Skolnick HS, Ochs HD, Futatani T, Winkelstein JA. Survival of wild polio by a patient with XLA. Ann Allergy Asthma Immunol. 2002;88:59–60.

    Article  PubMed  Google Scholar 

  16. Halliday E, Winkelstein J, Webster ADB. Enteroviral infections in primary immunodeficiency (PID): a survey of morbidity and mortality. J Infect. 2003;46:1–8.

    CAS  Article  PubMed  Google Scholar 

  17. Rudge P, Webster AD, Revesz T, et al. Encephalomyelitis in primary hypogammaglobulinaemia. Brain J Neurol. 1996;119:1–15.

    Article  Google Scholar 

  18. Jacobs ZD, Guajardo JR, Anderson KM. XLA-associated neutropenia treatment: a case report and review of the literature. J Pediatr Hematol Oncol. 2008;30:631–4.

    Article  PubMed  Google Scholar 

  19. Hernandez-Trujillo VP, Scalchunes C, Cunningham-Rundles C, et al. Autoimmunity and inflammation in X-linked agammaglobulinemia. J Clin Immunol. 2014;34:627–32.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. Sag AT, Saka E, Ozgur TT, et al. Progressive neurodegenerative syndrome in a patient with X-linked agammaglobulinemia receiving intravenous immunoglobulin therapy. Cogn Behav Neurol. 2014;27:155–9.

    Article  PubMed  Google Scholar 

  21. Richter D, Conley ME, Rohrer J, et al. A contiguous deletion syndrome of X-linked agammaglobulinemia and sensorineural deafness. Pediatr Allergy Immunol Off Publ Eur Soc Pediatr Allergy Immunol. 2001;12:107–11.

    CAS  Article  Google Scholar 

  22. Sedivá A, Smith CIE, Asplund AC, et al. Contiguous X-chromosome deletion syndrome encompassing the BTK, TIMM8A, TAF7L, and DRP2 genes. J Clin Immunol. 2007;27:640–6.

    Article  PubMed  Google Scholar 

  23. Fleisher TA, White RM, Broder S, et al. X-linked hypogammaglobulinemia and isolated growth hormone deficiency. N Engl J Med. 1980;302:1429–34.

    CAS  Article  PubMed  Google Scholar 

  24. Monafo V, Maghnie M, Terracciano L, Valtorta A, Massa M, Severi F. X-linked agammaglobulinemia and isolated growth hormone deficiency. Acta Paediatr Scand. 1991;80:563–6.

    CAS  Article  PubMed  Google Scholar 

  25. Duriez B, Duquesnoy P, Dastot F, Bougnères P, Amselem S, Goossens M. An exon-skipping mutation in the btk gene of a patient with X-linked agammaglobulinemia and isolated growth hormone deficiency. FEBS Lett. 1994;346:165–70.

    CAS  Article  PubMed  Google Scholar 

  26. Stewart DM, Tian L, Notarangelo LD, Nelson DL. X-linked hypogammaglobulinemia and isolated growth hormone deficiency: an update. Immunol Res. 2007;38:391–9.

    CAS  Article  PubMed  Google Scholar 

  27. ESID - European Society for Immunodeficiencies [Internet]. Available at: http://esid.org/Working-Parties/Registry/Diagnosis-criteria. Accessed on 16 Dec 2015.

  28. Borte S, von Döbeln U, Fasth A, et al. Neonatal screening for severe primary immunodeficiency diseases using high-throughput triplex real-time PCR. Blood. 2012;119:2552–5.

    CAS  Article  PubMed  Google Scholar 

  29. Bonagura VR, Marchlewski R, Cox A, Rosenthal DW. Biologic IgG level in primary immunodeficiency disease: the IgG level that protects against recurrent infection. J Allergy Clin Immunol. 2008;122:210–2.

    CAS  Article  PubMed  Google Scholar 

  30. Orange JS, Grossman WJ, Navickis RJ, Wilkes MM. Impact of trough IgG on pneumonia incidence in primary immunodeficiency: a meta-analysis of clinical studies. Clin Immunol. 2010;137:21–30.

