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1222 Part IX: Lymphocytes and Plasma Cells Chapter 80: Immunodeficiency Diseases 1223

viral infections (warts, molluscum contagiosum, herpes simplex) are espe- DEFECTIVE THYMIC DEVELOPMENT
cially common, but systemic viral disease (varicella, CMV, EBV) has been
also reported. Cutaneous infections frequently evolve into squamous cell DIGEORGE SYNDROME (22q 11.2 DELETION
carcinoma. Vascular thrombosis in the central nervous system has been
described in several patients. 138,139 Multiple immunologic abnormalities SYNDROME)
have been reported, 138–142 including a variable degree of lymphopenia that Definition
affects especially naïve T cells, increased proportion of CD8 T EMRA cells, The DiGeorge syndrome (DGS) is a developmental disorder caused by
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decreased in vitro proliferation to CD3 stimulation, impaired generation abnormal cephalic neural crest cell migration and differentiation in the
of Th17 cells, and defects of NK cytolytic function. Immunoglobulin levels third and fourth pharyngeal arches during early embryonic develop-
are variable, but IgM serum levels are often low. B-cell response to TLR9 ment. The vast majority of patients with DGS have partial monosomy
154
stimulation is defective, and specific antibody responses are blunted. Large, of human chromosome 22q11.2. However, a significant fraction (10 to
intragenic deletion of the gene has been frequently reported in affected 45 percent) of patients with DGS do not have a chromosome 22q11.2
139
patients, and lack of DOCK8 protein expression can be demonstrated deletion and some 2 percent have small deletions in chromosome 10p.
by flow cytometry. The disease has a poor prognosis, but can be cured
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by allogeneic HSCT. Good results have been reported in the treatment Clinical and Laboratory Features
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of severe herpetic infections with interferon (IFN)-α (see also “The Hyper- The clinical phenotype of DGS consists of the triad congenital car-
immunoglobulin E Syndromes” below). 145 diac defects, hypocalcemia as a result of parathyroid insufficiency,
and immune deficiency as a consequence of aplasia or hypoplasia of
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COMBINED IMMUNODEFICIENCY WITH the thymus. However, there is significant phenotypic variability.
Cardiac defects (especially interrupted aortic arch type B and truncus
MULTIPLE INTESTINAL ATRESIA arteriosus) occur in 50 to 80 percent of patients with 22q11.2 deletion.
Multiple intestinal atresia is a congenital disease characterized by Hypocalcemia is observed in 50 to 60 percent, and may cause neonatal
atresias that may affect the gastrointestinal tract, from stomach to seizures. Facial dysmorphisms include micrognathia, hypertelorism,
anus. 146–149 In many cases, CID is associated, with reduced number of antimongoloid slant of the eyes, and ear malformations. A third of DGS
T (and in some patients, B) lymphocytes, impaired in vitro prolifera- patients have velopharyngeal incompetence, leading to feeding difficul-
tion to mitogens, and profound hypogammaglobulinemia. A high risk ties and speech delay; 10 percent have a cleft palate. As young adults,
of sepsis because of Gram-negative bacteria has been reported, but viral, many develop social, behavioral, and psychiatric problems.
fungal, and opportunistic infections are also common. The disease is There is also significant variability of the severity of immunologic
inherited as an autosomal recessive trait and is caused by mutations of phenotype. Most patients have residual thymic tissue and hence mild to
the tetratricopeptide repeat domain 7A (TTC7A) gene, 146,147 which plays moderate T-cell lymphopenia (see Table 80–2). Approximately 1 per-
an important role in intestinal and immune homeostasis by maintain- cent of DGS patients lack T cells completely, resembling SCID (complete
ing cell polarity and regulation of cell survival, proliferation, adhesion, DGS). In some cases, generation of oligoclonal T cells that infiltrate tar-
and migration. 148,149 In the thymus, TTC7A is expressed both by thy- get tissues is associated with generalized skin rash and lymphadenopa-
mic epithelial cells and by thymocytes. 147,148 Multiple surgeries are often thy, resembling Omenn syndrome. This phenotype is known as atypical
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required to establish canalization of the gastrointestinal tract. Total complete DGS. As in other cellular immunodeficiencies, patients with
parenteral nutrition often leads to severe liver disease, and combined DGS have a high incidence of autoimmune diseases such as cytopenia
150
small bowel and liver transplantation may be needed. Most patients and thyroiditis. A retrospective analysis of TCR excision circle (TREC)
die early in life. Partial immune reconstitution has been reported in a levels at birth in patients with DGS has shown that approximately
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few cases following HSCT. 147 20 percent of them had low TRECs; these infants had lower CD8 T-cell
count and were more prone to viral infections than DGS infants with
VENOOCCLUSIVE DISEASE WITH normal TREC levels at birth. 156
IMMUNODEFICIENCY Treatment
Venoocclusive disease with immunodeficiency (VODI) is a congenital Cardiovascular anomalies require prompt attention and hypocalcemia
disorder characterized by liver abnormalities and immunodeficiency, appropriate medical treatment. Depending on the extent of the immune
151
with onset in the first months of life. Liver abnormalities include deficiency, patients may require antibiotic prophylaxis or IVIG therapy.
venoocclusive disease, fibrosis, hepatomegaly, and hepatic failure. However, patients with complete DGS (including complete atypical
Patients are prone to recurrent infections, sustained by viruses, bacte- phenotype) require more aggressive treatment. Allogenic thymic trans-
ria, and opportunistic pathogens (P. jirovecii, Candida, CMV). Throm- plantation may restore T-cell development and function in approxi-
bocytopenia is frequent. Infections may precede development of liver mately 75 percent of these patients. Unmanipulated marrow from
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abnormalities. Immunologic defects include low number of memory matched donors can also lead to immune reconstitution by providing
T and B lymphocytes, defective B-cell differentiation in vitro into anti- mature T lymphocytes contained in the graft. 157
151
body-secreting cells, and hypogammaglobulinemia. The disease is
more common in the Lebanese population. It is inherited as an auto-
somal recessive trait and is caused by mutations of the SP110 gene, COLOBOMA, HEART DEFECTS, ATRESIA
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which encodes for a nuclear body protein that acts as a transcription OF THE CHOANAE, RETARDED GROWTH,
factor driving expression of genes with a retinoic acid response element. GENITAL HYPOPLASIA AND EAR ANOMALIES
Treatment is based on immunoglobulin replacement therapy, prophy-
lactic antibiotics, prompt treatment of infections, and ursodiol; how- SYNDROME
ever, the prognosis remains dismal. HSCT is the only curative approach, A syndrome with a severe T-cell defect, CHARGE is caused by heterozy-
but the outcome is often problematic because of liver toxicity as a result gous de novo mutations in the CHD7 gene. Circulating T lymphocytes
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of conditioning regimen. 153 are decreased in most CHARGE patients and respond poorly to mitogens.

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