About Hyper IgM Syndrome
What is Hyper IgM Syndrome?
Hyper IgM Syndrome is a very rare, one-in-a-million, and potentially life-threatening genetic mutation that severely compromises the immune system. The most common form of Hyper IgM is X-Linked Hyper IgM, which primarily affects boys, except in rare cases. Other forms of Hyper IgM are inherited as autosomal recessive traits and can affect both boys and girls.
X-Linked Hyper IgM compromises the body’s ability to produce responses to pathogens such as bacteria and viruses. In a normal functioning immune system, a person will produce immunoglobulins or antibodies (IgG, IgA and IgE) in response to an encounter with a pathogen such as bacteria or a virus. These antibodies act like specialized forces, trained and capable to confront a more complicated pathogen. A person with Hyper IgM Syndrome, however, can only create very basic, primitive and largely ineffective IgM antibodies, and cannot “class switch” into the more effective and specialized antibodies to fight off the pathogen and create lasting immunity to the virus or bacteria.
As a result of their inability to produce antibodies, patients with Hyper IgM are at significant risk for opportunistic and repeated infections. In addition, the defect in the T-cells results in a decreased ability to identify and fight cancer cells as well as an inability to produce a response to pathogens. Combined with repeated infections over time, this defect in the T-cells poses a significantly increased risk for cancer.
Failure to Class-Switch
Since low to undetectable levels of immunoglobulins G (IgG’s) is the main phenotype of Hyper IgM, this family of syndromes is also known as Immunoglobulin (Ig) class switch recombination deficiencies (CSR-Ds). Patients with CSR-Ds or Hyper-IgM (HIGM) syndrome are susceptible to recurrent and severe infections and in some types of HIGM syndrome opportunistic infections and an increased risk of cancer as well. A number of different genetic defects can cause HIGM syndrome. As mentioned, the most common form is X-Linked Hyper IgM (X-HIGM), affecting mostly boys. Although girls are not generally affected by X-Linked Hyper IgM, they can be carriers and both pass along the genetic mutation to their sons, who have a 50% chance of inheriting the disease, and, in rare cases, can also have compromised immune systems due to having two weak X-chromosomes.
Antibodies are produced by B cells, but this process is tightly regulated to prevent unnecessary antibody production. In order to get activated and produce antibodies, B cells first need to meet their target (also called antigen). In addition, B cell can change the type of antibody they produce into a more potent type in a process called “Class Switching”. However, for that to happen, another activating signal is required. This signal is provided by T cells and sometimes described as “T cell help”. The protein responsible for providing this important signal is called CD40 Ligand (CD40L) and is expressed mostly on T cells. X-Linked Hyper IgM Syndrome (X-HIGM) patients have mutations that results in either zero expression of the CD40L protein on the surface of T-cells or no binding between that protein to the CD40 protein on B-cells. This results in lack of class-switching of the antibodies from IgM to IgG, IgA or IgE. Essentially, X-HIGM patients cannot produce antibodies as a result of not expressing the CD40L protein. So a mutation that mostly affects T cells, prevents these T cells from “helping” B cells and therefore looks like a B cell problem.
Patients with recurring infections, opportunistic infections (such as PJP/PCP) and low to absent IgGs, IgEs and IgA’s should be tested for Hyper IgM. A CD40 ligand flow cytometry test should be performed to determine the function of the T-cells. Ideally, genetic testing should be performed to confirm a diagnosis of Hyper IgM Syndrome.
In addition, it is recommended to test the mother of the patient to determine if she is a carrier. If she is a carrier, it is recommended that the parents undergo genetic counseling in connection with family planning, and it is further recommended that any of her sisters who are of childbearing age be tested for the genetic mutation as well, as they may also be carriers of this disease.
Since Hyper IgM patients are especially vulnerable to opportunistic bacterial, fungi and viral infections, they are often put on a regimen of both antibiotics to prevent pneumocystis jirovecii pneumonia (a deadly lung disease) as well as weekly or monthly infusions of immunoglobulin replacement therapy (IVIG, if monthly, and Subcutaneous IgG, if weekly). Click here for more on treatment and lifestyle changes for patients with Hyper IgM Syndrome.
A stem cell transplant (also known as a bone marrow transplant) is the only known cure. Although there is active research into the possibility of using new techniques such as gene editing or T-cell therapy for patients with Hyper IgM, this research is still in its nascent stages.
Although treatment and diagnosis of Hyper IgM has vastly improved over the past several decades, the mean life expectancy for a person with X-Linked Hyper IgM (absent a successful bone marrow transplant) is less than 30 years.
Click here for Q&A about Hyper IgM Syndrome.