eMedicine Specialties > Pediatrics: General Medicine > Allergy & Immunology

Bruton Agammaglobulinemia: Differential Diagnoses & Workup

Author: Terry Chin, MD, PhD, Associate Professor of Pediatrics, Pediatric Allergy/Immunology/Pulmonology, Department of Pediatrics, University of California Irvine School of Medicine; Associate Director, Miller Children's Hospital at Long Beach Memorial Medical Center
Contributor Information and Disclosures

Updated: Sep 3, 2008

Differential Diagnoses

Agammaglobulinemia
Severe Combined Immunodeficiency
Common Variable Immunodeficiency
T-Cell Disorders
Growth Hormone Deficiency
Transient Hypogammaglobulinemia of Infancy
IgA and IgG Subclass Deficiencies
X-linked Immunodeficiency With Hyper IgM
Lymphoproliferative Disorders

Other Problems to Be Considered

Diagnosing Bruton agammaglobulinemia, formally termed X-linked agammaglobulinemia (XLA), in male infants initially requires the exclusion of combined T-lymphocyte and B-lymphocyte deficiency. Diagnosis of SCID requires immediate intervention to allow stem cell transplantation or even gene therapy. Flow cytometric measurement of T-lymphocyte and B-lymphocyte populations and T-cell function assays are essential to rule out a broader defect of cell-mediated immunity.

In patients with no other affected family members, autosomal forms of agammaglobulinemia must be considered when the CD19 expression on B cells is minimal in a male patient (although 30-50% of XLA cases are believed to arise from new mutations). Currently, mutations in the genes for the IGHM, Ig-a, or lambda-5 (IGLL1) are unusual etiologies for agammaglobulinemia with absent CD19+ B cells. Mutations in other genes are predicted based on genetic defects in mice. In addition to BTK, murine B-cell proliferation and differentiation are under the control of SYK; PAX5; and genes that code for IL-7, l 5, Ig-b, IL-2R g, lyn, and bcl-2. Therefore, mutations in the human genes for these proteins may be found in the future as etiologies for agammaglobulinemia.

Other primary immunodeficiency diseases occasionally need to be considered, but assessment of B- and T-lymphocyte markers almost always allows the distinction of XLA from other disorders. Patients with X-linked hyper-IgM or common variable immunodeficiency (CVID) may appear clinically similar to patients with XLA.

Growth hormone deficiency associated with absent B cells is rare. Mutations in BTK may or may not be found in these patients.

Another rare syndrome of absent B cells is associated with intrauterine growth retardation, microcephaly, and progressive pancytopenia. No mutation in BTK or several other genes needed for B-cell proliferation has been detected in this syndrome.

