22q11 Deletion Disorders: DiGeorge and Velocardiofacial Syndromes
What are DiGeorge syndrome and velocardiofacial syndrome?
DiGeorge syndrome is a disorder described in the 1960’s by Dr. Angelo DiGeorge. He observed the combination of a lack of the thymus gland (which is important for certain aspects of immunity) and a lack of parathyroid glands (which results in low calcium levels in the blood). Subsequently, it was found that a high percentage of children with DiGeorge syndrome have certain forms of congenital heart disease.
Velocardiofacial syndrome (VCFS) is related disorder, first described by Dr. Robert Sprintzen in 1978. “Velo” refers to the palate in the mouth. Among children with VCFS, some will have a cleft palate. Like children with DiGeorge syndrome, children with VCFS often have congenital heart defects. There is a typical facial appearance among children with VCFS, which also resembles that observed among children with DiGeorge syndrome. Unlike DiGeorge syndrome, the immune system is not severely affected in VCFS although it can be slightly abnormal and the thymus may not be in its normal position in the chest. Low calcium levels sometimes occur in VCFS, just as in DiGeorge syndrome. Learning problems, particularly with speech and language, are also common. VCFS was also described independently in Japan by Dr. Atsuyoshi Takao, who called it the conotruncal anomaly face syndrome. The word “conotruncal” refers to the portion of heart that includes the aorta and pulmonary artery, which is most frequently abnormal in the types of heart defects observed in VCFS.
Over time, it has become apparent that DiGeorge syndrome and VCFS overlap in many ways. This includes many of the large number of other problems that children with these diagnoses may encounter. In addition, we now know that the disorders overlap in being caused by chromosome 22q11 deletions and that both syndromes can be observed within one family (for example, a mother with VCFS may have a child with DiGeorge syndrome).
What is a 22q11 deletion?
In humans, DNA, which encodes the master plan for our bodies, is organized as 23 pairs of chromosomes. One pair, the sex chromosomes, consists of either two X chromosomes (XX), resulting in a girl, or one X and one Y chromosome (XY), resulting in a boy. The other 22 pairs of chromosomes, referred to as the autosomes, are numbered 1 through 22. While some of the DNA code can vary between individuals, the overall appearance of each chromosome is unique when viewed under a microscope with staining. Each chromosome is organized into two or three parts: a short arm (not present for some chromosomes), a central portion called the centromere, and a long arm. The arms contain the DNA sequences that encode the genes. The long arm is called by the number of the autosome and “q”. Therefore, the long arm of chromosome 22 is called 22q. Chromosomal arms also have sections that appear as light or dark bands after special staining, which are numbered. Thus, 22q11 refers to the 11 band (pronounced one-one) on the long arm of chromosome 22.
Several years ago, investigators observed rare patients with DiGeorge syndrome who had changes affecting 22q11. These included some for whom that band was missing from one of their two copies of chromosome 22. Missing portions of chromosomes, which can be small or large, are referred to as deletions. With further work, a molecular test called Fluorescence In Situ Hybridization (abbreviated as FISH) was developed that tested for deletions of 22q11 that were too small to be seen under the microscope. Using the FISH test for 22q11, it was discovered that about 90% of patients with DiGeorge syndrome and VCFS have a deletion. This special FISH test for 22q11 deletions is available in many clinical laboratories that look at chromosomes (referred to as cytogenetics laboratories). This test is performed only when physicians instruct the laboratory that they suspect a 22q11 deletion in a person or fetus. That is, this FISH test is not done routinely for every amniocentesis (procedure where fluid and cells surrounding a developing fetus are sampled) or from every blood sample from patients.
If the FISH test for 22q11 deletion is negative, can my child still have DiGeorge syndrome or VCFS?
Yes! As noted in the previous section, approximately 90% of patients with DiGeorge syndrome or VCFS will have a positive FISH test. For those with a normal test, a small percentage may have a deletion affecting the short arm of chromosome 10 (which can be tested with a different FISH test) but most have no chromosomal abnormality that can be found currently. If the doctors caring for your child make the diagnosis of DiGeorge syndrome or VCFS on the basis of certain typical features (facial appearance, heart disease, etc.), then that remains true even if the FISH tests are normal.
Does the diagnosis of DiGeorge syndrome or VCFS change the care of my child’s heart problem?
