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.
There are two forms of hyper-IgM syndrome, defined by their patterns of inheritance. The more common of the two, known as X-linked hyper-IgM syndrome (XHIM), is caused by an abnormal gene on the X chromosome and affects only boys. The less common form, autosomal recessive hyper-IgM syndrome (ARHIM), occurs in children who have inherited an abnormal gene from both parents. ARHIM affects girls as well as boys.
Description
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 cariniipneumonia (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.
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.
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 cariniipneumonia in children with hyper-IgM syndrome was a useful clue to geneticists searching for the mutation that causes the disorder.
When to call the doctor
The Jeffrey Modell Foundation (JMF) and the American Red Cross have drawn up a list of 10 warning signs of hyper-IgM syndrome and other primary immunodeficiency disorders:
The child has eight or more ear infections within one year.
The child has two or more serious sinus infections within one year.
The child has been treated with antibiotics for two months or longer with little effect.
The child has been diagnosed with pneumonia more than twice within the past year.
If an infant, the child is not growing or gaining weight normally.
Other family members have been diagnosed with a primary immunodeficiency disorder.
Diagnosis
Most children with hyper-IgM syndrome are diagnosed before they are a year old; about 40 percent have PCP at the time of diagnosis. If the doctor has seen the child on a regular basis since birth, there will be a record of the number of infections the child has had, the length of time the child has had each infection, and the child's response to treatment. If the doctor suspects a primary immunodeficiency disorder, he or she will ask the parents about a family history of such disorders.
The next step in diagnosis is a thorough physical examination. Children with primary immunodefiencies are often underweight or small for their age and may look pale or generally unwell. The doctor will listen for unusual sounds in the lungs when the child breathes in and out and will check the child's skin and the inside of the mouth for rashes, ulcers, or sores. As the doctor palpates or feels the child's abdomen, he or she will pay particular attention to the size of the spleen and liver. The doctor will also examine the child's joints and the lymph nodes in the neck for signs of swelling.
The doctor will order a blood test to screen the child for an immunodeficiency disorder. The most common tests performed to screen for hyper-IgM syndrome are a complete blood count (CBC) and a quantitative immunoglobulin test. The CBC will help to determine whether the child has neutropenia. The quantitative test measures the levels of the different types of immunoglobulins in the blood as well as the total level of all immunoglobulins. A child with hyper-IgM syndrome will be found to have abnormally low levels of IgA and IgG antibodies and a normal or elevated level of IgM.
The doctor may also order x-ray studies of the child's chest or sinuses in order to determine whether lung damage has already occurred or to make a baseline evaluation of the child's lungs.
The diagnosis of hyper-IgM syndrome can be confirmed by molecular genetics testing for the defective CD40 gene. The test involves DNA sequencing and has been available since the early 2000s.
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 cariniipneumonia. 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.
Experimental and investigational treatments
Researchers have found that giving artificial CD40 ligand to specially bred immunodeficient mice improves their ability to make IgA and IgG antibodies. The National Institutes of Health (NIH) is in the early 2000s conducting studies to evaluate the effectiveness of this treatment in humans.
As of the early 2000s, researchers at the National Institutes of Health and the University of Pennsylvania are investigating the possibility of treating hyper-IgM syndrome with gene therapy. Gene therapy involves the insertion of a normal gene into a targeted cell to replace an abnormal gene by means of a vector or carrier molecule. The most common vectors are genetically altered viruses. Reports on this research published in 2004, however, indicate that gene therapy for hyper-IgM syndrome will be more complicated and take longer to develop than was originally expected.
Nutritional concerns
Proper nutrition is a lifelong concern for children with hyper-IgM syndrome because of the possibility of malnutrition caused by chronic diarrhea. A normal well-balanced diet is recommended for older children, with multivitamin supplements as prescribed by the child's primary doctor. Older children can be given a nutritional supplement (Ensure) during episodes of severe diarrhea. In extremely severe cases the child may require parenteral nutrition, which is a liquid food given intravenously. Parenteral nutrition is also known as hyperalimentation.
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.
