Hyper-IgM syndrome is an Ig deficiency characterized by normal or elevated serum IgM levels and decreased levels or absence of other serum Igs, resulting in susceptibility to bacterial infections.

Hyper-IgM syndrome may be X-linked or autosomal. Most cases are caused by mutations in a gene that is located on the X chromosome; this gene encodes a protein (CD154, or CD40 ligand) on the surfaces of activated helper T cells. In the presence of cytokines, normal CD40 ligand interacts with B cells and thus signals them to switch from producing IgM to producing IgA, IgG, or IgE.

In X-linked hyper-IgM syndrome, T cells lack functional CD40 ligand and cannot signal B cells to switch. Thus, B cells produce only IgM; IgM levels may be normal or elevated. Patients with this form may have severe neutropenia and often present during infancy with Pneumocystis jirovecii pneumonia. Otherwise, clinical presentation is similar to that of X-linked agammaglobulinemia and includes recurrent pyogenic bacterial sinopulmonary infections during the first 2 yr of life. Susceptibility to Cryptosporidium infections may be increased. Lymphoid tissue is very small because germinal centers are missing. Many patients die before puberty, and those who live longer often develop cirrhosis or B-cell lymphomas.

At least 4 autosomal recessive forms involve a B-cell defect. In 2 of these forms (deficiency of activation-induced cytidine deaminase or uracil DNA glycosylase [UNG]), serum IgM levels are much higher than in the X-linked form; lymphoid hyperplasia (including lymphadenopathy, splenomegaly, and tonsillar hypertrophy) is present, and autoimmune disorders may be present.

Diagnosis

Diagnosis is clinical and by detecting normal or elevated serum IgM levels and low levels or absence of other Igs.

Treatment

Treatment is IV immune globulin 400 mg/kg once/mo. For the X-linked form, granulocyte colony-stimulating factor is also given as needed for neutropenia, and because prognosis is poor, bone marrow transplantation is preferred if an HLA-identical sibling donor is available.

Last full review/revision September 2008 by Rebecca H. Buckley, MD