Babies born with DiGeorge syndrome or VCFS frequently have heart defects. Those defects range in severity from mild to life-threatening. Those with the more serious forms of heart involvement will require surgery in the newborn and infancy period. In general, decisions about the timing and the type of surgery that these young patients require is not affected by the diagnosis of a 22q11 deletion syndrome.
Once the physicians caring for an infant with a 22q11 deletion make that diagnosis, they will perform tests to check on the immune system and on blood calcium levels. Varying degrees of immune system dysfunction may be present. If the immune system is abnormal, there is a somewhat higher risk of certain types of infection after the heart surgery. In addition, if babies who require heart surgery need a blood transfusion, the blood is typically treated with radiation (irradiated) before it is given to the baby. This treatment kills any living white blood cells in the unit of blood. These white blood cells, if alive, could harm the body of a child with 22q11 deletion syndrome if the immune system is weak. This is called graft-versus-host disease and is prevented with the radiation of the blood prior to transfusion. In addition, physicians caring for young infants after heart surgery routinely monitor for low calcium levels in the blood and would be even more vigilant in a child with a 22q11 deletion syndrome. If this occurs, it is easy to treat by infusing some calcium-containing solution through an intravenous line.
If my child has a 22q11 deletion syndrome, what is the risk for my other children or others in our family?
Most children with a 22q11 deletion are the first person in their family to have that problem. Through some elegant scientific studies, we now understand that this area of chromosome 22 is prone to loss. Thus, there will always be a small risk of new 22q11 deletion for any pregnancy.
When someone with a 22q11 deletion has children of their own, there is a 50-50 chance of passing along a copy of chromosome 22 with that deletion with each pregnancy. This also means, of course, that there is an equal chance that their next child will not inherit the deletion. Like flipping coins for heads or tails, the results of previous pregnancies do not affect the next one. So, a person with a 22q11 deletion and a first child who did not inherit the deletion has the same 50-50 risk with their second child.
In a small percentage of cases, a parent of a child with a 22q11 deletion is also found to have that problem. Once an infant or child is identified as having the deletion, the geneticists will often take a history concerning the parents and examine them in order to decide whether or not one of the parents has it too. Since the severity of the disorder observed in individuals with 22q11 deletions can vary (discussed below), a parent may have gone without a diagnosis if the disorder is mild in them. When in doubt, the geneticist can test for the deletion in a blood sample using the same FISH test. If a parent is found to have the deletion, the geneticists will then turn their attention to others in the family who might have it too. These could include other children as well as the siblings and parents of the affected parent.
If the doctors decide that neither parent has a 22q11 deletion syndrome, then the risk for others in the family including their other children (siblings of the child with the 22q11 deletion) is no greater than anyone else in the world, which is estimated at 1 in 2,000 births.
If a sibling of a child with 22q11 deletion does not have the deletion, then they cannot pass it along to their children. The 22q11 deletion syndromes do not skip generations.
If a parent has a 22q11 deletion syndrome, what will their child who inherits the deletion be like?
The deletions of chromosome 22q11 that cause DiGeorge syndrome and VCFS are identical. Scientists are actively trying to figure out why the disease varies if the loss of the piece of chromosome 22 is the same, but we do not know at this point. It is clear, however, that a parent with VCFS can have a child inheriting the deletion who turns out to have DiGeorge syndrome. Similarly, a parent with VCFS and no heart problem can have a child with VCFS and a significant heart defect. Other aspects of the disorder also vary among family members with 22q11 deletions. The only reliable thing is that any child inheriting the deletion will have some disease features.
If my fetus has a 22q11 deletion, what will he or she be like?
As described in the previous answer, there is a lot of variability in the disease among patients with 22q11 deletions. This creates uncertainty about the status of a developing fetus if the amniocentesis reveals that there is a 22q11 deletion. Using ultrasound testing, specially trained obstetricians can look at the developing fetus and define certain aspects of the 22q11 disorders such as the number of kidneys. Similarly, specially trained pediatric cardiologists can look carefully at the heart of a developing fetus in order to detect serious heart defects. Some of the milder heart defects that babies with 22q11 deletions might be born with are not readily seen with this test. Fortunately, the most serious heart defects can be seen in nearly all fetuses. Definition of the heart defects enables physicians and parents to plan properly for the remaining pregnancy and the care of the baby after birth.
Developmental delay/learning issues are an important concern for children with 22q11 deletions although many children with them have minimal or mild learning problems. At present, there are no tools for predicting this aspect of the 22q11 deletion disorders in fetuses or newborns.