Hyper-IgM syndrome is a primary immunodeficiency disorder that involves combined humoral and cellular immunity deficiencies. It may be X-linked (most cases) or autosomal recessive. Manifestations vary depending on the mutation and its location.
Most cases are X-linked and caused by mutations in a gene on the X chromosome that 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 the X-linked form may have severe neutropenia and often present during infancy with Pneumocystis jirovecii pneumonia. Lymphoid tissue is very small because deficient CD 40 ligand signaling does not activate B cells. Otherwise, clinical presentation is similar to that of X-linked agammaglobulinemia and includes recurrent pyogenic bacterial sinopulmonary infections during the first 2 years of life. Susceptibility to Cryptosporidium infections may be increased. Many patients die before puberty, and those who live longer often develop cirrhosis or B-cell lymphomas.
In autosomal recessive hyper-IgM syndrome with CD40 mutation, manifestations are similar to those of the X-linked form.
At least 4 autosomal recessive forms involve a B-cell defect. In 2 of these forms (deficiency of activation-induced cytidine deaminase [AID] 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. Leukopenia is absent.
Diagnosis of hyper-IgM syndrome is suspected based on clinical criteria, including recurrent sinopulmonary infections, chronic diarrhea, and lymphoid hyperplasia. Serum Ig levels are measured; normal or elevated serum IgM levels and low levels or absence of other immunoglobulins support the diagnosis. Flow cytometry testing of CD40 ligand expression on T-cell surfaces should be done.
When possible, the diagnosis is confirmed by genetic testing. Prenatal genetic testing can be offered to women considering pregnancy if they have a family history of CD40 ligand deficiency. Genetic testing of other relatives is not routinely done.
Other laboratory findings include a reduced number of memory B cells (CD27) and absence of class-switched memory B cells (IgD-CD27).
Treatment of hyper-IgM syndrome usually includes immune globulin replacement therapy.
Patients with the X-linked form or CD40 mutations are given prophylactic trimethoprim/sulfamethoxazole to prevent P. jirovecii infection, and environmental precautions are taken to reduce the risk of Cryptosporidium infection (see Gastroenteritis : Prevention). However, because the prognosis is poor, hematopoietic stem cell transplantation is preferred if an human leukocyte antigen (HLA)-identical sibling donor is available.