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What

People with Hyper IgM (HIGM) syndrome have a defect or deficiency of their immune system which makes them susceptible to severe recurring infections, unusual kinds of pneumonias, anemia and liver disease.  These patients have elevated levels of the antibody IgM but usually have reduced levels of the other types of antibodies which are necessary for proper immune system function. 

Who

The frequency of the HIGM syndromes has not been accurately assessed. So far, clinical studies of the suspected syndrome have been limited to the United States and Europe. The number of people with X-linked HIGM is estimated to be 1 per million in the general population, and the autosomal recessive and autosomal dominant forms of the syndrome are even less common.  Children are almost always diagnosed in the first three years of life.

Signs and Symptoms

People with HIGM syndrome can have any or all of the following:

• Increased susceptibility to infection
• Upper and lower respiratory infections (mostly bacterial; some viral)
• Risk for an unusual pneumonia caused by Pneumocystis jiroveci, also called Pneumocystis carinii
• Gastrointestinal problems (usually diarrhea), and poor growth due to chronic infections and the inability to absorb sufficient nutrients from food
• Development of neutropenia (low white blood cell count), either transient or persistent
• Chronic arthritis
• Aplastic anemia, which is a lack of production of blood cells by the bone marrow, leading to anemia and bleeding. This is often caused through infection of  Parvovirus B19
• Liver problems, leading to jaundice and impaired liver function

Possible Causes

HIGM syndromes can be caused by a number of different genetic defects. The X-linked HIGM (XHIGM) syndrome, also called HIGM1, is caused by an affected protein called "CD40 ligand" which is made by a gene on the X-chromosome. This syndrome is inherited as an X-linked recessive trait and so it is almost always found only in boys, as boys have only one copy of the X chromosome. The boy's mother is a carrier of the affected gene on one of her X chromosomes, but she isn't affected by the syndrome because she has another X chromosome which functions normally. When her son receives the affected X chromosome, he does not have a second X chromosome (only a Y chromosome), and so he gets XHIGM syndrome. Thus, this primary immuno-deficiency disease is said to be inherited as an X-linked recessive trait.  The cause of the disease, the abnormal CD40 ligand, is a protein that is involved in sending instructions to special immune cells called B cells to make antibodies (like IgM, IgG, IgA) needed to fight infections. Because these antibodies cannot be made, the immune system does not work properly, and infections result.  There are at least 88 known mutations of the CD40 ligand gene that cause this disease; a full listing can be found at http://bioinf.uta.fi/CD40Lbase.

An autosomal recessive form of HIGM syndrome occurs in people who do not express the CD40 receptor on B cells.  In XHIGM, cells lack the CD40 ligand needed to interact with the CD40 receptor on B cells; however, in this form of autosomal recessive HIGM, it is the B cells which lack the CD40 receptor to interact with the CD40 ligand (which is being properly expressed on cells), and so the same end-result occurs.

Some patients may have a defect in a gene for a protein called activation-induced cytadine deaminase (called AICDA), which can be inherited in either an autosomal recessive or an autosomal dominant fashion, and which also leads to HIGM.  This gene produces a protein which is involved in allowing the B cells to produce different kinds of antibodies in response to the proper signal initiated by the CD40 ligand-CD40 receptor interaction.  If this gene is mutated, cells can communicate to the B cell, but the B cell will be unresponsive and will not make the proper antibodies.  These patients also tend to have autoimmune complaints, including hepatitis, low numbers of platelets, and hemolytic anemias.

A very small number of people may have mutations in one of two additional genes that produce proteins important in the B cell antibody-making process: uracil-DNA-glycosylase (UNG) or I-kappa-kinase. 

Finally, the molecular defect underlying the disease of HIGM has not been identified in more than half the cases described.  Presumably, the genetic defects are present in genes which encode proteins which regulate B-cell development in some fashion. 

Diagnosis

In general, to make a diagnosis of HIGM, people must have recurrent infections, anemia, or liver disease. Blood tests will show low or absent levels of IgG and IgA with normal or elevated IgM levels (these are specific kinds of antibodies made by B cells).  If a person is suspected of having X-linked HIGM (HIGM1), that person will also be male, have a failure to express CD40 ligand, and may have a DNA mutation identified in the gene for CD40 ligand. This type of DNA analysis can be done in several specialized laboratories and may take several weeks to be completed.  If a person is suspected of having one of the other forms of HIGM, either autosomal recessive or autosomal dominant, further DNA analysis and functional immunology studies will be necessary to identify the other possible causes.

Treatment

Because children with HIGM have a severe deficiency in IgG, regular infusions of IVIG (intravenous immunoglobulin) every 3 to 4 weeks are effective in decreasing the number of infections. Regular IVIG infusions replace the missing IgG, which is the primary antibody used to fight infections, and this often results in a reduction or normalization of the serum IgM level.  Since children with HIGM also have a marked susceptibility to Pneumocystis pneumonia, it is important to initiate preventative treatment for the pneumonia by starting affected infants on co-trimoxazole or trimethoprim-sulfamethoxazole prophylaxis as soon as the diagnosis of HIGM syndrome is made.  Prevention of liver disease requires careful monitoring liver function. The recommended treatment now is a bone marrow transplant when the children are young.  Though this is a difficult procedure, it provides the children with a new immune system that functions appropriately so they will not require monthly IVIG infusions or prophylactic antibiotics.  Stem cell transplant and umbilical cord blood transplant have also been proposed as potential solutions to this disorder. 

Prognosis

Therapies such as intravenous immunoglobulin (IVIG) and co-trimoxazole have greatly improved these children's lives. However, in one European study, only 20% of children with XHIGM were still alive at age 25 years. Severe infections in childhood, and liver disease as they grow older, are the major causes of death.  bone marrow transplant may improve their survival, although patients who received a bone marrow transplant had only a 68% survival rate.  Newer antibiotic treatments for infections may also allow these patients to survive longer.  As our options for gene therapy and stem cell transplant become better and more diverse, the prognosis for HIGM should also improve. 

Connect with other parents

In the spirit of community and support, Madisons Foundation offers the unique service of connecting parents of children with rare diseases. If you would like to be connected to other parents of children with this disease, please fill out this brief form.

Weblinks

National Primary immunodeficiency Resource Center

http://npi.jmfworld.org/.

This website has great information on XHIGM as well as links to ongoing research. This site also has links to where to find an expert in your local area, to a kid's corner, to Spanish translation, and to a message board.

Primary Immune

http://www.primaryimmune.org/pubs/book_pats/e_ch08.pdf

This is a very comprehensive article on XHIGM. You must have Acrobat Reader to view this but Acrobat Reader can be downloaded for free.

Google Search for Hyper IgM

References and Sources

www.emedicine.com

Apoil PA, Kuhlein E, Robert A, Rubie H, Blancher A. "HIGM syndrome caused by insertion of an AluYb8 element in exon 1 of the CD40LG gene," Immunogenetics (2007) 59: (1) 17-23. 

Durandy A, Peron S, and Fischer A. "Hyper IgM Syndromes," Curr Opin Rheumatol (2006) 18:369-376.

Etzioni A, Ochs HD, "The Hyper IgM Syndrome: An evolving story," Pediatr Res (2004) 56: 4.