Diagnostic Considerations

Diagnosing Bruton agammaglobulinemia, formally termed X-linked agammaglobulinemia (XLA), in male infants requires the determination of a mutation in the Btk protein. However, in clinical practice, in a male with low IgG levels, combined T-lymphocyte and B-lymphocyte deficiency needs to be excluded. Diagnosis of severe combined immunodeficiency requires immediate intervention to allow stem cell transplantation or even gene therapy. Therefore, 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.

Usually, absent CD19⁺ B cells in a male with hypogammaglobulinemia is sufficient to make the diagnosis, especially if there is a positive family history. However, some estimates suggest approximately 30% of patients who have a Btk mutation have normal protein expression. This is related to the position of the mutation in the gene and the antibody used for flow cytometric analysis. In addition to clinical correlation, genetic testing is recommended to confirm the diagnosis of XLA.

Most clinical laboratories can now perform both (BTKFP/89742 Bruton's Tyrosine Kinase (BTK) Genotype and Protein Analysis, Full Gene Sequence and Flow Cytometry). If a familial mutation has already been identified, then a limited panel can be ordered (BTKMP/89740 Bruton's Tyrosine Kinase (BTK) Genotype and Protein Analysis, Known Mutation Sequencing and Flow Cytometry).

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). Mutations in the genes for the for the µ heavy chin, Igα, Igβ, λ, B-cell linger (BLNK), leucine-rich repeat-containing 8 (LRRC8), CD79a, transcription factor E47, or the p85α subunit of phosphoinositide 3-kinase (PL13K) are unusual etiologies for agammaglobulinemia with absent CD19⁺ B cells. For more information, see 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.

Differential Diagnoses

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

Workup

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Media Gallery

This patient presented with recurrent otitis and areas of cellulitis in the diaper area. Pseudomonas aeruginosa and Staphylococcus aureus were isolated from the skin lesions. Autoimmune hemolytic anemia and autoimmune neutropenia were confirmed based on the presence of autoantibodies. The patient has a mutation on exon 15, A504T, which changed an asparagine residue to a valine residue.
Bruton agammaglobulinemia (ie, X-linked agammaglobulinemia [XLA]) in brothers. XLA was diagnosed in the less-robust younger brother when he presented with neutropenia and typhlitis. The older brother, with a history of 7 episodes of pneumonia, was then evaluated and diagnosed with XLA. In both brothers CD19- B cells were less than 1%; this finding is consistent with XLA.

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Table 1. Immune Globulin, Intravenous

Brand(Manufacturer)	Manufacturing Process	pH	Additives (IVIG products containing sucrose are more often associated with renal dysfunction, acute renal failure, and osmotic nephrosis, particularly with preexisting risk factors [eg, history of renal insufficiency, diabetes mellitus, age >65 y, dehydration, sepsis, paraproteinemia, nephrotoxic drugs].)	Parenteral Form and Final Concentrations	IgA Content mcg/mL
Carimune NF (ZLB Behring)	Kistler-Nitschmann fractionation, pH 4 incubation, nanofiltration	6.4-6.8	6% solution: 10% sucrose, < 20 mg NaCl/g protein	Lyophilized powder 3, 6, 9, 12%	Trace
Flebogamma (Grifols USA)	Cohn-Oncley fractionation, PEG precipitation, ion-exchange chromatography, pasteurization	5.1-6	Sucrose free, contains 5% D-sorbitol	Liquid 5%	< 50
Gammagard Liquid 10% (Baxter Bioscience)	Cohn-Oncley cold ethanol fractionation, cation and anion exchange chromatography, solvent detergent treated, nanofiltration, low pH incubation	4.6-5.1	0.25 M glycine	Ready-for-use liquid 10%	37
Gammar-P IV (ZLB Behring)	Cohn-Oncley fraction II/III, ultrafiltration, pasteurization	6.4-7.2	5% solution: 5% sucrose, 3% albumin, 0.5% NaCl	Lyophilized powder 5%	< 20
Gamunex (Talecris Biotherapeutics)	Cohn-Oncley fractionation, caprylate-chromatography purification, cloth and depth filtration, low pH incubation	4-4.5	Contains no sugar, contains glycine	Liquid 10%	46
Gammaplex (Bio Products)	Solvent/detergent treatment targeted to enveloped viruses; virus filtration using Pall Ultipor to remove small viruses including nonenveloped viruses; low pH incubation	4.8-5.1	Contains sorbitol (40 mg/mL); do not administer if fructose intolerant	Ready-for-use solution 5%	< 10
Iveegam EN (Baxter Bioscience)	Cohn-Oncley fraction II/III, ultrafiltration, pasteurization	6.4-7.2	5% solution: 5% glucose, 0.3% NaCl	Lyophilized powder 5%	< 10
Polygam S/D Gammagard S/D (Baxter Bioscience for the American Red Cross)	Cohn-Oncley cold ethanol fractionation followed by ultracentrafiltration and ion exchange chromatography, solvent detergent treated	6.4-7.2	5% solution: 0.3% albumin, 2.25% glycine, 2% glucose	Lyophilized powder 5%, 10%	< 1.6 (5% solution)
Octagam (Octapharma USA) 9/24/10: Withdrawn from market because of unexplained reports of thromboembolic events	Cohn-Oncley fraction II/III, ultrafiltration, low pH incubation, S/D treatment pasteurization	5.1-6	10% maltose	Liquid 5%	200
Panglobulin (Swiss Red Cross for the American Red Cross)	Kistler-Nitschmann fractionation, pH 4 incubation, trace pepsin, nanofiltration	6.6	Per gram of IgG: 1.67 g sucrose,< 20 mg NaCl	Lyophilized powder 3, 6, 9, 12%	720
Privigen (CSL Behring)	pH 4 incubation, octanoic acid fractionation, depth filtration, and virus filtration	4.6-5	10% solution; Preservative-free and sucrose- and maltose-free	Ready-to-use solution 10%	25