Hyper IgM syndrome is defined as a family of genetic disorders in which the level of Immunoglobulin M (IgM) antibodies is relatively high. The most common type is a result of a defect in a Th2 cell protein (CD40 ligand). The disorder causes immunodeficiencies, including a higher than normal susceptibility to various types of infections. Individuals with hyper-IgM syndrome typically also have a low number of neutrophils and platelets.
"The most common issue in all forms of HIGM syndrome is an increased susceptibility to infection, to include recurrent upper and lower respiratory tract infections. "
People with Hyper-IgM (HIGM) syndrome are susceptible to severe and recurrent infections. In some types of HIGM syndrome, people experience opportunistic infections and an increased risk of cancer. The disease is characterized by decreased levels of immunoglobulin G (IgG) in the blood and average or elevated levels of IgM. Several different genetic defects may cause HIGM syndrome. The most common form is inherited as an X-chromosome linked. The majority of the other forms are inherited as autosomal recessive traits and may affect both girls and boys.
Defining Hyper IgM Syndromes
People with HIGM syndrome have an inability to switch from the production of antibodies of the IgM type to antibodies of the IgA, IgG, or IgE types. Due to this, people with this disease have decreased levels of IgA and IgG, yet average or elevated levels of IgM in their blood. The different types of antibodies perform different functions and are all important where fighting infections is concerned. Usually, B-lymphocytes can produce IgM antibodies on their own, but they do require interactive help from T-lymphocytes in order to switch from IgM to IgG, IgA or IgE. HIGM results from a number of genetic defects that affect this interaction between B-lymphocytes and T-lymphocytes.
The most common form of HIGM 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,' because it binds or, 'ligates,' to a protein on B-lymphocytes called, 'CD40.' CD40 ligand is made by a gene on the X-chromosome. The primary immunodeficiency disease is inherited as an X-linked recessive trait.
As a consequence of the deficiency in CD40 ligand, the T-lymphocytes in people with X-linked Hyper IgM (XHIGM) are unable to instruct B-lymphocytes to switch their production of immunoglobulins from IgM to IgG, IgA and Ige. CD40 ligand is also important for additional functions performed by T-lymphocytes, so people with X-linked hyper IgM syndrome (XHIM) have defective cellular immunity and are also susceptible to a variety of infections, especially opportunistic infections and some forms of cancers.
Additional form of HIGM syndrome are inherited as autosomal recessive traits and have been noted in both girls and boys. One of these forms results from a defect in CD40 and is clinically identical to XHIGM. Other autosomal recessive forms of HIGM syndrome result from defects in genes that are involved in the CD40 signaling pathway. The function of these genes is limited to antibody switching, so the other T-lymphocyte functions of CD40 ligand are not affected and people are less likely to experience cancer or opportunistic infections.
A defect in another X-linked gene (NEMO) that is needed for the activation of the signaling molecule NF-kB has been identified in a form of HIGM syndrome that is associated with a skin condition called, 'ectodermal dysplasia.' People with this defect experience immunodeficiency with sparse hair and conical teeth, among other things. NF-kB is activated by other signaling pathways that results in antibody switching. Nf-kB is also activated by other signaling pathways that are important where fighting infections is concerned. Affected children are susceptible to a number of serious infections.
Clinical Presentation of Hyper IgM Syndromes
The majority of people with HIGM syndrome develop symptoms during their first or second year of life. The most common issue in all forms of HIGM syndrome is an increased susceptibility to infection, to include recurrent upper and lower respiratory tract infections. The most common serious infective agents are bacteria, yet viral illnesses are also more severe and frequent.
In people with XHIGM and autosomal recessive HIGM due to a CD40 defect, a number of additional microorganisms may also cause infections that are serious. For example; Pneumocystis jiroveci (carinii) pneumonia, which is an opportunistic infection, is fairly common during the affected person's first year of life and its presence might be the first clue that a child has HIGM syndrome. Viruses such as, 'Cytomegalovirus,' and fungi such as, 'Cryptococcus,' might also cause lung infections.
Gastrointestinal issues, most often malabsorption and diarrhea, also happen commonly in XHIGM and CD40 deficiency. One of the major organisms causing gastrointestinal symptoms in XHIGM is, 'Cryptosporidium.' A cryptosporidium infection might cause sclerosing cholangitis which is a severe and often times fatal disease of the person's liver.
