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Agammaglobulinemia

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NORD is very grateful to Charlotte Cunningham-Rundles, MD, PhD, Departments of Medicine, Pediatrics, The Immunology Institute, Mount Sinai School of Medicine, for assistance in the preparation of this report.

Synonyms of Agammaglobulinemia

Disorder Subdivisions

General Discussion

Agammaglobulinemia is a group of inherited immune deficiencies characterized by a low concentration of antibodies in the blood due to the lack of particular lymphocytes in the blood and lymph. Antibodies are proteins (immunoglobulins, (IgM), (IgG) etc) that are critical and key components of the immune system. They are essential if the immune system is to do its job of fighting off bacteria, viruses, and other foreign substances that threaten the body. The specialized precursor cells that produce gammaglobulins, fail to develop or function properly leading to the deficiency in the number of mature lymphocyte cells called B cells.

The types of agammaglobulinemia are: X-linked agammaglobulinemia (XLA), the much rarer X-linked agammaglobulinemia with growth hormone deficiency (about 10 cases reported), and autosomal recessive agammaglobulinemia (ARAG). All of these disorders are characterized by a weakened immune system that must be strengthened by the administration of gammaglobulin in order to fight off infections.

Symptoms

The major symptoms of agammaglobulinemia are serial bacterial infections resulting from failures in specific immune responses because of defects in B-lymphocytes. These lymphocytes govern the production of antibodies. Males with X-linked primary agammaglobulinemia usually begin to show signs of such infections only late in the first year of life, after the IgG antibodies from the mother have been depleted.

Infections by almost any of the enterovirus family and the poliomyelitis virus can result in unusually severe illness in children with agammaglobulinemia. Echovirus infection can cause a group of symptoms that closely resembles dermatomyositis. These symptoms may include muscle weakness, often in the hip and shoulder areas, and difficulty swallowing. Areas of patchy, reddish skin may appear around the eyes, knuckles and elbows and occasionally on the knees and ankles. (For more information on this disorder, choose "dermatomyositis" as your search term in the Rare Disease Database.)

Infections caused by mycoplasma bacteria can lead to severe arthritis including joint swelling and pain, in children with primary agammaglobulinemia. Hemophilus influenzae is the most common mucous- producing infection (pyogenic) that occurs in people with X-linked agammaglobulinemia. Children may also have repeated infections with pneumococci, streptococci, and staphylococci bacteria, and infrequently pseudomonas infections.

Males with X-linked form of agammaglobulinemia have very low levels of IgA, IgG, and IgM antibodies circulating in their blood. Specialized white blood cells (neutrophils) are impaired in their ability to destroy bacteria, viruses, or other invading organisms (microbes). This occurs because neutrophils require antibodies from the immune system to begin to destroy invading bacteria (opsonization). The levels of circulating neutrophils in children with agammaglobulinemia may be persistently low, or may wax and wane (cyclic, transient neutropenia) in people with these disorders. The number of B-lymphocytes in children with X-linked agammaglobulinemia is less than one one-hundredth of the normal number.

Only about 10 persons in 5 or 6 families have been diagnosed with X-linked agammaglobulinemia with growth hormone deficiency. The boys in these families have reduced or undetectable numbers of B-lymphocytes. Clinicians and geneticists speculate that a second mutation in the BTK gene, very close to the mutation in this gene that causes XLA, is responsible for the combination of agammaglobulinemia and very short stature.

Autosomal recessive agammaglobulinemia has been reported to be due to genes that affect B cell development.

Causes

X-linked agammaglobulinemia (B-lymphocyte defect) is inherited as an X-linked recessive genetic trait. The abnormal gene, named BTK, has been mapped to gene locus Xq21.3-q22. A different mutation in the BTK gene causes X-linked agammaglobulinemia with growth hormone deficiency. The genetic cause of ARAG is much more complex involving other genes that have been mapped to loci on different chromosomes: 22q11.21, 14q32.33, and 9q34.13. The genes at three sites are known as IGLL1, IGHM, and LCRR8 respectively.

Chromosomes are located in the nucleus of human cells and carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes numbered from 1 through 22 are called autosomes and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 21q11.21" refers to band 11.21 on the long arm of chromosome 21. Similarly 14q32.33 refers to band 32.33 on the long arm of chromosome 14, and 9q34.13 refers to band 34.13 on the long arm of chromosome 9. The site described as Xq21.3-q22 refers to a region on the long arm of the X chromosome between bands 21.3 and 22. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.