Prevention
As both forms of hyper-IgM syndrome are caused by genetic mutations, there is no way to prevent the disorders after the child is born. Parents who already have a child with hyper-IgM syndrome or who come from families with a history of primary immunodeficiency disorders may wish to consider genetic counseling and prenatal genetic testing with future pregnancies.
There are also some preventive measures that families can take to lower the risk of opportunistic infections and other complications in affected children. These precautions include the following:
Practicing good hygiene, including careful washing of the hands before and after meals and after using the toilet. Antibacterial hand wipes can be packed with the child's school lunches.
Careful cleansing of even small cuts or scrapes with an antiseptic liquid or cream.
Having the home water supply tested for possible contamination by Cryptosporidium parvum.
Avoiding crowded stores, theaters, or athletic events during flu season.
Giving the affected child his own room if possible.
Having other family members take primary responsibility for the care of household pets. Children with hyper-IgM syndrome are highly susceptible to infection from animal bites.
Parental concerns
Hyper-IgM syndrome has a major impact on the family of a child diagnosed with the disease. The following are some of the important concerns for parents:
High financial costs. Children diagnosed with hyper-IgM syndrome require careful monitoring for liver
KEY TERMS
Antibody—A special protein made by the body's immune system as a defense against foreign material (bacteria, viruses, etc.) that enters the body. It is uniquely designed to attack and neutralize the specific antigen that triggered the immune response.
B cell—A type of white blood cell derived from bone marrow. B cells are sometimes called B lymphocytes. They secrete antibodies and have a number of other complex functions within the human immune system.
Bronchiectasis—A disorder of the bronchial tubes marked by abnormal stretching, enlargement, or destruction of the walls. Bronchiectasis is usually caused by recurrent inflammation of the airway.
Cord blood—The blood that remains in the umbilical cord and placenta after birth. Stem cells from cord blood can be used in place of bone marrow for treating primary immunodeficiency disorders.
Gene therapy—An experimental treatment for certain genetic disorders in which a abnormal gene is replaced with the normal copy. Also called somatic-cell gene therapy.
Human leuckocyte antigen (HLA)—A group of protein molecules located on bone marrow cells that can provoke an immune response. A donor's and a recipient's HLA types should match as closely as possible to prevent the recipient's immune system from attacking the donor's marrow as a foreign material that does not belong in the body.
Immunoglobulin G (IgG)—Immunoglobulin type gamma, the most common type found in the blood and tissue fluids.
Ligand—Any type of small molecule that binds to a larger molecule. Hyper-IgM syndrome is caused by a lack of a ligand known as CD40 on the surfaces of the T cells in the child's blood.
Lymphocyte—A type of white blood cell that participates in the immune response. The two main groups are the B cells that have antibody molecules on their surface and T cells that destroy antigens.
Morbidity—A disease or abnormality. In statistics it also refers to the rate at which a disease or abnormality occurs.
Neutropenia—A condition in which the number of neutrophils, a type of white blood cell (leukocyte) is abnormally low.
Opportunistic infection—An infection that is normally mild in a healthy individual, but which takes advantage of an ill person's weakened immune system to move into the body, grow, spread, and cause serious illness.
Primary immunodeficiency disease—A group of approximately 70 conditions that affect the normal functioning of the immune system.
Prophylactic—Preventing the spread or occurrence of disease or infection.
Stem cell—An undifferentiated cell that retains the ability to develop into any one of a variety of cell types.
T cell—A type of white blood cell that is produced in the bone marrow and matured in the thymus gland. It helps to regulate the immune system's response to infections or malignancy.
Thrush—An infection of the mouth, caused by the yeast Candida albicans and characterized by a whitish growth and ulcers.
function, lung function, nutritional status, oral hygiene, and normal growth patterns as well as blood antibody levels. In most cases the child will be seen every three to six months by a clinical immunologist as well as his primary care doctor. Such procedures as bone marrow or cord blood transplantation are also costly.
Emotional wear and tear on the family. In addition to the extra time and attention required for the affected child, parents are likely to confront emotional problems in the family, ranging from resentment on the part of siblings to anxiety about the affected child's survival and decisions about future pregnancies. Support groups and/or family therapy may be helpful.
