At a Glance

The diagnosis of DiGeorge syndrome (DGS) should be considered in patients who have frequent or severe or atypical infections, congenital cardiac or aortic arch anomalies, or neonatal seizures or tetany with hypocalcemia. Demonstration of multiple anatomical anomalies in the chest, including absent or unusually small thymus gland in an infant, should suggest the diagnosis. Palatal defects, including cleft palate, and mental retardation may also be included as parts of the syndrome. When the anatomic defects are dominant, as is often the situation, the descriptive term “velo-cardio-facial syndrome” may be used, and patients given that diagnosis may also have immunodeficiency.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

The appropriate screening tests include measurement of serum calcium and ionized calcium in neonates (which will be low), flow cytometry to enumerate peripheral blood T-cells and B-cells in patients with infections (demonstrating low or absent T cells), and chest imaging with computerized tomography (CT) or magnetic resonance imaging (MRI) demonstrating anatomic congenital conditions. The chest imaging should evaluate the size of the thymus and parathyroid glands, which are absent or hypoplastic in DGS, and should look for anatomic variants or anomalies of the heart and great vessels. Demonstration of a combination of defects compatible with congenital pharyngeal arch abnormal development supports the diagnosis.

Patients with immunodeficiency as part of DGS usually have persistently low numbers of circulating T-cells, which can be identified as low CD3 population by flow cytometry.

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The diagnosis can be confirmed by demonstration of the genetic abnormality known to cause DGS. The most common genetic defect is a dominant (hemizygous) deletion of chromosomal region 22q11.2, which can be identified by fluorescence in situ hybridization (FISH) tests in about 90% of cases. Approximately 75% of patients with the genetic defect have identifiable immunodeficiency.

Given the complexity of testing for combined T-cell and B-cell immunodeficiencies, often referral to a clinical immunologist experienced in evaluating primary immunodeficiency is warranted, especially if severe combined immunodeficiency is suspected. (Table 1)

Table 1.
Serum calcium CD3 count Cytogenetics
7.0 mg/dL 200/mcL 22q11.2 deletion

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

Following infections, particularly some viral infections, transient lymphopenia, including T-cell lymphopenia, may be present. Persistence of T-cell lymphopenia over several months supports the diagnosis of T-cell immunodeficiency.

Age is an important determinant of normal immunoglobulin and lymphocyte concentrations. Appropriate reference ranges in children should be used. Some infants have a transiently low concentration of immunoglobulins, which can resolve spontaneously as the child grows.

The immunodeficiency of DGS is extremely variable. Some patients are immunologically normal, whereas a minority of patients with complete thymic aplasia as part of DGS may have severe immunodeficiency, with nearly complete absence of T-cells, severe defects in B-cells, and antibody production. These severe forms of DGS are included among the types of severe combined immunodeficiency (SCID), for which there are many different genetic causes.

Hypocalcemia during the neonatal period may be secondary to other conditions. The hallmark of DGS is the presence of hypocalcemia together with anatomic anomalies in the chest.

HIV and other chronic infections should be tested in patients with immunodeficiencies.

What Lab Results Are Absolutely Confirmatory?

Demonstration of one of the genetic causes of DGS, together with a compatible clinical diagnosis, is definitive. The most common genetic defect, present in about 95% of patients, is a dominant (hemizygous) deletion of chromosome 22q11, which can be identified by FISH performed in cytogenetics laboratories. Some of the patients without a diagnosis by FISH may have copy number variants or other abnormalities that can be detected by comparative genomic hybridization (CGH) or other techniques.

What Confirmatory Tests Should I Request for My Clinical Dx? In addition, what follow-up tests might be useful?

Patients with DGS have an increased risk for development of autoimmune diseases, such as juvenile idiopathic arthritis, and autoimmune hematologic disease, such as immune thrombocytopenia. An increased risk for allergic disorders may also be present. Laboratory tests for those conditions may be appropriate.

What Factors, if Any, Might Affect the Confirmatory Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

The 22.q11.2 deletion syndrome, encompassing DGS, velo-cardio-facial syndrome, and other named syndromes, is phenotypically extremely variable with variable penetrance. Testing relatives of patients with the 22.q11.2 deletion syndrome has allowed identification of subjects who carry the deletion, but who had not been diagnosed based on clinical features. Approximately one-half of these relatives carrying the same genetic abnormality as their symptomatic relatives, including both children and adults, have no clinical features of the syndrome, confirming that the genetic abnormality is associated with variable penetrance and severity.