Hyper-IgM syndrome is an immunoglobulin (Ig) deficiency characterized by normal or elevated serum IgM levels and decreased levels or absence of other serum immunoglobulins, resulting in susceptibility to bacterial infections. Diagnosis includes flow cytometry testing of CD40 ligand expression and genetic testing. Treatment is with immune globulin replacement and hematopoietic stem cell transplantation. Severe neutropenia can be treated with G-CSF.
(See also Overview of Immunodeficiency Disorders and Approach to the Patient With an Immunodeficiency Disorder.)
Hyper-IgM syndrome is a primary immunodeficiency disorder that involves combined humoral and cellular immunity deficiencies. It may be
X-linked (most cases)
Autosomal recessive
Manifestations vary depending on the mutation and its location.
X-linked hyper-IgM syndrome
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.
Autosomal recessive hyper-IgM syndrome
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
CD40 ligand expression and genetic testing
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).
Family members of known patients should be tested if they have a clinical picture consistent with the disease.
Treatment of Hyper-IgM Syndrome
Granulocyte colony stimulating factor (G-CSF) for severe neutropenia
Hematopoietic stem cell transplantation when possible
Treatment of hyper-IgM syndrome usually includes immune globulin replacement therapy. Severe neutropenia can be treated with G-CSF (1).
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, which can be curative, is preferred if an human leukocyte antigen (HLA)-identical sibling donor is available.
Treatment reference
1. França TT, Barreiros LA, Al-Ramadi BK, Ochs HD, Cabral-Marques O, Condino-Neto A: CD40 ligand deficiency: treatment strategies and novel therapeutic perspectives. Expert Rev Clin Immunol 15(5):529–540, 2019. doi:10.1080/1744666X.2019.1573674
