Summary

Hyper IgM is an antibody deficiency. People with hyper IgM syndrome have abnormal levels of antibodies or immunoglobulins. Although the condition’s name implies that affected individuals always have high levels of immunoglobulin M (IgM), some people have normal levels of this antibody. The common feature is that those affected have low levels of three other classes of antibodies: immunoglobulin G (IgG), immunoglobulin A (IgA) and immunoglobulin E (IgE). This makes it difficult for people with hyper IgM to fight off infections.

Hyper IgM syndrome results from a variety of genetic defects that affect the interaction between T-cells and B-cells, such that B-cells are not able to switch production of antibodies from IgM to IgG, IgA and IgE.

There are four different forms of hyper IgM syndrome. The most common form is X-linked hyper IgM syndrome that is inherited as an X-linked recessive pattern, is usually found only in boys and is caused by mutations in the CD40 ligand gene. Other forms of hyper IgM syndrome are inherited as autosomal recessive traits and affect both sexes. These are caused by mutations in genes affecting the signalling necessary between T- and B-cells to produce the full range of antibody types (IgM, IgG, IgA and IgE) needed to have a healthy immune system.

The severity of the condition varies within and among the different types of hyper IgM syndromes. Common symptoms are frequent severe infections in infancy and early childhood. Common infections include pneumonia caused by pneumocystis carinii, sinus infections (sinusitis) and ear infections (otitis). Infections often cause those affected to have chronic diarrhoea and they may fail to gain weight and grow at the expected rate, known as failure to thrive.

Treatment of hyper IgM syndrome is immunoglobulin replacement therapy and antibiotics, and many people affected lead normal, healthy lives, provided that they receive adequate replacement immunoglobulin and appropriate treatment for infections. Hematopoietic stem cell transplantation, such as a bone marrow transplant, can offer a permanent cure for people with hyper IgM syndrome.

In hyper IgM syndrome children usually become ill between the ages of six months and two years, once the protective antibodies they received from their mothers during pregnancy have disappeared. If the underlying immunodeficiency is not spotted and treated appropriately, there can be a risk of permanent damage to the lungs or ears.

Features that may lead to a diagnosis of hyper IgM syndrome include:

  • severe and/or very frequent infections usually affecting the ear, throat and chest
  • pneumonia known as pneumocystis carinii pneumonia (PCP) – common in infants with hyper IgM syndrome
  • enlarged tonsils, liver and spleen
  • diarrhoea – one particular infection that causes diarrhoea and is commonly associated with hyper IgM syndrome is cryptosporidium parvum
  • infections involving bones and joints, causing osteomyelitis (infection of the bone) or arthritis
  • neutropenia – lack of white blood cells known as neutrophils linked to the development of mouth ulcers
  • anaemia
  • inflammation and ulceration of the rectum, known as proctitis
  • low platelet count (thrombocytopenia), leading to bruising.

Enlarged lymph nodes are found in AID and UNG deficiency.

Infections in hyper IgM are caused mainly by bacteria, but viruses, fungi and parasites may be involved. These include:

  • pneumocystis jirovecii – a fungal infection causing pneumocystis jirovecii (carinii) pneumonia
  • cytomegalovirus – a virus causing lung infections
  • cryptococcus – a fungus causing lung infections
  • cryptosporidium – a parasite found in faeces and sewage-contaminated water.

Associated health complications

Liver disease

In recent years it has become clear that there is a particularly high rate of liver abnormalities in hyper IgM syndrome. The most common form of liver disease is known as sclerosing cholangitis and involves abnormalities of the bile ducts, which can eventually progress to severe liver damage and liver failure. The cause is uncertain. It is likely that infection with cryptosporidium plays a role, but autoimmunity and infection with viruses may also be involved.

Other types of liver disease that occur more frequently than usual in X-linked hyper IgM include hepatitis C and hepatitis B. Chronic liver disease caused by any of the above can progress to liver cancer. There is also an increased incidence of malignancy in the gastrointestinal tract (the gut).

Due to the high rate of serious liver problems and malignancy in X-linked hyper IgM, bone marrow transplantation is considered for all those affected and if successful can cure them of their immunodeficiency.

Autoimmune disorders

Autoimmune disorders may also occur in patients with hyper IgM syndrome. These may include arthritis, low platelet counts (thrombocytopenia), anaemia, hypothyroidism and kidney disease.

Diagnosis

Diagnosis is based on clinical symptoms and the results of testing. Although the name of this disorder might lead people to expect high levels of IgM, this is often not the case and not found in all patients.

X-linked hyper IgM syndrome should be considered in any boy presenting with a reduction in all types of immunoglobulins (known as hypogammaglobulinemia). The most usual findings are low or absent levels of IgG and IgA (with either normal or high levels of IgM).

Testing for X-linked hyper IgM syndrome includes looking for the absence of CD40 ligand on activated T-cells. However, in some forms of X-linked hyper IgM the CD40 ligand may be expressed at low levels and a definitive diagnosis depends on identifying the precise defect in the CD40 ligand gene using DNA analysis.

In the UK this can be done at the London North East Thames Regional Genetic Centre at Great Ormond Street Hospital.

It is then possible to analyse DNA from female family members to find out whether they are carriers of X-linked hyper IgM and to offer a prenatal genetic diagnostic test very early in pregnancy, should the family wish it.