Workup

Laboratory Studies

  • Measurement of IgG using quantitative techniques such as nephelometry supports the diagnosis of X-linked agammaglobulinemia (XLA) when the IgG level is less than 100 mg/dL. Confirmation of XLA requires low (<1%) or absent expression of CD19+ lymphocytes, low or absent expression of the heavy-chain µ on the surface, and the presence of normal-to-increased numbers of mature T lymphocytes.
  • Quantitative measurements of IgG, IgM, IgA, and IgE are readily available and inexpensive and require little blood.
    • IgG levels are less than 100 mg/dL in most patients with XLA who are aged 6 months or older. However, in some patients with XLA, IgG levels may be as high as 200-300 mg/dL.
    • Unlike IVIG, IMIG administration does not significantly affect this level.
    • IgM and IgA are usually undetectable in patients of any age. In patients with XLA, levels are usually far below age-related reference ranges; however, in mild cases of XLA and in other antibody deficiencies, Ig levels must be carefully compared with age-related reference ranges.
    • IgG subclass levels are not usually required because the total IgG is severely deficient. Determination of functional antibody levels as noted below is more appropriate in the rare case in which the total IgG level is indeterminate.
  • Fluorocytometric analysis (ie, flow cytometry) of B- and T-lymphocyte markers must be performed to confirm XLA diagnosis.
    • Absent or low (<1%) CD19+ B cells confirm the diagnosis of XLA in male patients. Numbers of CD4+ and CD8+ T cells are often increased or sometimes normal, but they are rarely low. Low T-cell percentages suggest a diagnosis of SCID or another T-cell disorder. In an infant or child, the presence of low absolute T-cell numbers suggests a form of SCID, not XLA. An inverted CD4/CD8 T-cell ratio occurs in some types of SCID and in human immunodeficiency virus (HIV) infection.
    • Markers for surface Ig expression are also customarily obtained using fluorocytometric analysis. Antibodies directed against the heavy-chain constant region of IgG, IgA, IgM, and IgD are used to detect these isotypes. The first 2 are expected to be absent, although some expression of IgM and IgD may be present. Cells that express IgM alone, without IgD, are considered less differentiated and, therefore, are more likely to be present.
  • Specific IgG antibody responses to T-cell–dependent and T-cell–independent antigens should also be measured.
    • Because the serum IgG level is contaminated from the presence of maternal antibody (due to transplacental transmission) in young infants (<6 mo), the physician cannot rely on Ig level determinations. However, obtaining specific serum diphtheria and tetanus antibody levels before and after (3-4 wk) a diphtheria, pertussis, and tetanus vaccine is administered is helpful. If specific diphtheria and tetanus levels are increased, the infant is able to produce antigen-specific antibodies, and XLA is unlikely.
    • Tetanus, diphtheria, and the conjugated H influenzae type b antigens require T-cell–dependent IgG antibody responses.
    • Unconjugated 23-valent pneumococcal vaccine elicits a T-cell–independent IgG antibody response.
  • IgM antibody function is assessed by measuring isohemagglutinin titers, antibodies directed against blood group A and B antigens. These antibody levels are age-related.
  • Measurement of Btk activity firmly establishes the diagnosis. However, in the setting of low serum Ig levels and absent mature B lymphocytes, this testing is probably not necessary.
  • Mutational analysis can also be performed; however, the clinical significance of the results is not certain unless population studies are performed.17,10

Imaging Studies

  • Plain radiographic studies may contribute to the diagnosis of XLA but are not an essential part of the workup.
    • Plain radiography of the head may reveal the absence of tonsillar and adenoid tissues.
    • Chest radiographs may be used to diagnose more extensive infection or a chronic infection that is not clinically apparent.
  • Imaging studies are primarily used to assess chronic sinopulmonary disease.
  • CT scanning of the sinuses and the lungs is more effective than plain radiography in documenting disease progression in these locations. One study found bronchiectasis in 58% patients with agammaglobulinemia.18
  • Some physicians advocate using brain MRI in patients with agammaglobulinemia or hypogammaglobulinemia who develop unexplained neurological symptoms and signs of meningeal inflammation despite extensive investigation of cerebral spinal fluid (CSF), including polymerase chain reaction (PCR) analyses.

Other Tests

  • The slowly progressive nature of chronic lung disease makes pulmonary function tests (PFTs) essential in XLA. These tests include spirometry, diffusion capacity tests, and lung volume tests. They are recommended annually. Children younger than 5 years may not be able to reliably undergo these tests.
  • PFT findings are evaluated upon diagnosis because the literature suggests that decreased parameters upon diagnosis of hypogammaglobulinemia correlate with chronic and progressive pulmonary disease such as bronchiectasis.19
  • Both restrictive and obstructive patterns of chronic lung disease may occur in antibody deficiency diseases.

Procedures

  • Bronchoscopy is an important adjunct for diagnosing pulmonary infections because it obviates most contamination with mouth flora and because it can be used to procure sputum from infants and others who are unable to voluntarily cough it out.
  • Examination of the GI tract using endoscopy and colonoscopy is necessary to assess the extent of inflammatory bowel disease. The biopsy results, videotapes, and photographs obtained from these procedures can be used to delineate the disease.

