Autosomal Agammaglobulinemia

At a Glance

Autosomal agammaglobulinemia is a disease characterized by a complete absence of B lymphocytes and complete lack of immunoglobulins.

Affected individuals have frequent infections of the respiratory and digestive tracts, which typically begin after the first 6 months of life, when the maternal IgG disappears from circulation. Typical causative agents are encapsulated bacteria and enteroviruses. There are no opportunistic infections, indicating presence of normal cellular immunity. However, severe meningoencephalitis can occur.

Most common presentation of the disease is otitis media and infections of the upper respiratory airways (sinusitis and pneumonia). Conjunctivitis, chronic recurrent diarrhea, and skin infections are also common.

Of note is that these individuals have undeveloped secondary lymphoid organs, such as lymph nodes, because of the absence of mature B cells.

Autosomal agammaglobulinemia is quite rare compared to X-linked agammaglobulinemia (XLA). However, this diagnosis should be considered in male patients with agammaglobulinemia who do not have a btk mutation, females with agammaglobulinemia, or patients who have family history consistent with autosomal recessive inheritance.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

The workup should start with a complete blood count (CBC) and differential. In the case of autosomal agammaglobulinemia, the number neutophils is within normal limits,

The workup should start with a complete blood count (CBC) and differential. In the case of autosomal agammaglobulinemia, the number neutophils is within normal limits, although severe neutropenia can be found in some patients if testing is performed during infection.

To detect defects in the B lymphocyte lineage, it is necessary to perform lymphocyte phenotyping of peripheral blood and bone marrow. In the blood, there is a complete absence (less than 1%) of circulating CD19+ CD20+ IgM+ kappa/lambda+ mature B cells (i.e., cells that carry CD19 and CD20 on their surface and express surface immunoglobulin M (IgM) and either kappa or lambda light immunoglobulin chain). Analysis of the bone marrow shows accumulation of immature B cells without pre-B cell receptors, confirming the blockage of B cell differentiation from pro-B to the pre-B cell stage and presence of less than 1% mature B cells.

Evaluation of serum immunoglobulins IgG, IgM, IgA, and IgE usually show lack of all immunoglobulins. Quantitative Ig analysis shows that IgG levels are typically below 200 mg/dL and IgM and IgA levels are below 20 mg/dL. However, it is possible that some residual IgM can be present.

There is a complete absence of antibodies to vaccinal and bacterial antigens.

To rule out XLA, perform Bruton's typrosoine kinase (btk) protein testing on circulating mononuclear cells. This protein should be present on Western blot testing. At the same time, molecular testing of the btk gene would show a normal sequence of the gene that encodes btk protein.

What Lab Results Are Absolutely Confirmatory?

Autosomal agammaglobulinemia is caused by mutations of several genes that code for proteins involved in the formation of the pre-B receptor heavy chain (IGHM) and surrogate light chain lambda 5 (IGLL1), as well as proteins involved in the signal transduction pathways of the pre-B (Ig alpha - CD79A) and B-cell receptors (BLNK). Testing for these mutations can be performed, and is confirmatory for the disease, but might not be readily available, as this testing is not very common.

Therefore, reduced number of circulating mature B cells and normal T cell levels, increased number of immature B cells in the bone marrow, decreased immunoglobulins combined with normal levels of btk protein, and absence of btk gene mutations are diagnostic of this disorder.

What Confirmatory Tests Should I Request for My Clinical Dx? In addition, what follow-up tests might be useful?

A prenatal diagnosis is possible by evaluating presence of circulating mature B-cells in the fetal circulation. In the case of autosomal agammaglobulinemia, there will be a complete absence of mature B cells (CD19+ Ig+ cells).

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