Patients with the X-linked Hyper IgM Syndrome have a deficiency of a protein, CD40 ligand, that is found on the surface of T-lymphocytes. As a consequence of the deficiency of this protein, their T-lymphocytes are unable to instruct B-lymphocytes to switch their production of gammaglobulins from IgM to IgG and IgA. As a result, patients have decreased levels of IgG and IgA and normal or elevated levels of IgM. In addition, since CD40 ligand is important to other functions of T-lymphocytes, they also have a defect in some of the protective functions of their T-lymphocytes.

Definition

Patients with the X-linked Hyper IgM (XHIGM) syndrome have a defect or deficiency of a protein that is found on the surface of T-lymphocytes. The affected protein is called "CD40 lig-and" and is made by a gene on the X-chromosome. Thus, 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 gammaglobulins from IgM to IgG and IgA. As a result, patients with this primary immunodeficiency disease have decreased levels of serum IgG and IgA and normal or elevated levels of IgM. In addition, since CD40 ligand is important to other functions of T-lymphocytes, they also have a defect in some of the protective functions of their T-lymphocytes.

A disease resembling the XHIGM syndrome has also been observed in females and in some males in whom the CD40 ligand gene is normal. The precise molecular basis for these other forms of the Hyper IgM syndrome is being studied and several defects have recently been identified.

Clinical Presentation

Most patients with the X-linked Hyper IgM (XHIGM) syndrome develop clinical symptoms during their first year or second year of life. Their most common problem is an increased susceptibility to infection.

The most common infections are recurrent upper and lower respiratory tract infections. The most frequent infective agents are bacteria. However, a variety of other microorganisms can also cause serious infections. For example, Pneumocystis carinii pneumonia is relatively common during the first few months of life and its presence may be the first clue that the child has XHIGM syndrome. Lung infections may also be caused by viruses such as Cytomegalovirus and fungi such as Cryptococcus.

Gastrointestinal complaints, most commonly diarrhea and malabsorption, have also been reported in some patients. One of the major organisms causing gastrointestinal symptoms is Cryptosporidium that may cause sclerosing cholangitis, a severe disease of the liver.

Approximately half of the patients with the XHIGM syndrome develop neutropenia (low white blood cell count), either transient or persistent. The cause of the neutropenia is unknown, although most patients respond to treatment with the colony stimulating factor, G-CSF. Neutropenia is often associated with oral ulcers, proctitis (inflammation of the rectum) and skin infections. Enlargement of the lymph nodes is seen more frequently in patients with the XHIGM syndrome than most of the other primary immunodeficiency diseases. As a result, patients often have enlarged tonsils, a big spleen and liver and enlarged lymph nodes.

Autoimmune disorders may also occur in patients with the XHIGM syndrome. Their manifestations may include chronic arthritis, low platelet counts (thrombocytopenia), hemolytic anemia, hypothyroidism, and kidney disease.

Diagnosis

The diagnosis of the X-linked Hyper IgM (XHIGM) 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 Common Variable Immune Deficiency may have a markedly depressed expression of CD40 ligand while their CD40 ligand gene is perfectly normal. Therefore, the final diagnosis of the XHIGM 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.

Inheritance

The X-linked Hyper IgM (XHIGM) syndrome is inherited as an X-linked recessive disorder. Therefore, only boys are affected. Inheritance for more complete information on how X-linked recessive disorders are passed on from generation to generation. Since this is an inherited disease, transmitted as an X-linked recessive trait, there may be brothers or maternal uncles (mother's brothers) who have similar clinical findings. However, as in other X-linked disorders, there may also be no other affected members of the family. If the precise mutation in the gene for CD40 ligand is known in a given family, and if the fetus is male, it is possible to make a prenatal diagnosis. Similarly, women in the family can be tested to see if they carry the mutation and are therefore at risk for having an affected son.

Treatment

Because patients with the X-linked Hyper IgM (XHIGM) syndrome have a severe deficiency in IgG, regular infusions of IVIG every 3 to 4 weeks are effective in decreasing the number of infections. Regular IVIG infusions replace the missing IgG and they also often result in a reduction or normalization of the serum IgM level.

Because patients with the XHIGM syndrome also have a marked susceptibility to Pneumocystis carinii pneumonia, it is important to initiate prophylactic treatment for pneumocystis carinii pneumonia by starting affected infants on trimetho-primsulfamethoxazole (Bactrim, Septra) prophylaxis as soon as the diagnosis of XHIGM syndrome is made.

Sometimes, neutropenia may improve during treatment with IVIG. 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 not recommended.

Boys with XHIGM, 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.

Since patients with the XHIGM syndrome have defects in T-lymphocyte function in addition to their hypogamma-globulinemia, treatment with IVIG may not fully protect them against all infections. Therefore, bone marrow transplantation or cord blood stem cell transplantation has been advocated in recent years. If healthy siblings who have the same parents are available, the entire family, including the patient and potential donors, should be tissue typed to determine whether there is an HLA identical sibling available who could serve as bone marrow transplant donor. More than a dozen patients with XHIGM 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. This strategy is especially promising if a matched sibling donor is not available. Matched unrelated donor (MUD) transplants are nearly as successful as matched sibling transplants, especially if performed when the recipient is young (less than 8 years). Because patients with the XHIGM syndrome have strong T-cell responses against organ transplants, including bone marrow transplants, immunosuppressive drugs or low dose radiation are required.

Expectations

The diagnosis of the X-linked Hyper IgM (XHIGM) 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 Common Variable Immune Deficiency may have a markedly depressed expression of CD40 ligand while their CD40 ligand gene is perfectly normal. Therefore, the final diagnosis of the XHIGM 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.

Although patients with the X-linked Hyper IgM syndrome have defects in both the production of IgG and IgM and some aspects of their T-lymphocyte function, a number of effective therapies exist which allow these children to grow into happy and successful adults.

For additional information please visit http://www.emedicine.com/ped/topic2457.htm .

We would like to thank the Immune Deficiency Foundation, www.primaryimmune.org , for their contribution of the above information.

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