Hyper IgM syndrome

Overview

Hyper IgM syndrome (HIGM) is a group of rare primary immunodeficiency disorders characterized by normal or elevated levels of immunoglobulin M (IgM) and low or absent levels of other immunoglobulin types such as IgG, IgA, and IgE. This immunological imbalance leads to a weakened immune system and increased susceptibility to recurrent infections. HIGM most commonly affects males and usually presents in infancy or early childhood.

Causes

Hyper IgM syndrome is caused by genetic mutations that disrupt the process of immunoglobulin class switching, a mechanism that allows B cells to produce different types of antibodies beyond IgM. Several genetic defects can lead to HIGM, including:

• X-linked Hyper IgM (HIGM1): Caused by mutations in the CD40LG gene (CD40 ligand), the most common form

• Autosomal recessive forms: Caused by mutations in genes such as AICDA, UNG, CD40, and PIK3CD

X-linked HIGM is inherited in an X-linked recessive pattern, while other forms are inherited in an autosomal recessive manner. The condition impairs communication between T cells and B cells, preventing the production of certain antibodies necessary for fighting infections.

Symptoms

Children with Hyper IgM syndrome typically begin showing symptoms in the first year of life. Common signs and symptoms include:

• Recurrent upper and lower respiratory tract infections (e.g., pneumonia, sinusitis)

• Chronic diarrhea and gastrointestinal infections

• Failure to thrive and poor growth

• Oral ulcers and mouth sores

• Skin infections and dermatitis

• Enlarged lymph nodes and liver or spleen

• Increased risk of opportunistic infections such as Pneumocystis jirovecii pneumonia (PCP)

Without treatment, the immune deficiency can lead to life-threatening infections and complications.

Diagnosis

Diagnosis of Hyper IgM syndrome involves a combination of clinical evaluation, laboratory testing, and genetic analysis. Diagnostic steps include:

• Immunoglobulin profile: Elevated or normal IgM with decreased IgG, IgA, and IgE levels

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

• Flow cytometry: To evaluate CD40 ligand expression on T cells (particularly in X-linked HIGM)

• Genetic testing: To confirm mutations in CD40LG or other related genes

Early diagnosis is crucial for initiating timely treatment and preventing severe infections.

Treatment

There is no cure for Hyper IgM syndrome, but treatment focuses on managing infections and restoring immune function. Common treatment approaches include:

• Immunoglobulin replacement therapy: Regular intravenous or subcutaneous IgG infusions to provide passive immunity

• Prophylactic antibiotics: To prevent infections, especially PCP

• Hematopoietic stem cell transplantation (HSCT): The only potential curative option, especially for X-linked HIGM

• Avoidance of live vaccines: Due to risk of severe infection

• Supportive care: Nutritional support and treatment of secondary complications

Multidisciplinary care by immunologists, infectious disease specialists, and transplant teams is essential.

Prognosis

The prognosis for individuals with Hyper IgM syndrome varies depending on the specific genetic type, timing of diagnosis, and effectiveness of treatment. With early diagnosis and appropriate therapy, many patients can lead relatively healthy lives. However, without treatment, the risk of severe and recurrent infections, organ damage, and early mortality is high. Stem cell transplantation offers the best long-term outcome in eligible patients, particularly those with the X-linked form.