Hyper-IgM syndrome type 2

Overview

Hyper-IgM syndrome type 2 (HIGM2) is a rare primary immunodeficiency disorder that impairs the immune system’s ability to produce different types of antibodies. It is characterized by elevated or normal levels of immunoglobulin M (IgM) and reduced or absent levels of immunoglobulin G (IgG), A (IgA), and E (IgE). This imbalance leaves affected individuals vulnerable to recurrent infections. Unlike type 1, HIGM2 is inherited in an autosomal recessive pattern and affects both males and females.

Causes

HIGM2 is caused by mutations in the AICDA gene, which encodes the enzyme activation-induced cytidine deaminase (AID). AID plays a critical role in class switch recombination and somatic hypermutation, processes essential for B cells to change the type of antibody they produce. When AID is deficient or non-functional, B cells are stuck producing only IgM, leading to a deficient immune response to many pathogens. The condition is inherited in an autosomal recessive pattern, requiring two copies of the mutated gene for the syndrome to manifest.

Symptoms

Symptoms of Hyper-IgM syndrome type 2 usually begin in early childhood and are similar to other forms of Hyper-IgM syndromes. They include:

• Recurrent bacterial infections, especially of the ears, sinuses, and lungs

• Chronic diarrhea and gastrointestinal infections

• Failure to thrive or poor weight gain

• Lymphoid hyperplasia (enlarged tonsils and lymph nodes)

• Autoimmune conditions (in some cases)

• Possible susceptibility to opportunistic infections, though less common than in HIGM1

Neurological development is usually unaffected, and the severity can vary between individuals.

Diagnosis

Diagnosis of HIGM2 involves a thorough clinical assessment, immune function testing, and genetic analysis. The diagnostic workup includes:

• Immunoglobulin panel: Elevated or normal IgM with very low levels of IgG, IgA, and IgE

• Flow cytometry: Shows normal expression of CD40 and CD40L (unlike HIGM1)

• B cell function tests: Confirm defective class switch recombination

• Genetic testing: Identification of biallelic mutations in the AICDA gene confirms the diagnosis

Family history and genetic counseling are also important, particularly in consanguineous families or communities with a higher prevalence of autosomal recessive conditions.

Treatment

There is no cure for HIGM2, but treatments focus on controlling infections and improving immune function. Management strategies include:

• Immunoglobulin replacement therapy: Lifelong intravenous or subcutaneous IgG to prevent infections

• Antibiotic prophylaxis: May be used during periods of high infection risk

• Vaccination strategy: Avoidance of live vaccines and use of inactivated vaccines with limited efficacy

• Management of complications: Treatment of infections, monitoring for autoimmune issues, and nutritional support

Unlike HIGM1, hematopoietic stem cell transplantation (HSCT) is not commonly used in HIGM2, since the defect is limited to B cells, and T cell function is typically preserved.

Prognosis

The prognosis for individuals with HIGM2 varies depending on the severity of symptoms and access to consistent medical care. With early diagnosis and regular immunoglobulin therapy, many patients can live relatively normal lives and avoid serious complications. However, without treatment, there is a high risk of recurrent infections, organ damage, and reduced quality of life. Lifelong monitoring by an immunologist is essential to optimize outcomes and prevent long-term complications.