X-linked agammaglobulinemia. A clinical and molecular analysis.

X-linked agammaglobulinemia (XLA), characterized by a profound deficiency of B lymphocytes due to an arrest in B lymphocyte development, is caused by mutations in the gene encoding Btk (Bruton tyrosine kinase). The BTK gene has been cloned and the genomic organization determined. BTK codes for 19 exons and is expressed in all hematopoietic cell lineages but is selectively down-regulated in T lymphocytes and plasma cells. The different Btk domains include PH, TH, SH3, SH2, and the kinase (SH1) domains. Btk, a cytoplasmic protein tyrosine kinase, is involved in cell signaling, although the precise pathway remains elusive. Mutation analysis has been performed in 236 families representing 282 patients. Mutations are scattered throughout the gene and consist of missense, nonsense, and splice site mutations as well as deletions and insertions. The major consequence of nonfunctional Btk appears to be a delay or block of the development of pro-B cells to pre-B cells and then to mature lymphocytes. Because IgG is actively transported across the placenta, affected newborns have normal levels of serum IgG at birth followed by gradually decreasing IgG levels and development of hypogammaglobulinemia and increased susceptibility to infections. Bacterial infections are the most common clinical manifestation. Resistance to viral infection is intact, except for an unusual susceptibility to infections with enteroviruses that may result in vaccine-related paralytic poliomyelitis or a dermatomyositis-meningoencephalitis syndrome. The diagnosis of XLA is based on the presence of lymphoid hypoplasia, markedly reduced serum levels of all 3 major classes of immunoglobulins, failure to make antibody to antigenic stimulation, and almost complete absence of B lymphocytes in the peripheral blood. Carrier detection and prenatal diagnosis are possible. The prophylactic infusion of high-dose intravenous immunoglobulin (IVIG) and the use of antibiotics have markedly improved the long-term prognosis of patients with XLA.