Hyper IgM Syndromes

Hyper-IgM (HIgM) syndromes are extremely rare, inherited primary immunodeficiency (PI) diseases characterized by decreased blood levels of immunoglobulin G (IgG) and normal or elevated levels of immunoglobulin M (IgM).

Most individuals with hyper IgM syndromes are susceptible to recurrent and severe infections including opportunistic infections – which are infections caused by organisms that do not normally cause disease in healthy individuals. Patients also have an increased risk of cancer, particularly liver cancer.

Several different genetic defects can cause hyper IgM syndromes. The most common form is inherited as an X-linked disease affecting boys (who only have one X chromosome). Most other forms of HIgM are inherited as autosomal recessive traits and can equally affect boys and girls.

X-linked hyper IgM syndrome affects about 2 in every 1 million boys. The autosomal recessive forms of HIgM are extraordinarily rare, affecting fewer than 1 in 1 million people in the general population. X-linked hyper IgM syndrome accounts for about 70% of individuals with HIgM syndromes.

Most children with hyper IgM syndrome will present with clinical symptoms in their first or second year of life. The most common symptoms of hyper IgM syndrome include:

• Increased susceptibility to bacterial and viral infections, specifically recurrent upper and lower respiratory tract infections and GI infections
• Gastrointestinal issues, including diarrhea, malabsorption and a cryptosporidium infection, which can lead to a severe and potentially fatal liver disease called sclerosing cholangitis
• Neutropenia, a low white blood cell count often associated with oral ulcers and skin infections

Other symptoms of HIgM syndrome may include:

• Development of autoimmune disorders, including hemolytic anemia and/or thrombocytopenia (abnormally low platelet counts)
• Chronic arthritis
• Hypothyroidism
• Inflammatory bowel disease
• Kidney disease
• Neurological symptoms
• Certain forms of cancer
• Enlarged lymph nodes and spleen

Hyper IgM syndromes are caused by abnormal variations in specific genes. When a pathologic variation of a gene occurs, the protein product the gene codes for may be faulty, inefficient, absent or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems in the body.

X-linked hyper IgM syndrome is caused by a variation in the CD40LG gene (CD40 ligand gene). Hyper IgM syndrome type 3 is caused by a variation in the CD40 gene.

A diagnosis of hyper IgM syndrome may be suspected based on signs and symptoms of the disorder, or family history. In most cases, symptoms of HIgM appear by age 2.

At Children’s Hospital of Philadelphia (CHOP), evaluation begins with a thorough medical history and physical examination of your child. Clinical experts will use a variety of diagnostic tests to diagnose hyper IgM syndromes and possible complications, including:

• Specialized blood tests, which can determine things like the level of IgM and other immunoglobulin classes in the blood and whether your child's white blood cells are functioning properly
• Molecular genetic testing, which can detect variations in specific genes known to cause hyper IgM syndromes
• Additional tests, including X-rays, blood and urine tests may be performed to guide early symptomatic treatment

We will also perform baseline blood tests while your child is feeling healthy so we can compare results with those obtained if your child becomes ill. Regular blood tests are vitally important for children with hyper IgM syndromes because they often identify problems before symptoms arise and can lead to quicker and more definitive treatment.

At CHOP, a multidisciplinary team of immunologists, geneticists and transplant physicians with the Program for Integrated Immunodeficiency and Cellular Therapy (PIICT), Immune Dysregulation Program and the Blood and Marrow Transplant Program work together to develop a coordinated treatment plan to address your child’s unique needs.

In most cases, treatment will include:

• Antibiotic prophylaxis, or low doses of antibiotics taken every day or a few days per week to prevent infections that a patient with HIgM syndrome may have difficulty avoiding on their own
• Immunoglobulin replacement therapy to prevent infections and treat autoimmune complications (administered by direct infusion [IVIG] or just below the surface of the skin [subcutaneous immunoglobulin])
• Restricted contact to avoid exposure to new potential infections
• An allogeneic bone marrow transplant (allogeneic hematopoietic stem cell transplant) that uses healthy blood stem cells from a matched donor to correct the immunodeficiency

Most children with hyper IgM syndrome will eventually need a bone marrow transplant. In some cases, a relative can be used as a donor. In other cases, a match may be found through the National Marrow Donor Program's Be the Match Registry.

While a bone marrow transplant is the only curative therapy for hyper IgM syndromes, it does carry the risk of serious complications including graft-versus-host disease and other long-term effects. Further studies to evaluate long-term outcomes in hyper-IgM syndromes are underway.

Gene therapy is also being investigated as a potential treatment for individuals with hyper IgM syndromes. More studies are needed and it’s still too early to tell if gene therapy could offer a viable treatment alternative.

• Immune Deficiency Foundation Patient & Family Handbook for Primary Immunodeficiency Disease, Chapter 5
• National Organization for Rare Disorders: Hyper IgM Syndromes
• ClinicalTrials.gov: Study of Immune Responses and Safety of Recombinant Human CD40 Ligand in Patients With X-linked Hyper IgM Syndrome
• HyperIgM Foundation