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Hyper-IgM Syndrome

By

James Fernandez

, MD, PhD, Cleveland Clinic Lerner College of Medicine at Case Western Reserve University

Last full review/revision Apr 2021| Content last modified Apr 2021
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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.

  • 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 Pneumocystis jirovecii Pneumonia Pneumocystis jirovecii is a common cause of pneumonia in immunosuppressed patients, especially in those infected with human immunodeficiency virus (HIV) and in those receiving systemic corticosteroids... read more 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 X-linked Agammaglobulinemia X-linked agammaglobulinemia is characterized by low levels or absence of immunoglobulins and absence of B cells, leading to recurrent infections with encapsulated bacteria. (See also Overview... read more 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 Cirrhosis Cirrhosis is a late stage of hepatic fibrosis that has resulted in widespread distortion of normal hepatic architecture. Cirrhosis is characterized by regenerative nodules surrounded by dense... read more 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).

Treatment of Hyper-IgM Syndrome

  • Prophylactic immune globulin (IgG) replacement therapy and sometimes trimethoprim/sulfamethoxazole

  • Hematopoietic stem cell transplantation when possible

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 Prevention Gastroenteritis is inflammation of the lining of the stomach and small and large intestines. Most cases are infectious, although gastroenteritis may occur after ingestion of drugs and chemical... read more ). However, because the prognosis is poor, hematopoietic stem cell transplantation Hematopoietic Stem Cell Transplantation Hematopoietic stem cell (HSC) transplantation is a rapidly evolving technique that offers a potential cure for hematologic cancers (leukemias, lymphomas, myeloma) and other hematologic disorders... read more , which can be curative, is preferred if an human leukocyte antigen (HLA)-identical sibling donor is available.

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