Autosomal recessive forms of hyper IgM syndrome are suspected if the patient has the characteristics of the X-linked form but is a female patient and/or has a normal CD40 ligand gene with normal expression on activated T-lymphocytes.

Diagnostic criteria for hyper IgM are available at www.esid.org/clinical-diagnostic-criteria-for-pid-73-0#Q16

There are four known types of hyper IgM syndrome:

  • CD40 ligand deficiency
  • CD40 deficiency
  • AID deficiency
  • UNG deficiency

CD40 ligand deficiency, also known as X-linked hyper IgM, is inherited in an X-linked recessive pattern. In this type of hyper IgM, T-cells cannot tell B-cells to switch their production of immunoglobulin.

CD40 ligand deficiency is caused by mutations in the CD40 ligand gene (also known as CD154). This gene encodes the instructions to make a protein called CD40 ligand found on the surface of T-cells. This protein ligand is essential for T-cells to interact with other cells of the immune system such as B-cells involved in making antibodies and is important for how T-cells mature to carry out their interactions and functions with other cells of the immune system.

Mutations in the CD40 ligand gene lead to the production of an abnormal CD40 ligand or prevent production of this protein. Without the proper interaction of CD40 ligand on T-cells with B-cells, the B-cells are only able to make the IgM type of antibody rather than being able to switch and make IgG, IgA or IgE antibodies.

It is usually found only in boys. Approximately 30% of cases of X-linked hyper IgM arise as ‘new mutations’ and in these cases there is no previous history of the disorder in the family.

CD40 deficiency is inherited in an autosomal recessive pattern. It is a B-cell defect. It is caused by mutations in the gene encoding the CD40 gene on chromosome 20q12-q13.2.

The gene encodes for the cell surface protein CD40 present on the surface of mature B-cells and other cells of the immune system. This protein interacts with the CD40 ligand protein present on T-cells and which is defective in X-linked hyper IgM.

The resulting condition is almost identical to X-linked hyper IgM.

AID deficiency is inherited in an autosomal recessive pattern. It is a B-cell defect caused by mutations in the gene encoding the enzyme activation-induced cytidine deaminase (AICDA) on chromosome 12p13. This gene is involved in B-cells switching their antibody production from IgM to IgG, IgA or IgE.

Associated functions of T-lymphocyte functions of CD40 ligand are not affected, so individuals affected are less likely to have infections caused by organisms that are controlled by T-cells.

UNG deficiency is inherited in an autosomal recessive pattern. It is caused by mutations in the gene encoding the enzyme uracil-DNA glycosylase (UNG).

Those affected are less likely to have infections caused by organisms that are controlled by T-cells.

Treatment

Keeping well with hyper IgM syndrome involves preventing infection and monitoring your health. This entails:

  • regular immunoglobulin replacement therapy either subcutaneously or intravenously to replace the missing IgG. This can sometimes result in a reduction or normalisation of the serum IgM level
  • taking daily antibiotics (prophylaxis) to prevent pneumonia due to pneumocystis jirovecii (PCP). This is especially used for affected infants with X-linked hyper IgM as they are at high risk of developing PCP during the first two years of life. Typical prophylaxis is trimethoprim/sulfamethoxazole (Bactrim, Septra)
  • possibly taking additional antibiotic prophylaxis to treat breakthrough infections
  • avoiding all live vaccines, as these can be a source of infection. You must check with your doctor what vaccines are recommended
  • protecting against infection from cryptosporidium, a parasite sometimes found in water. You should contact the authorities responsible for your local water supply and ask if the water is safe and tested for cryptosporidium. If not, it is advised to boil all drinking water, or install a professionally fitted high performance (<1 micron) filter on domestic water supplies
  • monitoring your health to look out for signs of long-term damage to organs. This may mean regular assessments by ear, nose and throat specialists and respiratory specialists, as well as specialised scans to detect early signs of lung damage.

Very careful monitoring for signs of liver problems is also needed. This will involve having regular liver function tests, including a special one called gamma-GT (gamma-glutamyl transferase), special X-rays and sometimes a liver biopsy.

Careful attention to dental hygiene is also important, since tooth decay can be a source of infection and ill health.

People with persistent neutropenia, the lack of white blood cells known as neutrophils, can improve with higher doses of immunoglobulin, but treatment with G-CSF (granulocyte colony stimulating factor), which stimulates the bone marrow to boost neutrophil production, may be needed. Anaemia (lack of red blood cells) and thrombocytopenia (lack of platelets) may also improve with higher doses of immunoglobulin.

Cure

Hematopoietic stem cell transplantation such as a bone marrow transplant (BMT) can offer a permanent cure for people with hyper IgM syndrome. Ideally, it is performed prior to the onset of life-threatening complications and organ damage.

BMT using tissue-matched HLA identical siblings as donors to treat X-linked hyper IgM syndrome and hyper IgM syndrome type 3 with good success. Stem cell transplants using cord blood stem cells, fully or partially matched, have also been used successfully. Significant advances are being made using matched unrelated donor transplants so that more people affected can be treated.

The need for transplantation is determined by the severity of the disease and the availability of a well-matched donor.

Immunisation

If on immunoglobulin replacement therapy, no immunisations are necessary. Avoid live vaccines if immunisations are being given.

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