Histologic Findings

  • Inflammatory responses are the most common findings in tissue biopsy samples obtained to evaluate infection.
  • Inflammation is usually nonspecific and is not helpful in distinguishing specific infectious agents.
  • The presence of pleocytosis in the spinal fluid is a special circumstance in which inflammation is associated with specific infection by an enterovirus.
  • Lymphoid tissues lack germinal centers, and plasma cells are absent in bone marrow and the lamina propria of the gut.

More on Bruton Agammaglobulinemia

Overview: Bruton Agammaglobulinemia
Differential Diagnoses & Workup: Bruton Agammaglobulinemia
Treatment & Medication: Bruton Agammaglobulinemia
Follow-up: Bruton Agammaglobulinemia
Multimedia: Bruton Agammaglobulinemia
References
[ CLOSE WINDOW ]

References

  1. Bruton OC. Agammaglobulinemia. Pediatrics. Jun 1952;9(6):722-8. [Medline].

  2. Sochorova K, Horvath R, Rozhova D et al. Impaired Toll-like receptor 8-mediated IL-6 and TNF-alpha production in antigen-presenting cells from patients with X-linked agammaglobulinemia. Blood. 2007;109:2553-6. [Medline].

  3. Doyle SL, Jefferies CA, Feighery C, O'Neill LA. Signaling by Toll-like receptors 8 and 9 requires Bruton's tyrosine kinase. J Biol Chem. Dec 21 2007;282(51):36953-60. [Medline].

  4. Taneichi H, Kanegane H, Sira MM, et al. Toll-like receptor signaling is impaired in dendritic cells from patients with X-linked agammaglobulinemia. Clin Immunol. Feb 2008;126(2):148-54. [Medline].

  5. Hasan M, Lopez-Herrera G, Blomberg KE. Defective Toll-like receptor 9-mediated cytokine production in B cells from Bruton's tyrosine kinase-deficient mice. Immunology. 2008;123:239-49. [Medline].

  6. Schmidt NW, Thieu VT, Mann BA et al. Bruton's tyrosine kinase in required for TLR-induced IL-10 production. J Immunol. 2006;117:7203-10. [Medline].

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

  8. Chun JK, Lee TJ, Song JW, Linton JA, Kim DS. Analysis of clinical presentations of Bruton disease: a review of 20 years of accumulated data from pediatric patients at Severance Hospital. Yonsei Med J. Feb 29 2008;49(1):28-36. [Medline].

  9. De Silva R, Gunawardena S, Wickremesinghe G, Ranasinghe B, Namasivayam Y. Primary immune deficiency among patients with recurrent infections. Ceylon Med J. Sep 2007;52(3):83-6. [Medline].

  10. Aghamohammadi A, Fiorini M, Moin 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. [Medline].

  11. Freeman AF, Holland SM. Persistent bacterial infections and primary immune disorders. Curr Opin Microbiol. 2007;10:70-5. [Medline].

  12. Arai A, Kitano A, Sawabe E, et al. Miura ORelapsing Campylobacter coli bacteremia with reactive arthritis in a patient with X-linked agammaglobulinemia. Intern Med. 2007;46:605-9. [Medline].

  13. Mamishi S, Shahmahmoudi S, Tabatabaie H, et al. Novel BTK mutation presenting with vaccine-associated paralytic poliomyelitis. Eur J Pediatr. Mar 4 2008;[Medline].

  14. Katamura K, Hattori H, Kunishima T, et al. Non-progressive viral myelitis in X-linked agammaglobulinemia. Brain Dev. Mar 2002;24(2):109-11. [Medline].

  15. Sikora AG, Lee KC. Otolaryngologic manifestations of immunodeficiency. Otolaryngol Clin North Am. Aug 2003;36(4):647-72. [Medline].

  16. Stewart DM, Tian L, Notarangelo LD, Nelson DL. Update on X-linked hypogammaglobulinemia with isolated growth hormone deficiency. Curr Opin Allergy Clin Immunol. Dec 2005;5(6):510-2. [Medline].

