What is Hyper IgM Syndrome?

Hyper-IgM syndrome is a primary immunodeficiency disorder in which the child's body fails to produce certain specific types of antibodies. The term primary means that the disorder is present from birth, in contrast to secondary immunodeficiencies (such as AIDS ), which are acquired later in life by previously healthy persons. Hyper-IgM syndrome is caused by mutations in a gene or genes in the body's T cells, which are a type of white blood cell or lymphocyte. T cells regulate the production of antibodies, which are protein molecules produced as the first line of the immune system's defense against disease-causing organisms. Hyper-IgM syndrome is also known as hypogammaglobulinemia with hyper IgM.

Hyper-IgM syndrome appears during the first year of life when the child develops recurrent infections of the respiratory tract that do not respond to standard antibiotic treatment, along with chronic diarrhea . Other early symptoms may include enlarged tonsils; swelling of the liver and spleen; enlarged lymph nodes; or opportunistic infections. Children with XHIM are more likely to develop enlarged lymph nodes than children with other primary immunodeficiency disorders. Opportunistic infections are caused by organisms that do not usually cause disease in people with normally functioning immune systems. The most common opportunistic infection in children with XHIM is a lung disease known as Pneumocystis carinii pneumonia (PCP). Children with either XHIM or ARHIM who are not diagnosed early may show delays in growth and normal weight gain.

Hyper-IgM syndrome is a disorder with a high degree of morbidity, which means that patients diagnosed with it often suffer from other diseases or disorders. The most common morbid conditions associated with XHIM include the following:

  • Recurrent and chronic infections of the lungs and sinuses leading to chronic dilation of the bronchi (the larger air passageways) in the lungs. This condition, called bronchiectasis, is marked by frequent attacks of coughing that bring up pus-streaked mucus.
  • Chronic diarrhea leading to weight loss and malnutrition . The diarrhea is usually caused by opportunistic infections of the digestive tract; the most common disease agents are Cryptosporidium parvum Giardia lamblia Campylobacter , or rotaviruses.
  • Frequent mouth ulcers, skin infections, and inflammation of the area around the rectum (proctitis). These complications are associated with neutropenia, a condition in which the blood has an abnormally low number of neutrophils. Neutrophils are a special type of white blood cell that ingests bacteria and other foreign substances. The connection between hyper-IgM syndrome and neutropenia was not as of 2004 yet fully understood.
  • Infections of the bones and joints leading to arthritis or osteomyelitis.
  • Disorders of the nervous system caused by meningoencephalitis, or inflammation of the brain and its overlying layers of protective tissue. Patients with these disorders may have problems with thinking clearly, have difficulty walking normally, or develop paralysis on one side of the body (hemiplegia).
  • Liver disease. About 70 percent of patients with XHIM develop liver disease by age 30, usually as a result of recurrent Cryptosporidium infections.
  • Malignant tumors, most commonly non-Hodgkin's lymphoma or cancers of the gall bladder and liver.

How common is X-linked hyper IgM syndrome?

Both XHIM and ARHIM are rare disorders. One group of researchers at Johns Hopkins University estimates the incidence of XHIM in the general North American population as one in 1,030,000 males. In the early 2000s, however, it is thought that the disorder may be underdiagnosed. The incidence of ARHIM has not been established as of 2004, but it is known to be much less common than XHIM. As of the early 2000s, researchers do not know whether these disorders are more common in some racial or ethnic groups than others or whether they are equally common in all parts of the world. The only registries of patients as of 2004 diagnosed with hyper-IgM syndrome are located in Europe and the United States. The registry that was established in the United States in 1997 contains the records of 79 patients from 60 unrelated families, while the European database contains the records of XHIM patients from 130 unrelated families.

Causes

Hyper-IgM syndrome is caused by a mutation in a gene on the X chromosome that affects the patient's T cells. The gene has been identified at locus Xq27. Normal T cells produce a ligand (a small molecule that links to larger molecules) known as CD40. CD40 is a protein found on the surface of T cells that signals B cells to stop producing IgM, which is the antibody that is first produced in response to invading organisms and switch to producing IgG and IgA, which are more specialized antibodies. As a result, boys with XHIM have abnormally low levels of IgG and IgA in their blood, with normal or higher than normal levels of IgM. Because they lack these "second line of defense" antibodies, they are more vulnerable to infections.

About 70 percent of patients diagnosed with XHIM have inherited the disorder through their mother; about 30 percent of cases, however, are caused by new mutations. Females who carry the defective gene have a 50 percent chance of passing it on to their sons but are not affected themselves by the disorder. The daughters of carriers have a 50 percent risk of carrying the defective gene to the next generation.

