Hyper-IgM syndrome type 5

Overview

Hyper-IgM syndrome type 5 (HIGM5) is a very rare form of Hyper-IgM syndrome, a group of primary immunodeficiency disorders characterized by defective class switch recombination in B cells. This condition results in normal or elevated levels of immunoglobulin M (IgM) and significantly reduced levels of immunoglobulin G (IgG), A (IgA), and E (IgE). HIGM5 is caused by mutations in the UNG gene and leads to impaired humoral immunity, leaving individuals susceptible to recurrent infections.

Causes

HIGM5 is caused by mutations in the UNG gene, which encodes the enzyme uracil-DNA glycosylase. This enzyme plays a critical role in somatic hypermutation and class switch recombination during B cell development. Without functional UNG, B cells cannot effectively switch from producing IgM to other antibody classes. The condition is inherited in an autosomal recessive manner, meaning both parents must carry a defective copy of the gene for a child to be affected.

Symptoms

Clinical features of HIGM5 typically appear in infancy or early childhood and may include:

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

• Chronic diarrhea and gastrointestinal infections

• Failure to thrive and poor growth

• Lymphoid hyperplasia (enlarged tonsils, adenoids, and lymph nodes)

• Skin infections or oral ulcers

• Autoimmune complications in some cases

Despite defective class switching, T cell function is usually preserved, and the clinical severity can be variable depending on the degree of immune dysfunction.

Diagnosis

Diagnosis of Hyper-IgM syndrome type 5 involves clinical evaluation, immunologic testing, and genetic confirmation. The diagnostic workup includes:

• Immunoglobulin profile: Normal or high IgM with low IgG, IgA, and IgE

• Flow cytometry: Normal CD40 and CD40L expression on T and B cells

• B cell function assays: Impaired class switch recombination and somatic hypermutation

• Genetic testing: Identification of biallelic mutations in the UNG gene

Confirming the specific genetic defect is important for appropriate classification, family counseling, and long-term management planning.

Treatment

Treatment of HIGM5 focuses on preventing infections and managing complications. Key components of care include:

• Immunoglobulin replacement therapy: Regular intravenous or subcutaneous IgG to maintain protective antibody levels

• Prophylactic antibiotics: To reduce the risk of recurrent bacterial infections

• Supportive care: Including treatment of acute infections, nutritional support, and growth monitoring

• Live vaccines: Should be avoided due to the risk of vaccine-related infections

Hematopoietic stem cell transplantation (HSCT) is not typically indicated for HIGM5, as T cell function remains intact and immunoglobulin replacement is often sufficient.

Prognosis

The prognosis for individuals with Hyper-IgM syndrome type 5 varies depending on the severity of infections and access to treatment. With early diagnosis and consistent immunoglobulin therapy, most patients can lead relatively stable lives and avoid life-threatening complications. However, without appropriate management, the risk of chronic lung disease, organ damage, and other complications increases. Lifelong follow-up with an immunologist is essential for optimizing outcomes and improving quality of life.