Pediatric Bruton Agammaglobulinemia Differential Diagnoses

Updated: Mar 18, 2019
  • Author: Terry W Chin, MD, PhD; Chief Editor: Harumi Jyonouchi, MD  more...
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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