Incidence

The occurrence of DiGeorge Syndrome is sporadic. However, a few cases of familial DiGeorge Syndrome have been reported.

Disease Description

DiGeorge Syndrome is also called thymic aplasia (failure of the thymus to develop naturally), thymic hypoplasia (defective development of tissue), or third and fourth pharyngeal arch or pouch syndrome. This is a congenital immune disorder characterized by lack of embryonic development (stage in prenatal development between 2-8 weeks inclusive) or underdevelopment of these pharyngeal pouches. The syndrome is often associated with congenital heart defects, abnormalities of the large blood vessels around the heart, failure of the esophageal tube to develop, abnormalities of facial structures, and of hypoparathyroidism (insufficient secretion of the parathyroid glands). In most cases, there is a chromosomal defect on chromosome 22.

Pathologically, DiGeorge Syndrome is characterized by absence or incomplete development of the thymus and parathyroids with varying degrees of T-cell immunodeficiency. Deficiency of T-cell function may result in increased susceptibility to infection. Depending on the degree of parathyroid or thymic hypoplasia, seizures due to low serum calcium may be present. If the thymic development is strongly affected, deficiency of T-cell immunity may result in increased susceptibility to infection.

DiGeorge Syndrome arises from a disturbance of a normal embryological development (stage in prenatal development between 2-8 weeks) of the pharyngeal pouches between the 6th and 10th weeks of gestation. This disturbance can affect the first, second, third, fourth and sixth pharyngeal pouches, depending on when during this key time period the disturbance occurs. For example, a disturbance of the third and fourth pharyngeal pouches affects development of the thymus and aorta. Disturbances in the third pharyngeal pouch also affect development of the parathyroid, while disturbances of the pulmonary artery is influenced by the sixth pharyngeal pouch.

Clinical Signs and Symptoms

DiGeorge Syndrome has been categorized into three forms: complete, partial, and transient. Regardless of the form or severity of involvement, some patients are recognized clinically by characteristic external features.

• Hypertolerism or abnormally increased interorbital distance (distance between the eyes)
• Anti-mongoloid slant of the eyes (upward slant)
• Low set, prominent ears with notched ear fold
• Unusual smallness of the jaws
• Mouth with loss of the usual bow shaped lip

Other clinical characteristics described include a bifid uvula (cleft or split into two parts), a high, arched palate and nasal speech. Urinary tract abnormalities may be present. While congenital heart disease is a hallmark of DiGeorge Syndrome, there is the occasional patient with no evidence of cardiac problems.

Cardiac abnormalities associated with DiGeorge Syndrome include one or more of the following:

• Right sided aortic arch
• Truncus arteriosis (the arterial crest of the aorta as it passes over the esophagus and trachea; divides the ascending and descending aorta)
• Abnormal left subclavian artery
• Right ventricular stenosis
• Ventricular septal defects
• Tetralogy of Fallot, which is a complex of four congenital defects - ventricular septal defect, pulmonary stenosis, right ventricular hypertrophy and rotation of the aorta
• Atrial septal defect
• Pulmonary artery atresia
• Poorly developed pulmonary artery

Tetany (intermittent tonic spasms usually paroxysmal, involving extremities) secondary to hypocalcemia (abnormally low blood calcium) usually occurs within the first 24 to 48 hours of life, caused by low serum calcium levels, and elevated phosphorus due to a low or absent parathyroid hormone. However, recent studies have shown immunological defects in these patients are quite variable and spontaneous remissions have been reported.

If an infant with severe DiGeorge Syndrome survives the neonatal period, he or she might exhibit increased susceptibility to infection, characterized by chronic runny nose, recurrent pneumonia, including Pneumocystis carinii pneumonia, oral candidiasis, (thrush), mucocutaneous candidiasis, diaper rash, and diarrhea. These patients are weak, fail to thrive, and may be susceptible to sudden death.

Diagnosis

The presence of prolonged hypocalcemia non-responsive to treatment, along with congenital hypoparathyroidism suggested by calcium levels of less than 7 mg/dl, and elevated serum phosphorus in a child with congenital heart disease is suggestive of DiGeorge Syndrome. X-ray examination of the chest may reveal congenital malformation of the heart and vessels and absence of thymic shadow. Genetic studies using chromosomal markers to study chromosome 22 are usually performed.

These children may also have depressed antibody response to specific antigens, and in older patients, defective primary and secondary antibody responses to multiple agents are also noted.

Patients diagnosed with the complete form of DiGeorge Syndrome meet the following criteria:

• Characteristic facial features
• Absent T-cell immunity
• Abnormal B-cell immunity
• Perhaps graft vs. host disease

Patients diagnosed with partial forms of DiGeorge Syndrome, which are much more common, have more variable abnormalities. Some of the characteristics include:

• Charateristic facial features
• Partial T-cell immunodeficiency
• Partial B-cell immunodeficiency
• Hypocalcemia in some
• Variable cardiac defects

Partial forms of DiGeorge Syndrome are characterized by the following three patterns:

• Characteristic facial features, normal T-cell immunity, normal B-cell immunity, and subsequent loss of T-cell immunity; or
• Characteristic facial features, abnormal T-cell immunity, abnormal
  B-cell immunity, and subsequent spontaneous correction of immunodeficiency; or
• Characteristic facial features, abnormal T-cell immunity, hypogammaglobulinemia, subsequent spontaneous correction of immunodeficiency and hypoparathyroidism.

Most patients with DiGeorge Syndrome have a partial defect, and will, over time, become normal or nearly normal immunologically.

Treatment

The initial treatment emphasis is to control the hypoparathyroidism. Intravenous calcium gluconate is administered to stop and prevent hypocalcemic seizures, followed by a low phosphorus diet, calcium supplements and vitamin D.

The best treatment of the immune defects of DiGeorge Syndrome is controversial. Whether transplant with fetal thymus (thymus of 10 to 15 week old stillborn fetus) works or not is debated. Thymic factor replacement and bone marrow transplantation (transplant of bone marrow from normal sister or brother) have been tried with variable results. Correction of congenital heart defects (if present) is usually needed.

Patients with this immune defect require prompt treatment of infection, may benefit from Pneumocystitis carinii antibiotic prophylaxis, and must avoid live virus vaccinations.

Prognosis

The prognosis of this illness is quite varied. Most patients undergo spontaneous T-cell improvement and spontaneous hypoparathyroid correction.

Prevention

Genetic studies may be helpful since a chromosomal defect is present in most cases.

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