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Primary Immunodeficiency Diseases

Incidence  |  Description  |  Symptoms  |  Diagnosis  |  Treatment  |  Prognosis  |  Prevention


X-Linked Agammaglobulinemia

Incidence

The incidence of X-Linked Agammaglobulinemia is reported to be 1 in 10,000.

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Disease Description

X-Linked Agammaglobulinemia was the first immunodeficiency to be identified. It is sometimes called Bruton Type Agammaglobulinemia, X-Linked Infantile Agammaglobulinemia, or Congenital Agammaglobulinemia. It is an inherited disorder localized to the central region of the long arm of the X chromosome and is thus found in males. However, this X-linked pattern of transmission cannot be demonstrated in all families, possibly because of small family size, and because in a certain percentage of cases, a new mutation in the gene locus on the X chromosome has occurred. The gene locus is a specific enzyme (BtK) which prompts B-cells to become mature and able to produce antibodies.

Persons with X-Linked Agammaglobulinemia are unable to produce antibodies (or binding proteins) that comprise the gammaglobulins (immunoglobulins) in blood plasma. Most of these patients have pre B-lymphocytes, but very few of these immature B-cells go on to become mature B-lymphocytes. A few B-cells are present in the bone marrow and circulation, but they may be reduced 100 fold or more. Other histologic (tissue) hallmarks of the disease are lack of germinal centers (lymphocyte-producing cells) in the lymph nodes or spleen, and in the absence of tonsils and adenoids.

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Clinical Signs and Symptoms

These male patients are prone to develop serious, pyogenic (pus producing) bacterial or viral infections. This process begins in infancy or early childhood, typically at 6 to 9 months of age, when maternally derived IgG antibodies have catabolized (broken down). Common sites are the inner ear, sinuses, and respiratory tract, leading to recurrent problems such as sinusitis, rhinitis (nasal infection), pyoderma (skin infection), conjunctivitis (eye infection), osteomyelitis (bone infection) meningitis (spinal cord infection), sepsis (bloodstream infection), bronchitis, and pneumonia. Recurrent gastrointestinal infections occur occasionally, resulting in diarrhea. Since X-Linked Agammaglobulinemia patients have no antibodies, infections can go beyond the mucosal surface and into the bloodstream and internal organs.

Bacteria which are particularly common causes of infection in these patients include pneumococcus, streptococcus, staphylococcus, Pseudomonas aeruginosa, and Hemophilus influenzae. Giardia lamblia can cause gastrointestinal infections, but it is not nearly as common in X-Linked Agammaglobulinemia as in Common Variable Immunodeficiency or Selective IgA Deficiency.

While the cellular immunity (immune response of T-cells and not antibodies) of these patients is generally intact and they are able to cope with most viral infections, there are some exceptions. These patients are quite susceptible to a few viruses that cause serious, life threatening illness. Examples are the hepatitis virus, poliomyelitis virus, and enterovirus (ECHO virus). Resistance to such infections as measles, chicken pox, tuberculosis, histoplasmosis, and Pneumocystis carinii pneumonia is usually normal.

Besides signs of recurrent infections, other physical findings include growth failure, rales and wheezes, and the absence of tonsils and adenoids. While these patients test negative for rheumatoid factor, they may develop a joint disease, especially in the knees, resembling juvenile rheumatoid arthritis, which frequently clears with administration of gammaglobulin. In some cases, this arthritic manifestation may be due to mycoplasma infections and responds to appropriate antibiotics.

Other unusual features described in these patients include autoimmune hemolytic anemia (red blood cell breakdown), glomerulonephritis (kidney inflammation), neutropenia (decreased neutrophils in blood), and dermatomyositis (skin and muscle inflammation). A chronic progressive encephalitis (brain infection) possibly caused by a virus used to be relatively common, but with the increased use of intravenous gammaglobulin, the incidence appears to be greatly reduced.

Malignancies, including leukemia, lymphoma, and possibly colon cancer in the older subjects, have been reported in a small percentage of X-Linked Agammaglobulinemia patients.

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Diagnosis

A diagnosis of X-Linked Agammaglobulinemia is established by several tests which measure the mounts of immunoglobulin in the blood. In these patients, tests will show marked decreases or absences of all five immunoglobulin classes. IgG is generally less than 200 mg/dl, with IgA, IgM, IgD, and IgE usually low or absent.

For some patients for whom the exact diagnosis is still unclear, it may be important to test the function of these immunoglobulins that are present. These patients are unable to respond with antibody formation following immunization. Confirmation of this disease can be made by genetic studies, analyzing the gene which produces the B-cell enzyme BtK. When a specific defect is found in the affected male, research laboratories can then test female members to diagnose those who carry the abnormal X chromosomes.

White blood cell counts are normal, but B-lymphocytes, measured by immunofluorescent techniques in the laboratory are usually absent. T-cell development, as well as T-cell responses are normal.

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Treatment

There is no cure for X-Linked Agammaglobulinemia at this time. Treatment focuses on providing antibody replacement through gammaglobulin therapy. This treatment helps these patients by providing them with the antibodies they cannot make to protect against the spread of infections into the bloodstream and to body organs and tissues.

The usual treatment is intravenous immunoglobulin given at a dose of 300 mg/kg every 3 weeks, or 400 mg/kg or more monthly. The goal is to maintain serum IgG levels above 500 mg/dl. However, this serum IgG level may not be sufficient to eradicate chronic sino-pulmonary infections or to prevent development of secondary bronchiectasis (widening and scaring of bronchial airways); postural drainage and prophylactic and/or continuous broad spectrum antibiotics are indicated.

In patients who have developed recurrent or chronic infections, it may be necessary to obtain specimens of sputum, stool, or the infected tissue in order to allow institution of specific antibiotic therapy. In the case of chronic sinusitis or bronchiectasis (widening of airways), postural drainage and prophylactic and/or continuous broad spectrum antibiotics are indicated.

These patients should not be given live viral vaccines because they could develop the disease for which the vaccination was given. Polio is an example. Some research laboratories are attempting gene therapy experiments to transfer a normal gene into cultured B-cells; the results are still very preliminary and have not yet been attempted in patients.

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Prognosis

Without gammaglobulin treatment, these patients may die from infections at an early age. However, patients who are diagnosed early, receive regular gammaglobulin injections and appropriate antibiotics for infections, are able to lead relatively normal lives. They need not be isolated and should be encouraged to lead active lives. However, the life span of patients with X-Linked Agammaglobulinemia may be shortened if chronic lung disease with bronchiectasis (widening and scaring of airways) has already developed.

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Prevention

Laboratory tests in the research stage can identify women who carry the defective X chromosome that transmits X-Linked Agammaglobulinemia to their male offspring and confirm the presence of X-Linked Agammaglobulinemia in the patient. Testing of fetal tissue is also possible.

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Disclaimer: The information contained on these pages is not intended to provide specific medical advice; rather it is intended for informational purposes only, in order to provide a better understanding of these diseases. Please consult with a qualified physician for diagnosis and answers to your questions.

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