Agammaglobulinemia

Agammaglobulinemia, also known as Bruton agammaglobulinemia, X-linked agammaglobulinemia (XLA), or Bruton tyrosine kinase (BTK) deficiency, is a primary immunodeficiency characterized by recurrent bacterial infections in affected males. Laboratory testing includes nonspecific tests, such as immunoglobulin testing, and more specific testing, such as gene variant analysis.

Tabs Content

Clinical Overview

Diagnosis

Indications for Testing

Recurrent infections in males during infancy or early childhood
- Respiratory tract (lungs, ears, sinuses)
- Meningitis
- Sepsis
- Gastrointestinal
- Cutaneous infections

Laboratory Testing

Nonspecific testing
- CBC with white blood cell differential
  - Severe neutropenia seen in 10-20% of patients if performed when patient has an infection
- Immunoglobulin testing – quantitative IgG, IgM, IgA, and IgE
  - IgG typically <200 mg/dL
    - Most between 100-200 mg/dL
    - 10% ≥200 mg/dL
  - IgM and IgA typically <20 mg/dL
- Measurement of specific antibodies to vaccine
  - Test protein and polysaccharide vaccines (polyvalent pneumococcal or diphtheria toxoid)
  - Typically no response to vaccination
- Isohemagglutinin testing
  - Absent in all but type AB individuals
  - Presence is suggestive of antibody deficiency disorder
- Lymphocyte cell surface markers
  - Significantly decreased CD19+ cells (B lymphocytes)
  - <1% in circulation
Specific testing
- Bruton tyrosine kinase (BTK) protein expression by flow cytometry – if protein expression is absent or reduced, suggests X-linked agammaglobulinemia (XLA) in males
- Gene variant analysis
  - Presence of BTK gene variant is confirmatory
  - Other gene variants causative for agammaglobulinemia are typically autosomal recessive (eg, BLNK deficiency), but autosomal dominant variants may be difficult to differentiate from X-linked disease (eg, LRRC8A variants)

Differential Diagnosis

X-linked hyper IgM syndrome
X-linked severe combined immunodeficiency
X-linked lymphoproliferative disease
HIV

Background

Epidemiology

Incidence – estimated 1/250,000-700,000 male births
Age
- 50% diagnosed by 2 years
- 80% diagnosed by 5 years
Sex – >99% male
Ethnicity – most commonly diagnosed in Caucasians

Pathophysiology

BTK gene mutation – X-linked inheritance
- Leads to impaired development of mature B-cell lymphocytes
  - B-cell development in bone marrow is blocked at pro-B-cell stage to pre-B-cell stage
- Results in marked reduction in all classes of immunoglobulins (B-cell products)
- Hypogammaglobulinemia results in predisposition to life-threatening infections, especially
  - Encapsulated bacteria
  - Gram-negative bacteria
  - Enteroviruses
  - Giardia duodenalis
  - Unusual pathogens – Helicobacter cinaedi

Clinical Presentation

Infants are usually asymptomatic during first 3 months of life due to passive transfer of immunoglobulins by their mothers
Most common clinical presentation is respiratory infections with encapsulated organisms
- Otitis media
- Sinusitis
- Pneumonia/empyema
Other common infections
- Conjunctivitis
- Chronic, recurrent diarrhea
- Cellulitis
Life-threatening infections uncommon
- Sepsis
- Meningitis/encephalitis
- Septic arthritis/osteomyelitis

ARUP Lab Tests

Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

Immunoglobulins (IgA, IgG, IgM), Quantitative 0050630
Method: Quantitative Nephelometry

Recommended Use

Initial test in the workup of immunoglobulin disorders

Order in conjunction with serum protein electrophoresis and immunofixation to rule out plasma cell dyscrasia in adults and older children (>15 years) with suspected hypogammaglobulinemia

Test components include serum quantitative IgA, IgG, and IgM

B-Cell Memory and Naive Panel 2008901
Method: Flow Cytometry

Recommended Use

Assess B-cell subsets in immunodeficiencies (eg, common variable immunodeficiency [CVID], B-cell reconstitution after bone marrow or hematopoietic stem cell transplantation)

Supports the diagnosis of CVID and may help predict the clinical phenotype

Assess B-cell reconstitution after bone marrow or hematopoietic stem cell transplantation

Measures B cells (CD19+), total memory B cells (CD19+/CD27+), class-switched memory B cells (CD19+/CD27+/IgD-), nonswitched/marginal-zone memory B cells (CD19+/CD27+/IgD+), and naive B cells (CD19+/CD27-/IgD+)

Not recommended for rituximab monitoring; refer to B-cell CD20 expression test

Lymphocyte Subset Panel 7 - Congenital Immunodeficiencies 0095899
Method: Quantitative Flow Cytometry

Recommended Use

Acceptable lymphocyte subset panel for the investigation of primary immunodeficiency disorders

Panel includes percentage and absolute counts for CD2, CD3 (total T cells), HLA-DR, CD4 (helper T cells), CD45RA (naive helper T cells), CD45RO (memory helper T cells), CD8 (cytotoxic T cells), CD19 (B cells), NK cells, and CD4:CD8 ratio

Bruton Tyrosine Kinase (BTK) Protein Expression by Flow Cytometry 2012002
Method: Qualitative Flow Cytometry

Recommended Use

Preferred test for initial screening for individuals with clinical suspicion of X-linked agammaglobulinemia (XLA)/hypogammaglobulinemia

