Hyper-IgM syndrome type 3

Overview

Hyper-IgM syndrome type 3 (HIGM3) is a rare autosomal recessive primary immunodeficiency disorder characterized by elevated or normal levels of immunoglobulin M (IgM) and low or absent levels of other antibody classes such as IgG, IgA, and IgE. This condition impairs the body’s ability to fight off infections due to a defect in the communication between T cells and B cells required for immunoglobulin class switching. HIGM3 is caused by mutations in the CD40 gene, which plays a central role in immune system signaling.

Causes

HIGM3 is caused by mutations in the CD40 gene, which encodes the CD40 protein—a receptor found on B cells, dendritic cells, and other immune cells. This receptor interacts with the CD40 ligand (CD40L) on T cells to trigger class switch recombination in B cells. Mutations in CD40 disrupt this interaction, preventing B cells from switching from producing IgM to other antibody isotypes. The disorder follows an autosomal recessive inheritance pattern, meaning both copies of the CD40 gene must be mutated for the condition to manifest.

Symptoms

Symptoms of Hyper-IgM syndrome type 3 typically begin in infancy or early childhood. Common signs and symptoms include:

• Recurrent upper and lower respiratory tract infections

• Chronic diarrhea and gastrointestinal infections

• Failure to thrive and growth delays

• Enlarged tonsils and lymph nodes

• Mouth ulcers and persistent oral infections

• Increased risk of opportunistic infections (e.g., Pneumocystis jirovecii)

• Liver and biliary tract disease in some patients

Because both cellular and humoral immunity are affected, individuals are at high risk for severe, recurrent infections.

Diagnosis

Diagnosis of HIGM3 involves a combination of clinical evaluation, immunological studies, and genetic testing. Key diagnostic steps include:

• Serum immunoglobulin levels: Elevated or normal IgM with reduced or absent IgG, IgA, and IgE

• Flow cytometry: Normal CD40L expression on T cells, but absence or dysfunction of CD40 on B cells

• Lymphocyte subset analysis: To assess B and T cell populations and function

• Genetic testing: Confirmation of biallelic pathogenic mutations in the CD40 gene

Early and accurate diagnosis is crucial for initiating appropriate treatments and improving outcomes.

Treatment

Treatment for HIGM3 focuses on preventing and managing infections and restoring immune function where possible. Common treatments include:

• Immunoglobulin replacement therapy: Regular IVIG or subcutaneous IgG infusions to compensate for antibody deficiencies

• Antibiotic prophylaxis: To prevent opportunistic infections such as Pneumocystis jirovecii pneumonia

• Avoidance of live vaccines: Due to increased risk of vaccine-related infections

• Hematopoietic stem cell transplantation (HSCT): The only curative option, recommended especially for severe or early-onset cases

Management of complications such as liver disease and growth delays may also be required with supportive therapies.

Prognosis

The prognosis for individuals with HIGM3 depends on the severity of the immune defect, the timing of diagnosis, and the availability of treatment. Without treatment, the condition can lead to life-threatening infections and organ damage. With regular immunoglobulin therapy and infection prophylaxis, many patients experience a significant reduction in infections. Hematopoietic stem cell transplantation offers the possibility of long-term immune reconstitution and a potential cure. Lifelong follow-up with an immunologist is essential for managing the disease and improving quality of life.