IDF PATIENT/FAMILY HANDBOOK | CHAPTER IX
The DiGeorge Syndrome
The DiGeorge Syndrome is a primary immune deficiency disease which is caused by abnormal development of certain cells and tissues of the neck during growth and differentiation of the fetus. As part of the developmental defect, the thymus gland may be affected and T-lymphocyte function may be impaired.
DEFINITION: The DiGeorge Syndrome is a primary immune deficiency disease which is caused by abnormal development of certain cells and tissues of the neck during growth and differentiation of the fetus. Tissues which are dependent upon a single group of embryonic cells for their normal fetal development are called “fields.” Although the tissues and organs that ultimately develop from a “field” may appear to be unrelated in the fully formed child, they are related in that they have developed from the same embryonic or fetal tissues. Most patients with the DiGeorge Syndrome have a small deletion in a specific part of chromosome number 22 at position 22q11.2. Thus, another name for the syndrome is the 22q11.2 deletion syndrome.
The “field”, or region, of the developing embryo that is affected in the DiGeorge Syndrome controls the development of the face, parts of the brain, the thymus, the parathyroid glands, the heart and the aorta. The original control of the development of this field is found in a group of cells that originate in the back of the neck of the developing embryo. In order for the components of the field to develop properly, cells must migrate out from the neck during fetal development to areas of the developing face, thymus, parathyroid glands and heart. If this does not occur, normal facial, thymus, parathyroid and heart development may not occur. The anomalies seen in the DiGeorge Syndrome are the consequence of abnormal development of this field.
Patients with the DiGeorge Syndrome do not all show the same organ involvement. A given organ may be uninvolved, or so mildly involved that the organ appears to be normal. Patients with the DiGeorge Syndrome may have any or all of the following:
Facial appearance - affected children may have an upward bowing of their mouth, an underdeveloped chin, eyes that slant somewhat downward, low set ears and defective upper portions of their ear lobes. These facial characteristics vary greatly from child to child and may not be very prominent in many affected children.
Parathyroid gland abnormalities - affected children may have underdeveloped parathyroid glands (hypoparathyroidism). The parathyroids are small glands found in the neck near the thyroid gland (hence the name “parathyroid”). They function to control the normal metabolism and blood levels of calcium. Children with the DiGeorge Syndrome may have trouble maintaining normal levels of calcium, and this may cause them to have seizures (convulsions). In some cases, the parathyroid abnormality is relatively mild or not present at all. The parathyroid defect may become less severe with time.
Heart defects - affected children may have a variety of heart (or cardiac) defects. For the most part, these anomalies involve the aorta and the part of the heart from which the aorta develops. As with other organs affected in the DiGeorge Syndrome, heart defects vary from child to child. In some children, heart defects may be very mild or absent.
Thymus gland abnormalities - affected infants and children may have abnormalities of their thymus. The thymus gland is normally located in the upper area of the front of the chest. However, the thymus begins its development high in the neck during the first three months of development in the uterus. As the thymus matures and gets bigger, it drops down into the chest to its ultimate location under the breastbone and over the heart.
The thymus controls the development and maturation of one kind of lymphocyte, the T-lymphocyte (“T” for “Thymus”). Tlymphocytes are essential for resistance to certain viral and fungal infections. T-lymphocytes also help B-lymphocytes to develop into plasma cells and produce immunoglobulins or antibodies (see chapter on the Normal Immune System). Patients with the DiGeorge Syndrome may have defects in their T-lymphocyte function, and as a result, they have an increased susceptibility to viral, fungal and bacterial infections. As with the other defects in the DiGeorge Syndrome, the T-lymphocyte defect varies from patient to patient. In addition, small or mild deficiencies may disappear with time.
Miscellaneous clinical features - in addition to the above features, patients with the DiGeorge Syndrome may occasionally have a variety of other developmental abnormalities including cleft palate, poor function of the palate, delayed acquisition of speech and difficulty in feeding and swallowing. In addition, some patients have learning disabilities and hyperactivity.