Limitations

Normal expression of BTK protein occurs in 20-30% of patients with XLA due to truncated or inactive BTK protein with abnormal function; genetic analysis is recommended

Test does not exclude mutations or defective protein function, does not rule out XLA in males, and does not rule out XLA carrier status in females

Primary Antibody Deficiency Panel, Sequencing and Deletion/Duplication 2011156
Method: Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray

Recommended Use

Preferred genetic test for individual with clinical phenotype of primary antibody deficiency, agammaglobulinemia, hyper IgM syndrome, CVID, atypical severe combined immunodeficiency, or other related immunodeficiency disorders

Genes sequenced – ADA, AICDA, ATM, BLNK, BTK, CD19, CD40, CD40LG, CD79A, CD79B, CD81, CR2, ICOS, IGHM, IGLL1, IKBKG, LRBA, LRRC8A, MRE11A, MS4A1, NBN/NBS1, NFKB2, NFKBIA, PIK3CD, PIK3R1, PLCG2, PRKCD, PTPRC, RAG2, SH2D1A, TNFRSF13B, TNFRSF13C, UNG, VAV1, XIAP/BIRC4

Genes analyzed for deletions/duplications – ADA, AICDA, ATM, BLNK, BTK, CD19, CD40, CD40LG, CD79A, CD79B, CD81, CR2, ICOS, IGHM, IGLL1, MRE11A, MS4A1, NBN/NBS1, NFKB2, NFKBIA, PTPRC, RAG2, TNFRSF13B, TNFRSF13C, UNG, VAV1

Clinical sensitivity – 20% (CVID); 75-80% (hyper IgM syndrome); 90% (agammaglobulimenia)

Limitations

Not determined or evaluated – variants in genes not included on the panel, deep intronic and regulatory region variants, breakpoints for large deletions/duplications, translocations

Deletions/duplications will not be detected in IKBKG, LRBA, LRRC8A, PIK3CD, PIK3R1, PLCG2, PRKCD, SH2D1A, or XIAP/BIRC4 gene

Small deletions or insertions may not be detected

Diagnostic errors can occur due to rare sequence variations

Lack of a detectable gene mutation does not exclude a diagnosis of primary antibody deficiency

Medical Experts

Delgado, Julio, MD, MS, Chief Medical Officer; Director of Laboratories; Chief, Division of Clinical Pathology at ARUP Laboratories; Associate Professor of Clinical Pathology, University of Utah

Kumanovics, Attila, MD, Assistant Medical Director, Co-Director, Immunology Laboratory, Immunogenetics at ARUP Laboratories; Assistant Professor of Clinical Pathology, University of Utah

Wittwer, Carl T., MD, PhD, Medical Director, Immunologic Flow Cytometry at ARUP Laboratories; Professor of Clinical Pathology, University of Utah

References

Guidelines

Diagnostic & Clinical Care Guidelines for Primary Immunodeficiencies. Immune Deficiency Foundation. Towson, MD [Accessed: Dec 2017]

General References

Al-Herz W, Bousfiha A, Casanova J, Chatila T, Conley ME, Cunningham-Rundles C, Etzioni A, Franco JL, Gaspar B, Holland SM, Klein C, Nonoyama S, Ochs HD, Oksenhendler E, Picard C, Puck JM, Sullivan K, Tang ML. Primary immunodeficiency diseases: an update on the classification from the International Union of Immunological Societies expert committee for primary immunodeficiency. Front Immunol. 2014; 5: 162. PubMed

Chun J, 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. 2008; 49(1): 28-36. PubMed

Locke BA, Dasu T, Verbsky JW. Laboratory diagnosis of primary immunodeficiencies. Clin Rev Allergy Immunol. 2014; 46(2): 154-68. PubMed

Lougaris V, Ferrari S, Cattalini M, Soresina A, Plebani A. Autosomal recessive agammaglobulinemia: novel insights from mutations in Ig-beta. Curr Allergy Asthma Rep. 2008; 8(5): 404-8. PubMed

Smith C, Berglof A. X-Linked Agammaglobulinemia. In: Pagon RA, Adam MP, Ardinger HH, et al, editors. GeneReviews, University of Washington, 1993-2018. Seattle, WA [Last Update: Aug 2016; Accessed: Nov 2018]

Testing Algorithms

Immunodeficiency Evaluation for Chronic Infections in Infants and Children Testing Algorithm

Read more about Immunodeficiency Evaluation for Chronic Infections in Infants and Children Testing Algorithm

Educational Videos

Content Review:

November 2017

Last Update: June 2018

Agammaglobulinemia

Diagnosis

Indications for Testing

Laboratory Testing

Differential Diagnosis

Background

Epidemiology

Pathophysiology

Clinical Presentation

ARUP Lab Tests

Medical Experts

References

Guidelines

General References

Immunodeficiency Evaluation for Chronic Infections in Infants and Children Testing Algorithm

ARUP Laboratories

ARUP Websites

ARUP Consult


	[X] Topic Name Message * If ARUP Consult does not answer your test selection and interpretation questions, or if you’d like to suggest ways to improve content or usability, please leave a message for the ARUP clinical content team. Please do not include any patient-specific or personal health information (PHI) in your message. Email Address An email address is not required, but providing one allows the ARUP Consult clinical content team to respond directly. ARUP will only use your email address to respond to your feedback. See the ARUP privacy policy for more information regarding email use. Leave this field blank


	Agammaglobulinemia. ARUP Consult^©. Retrieved December 11, 2018, from: https://arupconsult.com/content/agammaglobulinemia