Around 50% of people with XHIGM or CD40 deficiency develop neutropenia, which is a low count of granulocyte white blood cells, either persistently or transiently. The cause of neutropenia is unknown at this time, although the majority of people affected respond to treatment with colony stimulating factor, 'G-CSF.' Severe neutropenia is often times associated with skin infections, oral ulcers and proctitis. Autoimmune disorders might also occur in people with XHIGM syndrome or CD40 defects. Their manifestations may include:
As for the risk of cancer, especially liver cancer, the risk is increased in people with XHIGM or CD40 deficiency. A few people with HIGM syndrome have developed a rapidly progressive neuroendocrine carcinoma. Enlargement of the lymph nodes and spleen is frequently seen in people with autosomal recessive HIGM syndrome due to defects of UNG or AID. The results is people affected experiencing enlarged adenoids and tonsils that might cause obstructive sleep apnea or snoring.
Diagnosing Hyper IgM Syndromes
XHIGM should be considered in any boy presenting with severe recurrent respiratory infections, or an opportunistic infection, who has low or even absent IgG and average or elevated IgM levels. Failure to express CD40 ligand on activated T-cells is a characteristic finding. There are some people; however, with other forms of immunodeficiency who might have a markedly depressed expression of CD40 ligand while their CD40 ligand gene is perfectly average, these people do not have HIGM. The precise diagnosis of XHIM syndrome depends upon the identification of a mutation affecting the CD40 ligand gene. A DNA analysis may be performed in a specialized laboratory.
The autosomal recessive forms of HIGM might be suspected if a person has the characteristic of XHIGM, but is either a female and/or has an average CD40 ligand gene with average expression on activated T-lymphocytes. NEMO might be suspected in a person who has features of ectodermal dysplasia and experiences recurrent infections, average or elevated IgM and low IgA, IgG and IgE, as well as average CD40 ligand expression on activated T-lymphocytes. A diagnosis of these different forms of autosomal recessive HIGM may also be confirmed by mutation analysis of the genes known to cause these disorders.
Hyper IgM Syndromes and Inheritance
X-linked hyper IgM (XHIGM) and NEMO with immunodeficiency are inherited as X-linked recessive disorders and only boys are affected. Since the autosomal recessive forms of HIGM require that the gene on both chromosomes be affected they are less common than the X-linked conditions.
If the exact mutation in the affected gene is known in a given family, it is possible to make a prenatal diagnosis or test family members to find out if they are carriers of the mutation. Early diagnosis of any of the HIGM syndromes allows for initiation of treatment before the development of long-term consequences from serious infections.
Treating Hyper IgM Syndromes
Since people with all forms of HIGM syndrome have a severe IgG deficiency, they do need immunoglobulin replacement therapy. The immunoglobulin replaces the missing IgG and often times results in a reduction of the person's serum IgM level.
Because people with XHIGM or CD40 deficiency also have a notable susceptibility to pneumocystis jiroveci, they should be started on prophylactic treatment with trimethoprim-sulfamethoxazole as soon as the diagnosis of XHIGM is achieved. Additional medications for this are available if the person is allergic to sulfa-based medications.
When it is present, neutropenia might also improve during IgG replacement. People with persistent neutropenia might also need granulocyte colony stimulating factor therapy, particularly if they experience infections, mouth sores, or other kinds of complications associated with the neutropenia. Treatment; however, is only needed in selected people and long-term treatment is usually not something that is recommended.
People with XHIGM or CD40 defects should not receive live virus vaccines because there is a small possibility that the vaccine strain of the virus could cause disease. Bottled water should be used to avoid exposure to cryptosporidium.
People with XHIGM or CD40 deficiency have defects in T-lymphocyte function along with their antibody deficiency and treatment with immunoglobulin replacement might not completely protect them against all infections. Hemotopoietic stem cell transplantation has been successfully performed in many people with XHIM. Even though a permanent cure is anticipated following successful stem cell transplant, the long-term prognosis for people affected remains unknown. Since people with autosomal recessive HIGM caused by mutations in UNG or AID only experience defects of antibody production with no defect in T-cell function, stem cell transplants are not recommended.
Hyper-IgM syndrome type 1 - (X-linked) - Characterized by mutations of the CD40LG gene. In this type, T cells cannot tell B cells to switch classes.
Hyper-IgM syndrome type 2 - (autosomal recessive) - characterized by mutations of the AICDA gene. In this type, B cells cannot recombine genetic material to change heavy chain production, which is a required step in switching classes.
Hyper-IgM syndrome type 3 - Characterized by mutations of the CD40 gene. In this type, B cells cannot receive the signal from T cells to switch classes.
Hyper-IgM syndrome type 4 - A defect in class switch recombination downstream of the AICDA gene that does not impair Somatic Hyper Mutation.
Hyper-IgM syndrome type 5 - Characterized by mutations of the UNG gene.
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