Hyper IgM syndrome: Description, Causes and Risk Factors:
Abbreviation: HIM syndrome.
IgM antibodies are the largest antibody. They are found in blood and lymph fluid and are the first type of antibody made in response to an infection. They also cause other immune system cells to destroy foreign substances. IgM antibodies are about 5% to 10% of all the antibodies in the body.
Patients with the hyper IgM (HIM) syndrome have an inability to switch their antibody (immunoglobulin) production from IgM to IgG, IgA, and IgE. As a result, patients have decreased levels of IgG and IgA and normal or elevated levels of IgM. A number of different genetic defects can cause the hyper IgM syndrome. The most common form is inherited as an X-chromosome linked trait and affects only boys. Most of the other forms are inherited as autosomal recessive traits and affect both girls and boys.
The most common form of hyper IgM syndrome results from a defect or deficiency of a protein that is found on the surface of activated T-lymphocytes. The affected protein is called "CD40 ligand or CD40L" because it binds to a protein on B-lymphocytes called CD40. CD40 ligand is made by a gene on the X-chromosome. Therefore, this primary immunodeficiency disease is inherited as an X-linked recessive trait and usually found only in boys. As a consequence of their deficiency in CD40 ligand, affected patients' T-lymphocytes are unable to instruct B-lymphocytes to switch their production of immunoglobulins from IgM to IgG, IgA and IgE. In addition, CD40 ligand is important for other T-lymphocyte functions, and therefore, patients with X-linked hyper IgM syndrome (XHIM) also have a defect in some of the protective functions of their T-lymphocytes.
Other forms of hyper IgM syndrome are inherited as autosomal recessive traits and have been observed in females and males. The molecular bases for some of the other forms of hyper IgM syndrome have been discovered. These forms of hyper IgM syndrome result from defects in the genes that are involved in the CD40 signaling pathway. Genetic defects in CD40 are very rare and have been described in few families. The resulting disease is almost identical to XHIM because although the CD40 ligand is present on T-lymphocytes, the CD40 found on B-lymphocytes and other cells of the immune system is either not present or does not function normally. Two other genes (AID and UNG) have been identified that are necessary for B-lymphocytes to switch their antibody production from IgM to IgG, IgA or IgE. Defects in both of these genes have been found in patients with hyper IgM syndrome. Since the function of these genes is limited to antibody switching, the other T-lymphocyte functions of CD40 ligand are not affected, and these patients are less likely to have infections caused by organisms that are controlled by T-cells.
Symptoms and physical findings associated with the disorder usually become apparent in the first or second year of life. Hyper-IgM syndrome may be characterized by recurrent pus-producing (pyogenic) bacterial infections of the upper and lower respiratory tract including the sinuses (sinusitis) and/or the lungs (pneumonitis or pneumonia); the middle ear (otitis media); the membrane that lines the eyelids and the white portions (sclera) of the eyes (conjunctivitis); the skin (pyoderma); and/or, in some cases, other areas. Individuals with Hyper-IgM syndrome are also susceptible to "opportunistic" infections, i.e., infections caused by microorganisms that usually do not cause disease in individuals with fully functioning immune systems (non-immunocompromised) or widespread (systemic) overwhelming disease by microorganisms that typically cause only localized, mild infections. In individuals with Hyper-IgM syndrome, such opportunistic infections
may include those caused by Pneumocystis carinii, a microorganism that causes a form of pneumonia
, or Cryptosporidium, a single-celled parasite (protozoa) that can cause infections of the intestinal tract. In addition, individuals with Hyper-IgM syndrome are prone to certain autoimmune disorders affecting particular elements of the blood, such as neutropenia, a condition in which there is an abnormal decrease of certain white blood cells (neutrophils).
Additional physical findings often associated with the disorder may include enlargement (hypertrophy) of the tonsils, enlargement of the liver and spleen (hepatosplenomegaly), chronic diarrhea and impaired absorption of nutrients by the intestinal tract (malabsorption), and/or other symptoms.
The range and severity of symptoms and physical features associated with this disorder may vary from case to case. Because approximately 70% of reported cases of Hyper-IgM syndrome are inherited as an X-linked recessive genetic trait, the vast majority of affected individuals are male. However, some cases of autosomal recessive and autosomal dominant genetic inheritance have been reported. In addition, a rare acquired form of the disorder has been described in the medical literature.
Although the name of this disorder might lead people to expect high levels of IgM (one of the three major classes of antibodies) - and this is often the case, this is not found in all patients. The most usual findings are low levels of IgG and IgA with either normal or high levels of IgM.
