Hyper IgM syndrome is a rare primary immune deficiency disorders characterized by low or absent levels of serum IgG, IgA, IgE and normal or increased levels of serum IgM. They are resulting from mutations in the pathway from B-cell activation to isotype class switching. Patients with HIGM are usually diagnosed within the first two years of life and experience severe immunosuppression. This syndrome is also known as immunoglobulin class switch recombination (Ig-CSR) deficiencies. The most common causes are mutations in the CD40 Ligand (CD40LG) gene located at Xq26.3-27 leading to X-linked HIGM (XHIGM) in males.

Types

Five types of hyper IgM syndrome have been characterized:

Signs and symptoms

The majority of patients with HIGM syndrome present with a broad spectrum of clinical symptoms even with a same genetic defects. They usually develop symptoms in infancy and second year of life, including increased susceptibility to infections by extracellular bacteria, sinus & ear infections, skin infections. Furthermore, these patients are prone to pulmonary complications, gastrointestinal manifestations, autoimmune disorders, hematologic abnormalities, lymphoproloferation and malignancies. Heterozygous females in X-linked hyper IgM syndrome (HIGM1) are usually asymptomatic. However, immunologic testing has revealed that they exhibit reduced expression of CD40L when CD4+ T lymphocytes are activated. In some cases, females with significant reduction in circulating lymphocytes carrying the CD40L mutation due to skewed X-chromosome inactivation can present with symptoms resembling HIGM1 or common variable immunodeficiency. Among the presentation consistent with hyper IgM syndrome are the following:

Cause

Different genetic defects cause HIgM syndrome, the vast majority are inherited as an X-linked recessive genetic trait and most with the condition are male. IgM is the form of antibody that all B cells produce initially before they undergo class switching due to exposure to a recognized antigen. Healthy B cells efficiently switch to other types of antibodies as needed to attack invading bacteria, viruses, and other pathogens. In people with hyper IgM syndromes, the B cells keep making IgM antibodies because they can't switch to a different antibody. This results in an overproduction of IgM antibodies and an underproduction of IgA, IgG, and IgE.

Pathophysiology

CD40 is a co-stimulatory receptor on B cells that, when bound to CD40 ligand (CD40L), sends a signal to the B-cell receptor. Defective interaction of CD40L-CD40 between CD4+ T cells and antigen presenting cells (APCs) is known as the underlying cause of HIGM syndromes. CD40L-CD40 interaction is the first step in B cell stimulation for class switch recombination (CSR) and somatic hyper mutation (SHM) resulting in the generation of various Ig isotypes. Consequently, humoral immune response is affected. Certain insults, usually from encapsulated bacteria and toxin, then have a greater opportunity to damage the body.

Diagnosis

The diagnosis of X-linked hyper IgM syndrome (HIGM1) is established in males with typical clinical and laboratory findings by identifying a hemizygous pathogenic variant in the CD40LG gene through molecular genetic testing. In females, the diagnosis of HIGM1 is extremely rare. Heterozygous females are usually asymptomatic unless there is skewed X-chromosome inactivation. The diagnosis of hyper IgM syndrome can be done via the following methods and tests:

Treatment

The primary goal is to address the underlying defect in CD40L or other gene mutations causing HIGM. The potential for precise correction of the CD40LG gene in T cells and hematopoietic stem/progenitor cells (HSPC) to treat X-linked hyper-IgM Syndrome (HIGM1) is a promising avenue of research. However, the actual therapeutic efficacy of this approach is not yet fully understood and requires further investigation to determine its true potential. In addition to HSCT, supportive measures are crucial for managing infections and complications associated with HIGM. This may include antimicrobial prophylaxis, immunoglobulin replacement therapy, and close monitoring of respiratory and gastrointestinal infections. Additionally, anti-microbial therapy, use of granulocyte colony-stimulating factor, immunosuppressants, as well as other treatments, may be needed.

Epidemiology

All forms of hyper-IgM syndrome are rare. According to the US X-HIGM registry, the prevalence of X-linked hyper IgM syndrome (X-HIGM) during the period from 1984 to 1993 was approximately 1 in 1,000,000 live births. The estimated frequency of CD40L deficiency, a subtype of X-HIGM, is 2 in 1,000,000 in males. Limited data is available on the frequency of AICDA deficiency, another subtype of X-HIGM, but it is believed to affect less than 1 in 1,000,000 individuals. Globally, all forms of HIGM make up approximately 0.3% to 2.9% of all patients diagnosed with primary immunodeficiency disorders (PIDs).