Detection of Bruton's tyrosine kinase mutations in hypogammaglobulinaemic males registered as common variable immunodeficiency (CVID) in the Japanese Immunodeficiency Registry

Abstract

CVID is frequently diagnosed in male and female individuals with hypogammaglobulinaemia of unknown aetiology. To examine the possibility that sporadic male cases with X-linked agammaglobulinaemia (XLA), which is caused by mutations in the Bruton's tyrosine kinase (Btk) gene, might be misregistered as having CVID, we employed a flow cytometric test to identify XLA in hypogammaglobulinaemic males registered as CVID in the Japanese Immunodeficiency Registry. From 30 male cases registered as having CVID between 1992 and 1998, we selected 21 males with low or unreported peripheral B cell counts. Blood samples could be obtained from 11 patients and their mothers. Using flow cytometric analysis, the Btk-deficient status in monocytes was demonstrated in seven out of nine cases with decreased numbers of peripheral B cells. The diagnosis of XLA was confirmed in each of the seven patients by demonstration of Btk gene mutations in the patients or cellular mosaicism in the mother. This study demonstrates misregistration of XLA as CVID.

Fig. 1

Flow cytometric analysis of Btk expression profiles in hypogammaglobulinaemic males (P1–P9) with decreased B cell numbers and their mothers (mo). Each histogram represents the analysis of CD14⁺ monocytes. The shaded area and the dashed line indicate staining with anti-Btk and control antibodies, respectively. Monocyte Btk expression in seven patients (P1–P7) is markedly weaker than that seen in a normal control. The mothers from four (P1–P4) of seven patients showing Btk deficiency exhibited a bimodal Btk expression in monocytes, implying that they were obligate X-linked agammaglobulinaemia carriers.