X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and occur mostly in males. Females that have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and one is inactivated so that the genes on that chromosome are nonfunctioning. It is usually the X chromosome with the abnormal gene that is inactivated. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a disease gene he will develop the disease. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.

Males with X-linked disorders pass the disease gene to all of their daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.

Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.

All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

Affected Populations

Primary Agammaglobulinemia is a rare disorder that occurs almost exclusively in males although some females have been affected by certain types of this disorder.

Related Disorders

Symptoms of the following disorders can be similar to those of primary agammaglobulinemias. Comparisons may be useful for a differential diagnosis:

Common Variable Immunodeficiency (CVID) is rare immunodeficiency disorder characterized by recurrent infections in the lungs, sinuses or ears. The range and severity of symptoms and findings associated with CVI may vary from case to case. In some cases, individuals with CVID have an increased tendency to develop infections of the gastrointestinal system and may have a higher risk for some types of cancer such as non-Hodgkin lymphoma and stomach cancer. In addition, some individuals with CVID have an autoimmune disorder such as immune thrombocytopenia purpura that causes abnormal bruising and bleeding. The symptoms of CVI usually become apparent during the second to the fourth decade of life. CVID is thought to be caused by mutations in genes involved in the production of B cells that produce antibodies against infectious agents. CVID is likely to be caused by a combination of genetic and environmental factors in most cases, but autosomal recessive and autosomal dominant inheritance has been described in some families. (For more information on this disorder, choose "CVID" as your search term in the Rare Disease Database.)

Hyper-IgM Syndrome (HIGM) is a rare primary immunodeficiency disorder that is usually inherited as an X-linked recessive condition. People with this disorder have low levels of IgG, IgA and IgE antibodies. Levels of IgM antibodies may be high or in the normal range. Symptoms and physical findings usually become apparent in the first or second year of life. HIGM is characterized by recurrent bacterial infections of the middle ear, sinuses, lungs, the membrane that lines the eyelid and the white portion of the eyes, the skin, and/or other areas. Affected children may have an impaired absorption of nutrients, chronic diarrhea and failure to gain weight (failure to thrive) and enlargement of the tonsils and/or enlargement of the liver and spleen (hepatosplenomegaly). In addition, affected individuals are prone to the development of autoimmune disorders of the blood such as neutropenia, in which there is a decreased level of certain white blood cells. Because approximately 70 percent of reported cases of HIGM are X-linked, the vast majority of affected individuals are male. However, autosomal recessive and autosomal dominant forms of the disorder have also been described. (For more information on this disorder, choose "Hyper IgM" as your search term in the Rare Disease Database.)

Severe combined immunodeficiency (SCID) is the most grave of the primary immunodeficiency disorders. A person with SCID is subject to recurring infections because neither B nor T lymphocytes are present in sufficient numbers or they are malfunctioning. If untreated, this disorder may result in frequent, severe infections, growth retardation, and can be life-threatening. Other symptoms of this disorder may include weight loss, weakness, infections of the middle ear, and skin infections. (For more information on this disorder, choose "severe combined immunodeficiency" as your search term in the Rare Disease Database.)

The WAS-related disorders are a spectrum of conditions affecting the immune system that are caused by mutations in the WAS gene. These disorders include Wiskott-Aldrich syndrome, X-linked thrombocytopenia and X-linked congenital neutropenia. The WAS gene abnormality results in a deficiency in the WASP protein that leads to a low platelet count (thrombocytopenia). WAS-related disorders usually present in infancy and are characterized by bloody diarrhea, recurrent infections, scaling, itchy, skin rashes (eczema), and the appearance of small purple spots on the skin (petechia). The development of Pneumocystis carinii pneumonia (PCP) and intracranial bleeding are possible early, life-threatening complications. Later potential complications include destruction of red blood cells (hemolytic anemia), arthritis, vasculitis, kidney and liver damage. Affected individuals have an increased risk of developing lymphomas, especially after exposure to Epstein-Barr virus. WAS-related disorders are extremely variable, even in individuals in the same family. (For more information on this disorder, choose "WAS" as your search term in the Rare Disease Database.)

