Porth's Essentials of Pathophysiology, 4e

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Disorders of the Immune Response

C h a p t e r 1 6

Thymic Hypoplasia: DiGeorge Syndrome. DiGeorge syndrome stems from an embryonic developmental defect. 35 The defect is thought to occur before the 12th week of gestation, when the thymus gland, parathyroid gland, and parts of the head, neck, and heart are devel- oping. The disorder affects both males and females and is relatively more common than other T cell immuno- deficiencies. Formerly thought to be caused by a vari- ety of factors, including extrinsic teratogens, this defect has been traced to microdeletion of specific deoxyribo- nucleic acid (DNA) sequences from chromosome 22 (22q11). 1,35,39 Infants born with this defect have partial or com- plete failure in development of the thymus and para- thyroid glands and have congenital defects of the head, neck, and/or heart. The extent of immune and parathyroid abnormalities is highly variable, as are the other defects. In some children, the thymus is not absent but is in an abnormal location and is extremely small. These infants can have partial DiGeorge syn- drome, in which hypertrophy of the thymus occurs with development of normal immune function. The facial disorders can include hypertelorism (increased distance between the eyes); micrognathia (abnormally small jaw); low-set, posteriorly angulated ears; split uvula; and high-arched palate (Fig. 16-7). Urinary tract abnormalities also are common. The most fre- quent presenting sign is hypocalcemia and tetany that develop within the first 24 hours of life. It is caused by the absence of the parathyroid gland and is resistant to standard therapy. Children who survive the immediate neonatal period may have recurrent or chronic infections because of impaired T-cell immunity. Children also may have an absence of immunoglobulin production, caused by a lack of helper T-cell function. For children who do require treatment, thymus transplantation can be performed to reconstitute T-cell immunity. Bone marrow transplanta- tion also has been successfully used to restore normal T-cell populations. If blood transfusions are needed, as during corrective heart surgery, special processing is required to prevent graft-versus-host disease. Severe combined immunodeficiency (SCID) is a syn- drome of diverse genetic causes characterized by pro- found deficiencies in T- and B-cell function, and in some cases NK cells and function. 1,35 Mutations in 13 different genes have been found to cause the condi- tion, which is usually fatal in the first 2 years of life unless reconstitution of the immune system can be accomplished. Although they appear normal at birth, affected infants begin to develop frequent episodes of diarrhea, pneumonia, otitis media, sepsis, and cutane- ous lesions within the first few months of life. Growth may appear normal, but extreme wasting develops after infections and diarrhea begin. Exposure to live vaccines, nonirradiated blood products, and infections can prove life threatening. Severe Combined Immunodeficiency Disorders

Pathogenesis and Etiology. The most common form of SCID, accounting for about half of all cases in the United States, is X-linked, and hence is more common in boys than girls. These mutations are recessive so that heterozygous girls are usually normal carriers of the gene, whereas boys who inherit the abnormal chromo- some manifest the disease. 40,41 The genetic defect in the X-linked form of SCID is due to a mutation in a trans- membrane protein that is responsible for the survival and proliferation of T-lymphocyte precursors. T-cell numbers are greatly reduced in number and, although B cells are normal, antibody synthesis is greatly impaired because of a T–cell help. There may also be a deficiency in NK cells. The remaining cases of SCID show an autosomal recessive pattern of inheritance, with the most common cause being mutations in the gene encoding adenos- ine deaminase (ADA), an enzyme involved in purine FIGURE 16-7. An infant with DiGeorge syndrome.The surgical scar on the chest indicates repair of heart disease caused by truncus arteriosus or interrupted aortic arch, which is common in this syndrome.The infant also has the facial features of a child with DiGeorge syndrome, as illustrated by hypertelorism, low-set ears, hypoplastic mandible, and bowing upward of the upper lip. (From Roberts R. Atlas of Infectious Diseases. Edited by Gerald Mandell [series editor], Catherine M. Wilfert. © 1998 Current Medicine, Inc. With kind permission of Springer Science + Business Media.)