Symptoms

The symptoms of hyper-IgM syndrome usually become noticeable after the baby is six months to a year old. At this point the antibodies received from the mother during pregnancy are no longer present in the baby's blood. The child develops a series of severe ear, throat, or chest infections that do not clear up with standard antibiotic treatment. Another early warning sign is recurrent or chronic diarrhea. In addition, the child may have more than one infection at the same time. The most common telltale symptom, however, is PCP; in fact, the frequency of Pneumocystis carinii pneumonia in children with hyper-IgM syndrome was a useful clue to geneticists searching for the mutation that causes the disorder.

Treatment

Intravenous immunoglobulin (IVIG) therapy

Intravenous immunoglubulin (IVIG) has been the mainstay of treatment for a number of primary immunodeficiencies since it was first approved by the Food and Drug Administration (FDA) in the early 1980s. IVIG involves the infusion of immunoglobulins derived from donated blood plasma directly into the patient's bloodstream as a protection against infection. In the case of children with XHIM, IVIG is given to replace the missing IgG antibodies and to reduce or normalize the IgM level. IVIG infusions are usually given every three to four weeks for the remainder of the patient's life. They can be given in an outpatient clinic or in the patient's home. Patients with neutropenia may be treated with G-CSF (Neupogen), a protein given by injection that stimulates the body to produce more neutrophils.

IVIG therapy is the only effective treatment for ARHIM as of the early 2000s.

Antibiotics

Boys diagnosed with XHIM are given antibiotics as a prophylactic (preventive) treatment to protect them against Pneumocystis carinii pneumonia. They are usually started on a regimen of trimethoprim-sulfamethoxazole (Bactrim or Septra) as soon as they are diagnosed.

Bone marrow transplantation

A subsequent treatment for XHIM is bone marrow transplantation(BMT), which is also referred to as hematopoietic stem cell transplantation (HSCT). It is considered to be a cure for primary immunodeficiency disorders. Although BMT has been performed on children with severe immunodeficiency disorders since the 1980s, it was usually restricted to those with limited life expectancy because of complications associated with transplantation. Several advances since the late 1990s, however, have made this form of treatment more feasible for boys with XHIM. These advances include better matching of potential donors and recipients through more accurate tissue typing and improved surgical techniques. As of 2004, however, doctors recommended that boys with XHIM be given BMT before significant infections or organ damage occur. This form of treatment is not recommended for patients who already have signs of liver damage.

The best source of bone marrow for transplantation is the affected child's siblings. They will be tissue-typed to determine whether their bone marrow has the same human leukocyte antigens (HLA) as the affected child. Human leukocyte antigens are genetically determined proteins that allow the body to distinguish between its own cells and those from an outside source. The closer the HLA match between a bone marrow donor and recipient, the lower the chances that the recipient's body will reject the transplanted tissue. In addition to siblings, another choice is bone marrow from one of the parents, who shares half the affected child's HLA antigens. With the expansion of bone marrow registries since the early 2000s, it is also possible to use bone marrow from an unrelated donor whose tissues closely match those of the affected child. These are called matched unrelated donor (MUD) transplants. The most successful bone marrow transplants in hyper-IgM children, however, have used marrow donated by HLA-identical siblings.

Cord blood stem cell transplantation

Another approach to transplantation as a cure for hyper-IgM syndrome is the use of stem cells from cord blood. This technique was first used for immunodeficiency disorders in 1988. Stem cells are undifferentiated precursor cells whose daughter cells can differentiate into more specialized cells. The stem cells used for transplantation are taken from blood collected from a baby's umbilical cord or the placenta (afterbirth) immediately following delivery. Cord blood from healthy siblings can be used for transplantation to treat XHIM patients. Stem cell transplants from cord blood have two advantages over bone marrow transplants: they have a lower rate of rejection in recipients, and they can be stored ahead of time. Families with a history of primary immunodeficiency disorders can save cord blood in private storage facilities for later use if needed.

Prognosis

The prognosis for children diagnosed with XHIM is poor as of the early 2000s; morbidity and mortality for this disorder are significantly higher than for other primary immunodeficiency disorders. A study done in 2000 indicated that only 20 percent of patients with hyper-IgM syndrome survived to the age of 25. However, researchers expect the outlook to improve for children in treatment in 2004, particularly those patients who are good candidates for bone marrow transplantation. In one Japanese study, five out of seven patients who received BMT survived, with four of the five producing T cells with normal CD40 ligand without supplementary IVIG therapy. In general, children who are treated with IVIG and/or BMT as infants have a better prognosis than those who are diagnosed after the age of two years.