IgA deficiency is an antibody deficiency that is related to agammaglobulinemia and is characterized by low levels of IgA in the blood in the presence of normal or increased levels of IgG and IgM. IgA deficiency is the most common primary immunodeficiency. Other deficiencies of immunoglobulin isotopes are IgM deficiency and IgG subclass deficiencies.

Complement component 3 deficiency, is a rare inherited immune deficiency characterized by recurrent respiratory infections, skin infections, repeated middle ear infections, and sinusitis. The symptoms of this disorder are very similar to those of some of the agammaglobulinemia. Other symptoms may include pneumonia, bacterial infection of the blood (septicemia), and/or inflammation of the membranes that line the brain (meningitis). Other disorders may also be associated with complement component 3 deficiency including inflammation of blood vessels (vasculitis), joint pain (arthralgias), and autoimmune diseases such as lupus (systemic lupus erythematosus).

Standard Therapies

The administration of intravenous gammaglobulin replacement therapy is a standard treatment for agammaglobulinemia. Intravenous gammaglobulin or subcutaneous is used to treat agammaglobulinemias and common variable immunodeficiency.

Antibiotics are prescribed for people with agammaglobulinemia when bacterial infections occur. Some patients are treated with antibiotics as a preventive measure (prophylactically). All people who are immunodeficient should be protected as much as possible from exposure to infectious diseases. Corticosteroids or any drug that depresses the immune system (immunosuppressant drugs) should be avoided as much as possible, as well as physical activities such as rough contact sports that risk damage to the spleen.

In people with immunodeficiency with elevated IgM, there is a tendency to bleed excessively associated with abnormally low levels of circulating platelets in the blood (thrombocytopenia). This may complicate any surgical procedure.

Genetic counseling is recommended for people with agammaglobulinemias and their families. Other treatment is symptomatic and supportive.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

Organizations related to Agammaglobulinemia

References

TEXTBOOKS
Beers MH, Berkow R., eds. The Merck Manual, 17th ed. Whitehouse Station, NJ: Merck Research Laboratories; 1999:1035.

Berkow R., ed. The Merck Manual-Home Edition.2nd ed. Whitehouse Station, NJ: Merck Research Laboratories; 2003:819-20.

Janeway CAJr, Travers P, Walport M, Shlomchik MJ. Immunobiology, 6th ed. Garland Science Publishing. New York, NY; 2005:474-75.

JOURNAL ARTICLES
Kumar A, Teuber SS, Gershwin ME. Current perspectives on primary immunodifieciency diseases. Clin Dev Immunol. 2006;13:223-59.

Stangel M, Pul R. Basic principles of intravenous immunoglobulin (IVIg) treatment. J Neurol. 2006;253 Suppl 5:v18-v24.

Winkelstein JA, Marino MC, Lederman HM et al. X-linked agammaglobulinemia: report on a United States registry of 201 patients. Medicine (Baltimore). 2006;85:193-202.

Rose ME, Lang DM. Evaluating and managing hypogammaglobulinemia. Cleve Clin J Med. 2006;73:133-37, 140, 143-44.

Lawrence T, Puel A, Reichenbach j, et al. Autosomal-dominant primary immunodeficiencies. Curr Opin Hematol. 2005;12:22-30.

FROM THE INTERNET
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Bruton agammaglobulinemia tyrosine kinase: BTK. Entry No: 300300; Last Update:10/11/2006.

McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Agammaglobulinemia, X-Linked. Entry No: 300755; Last Update:12/19/08.

McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Agammaglobulinemia, Non-Bruton Type, Autosomal recessive. Entry No. 601495; Last Update: 1/6/06.

McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Hypogammaglobulinemia and isolated growth hormone deficiency, X-linked. Entry No. 307200; Last Update: 9/27/01.

Conley ME and Howard VC. Updated 12/21/05. X-Linked Agammaglobulinemia. In: GeneReviews at Genetests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2009. Available at http://www.genetests.org. Accessed 1/09.

Little FF. Agammaglobulinemia. Medical Encyclopedia. MedlinePlus. Update date 6/21/2006. 3pp.
www.nlm.nih.gov/medlineplus/ency/article/001307.htm
Accessed on 1/04/2007

X-linked Agammaglobulinemia. Children's Hospital Boston. ©2006. 3pp.
www.childrenshospital.org/az/Site1803/mainpageS1803P0.html
Accessed on 1/04/2007

Report last updated: 2010/06/16 00:00:00 GMT+0