  17. Lopez-Granados E, Perez de Diego R, Ferreira Cerdan A, et al. A genotype-phenotype correlation study in a group of 54 patients with X-linked agammaglobulinemia. J Allergy Clin Immunol. Sep 2005;116(3):690-7. [Medline].

  18. Bondioni MP, Duse M, Plebani A, et al. Pulmonary and sinusal changes in 45 patients with primary immunodeficiencies: computed tomography evaluation. J Comput Assist Tomogr. Jul-Aug 2007;31(4):620-8. [Medline].

  19. Gharagozlou M, Ebrahimi FA, Farhoudi A, et al. Pulmonary complications in primary hypogammaglobulinemia: a survey by high resolution CT scan. Monaldi Arch Chest Dis. Jun 2006;65(2):69-74. [Medline].

  20. Moreau T, Calmels B, Barlogis V, et al. Potential application of gene therapy to X-linked agammaglobulinemia. Curr Gene Ther. Aug 2007;7(4):284-94. [Medline].

  21. Ballow M. Safety of IGIV therapy and infusion-related adverse events. Immunol Res. 2007;38(1-3):122-32. [Medline].

  22. Chinen J, Shearer WT. Subcutaneous immunoglobulins: alternative for the hypogammaglobulinemic patient?. J Allergy Clin Immunol. Oct 2004;114(4):934-5. [Medline].

  23. Ochs HD, Gupta S, Kiessling P, Nicolay U, Berger M. Safety and efficacy of self-administered subcutaneous immunoglobulin in patients with primary immunodeficiency diseases. J Clin Immunol. May 2006;26(3):265-73. [Medline].

  24. Gustafson R, Gardulf A, Hansen S, et al. Rapid subcutaneous immunoglobulin administration every second week results in high and stable serum immunoglobulin G levels in patients with primary antibody deficiencies. Clin Exp Immunol. May 2008;152(2):274-9. [Medline].

  25. Orange JS, Hossny EM, Weiler CR, et al. Use of intravenous immunoglobulin in human disease: a review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology. J Allergy Clin Immunol. Apr 2006;117(4 Suppl):S525-53. [Medline].

  26. Howard V, Myers LA, Williams DA, et al. Stem cell transplants for patients with X-linked agammaglobulinemia. Clin Immunol. May 2003;107(2):98-102. [Medline].

  27. Leal RC, Bertelli EC, Soler ZA. Recurrent pneumonia caused by genetic immunodeficiency: a prophylactic and rehabililtative approach. Braz J Infect Dis. 2007;11:307-10. [Medline].

  28. Buckley RH. Pulmonary complications of primary immunodeficiencies. Paediatr Respir Rev. 2004;5 Suppl A:S225-33. [Medline].

  29. Ziegner UH, Kobayashi RH, Cunningham-Rundles C, et al. Progressive neurodegeneration in patients with primary immunodeficiency disease on IVIG treatment. Clin Immunol. Jan 2002;102(1):19-24. [Medline].

  30. Papapetropoulos S, Friedman J, Blackstone C, Kleiner GI, Bowen BC, Singer C. A progressive, fatal dystonia-Parkinsonism syndrome in a patient with primary immunodeficiency receiving chronic IVIG therapy. Mov Disord. Aug 15 2007;22(11):1664-6. [Medline].

  31. Brosens LA, Tytgat KM, Morsink FH, et al. Multiple colorectal neoplasms in X-linked agammaglobulinemia. Clin Gastroenterol Hepatol. Jan 2008;6(1):115-9. [Medline].

  32. Skull S, Kemp A. Treatment of hypogammaglobulinaemia with intravenous immunoglobulin, 1973-93. Arch Dis Child. Jun 1996;74(6):527-30. [Medline].

  33. Morwood K, Bourne H, Gold M, et al. Phenotypic variability: clinical presentation between the 6th year and the 60th year in a family with X-linked agammaglobulinemia. J Allergy Clin Immunol. Apr 2004;113(4):783-5. [Medline].

