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Chapter: Biology of Disease: Disorders of the Immune System

The DiGeorge anomaly and the Wiskott Aldridge syndrome - Primary Immunodeficiency Disease

The third group of PIDs (Table 5.3) contains a number of well-defined immunodeficiency syndromes, of which the DiGeorge anomaly and the Wiskott Aldridge syndrome are well-known examples.

The DiGeorge anomaly and the Wiskott Aldridge syndrome

The third group of PIDs (Table 5.3) contains a number of well-defined immunodeficiency syndromes, of which the DiGeorge anomaly and the Wiskott Aldridge syndrome are well-known examples.

The DiGeorge anomaly (DGA) is a developmental disorder involving organs that develop from the third and fourth pharyngeal pouches of the embryo. It is associated with a deletion or partial monosomy of chromosome 22 that results in a range of defects. Several different patterns of inheritancehave been reported, including autosomal dominant and autosomal recessive. Its incidence has been estimated to be between one in 20 000 to 66 000, depending on the country.



The DGA is characterized by facial abnormalities, hypoparathyroidism and hypocalcemia with symptoms of convulsions and tetany, congenital heart disease that may be so severe as to be life threatening, and a small under-developed or sometimes absent thymus that results in a profound immuno-deficiency. Patients suffer severe and recurring viral and fungal infections.

Indeed, the immunological defects are the second commonest cause, after heart conditions, of death in DGA patients. The number of circulating T lymphocytes is severely reduced leading to defects in cell-mediated immunity. T cell proliferative responses to mitogens vary in DGA patients, such that they can be classified either as partial or complete. In the former, proliferation is reduced but in the latter it is completely absent. The absence of helper T lymphocytes reduces antibody production, so that antibacterial immunity may also be compromised, even though the number of circulating B lymphocytes is normal.

A diagnosis of DGA is based on the cardiac malformations, hypopara-thyroidism resulting in hypocalcemia and a small or absent thymus. T lymphocytes in the circulation are reduced and the proliferative response to mitogens is impaired. Fluorescence in situ hybridization (FISH) has been used to detect deletions in chromosome 22 in the majority of patients (Margin Note 5.1). Other syndromes, without any apparent genetic link, but which have known environmental causes, bear some resemblance to DGA. One example is fetal alcohol syndrome, which results from prolonged exposure to alcohol during fetal development. Children with fetal alcohol syndrome also show the characteristic facial features associated with DGA.


Attempts have been made to treat the immunological deficit in DGA with thymus transplants, although results have been variable. The associated hypocalcemia is treated with calcium and vitamin D supplements, while cardiac malformations must be rectified surgically. The prognosis for patients with DGA is variable and depends mostly on the degree of cardiovascular abnormality. For patients with severe cardiac problems it is poor, with a mortality rate of over 80% at the age of six months.

The Wiskott Aldridge syndrome (WAS) arises from mutation in the WAS gene, which was identified on the short arm of the X chromosome in 1994. The gene codes for the cytoskeletal protein sialophorin, found in lymphocytes and platelets, that is involved in the assembly of actin filaments. The incidence of WAS is approximately one per 250 000 male births.

 

The syndrome is characterized by decreased levels of IgM but often with increased production of IgE and IgA. In the early stages, T and B cell numbers in the blood are normal. Since IgM is the prevalent antibody in immune responses to bacterial polysaccharides, there is an increased incidence of infections with encapsulated bacteria. Sufferers may also develop eczema. Blood platelets are small, short-lived and reduced in number, leading to thrombocytopenia and increased bleeding times which may prove fatal . As WAS progresses, there is a loss of both humoral and cell-mediated immunity and, along with severe infections, there is also an increase in leukemia and lymphoid tumors.

The treatment for WAS includes antibiotics for infections and platelet transfusions to prevent bleeding. Immunoglobulin replacement therapy may also be given to provide some protection against infection. Bone marrow transplants have been successful in some cases. Unfortunately the prognosis for WAS sufferers is poor, with death commonly occurring before the age of four years usually from severe infection and bleeding. Genetic counseling is recommended for women who have had a child with WAS. Detection of the abnormal gene in cells obtained by chorionic villus sampling or amniocentesis allows a prenatal diagnosis, with the possibility of terminating the pregnancy if the fetus is found to be affected.


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