Immunodeficiency With Hyper-Igm, Type 4

Description

Hyper-IgM syndrome is a condition characterized by normal or increased serum IgM concentrations associated with low or absent serum IgG, IgA, and IgE concentrations, indicating a defect in the class-switch recombination (CSR) process (summary by Imai et al., 2003).

For a discussion of genetic heterogeneity of immunodeficiency with hyper-IgM, see HIGM1 (308230).

Clinical Features

Imai et al. (2003) investigated the clinical and immunologic characteristics of 15 patients with an unidentified form of HIGM. Although the clinical manifestations were similar to those observed in HIGM2 (605258), which is caused by mutation in the gene encoding activation-induced cytidine deaminase (AICDA; 605257), these patients exhibited a slightly milder HIGM syndrome with residual IgG production. Imai et al. (2003) found that B-cell CSR was intrinsically impaired. However, the generation of somatic hypermutations was observed in the variable region of the Ig heavy chain gene, as in control B lymphocytes. In vitro studies showed that the molecular defect responsible for this HIGM entity, which the authors called HIGM4, occurred downstream of the AICDA activity, as the AICDA gene was induced normally and AICDA-induced DNA double-strand breaks in the switch mu region of the Ig heavy chain locus (147020) were detected during CSR as normal. Imai et al. (2003) concluded that HIGM4 is probably the consequence of a selective defect either in a CSR-specific factor of the DNA repair machinery or in survival signals delivered to switched B cells.