  34. Aghamohammadi A, Moin M, Farhoudi A, et al. Efficacy of intravenous immunoglobulin on the prevention of pneumonia in patients with agammaglobulinemia. FEMS Immunol Med Microbiol. Mar 8 2004;40(2):113-8. [Medline].

  35. Black C, Zavod MB, Gosselin BJ. Haemophilus influenzae lymphadenopathy in a patient with agammaglobulinemia: clinical-histologic-microbiologic correlation and review of the literature. Arch Pathol Lab Med. Jan 2005;129(1):100-3. [Medline].

  36. Conley ME, Broides A, Hernandez-Trujillo V, et al. Genetic analysis of patients with defects in early B-cell development. Immunol Rev. Feb 2005;203:216-34. [Medline].

  37. Conley ME, Howard V. Clinical findings leading to the diagnosis of X-linked agammaglobulinemia. J Pediatrics. 2002;141:566-71. [Medline].

  38. Delves PJ, Roitt IM. The immune system. Second of two parts. N Engl J Med. Jul 13 2000;343(2):108-17. [Medline].

  39. Eijkhout HW, van Der Meer JW, Kallenberg CG, et al. The effect of two different dosages of intravenous immunoglobulin on the incidence of recurrent infections in patients with primary hypogammaglobulinemia. A randomized, double-blind, multicenter crossover trial. Ann Intern Med. Aug 7 2001;135(3):165-74. [Medline].

  40. Hermaszewski RA, Webster AD. Primary hypogammaglobulinaemia: a survey of clinical manifestations and complications. Q J Med. Jan 1993;86(1):31-42. [Medline].

  41. Kornfeld SJ, Haire RN, Strong SJ, et al. A novel mutation (Cys145-->Stop) in Bruton's tyrosine kinase is associated with newly diagnosed X-linked agammaglobulinemia in a 51-year-old male. Mol Med. Sep 1996;2(5):619-23. [Medline].

  42. LeBien TW. Fates of human B-cell precursors. Blood. Jul 1 2000;96(1):9-23. [Medline].

  43. Lopez-Herrera G, Berron-Ruiz L, Mogica-Martinez D, Espinosa-Rosales F, Santos-Argumedo L. Characterization of Bruton's tyrosine kinase mutations in Mexican patients with X-linked agammaglobulinemia. Mol Immunol. Feb 2008;45(4):1094-8. [Medline].

  44. Macpherson AJ, Gatto D, Sainsbury E, et al. A primitive T cell-independent mechanism of intestinal mucosal IgA responses to commensal bacteria. Science. Jun 23 2000;288(5474):2222-6. [Medline].

  45. Minegishi Y, Coustan-Smith E, Rapalus L, et al. Mutations in Igalpha (CD79a) result in a complete block in B-cell development. J Clin Invest. Oct 1999;104(8):1115-21. [Medline].

  46. Morales P, Hernandez D, Vicente R, et al. Lung transplantation in patients with x-linked agammaglobulinemia. Transplant Proc. Aug 2003;35(5):1942-3. [Medline].

  47. Moschese V, Oralndi P, DiMatteo G, et al. Insight into B cell development and differentiation. Acta Paediatr Suppl. 2004;93:48-51. [Medline].

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

  49. Plebani A, Soresina A, Rondelli R, et al. Clinical, immunological, and molecular analysis in a large cohort of patients with X-linked agammaglobulinemia: an Italian multicenter study. Clin Immunol. Sep 2002;104(3):221-30. [Medline].

  50. Quartier P, Debre M, De Blic J, et al. Early and prolonged intravenous immunoglobulin replacement therapy in childhood agammaglobulinemia: a retrospective survey of 31 patients. J Pediatr. May 1999;134(5):589-96. [Medline].

