The Immunodeficiency Disorders

For the sake of ease of discussion, dividing the immunodeficiency disorders into categories of primary and secondary is helpful. The genetic abnormalities have been described for many of the primary immunodeficiency disorders, and examples of these disorders, the genetic lesion, and typical presentation are listed in Table 1. In general, the primary immunodeficiency disorders result from inherent defects in immunity. Secondary immunodeficiency disorders occur when some external force disrupts normal immunity.

Secondary causes of immune dysfunction must be considered when one is evaluating for immunodeficiency, since secondary disorders occur much more commonly than the primary disorders (Table 2). For the individual with recurrent sinusitis and pneumonia, disorders resulting in impairment of mucus clearance from the respiratory tract such as cystic fibrosis and ciliary dysfunction should be considered. Similarly, the chronic congestion associated with perennial allergic rhinitis can predispose to URI. Opportunistic infection and wasting are hallmark findings of AIDS; however, recurrent bacterial infection is common in HIV infection, especially in children. Immunodeficiency related to a single site that is associated with loss of protein in the stool or urine should trigger an

Examples of Genetic Defects Known to Cause Primary Immunodeficiencies

Disorder

Chromosomal location Known affect on immune response

Typ ica 1 clin ica 1 find in g s

X-Linked agammaglobulinemia Autosomal recessive agammaglobulinemia

X-Linked hyper-IgM

syndrome NEMO deficiency

DiGeorge anomaly

X-Linked SCID

SCID-CD8 lymphocytopenia (Zap-10 Deficiency)

Jak3 deficiency

Adenosine deaminase deficiency

Purine nucleoside Phosphorylase deficiency

Recombinant activating gene (RAG)l and RAG2 deficiency

Xq22

Xq28

22ql 1.2, 10pl3

Xql3 2ql2

5pl3 19pl3.1

20ql3.11

14ql3.1

1 lpl3

Absence of Bruton's tyrosine kinase results in arrest of B-cell development Defects in Ig receptor proteins results in arrest of B-cell development

CD40 ligand (CD 154) is not expressed on T-cells Defective signaling and activation of nuclear factor k-B

Absence of thymus

Absence of the common y chain of the receptor for cytokines 2, 4, 7, 9, 15

Deficiency of T-cell kinase involved in thymic T-cell maturation and in intracellular signal transduction

Defective IL-7 receptor expression

Disruption of T-cell intracellular

Lymphopenia and poor T-cell function due to toxic effect of adenosine metabolites

Abnormal purine metabolism

Defects result in an inability to make DNA double-strand breaks durng V(D)J recombination in T- and B-cells

Recurrent, serious pyogenic infections Recurrent, serious pyogenic infections

Recurrent, serious pyogenic infections; also opportunistic infections Recurrent bacterial and mycobacterial infections of respiratory tract, soft tissues, and GI tract

Hypocalcemic seizures due to hypoparathyroidism, cardiac disease, abnormal facies, opportunistic infection

Failure to thrive, opportunistic infection, rash Failure to thrive, opportunistic infections, rash

Failure to thrive, opportunistic infection, rash Failure to thrive, opportunistic infection, rash signal transduction Opportunistic infection, poor growth, skin rash

Opportunistic infection, poor growth, skin rash

Opportunistic infection, poor growth, skin rash

Artemis defïcency 10pl3

X-Linked Xq25 lymphoproliferative Syndrome

Wiskott-Aldrich syndrome Xpl 1.22-pl 1.23

Ataxia-telangiectasia llq22-23

Nijmegen breakage 8q21

syndrome

Chronic granulomatous Xq21.1 (gp9 lphox), disease" 16q24 gp22Phox),

7ql 1.23 (gp47Phox), lq25 (gp67Phox)

Leukocyte adhesion 21q22.3 (CD18)

deficiency 1

Defects in repairing the DNA double-strand breaks made during V(D)J recombination

Unregulated stimulation of B-cells by EBV leading to malignant transformation

WASP is abnormal; abnormalities are seen in the cytoskeleton structure of T-cells

Defective DNA-dependent kinase involved in cell cycle control and DNA recombination. Specific etiology of immune system defects still under study

Deficient DNA repair and cell-cycle control due to the loss of function of nibrin

Phagocytes cannot generate respiratory burst because of lack of a component needed for oxidative metabolism

Absence or poor upregulation of adhesion molecules

Opportunistic infection, poor growth, skin rash increased sensitivity to ionizing radiation

Lymphadenopathy, hepatosplenomegaly, recurrent opportunistic infections

Thrombocytopenia with bleeding and bruising, eczema, recurrent infection with encapsulated organisms

Chronic sinopulmonary disease, cerebellar ataxia, malignancy oculocutaneous telangiectasia

Chronic sinopulmonary disease, facial dymorphism, mental retardation, and microcephaly

Deep-seated infection, abscess especially with catalase-positive organisms

Recurrent serious bacterial infections, especially on mucosal surfaces or wound sites; poor wound healing, lack of pus

IL, interleukin; EBV, Epstein-Barr virus, GI, gastro intestinal

458

Knight et al.

Table 2

Secondary Immunodeficiency

Category

Examples

Malnutrition

Developing country, associated with chronic disease

Organ system dysfunction

Nephrotic syndrome, protein-losing enteropathy, diabetes

mellitus, uremia

Immunosuppressive agents

Corticosteroids, cytotoxic drugs, cyclosporine, radiation

Infectious diseases

HIV infection, mycobacterial infection, EBV infection,

cytomegalovirus infection

Infiltrative disease

Malignant disease, histiocytosis, lymphoproliferative

disease, sarcoidosis, multiple myeloma

Surgery and trauma

Burns, splenectomy, head injury

Hereditary diseases

Down syndrome, chromosomal instability syndromes,

congenital asplenia, hemoglobinopathies, storage

diseases, galactosemia

EBV, Epstien-Barr virus.

EBV, Epstien-Barr virus.

evaluation for a structural or anatomical problem that may have occurred during fetal development or surgery or that may be secondary to trauma. Also, foreign bodies, for example, nasogastric tubes and intravenous catheters, predispose to infection. Several specific systemic diseases that result in immunodeficiency are listed in Table 2.

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