DIAGNOSIS: The diagnosis of the DiGeorge Syndrome is usually made on the basis of signs and symptoms that are present at birth or develop soon after birth. Some children may have the facial features that are characteristic of the DiGeorge Syndrome. Affected children may also show signs of low blood calcium levels as a result of their hypoparathyroidism. This may show up as low blood calcium on a routine blood test, or the infant may be “jittery” or have seizures (convulsions). Affected children may also show signs and symptoms of a heart defect. They may have a heart murmur that shows up on a routine physical exam, they may show signs of heart failure, or they may have low oxygen content of their arterial blood and appear “blue” or cyanotic. Finally, affected children may show signs of infection because of the underdevelopment of their thymus gland and low T-lymphocyte function. Some children have signs or symptoms at birth or while they are in the hospital nursery; others may not show signs or symptoms until they are a few weeks or months older.
There is a great deal of variation in the DiGeorge Syndrome from child to child. In some children, all of the different organs and tissues are affected. These children have the characteristic facial characteristics, low blood calcium from hypoparathyroidism, heart defects and a deficiency in their T-lymphocyte number and function. In other children, all of the different organs and tissues may not be affected and the organs and tissues that are affected may be affected to different degrees. Not only do children differ in the organs and tissues that are affected, but they also differ from each other in terms of how severely a given organ or tissue is affected.
In the past, the diagnosis of DiGeorge Syndrome was usually made when at least three of the characteristic findings described above were present. However, many mild cases were missed. In recent years, the genetic basis for the syndrome has been discovered. Over 90% of patients with the clinical diagnosis of the DiGeorge Syndrome have a small deletion of a specific portion of chromosome number 22 at position 22q11.2. This can be identified in a number of ways, but the most common way is a FISH analysis (for Fluorescent In Situ Hybridization). Use of a FISH analysis test has made the diagnosis of the DiGeorge Syndrome more precise.
THERAPY: Therapy for DiGeorge Syndrome is aimed at correcting the defects in the organs or tissues that are affected. Therefore, therapy depends on the nature of the defect and its severity. Treatment of the low calcium and hypoparathyroidism may involve calcium supplementation and replacement of the missing parathyroid hormone. A heart (or cardiac) defect may require medications to improve the function of the heart or corrective surgery. If surgery is required, the exact nature of the surgery depends on the heart defect. Surgery can be performed before any immune defects are corrected. However, all the precautions that are usually taken with children with T-cell immunodeficiencies need to be observed, such as irradiating all blood products to prevent graft-vs-host disease (see chapter on Specific Medical Therapy).
As mentioned above, the immunologic defect in T-lymphocyte function varies from child to child. Therefore the need for therapy of the T-lymphocyte defect varies from child to child. Many children with the DiGeorge Syndrome have perfectly normal T-lymphocyte function and require no therapy for immunodeficiency. Other children initially have mild defects in T-lymphocyte function which improve as they grow older. This spontaneous improvement and increase in T-lymphocyte immunity is related to growth of a tiny but otherwise normal thymus gland. In most cases of the DiGeorge Syndrome, the tiny thymus ultimately grows enough to provide adequate T-lymphocyte function. In the remaining children (approximately 25%), the thymus is either completely absent or never grows enough to develop adequate numbers of T-lymphocytes. The severity of the defect depends upon how much thymus tissue the child develops. In some children with the DiGeorge Syndrome, the T-lymphocyte defect is significant enough to cause the B-lymphocytes to fail to make sufficient antibodies. This occurs because antibodies are produced by B-lymphocytes under the direction of a specific subset of T-lymphocytes (see chapter on the Normal Immune System).
As can be seen from the preceding paragraph, not all children with the DiGeorge Syndrome require therapy for their immune deficiency. In children who do require therapy for their immunodeficiency, some form of transplantation of normal immune system tissue may help. The immune defect in the DiGeorge Syndrome involves the thymus and T-lymphocytes. Therefore, thymus transplants have been used in children with the DiGeorge Syndrome. In fact, fetal thymuses were successfully transplanted for the DiGeorge Syndrome as early as 1968. The overall success rate is difficult to determine because of different techniques and because some children who received the transplant may have improved spontaneously without the transplant. Recently, bone marrow transplants from matched sibling donors (see chapter on Therapy) have been performed in patients with severe T- and Blymphocytes defects with successful outcomes. Also, newer methods of thymus transplantation have improved long term outcomes.
EXPECTATIONS: The outlook for a child with the DiGeorge Syndrome depends on the degree to which the child is affected. The severity of the heart disease is usually the most important determining factor. As mentioned above, most children have no immune defect or only a transient problem with their immune system. If the immunodeficiency is severe and persistent, correction is necessary.