Genetic testing. Genetic counselors recommend having the affected child's siblings tested to see whether they are carriers of the defective gene.
Education and future employment. Children who are receiving IVIG treatment can attend a regular school and participate in most sports provided that minor injuries are treated promptly. Adults with hyper-IgM syndrome can attend college or graduate school and work in most fields of employment.
Peer pressure in adolescence. It is important for parents to warn children with hyper-IgM syndrome that smoking, alcohol consumption, and the use of recreational drugs are far more dangerous for them than for adolescents with normal immune systems.
"Biology of the Immune System," sect. 12, chap. 146 in The Merck Manual of Diagnosis and Therapy, edited by Mark H. Beers and Robert Berkow. Whitehouse Station, NJ: Merck Research Laboratories, 2002.
IDF Patient and Family Handbook for the Primary Immune Deficiency Diseases, 3rd ed. Towson, MD: Immune Deficiency Foundation (IDF), 2001.
PERIODICALS
Chinen, G., and W. T. Shearer. "Advances in Asthma, Allergy, and Immunology Series 2004: Basic and Clinical Immunology." Journal of Allergy and Clinical Immunology 114 (August 2004): 398–405.
Cooper, Megan A., Thomas L. Pommering, and Katalin Koranyi. "Primary Immunodeficiencies." American Family Physician 68 (November 15, 2003): 2001–08.
Cron, R. N. "CD154 Transcriptional Regulation in Primary Human CD4 T Cells. Immunologic Research 27 (2003): 185–202.
Dimicoli, S., et al. "Complete Recovery from Cryptosporidium parvum Infection with Gastroenteritis and Sclerosing Cholangitis after Successful Bone Marrow Transplantation in Two Brothers with X-Linked Hyper-IgM Syndrome." Bone Marrow Transplantation 32 (October 2003): 733–37.
Paul, Mary E. "Diagnosis of Immunodeficiency: Clinical Clues and Diagnostic Tests." Current Science 2 (2002): 349–55.
Tomizawa, D., et al. "Allogeneic Hematopoietic Stem Cell Transplantation for Seven Children with X-Linked Hyper-IgM Syndrome: A Single-Center Experience." American Journal of Hematology 76 (May 2004): 3339.
Winkelstein, J. A., et al. "The X-Linked Hyper-IgM Syndrome: Clinical and Immunologic Features of 79 Patients." Medicine (Baltimore) 82 (November 2003): 373–84.
ORGANIZATIONS
American Academy of Allergy, Asthma, and Immunology (AAAAI). 611 East Wells Street, Milwaukee, WI 53202. Web site: <www.aaaai.org>.
Immune Deficiency Foundation (IDF). 40 West Chesapeake Avenue, Suite 308, Towson, MD 21204. Web site: <www.primaryimmune.org>.
Jeffrey Modell Foundation (JMF). 747 Third Avenue, New York, NY 10017. Web site: <www.jmfworld.com>.
National Institute of Allergy and Infectious Diseases (NIAID). Building 31, Room 7A50, 31 Center Drive, MSC 2520, Bethesda, MD 20892–2520. Web site: <www.niaid.nih.gov>.
National Institute of Child Health and Human Development (NICHD). 31 Center Drive, Room 2A32, Bethesda, MD 20892–2425. Web site: <www.nichd.nih.gov>.
National Organization for Rare Disorders Inc. (NORD). 55 Kenosia Avenue, Danbury, CT 06813–1968. Web site: <www.rarediseases.org>.
WEB SITES
Shigeoka, Anne O'Neill. "X-Linked Immunodeficiency with Hyper IgM." eMedicine, October 4, 2002. Available online at <www.emedicine.com/neuro/topic664.htm>.
OTHER
National Institute of Allergy and Infectious Diseases (NIAID). Fact Sheet: Primary Immune Deficiency. Bethesda, MD: NIAID, 2003.
National Institute of Child Health and Human Development (NICHD). Primary Immunodeficiency. NIH Publication No. 99–4149. Bethesda, MD: NICHD, 2004.