    CAS  Article  PubMed  Google Scholar 

  31. Lucas M, Lee M, Lortan J, Lopez-Granados E, Misbah S, Chapel H. Infection outcomes in patients with common variable immunodeficiency disorders: relationship to immunoglobulin therapy over 22 years. J Allergy Clin Immunol. 2010;125:1354–60.e4.

    CAS  Article  PubMed  Google Scholar 

  32. Quinti I, Soresina A, Guerra A, et al. Effectiveness of immunoglobulin replacement therapy on clinical outcome in patients with primary antibody deficiencies: results from a multicenter prospective cohort study. J Clin Immunol. 2011;31:315–22.

    CAS  Article  PubMed  Google Scholar 

  33. Milito C, Pulvirenti F, Pesce AM, et al. Adequate patient’s outcome achieved with short immunoglobulin replacement intervals in severe antibody deficiencies. J Clin Immunol. 2014;34:813–9.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. Singh S, Aulakh R, Bhalla AK, et al. Is Kawasaki disease incidence rising in Chandigarh, north India? Arch Dis Child. 2011;96:137–40.

    Article  PubMed  Google Scholar 

  35. Rohrer J, Conley ME. Correction of X-linked immunodeficient mice by competitive reconstitution with limiting numbers of normal bone marrow cells. Blood. 1999;94:3358–65.

    CAS  PubMed  Google Scholar 

  36. Porpiglia AS, Rohrer J, Conley ME. Reconstitution of B cell function in murine models of immunodeficiency. Clin Immunol. 2003;107:90–7.

    CAS  Article  PubMed  Google Scholar 

  37. Howard V, Myers LA, Williams DA, et al. Stem cell transplants for patients with X-linked agammaglobulinemia. Clin Immunol. 2003;107:98–102.

    CAS  Article  PubMed  Google Scholar 

  38. Abu-Arja RF, Chernin LR, Abusin G, et al. Successful hematopoietic cell transplantation in a patient with X-linked agammaglobulinemia and acute myeloid leukemia. Pediatr Blood Cancer. 2015;62:1674–6.

    CAS  Article  PubMed  Google Scholar 

  39. Yamamoto H, Ishimura M, Ochiai M, et al. BTK gene targeting by homologous recombination using a helper-dependent adenovirus/adeno-associated virus hybrid vector. Gene Ther. 2015. doi:10.1038/gt.2015.91 Epub ahead of print.

    Google Scholar 

  40. Soresina A, Nacinovich R, Bomba M, et al; Italian Network for Primary Immunodeficiencies. The quality of life of children and adolescents with X-linked agammaglobulinemia. J Clin Immunol. 2009;29:501–7.

  41. Howard V, Greene JM, Pahwa S, et al. The health status and quality of life of adults with X-linked agammaglobulinemia. Clin Immunol. 2006;118:201–8.

    CAS  Article  PubMed  Google Scholar 

  42. Mohammadzadeh I, Yeganeh M, Khaledi M, Salehiomran MR, Aghamohammadi A, Rezaei N. Debilitating progressive encephalitis in a patient with BTK deficiency. Acta Microbiol Immunol Hung. 2012;59:335–42.

    CAS  Article  PubMed  Google Scholar 

  43. van der Meer JW, Weening RS, Schellekens PT, van Munster IP, Nagengast FM. Colorectal cancer in patients with X-linked agammaglobulinaemia. Lancet. 1993;341:1439–40.

    Article  PubMed  Google Scholar 

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Contributions

DS, AR, SS contributed equally to manuscript preparation. SS will act as guarantor for the paper.

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  1. Pediatric Allergy and Immunology Unit, Department of Pediatrics, Advanced Pediatrics Center, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India

    Deepti Suri, Amit Rawat & Surjit Singh

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  1. Deepti Suri
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  2. Amit Rawat
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  3. Surjit Singh
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Correspondence to Deepti Suri.

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Suri, D., Rawat, A. & Singh, S. X-linked Agammaglobulinemia. Indian J Pediatr 83, 331–337 (2016). https://doi.org/10.1007/s12098-015-2024-8

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Keywords

  • Brutons disease
  • Immunoglobulins
  • Antibody deficiency
  • Hypogammaglobulinemia