For XHIM a specific test is now available which confirms the diagnosis reliably, and in most cases the precise gene mistake can also be identified. It is then possible to analyze DNA from female family members to find out whether they are carriers of XHIM and to offer a prenatal diagnostic test very early in pregnancy, should the family wish it.
The diagnosis of X-linked hyper IgM (XHIM) syndrome should be considered in any boy presenting with hypogammaglobulinemia, characterized by low or absent IgG and IgA and normal or elevated IgM levels. Failure to express CD40 ligand on activated T-cells is a characteristic finding. However, some patients with other forms of immunodeficiency may have a markedly depressed expression of CD40 ligand while their CD40 ligand gene is perfectly normal. Therefore, the final diagnosis of XHIM syndrome depends on the identification of a mutation affecting the CD40 ligand gene. This type of DNA analysis can be done in several specialized laboratories.
The autosomal recessive forms of hyper IgM syndrome can be suspected if a patient has the characteristics of XHIM but is either a female patient and/or has a normal CD40 ligand gene with normal expression on activated T-lymphocytes.
Ectodermal dysplasia with immunodeficiency, another X-linked form of hyper IgM syndrome, can be suspected in a patient who has features of ectodermal dysplasia (e.g. sparse hair and conical teeth) and recurrent infections, normal or elevated IgM and low IgG, IgA and IgE.
The diagnosis of the different forms of autosomal recessive hyper IgM syndrome or of ectodermal dysplasia with immunodeficiency can be confirmed by mutation analysis of the genes known to cause these disorders.
X-linked hyper IgM (XHIM) syndrome isdistinguished fromagammaglobulinemia by the presence of circulating B-lymphocytes and polyclonallgM in the former.
Patients with hyper IgM syndrome have a severe deficiency in IgG. Regular treatment with immunoglobulin replacement therapy every 3 to 4 weeks is effective in decreasing the number of infections. The immunoglobulin replaces the missing IgG and often results in a reduction or normalization of the serum IgM level. Since patients with the XHIM syndrome also have a marked susceptibility to Pneumocystis jiroveci (carinii) pneumonia, many physicians feel it is important to initiate prophylactic or preventative treatment for Pneumocystis jiroveci pneumonia by starting affected infants on Trimethoprim/sulfamethoxazole (Bactrim, Septra) prophylaxis as soon as the diagnosis of XHIM syndrome is made. Sometimes, neutropenia may improve during treatment with IVIG (intravenous immunoglobulin). Patients with persistent neutropenia may also respond to granulocyte colony stimulating factor (G-CSF) therapy. However, G-CSF treatment is only necessary in selected patients and long-term treatment with G-CSF is usually not recommended. Boys with hyper IgM syndrome, similar to other patients with primary immunodeficiency diseases, should not receive live virus vaccines since there is a remote possibility that the vaccine strain of the virus may cause disease. It is also important to reduce the possibility of drinking water that is contaminated with Cryptosporidium because exposure to this organism may cause severe gastrointestinal symptoms and chronic liver disease. The family should be proactive and contact the authorities responsible for the local water supply and ask if the water is safe and tested for Cryptosporidium.
Patients with XHIM syndrome have defects in T-lymphocyte function in addition to their antibody deficiency, and patients with ectodermal dysplasia with immunodeficiency also have defects in other aspects of their immune system. Treatment with immunoglobulin may not fully protect these patients against all infections. In recent years, bone marrow transplantation (BMT) or cord blood stem cell transplantation have been advocated. More than a dozen patients with XHIM have received an HLA-identical sibling bone marrow transplant with excellent success. Thus, a permanent cure for this disorder is possible. Cord blood stem cell transplants, fully or partially matched, have also been successfully performed, resulting in complete immune reconstitution. Matched unrelated donor (MUD) transplants are nearly as successful as matched sibling transplants. Since patients with the XHIM syndrome may have strong T-cell responses against organ transplants, including bone marrow transplants, immunosuppressive drugs or low dose irradiation are usually required.
Now that the genetic defect underlying XHIM has been discovered, there is a real possibility of the development of gene therapy. This is a complex challenge, but early successes are being reported in another form of immune deficiency (X-linked severe combined immunodeficiency) and the range of disorders for which gene therapy may be available is likely to increase over the next few years.
NOTE: The above information is educational purpose. The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition.
DISCLAIMER: This information should not substitute for seeking responsible, professional medical care.