Information on the following diseases can be found in the Related Disorders section of this report:

• Acquired Immunodeficiency Syndrome (AIDS)
• Ataxia Telangiectasia
• Severe Combined Immunodeficiency
• Wiskott-Aldrich Syndrome
• IgA Deficiency (General)
• Complement Component 3, Deficiency of (Immunodeficiency, Complement Component 3)

The major symptoms of primary agammaglobulinemias are serial infections; bacterial, viral, or fungal, resulting from failures in specific immune responses because of defects in T-lymphocytes (also called "killer cells") and B-lymphocytes. These lymphocytes govern the production of antibodies. Males with X-linked primary agammaglobulinemia usually begin to show signs of such serial 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 primary agammaglobulinemias. 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 agammaglobulinemias. Hemophilus influenzae is the most common mucous-producing infection (pyogenic) that occurs in people with X-linked primary agammaglobulinemia. Children may also have repeated infections with pneumococci, streptococci, and staphylococci bacteria, and infrequently pseudomonas infection.

People with X-linked agammaglobulinemia have abnormally 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 primary agammaglobulinemias may be persistently low, or may wax and wane (cyclic, transient neutropenia) in people with these disorders. The are fewer than one one-hundredth of the normal number of B-lymphocytes in children with X-linked primary agammaglobulinemia. XLAG patients are usually without tonsils, which are composed mostly of B-lymphocytes. (For more information, choose "Neutropenia" as your search term in the Rare Disease Database.)

Only about 10 persons in 5 or 6 families have been diagnosed with X-linked agamma-globulinemia 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 XLAG, is responsible for the combination of agammaglobulinemia and very short stature. Even fewer (5-6) cases of autosomal recessive agammaglobulinemia have been reported. Except for one boy, all cases of autosomal recessive agammaglobulinemia have occurred in girls.

X-linked agammaglobulinemia (B-lymphocyte defect) is inherited as an X-linked recessive genetic trait. This means that males are affected by the disorder and females may be carriers. The malfunctioning gene, named BTK, has been tracked to gene map locus Xq21.3-q22. A second and different change (mutation) in the same gene causes X-linked agammaglobulinemia with growth hormone deficiency. The genetic cause of ARAG is much more complex involving at least three genes that have been traced to gene map loci at 22q11.21, 14q32.33, and 9q34.13. The genes at these three sites are known as IGLL1, IGHM, and LCRR8 respectively.

Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 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 recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is "turned off"' and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is "turned off". A male has one X chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. 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. Female carriers of an X-linked disorder have a 25 percent chance with each pregnancy to have a carrier daughter like themselves, a 25 percent chance to have a non-carrier daughter, a 25 percent chance to have a son affected with the disease, and a 25 percent chance to have an unaffected son.

Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait 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, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent 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 percent. 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.

Primary agammaglobulinemias are rare disorders that occurs almost exclusively in males although some females have been affected by certain types of this disorder.
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Symptoms of the following disorders can be similar to those of primary agammaglobulinemias. Comparisons may be useful for a differential diagnosis:

Acquired immune deficiency syndrome (AIDS) is an immunosuppressive disorder caused by infection with the human immunodeficiency virus (HIV). The immune deficiency is a result of a viral infection and the destruction of specific T cells. Initially HIV infection is characterized by a period without symptoms. This may be followed by the development of swollen lymph nodes (lymphadenopathy). Eventually most people with acquired immune deficiency syndrome experience a progression of symptoms that occur as a result of a compromised immune system. However, AIDS is a contagious disease whereas primary agammaglobulinemias are not transmitted from person to person except through hereditary. (For more information on this disorder, choose "AIDS" as your search term in the Rare Disease Database.)

Ataxia Telangiectasia is a severe, rare, inherited disorder that affects the nervous and immune systems. It is characterized by the progressive loss of motor coordination in the arms, legs, and head (cerebellar ataxia). Some cases of this disorder are associated with immunodeficiencies (IgA or IgE). Mental development may be normal in the early stages of the disease, but progressive dementia may occur. This disease usually begins in infancy but may not be apparent until the child is school age. Classic red spots or telangiectasia appear in the eyes, and later on the face and roof of the mouth. (For more information on this disorder, choose "Ataxia Telangiectasia" 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.)

Wiskott-Aldrich Syndrome is a rare X-Linked inherited disorder of childhood characterized by immunodeficiency that results in recurrent skin rashes (eczema) and abnormally low levels of circulating platelets in the blood (thrombocytopenia) that results in bleeding disorders which, in the form of bloody diarrhea, may be the first symptom recognized. Symptoms of this disorder may include excessive bleeding from circumcision or minor trauma. Skin rashes that are red (petechiae) are typically present. Children suffering from this disorder who live beyond ages 10 or 11 tend to develop lymphoma or leukemia. (For more information on this disorder, choose "Wiskott-Aldrich" as your search term in the Rare Disease Database.)

IgA Deficiency is an antibody deficiency that is related to primary agammaglobulinemias 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 Primary Hypogammaglobulinemias. 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).
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The administration of intravenous gammaglobulin replacement therapy is a standard treatment for primary agammaglobulinemias. Intravenous gammaglobulin is used to treat most of the agammaglobulinemias including common variable immunodeficiency and X-linked agammaglobulinemia. Gammaglobulin may also be of value in transient hypogammaglobulinemia of infancy although there is risk that the body will delay production of immune factors in some infants.

Antibiotics are prescribed for people with primary agammaglobulinemias 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 will be of benefit for people with primary agammaglobulinemias and their families. Prenatal testing is being developed to detect these disorders before birth, particularly in the developing fetus of mothers who already have a child with X-Linked Primary Agammaglobulinemia. More studies are needed before this testing is widely available. Other treatment is symptomatic and supportive.

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

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.

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
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