  51. Revy P, Busslinger M, Tashiro K, et al. A syndrome involving intrauterine growth retardation, microcephaly, cerebellar hypoplasia, B lymphocyte deficiency, and progressive pancytopenia. Pediatrics. Mar 2000;105(3):E39. [Medline].

  52. Smith CIE, Witte ON. X-linked agammaglobulinemia: a disease of Btk tyrosine kinase. In: Ochs HD, ed. Primary Immunodeficiency Diseases: A Molecular and Genetic Approach. 1999;263-284.

  53. Yu PW, Tabuchi RS, Kato RM, et al. Sustained correction of B-cell development and function in a murine model of X-linked agammaglobulinemia (XLA) using retroviral-mediated gene transfer. Blood. 2004;104:1281-90. [Medline]. [Full Text].

[ CLOSE WINDOW ]

Further Reading

[ CLOSE WINDOW ]

Keywords

Bruton agammaglobulinemia, Bruton's agammaglobulinemia, severe combined immunodeficiency, X-linked agammaglobulinemia, XLA, Bruton type agammaglobulinemia, X-linked hypogammaglobulinemia, X-linked infantile hypogammaglobulinemia, Bruton disease, Bruton's disease, congenital agammaglobulinemia, Glanzmann-Riniker syndrome, primary agammaglobulinemia, pneumonia, Streptococcus pneumoniae, Haemophilus influenzae, meningoencephalitis, enterovirus, bronchiectasis, inflammatory bowel disease, malnutrition, meningitis, osteomyelitis, sepsis, gastroenteritis, diarrhea, otitis media, sinusitis, Mycoplasma, Ureaplasma, Giardia, Campylobacter, bacteremia, reactive arthritis, poliomyelitis

[ CLOSE WINDOW ]

Contributor Information and Disclosures

Author

Terry Chin, MD, PhD, Associate Professor of Pediatrics, Pediatric Allergy/Immunology/Pulmonology, Department of Pediatrics, University of California Irvine School of Medicine; Associate Director, Miller Children's Hospital at Long Beach Memorial Medical Center
Terry Chin, MD, PhD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Association of Immunologists, American College of Allergy, Asthma and Immunology, American College of Chest Physicians, American Thoracic Society, California Thoracic Society, Clinical Immunology Society, and Western Society for Pediatric Research
Disclosure: Nothing to disclose.

Medical Editor

James M Oleske, MD, MPH, François-Xavier Bagnoud Professor of Pediatrics, Director, Division of Pulmonary, Allergy, Immunology and Infectious Diseases, Department of Pediatrics, New Jersey Medical School
James M Oleske, MD, MPH is a member of the following medical societies: Academy of Medicine of New Jersey, American Academy of Pediatrics, American Public Health Association, American Society for Microbiology, Infectious Diseases Society of America, and Pediatric Infectious Diseases Society
Disclosure: "no financial interest" None None

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from broker recommendation; Avanir Pharma Stock Investment from broker recommendation

Managing Editor

John Wilson Georgitis, MD, Consulting Staff, Lafayette Allergy Services
John Wilson Georgitis, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association for the Advancement of Science, American College of Chest Physicians, American Lung Association, American Medical Writers Association, and American Thoracic Society
Disclosure: Nothing to disclose.

CME Editor

David Pallares, MD, Clinical Assistant Professor, Department of Pediatrics, Division of Allergy and Immunology, University of Louisville
David Pallares, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology
Disclosure: Nothing to disclose.

Chief Editor

Harumi Jyonouchi, MD, Associate Professor, Division of Pulmonary Allergy/Immunology and Infectious Diseases, Department of Pediatrics, UMDNJ-New Jersey Medical School
Harumi Jyonouchi, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association of Immunologists, American Medical Association, Clinical Immunology Society, New York Academy of Sciences, Society for Experimental Biology and Medicine, Society for Mucosal Immunology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

 
 
HONcode

We subscribe to the
HONcode principles of the
Health On the Net Foundation

All material on this website is protected by copyright, Copyright© 1994- by Medscape.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.