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Primary Defects of Cellular Immunity
Defects in cellular immunity, historically referred to T-cell defects, comprise a large number of distinct immune deficiencies. The manifestations usually include prolonged viral infections, opportunistic fungal or mycobacterial infections, and a predisposition to autoimmunity. To facilitate conceptualization of this large and complex category, this chapter describes immunodeficiencies where the defect primarily affects T cells and those where the defect alters function of many cell types. Chapter 152.1 describes severe combined immunodeficiency (SCID). These disorders are further approached clinically by considering whether or not nonhematologic features are present.
Chromosome 22Q11.2 Deletion Syndrome
Chromosome 22q11.2 deletion syndrome is the most common of the T-cell disorders, occurring in about 1 in 3,000 births in the United States. Chromosome 22q11.2 deletion disrupts development of the 3rd and 4th pharyngeal pouches during early embryogenesis, leading to hypoplasia or aplasia of the thymus and parathyroid glands. Other structures forming at the same age are also frequently affected, resulting in anomalies of the great vessels (right-sided aortic arch), esophageal atresia, bifid uvula, congenital heart disease (conotruncal, atrial, and ventricular septal defects), a short philtrum of the upper lip, hypertelorism, an antimongoloid slant to the eyes, mandibular hypoplasia, and posteriorly rotated ears (see Chapters 98 and 128 ). The diagnosis is often first suggested by hypocalcemic seizures during the neonatal period.
Genetics and Pathogenesis
Chromosome 22q11.2 deletions occur with high frequency because complex repeat sequences that flank the region represent a challenge for DNA polymerase. This condition is inherited in an autosomal dominant fashion and occurs with comparable frequency in all populations. Within the deleted region, haplosufficiency for the TBX1 transcription factor appears to underlie the majority of the phenotype. The phenotype is highly variable; a subset of patients has a phenotype that has also been called DiGeorge syndrome , velocardiofacial syndrome , or conotruncal anomaly face syndrome .
Variable hypoplasia of the thymus occurs in 75% of the patients with the deletion, which is more frequent than total aplasia; aplasia is present in <1% of patients with 22q11.2 deletion syndrome. Slightly less than half of patients with complete thymic aplasia are hemizygous at chromosome 22q11.2. Approximately 15% are born to diabetic mothers. Another 15% of infants have no identified risk factors. Approximately one third of infants with complete DiGeorge syndrome have CHARGE association ( c oloboma, h eart defect, choanal a tresia, growth or developmental r etardation, g enital hypoplasia, and e ar anomalies including deafness). Mutations in the chromodomain helicase DNA-binding protein 7 (CHD7) gene on chromosome 8q12.2 are found in approximately 60–65% of individuals with CHARGE syndrome; a minority have mutations in SEMA3E .
Absolute lymphocyte counts are usually only moderately low for age. The CD3 T-cell counts are variably decreased in number, corresponding to the degree of thymic hypoplasia. Lymphocyte responses to mitogen stimulation are absent, reduced, or normal, depending on the degree of thymic deficiency. Immunoglobulin levels are often normal, but there is an increased frequency of IgA deficiency, low IgM levels, and some patients develop progressive hypogammaglobulinemia.
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