X-Linked agammaglobulinemia (XLA) is characterized by absent B cell development due to defects in the BTK gene. Patients with this condition have B cell aplasia as well as agammaglobulinemia and impaired vaccine responsiveness. Here, we present an unusual case of a male child found to have a pathogenic variant in BTK with absent circulating B cells and absent IgA but with preserved IgG and IgM production and responsiveness to tetanus toxoid prior to initiation of immunoglobulin therapy.
A 6-year-old fully vaccinated male referred to immunology due to a history of Haemophilus influenzae bacteremia as well as recurrent cellulitis requiring hospital admission and IV antibiotics to clear. He had one lifetime episode of pneumonia.
Patient was initially found to have undetectable IgA, normal IgG and IgM, and absent tetanus, H. influenzae, and pneumococcal titers. Patient underwent a vaccine response assessment where he demonstrated a normal response to tetanus toxoid (2.83 IU/ml), suboptimal response to pneumococcal conjugate PCV-20 (3/20 serotypes protective), and an absent response to H. influenzae (<0.15 mcg/ml). Lymphocyte subset analysis by flow cytometry surprisingly showed absent CD19+ cells. We evaluated CD20 as an additional B cell marker, which was also absent. CD3+ cells and CD16/56+ cells were normal. Genetic testing demonstrated a hemizygous pathogenic variant in BTK (c.1517G>A, p.Cys506Tyr). This missense change has previously been observed in individuals with agammaglobulinemia. The patient’s mother was unavailable to pursue familial variant analysis. Insurance constraints prohibited our ability to evaluate BTK expression in monocytes.
This case demonstrates a rather unusual presentation of XLA. We postulate his mutation to be hypomorphic and presume there is a small population of B cells that have developed and entered lymphoid tissues and are able to mount some degree of antibody response to particularly immunogenic antigens. Further testing has been limited due to insurance constraints. Atypical presentations of inborn errors of immunity should be considered during the evaluation of individuals with unusual infectious histories.
