DiGeorge syndrome, also known as velocardiofacial syndrome or CATCH 22 syndrome (cardiac anomalies, abnormal facies, thymic hypoplasia, cleft palate, and hypocalcemia), is the result of dysmorphogenesis of the third and fourth pharyngeal pouches, resulting in hypoplasia of the thymus required for T-cell maturation. Most, but not all, patients with DiGeorge syndrome have a defect on chromosome 22q11.2.DiGeorge syndrome is classically characterized by hypocalcemic tetany, conotruncal and aortic arch anomalies, and increased infections. The diagnosis is established by fluorescent in situ hybridization or a polymerase chain reaction with a DNA probe to detect deletions in chromosome 22q11.2.Most patients have partial immune defects with low T-cell numbers and function that generally improve with age. Severe T-cell deficiency is rare, but it results in SCID due to a complete lack of T cells. Most important, DiGeorge syndrome and bare lymphocyte syndrome do not respond well to bone marrow transplantation as do other forms of SCID because the defects are in the thymus, although transfer of mature T cells during transplant may confer some immune function.
Wiskott-Aldrich syndrome is an X-linked disorder characterized by thrombocytopenia, eczema, defects in cell-mediated and humoral immunity, and a predisposition to lymphoproliferative disease (Table 73-3). It is caused by mutations of the gene on chromosome Xp11.22 coding for the Wiskott-Aldrich syndrome protein (WASP), expressed in lymphocytes, platelets, and monocytes. Deficiency of this protein results in elevated levels of IgE and IgA, decreased IgM, poor responses to polysaccharide antigens, waning T-cell function, and profound thrombocytopenia. Opportunistic infections and autoimmune cytopenias become problematic in older children. Isolated X-linked thrombocytopenia also results from mutations of the identical gene. One third of patients with Wis-kott-Aldrich syndrome die as a result of hemorrhage, and two thirds die as a result of recurrent infection caused by bacteria, cytomegalovirus, P. jiroveci (carinii), or herpes simplex virus. Stem cell transplantation has corrected the immunologic and hematologic problems in some patients.
Ataxia-telangiectasia is a syndrome caused by the ATM (ataxia-telangiectasia, mutated) gene on chromosome 11q22.3(see Table 73-3). Patients have cutaneous and conjunctival
Wiskott-Aldrich X-linked, Early infancy Thrombocytopenia, atopic 53-kD protein (WASP) Polysaccharide antibody syndrome (Xp11.22) dermatitis, recurrent defect deficiency, small infections platelets, decreased cell-mediated immunity, lymphoproliferation
AD, Autosomal dominant; AR, autosomal recessive; NK, natural killer.
telangiectasias and progressive cerebellar ataxia with degeneration of Purkinje cells. IgA deficiency, IgG2 subclass deficiencyof variable severity, low IgE levels, and variably depressedT-cell function may be seen. The normal function of the ATM gene is not clear but appears to be involved in detecting DNAdamage, blocking cell growth division until the damage isrepaired, or both. Ataxia-telangiectasia cells are exquisitelysensitive to irradiation. Leukemias, lymphomas, and diabetesalso may be present. Sexual maturation is delayed. There isno uniformly effective therapy, but antimicrobial therapy andintravenous immunoglobulin (IVIG) replacement therapymay be helpful.
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