The History of the 22q11.2 Deletion
by Donna M. McDonald-McGinn, M.S. and Elaine H. Zackai, M.D.

What is the 22q11.2 deletion?

Well, its history is quite interesting and worth reviewing, but first we need to step back and describe some terminology, so that everyone reading this will begin on the same footing.

As you may know, a syndrome is really a collection of findings that has been seen recurring over and over again in patients. For example, one common group of associated features includes: a heart problem; an opening in the roof of the mouth (often described as a cleft palate); and a difference in learning style. Syndromes are generally names after the person or persons who first described the collection of findings. Once an underlying cause is identified, the name may be changed to reflect the specific chemical abnormality, chromosome difference, or gene change that caused the problem.

Genes are made up of a chemical called DNA and are housed on larger structures called chromosomes. Most people have 23 pairs of chromosomes (46 total), with one of each pair coming from the mother and the other from the father. Chromosomes are number 1 through 22; the 23rd pair are called sex chromosomes because they determine a person's sex (male or female). The chromosomes are found in every cell in the body. Cells are so small that they, and the chromosomes they contain, can only be seen under a microscope.

Since genes are housed inside the chromosomes, they can't be seen under a microscope, but they can be measured by using special "molecular" tests. A good way to think about chromosomes and genes is to compare them to a train. A train has a number of box cars just as a chromosome has a number of stripes. We can see the box cars when we look at a train, just as we can see the chromosomes and their stripe patterns when we look under the microscope. We cannot, however, see the packages inside the boxcar without first opening the door. The same is true for a chromosome - the genes are the packages inside.

When a baby is conceived with either too much or too little chromosomal material, birth problems can occur. This may include a whole extra chromosome, as in Down syndrome (an extra number 21), a whole missing chromosome, as in Turner syndrome (a missing X), a piece of material missing or extra, or a complex rearrangement of chromosomal material. When chromosomal material is missing or extra, genes are generally missing or extra. Since genes are the blueprint of the body, when they are lost or extra, the body's blueprint changes, frequently leading to birth problems and learning differences.

So again you ask, what is the 22q11.2 deletion?

People with a 22q11.2 deletion have a very small piece of chromosome 22 missing (thus it is called a deletion). The q11.2 tells everyone who works in genetics that the area missing is in a very specific spot on the "q" arm, which is also called the long arm of the chromosome. (Chromosomes are divided into two parts, the top half being called the "p" arm and the bottom half called the "q" arm.) It is very important to know the location of a missing piece of chromosomal material in order to make some general comparisons (although no two people are exactly alike), because if two children have different areas of the same chromosome missing, it would be like comparing "apples to oranges".

In 1981, Dr. de la Chapelle in France, and in 1982, Richard Kelley, M.D., along with Elaine Zackai, M.D. and Beverly Emanuel, Ph.D. at the Children's Hospital of Philadelphia in the U.S.A., found that patients with DiGeorge syndrome had a rearrangement of chromosome 22 which caused them to be missing a very small piece of chromosomal material on the long arm (q11.2) of chromosome 22. This rearrangement was able to be seen under the microscope. This piece of information is important, as you will see when you read on, because most 22q11.2 deletions are not seen under the microscope because they are too small.

Patients with DiGeorge syndrome have a collection of findings which include: a characteristic heart defect (interrupted aortic arch, truncus arteriosus, conoventricular septal defect, tetralogy of Fallot, etc.), problems with calcium, trouble with infection (due to abnormalities of the thymus gland), and occasionally a cleft palate. Dr. Angelo DiGeorge, who first diagnosed this collection of findings, was and still is an endocrinologist at St. Christopher's Hospital for Children in Philadelphia.

Over the years, Dr. Emanuel's group at the Children's Hospital of Philadelphia worked very hard to establish the fact that 25% of patients with DiGeorge syndrome had a visible deletion of material on chromosome 22 when they looked under the microscope. But they were still puzzled about the other 75% of patients with DiGeorge syndrome who did not have a visible deletion. In 1991, Deborah Driscoll, M.D., a member of Dr. Emanuel's laboratory group, detected a submicroscopic deletion of chromosome 22q11.2 in the majority of patients with DiGeorge syndrome using special "molecular" tests. This meant that although you could not see the material under the microscope, you could prove that the piece was absent by using a special DNA test called FISH (fluorescence in situ hybridization). This test works like a lock and key. The person in the laboratory has the key which lights up (fluoresces) if it finds its matching lock in the chromosomes. If the lock is missing from one of the pair of chromosomes 22s, only one chromosome 22 will light up in the area in question (q11.2), confirming that the patient is missing material on chromosome 22.

The majority of patients who had a 22q11.2 deletion, which caused their DiGeorge syndrome, did not have an affected parent, therefore, the change in their chromosome 22 was a "new mutation" in them. This was and still is important information for families, because, if the parents' chromosomes are normal, then the chance of recurrence in a future pregnancy is quite low. About 10% of the time, a parent is also affected with some medical problem like a heart defect and also has the 22q11.2 deletion. If the deletion is present, then that individual has a 50% chance of passing on the chromosome 22 with the deletion to his or her children. The chance of having more than one child affected when the parent has the deletion is random (like the chance of flipping a coin twice in a row and finding "heads" twice in a row). When a child receives the chromosome 22 with the deletion, the medical problems can be quite variable. For example, from a very mild heart problem to a very severe heart problem, or no heart problem at all.

So, what else happened in the history of the 22q11.2 deletion?

Well, backing up a bit, in 1968, William Strong, M.D., a physician from Cleveland, reported an association of cardiac abnormalities (right sided aortic arch), learning differences, and a characteristic facial appearance in four members of one family. In 1976, Dr. Kinouchi, a physician in Japan, reported a typical facial appearance specifically seen in patients with heart problems (conotruncal anomalies) and called it conotruncal anomaly face syndrome (CTAF). IN 1978, Robert Shprintzen, Ph.D., a speech pathologist from New York, described a disorder running in families where the patients had a combination of cleft palate or VPI (velopharyngeal-incompetence - the failure of the back of the palate and the throat to close the space connecting the mouth and the nose during normal speech, which causes the patient to sound like he or she has a cold), heart defects, learning disabilities, and a characteristic facial appearance. He called this condition velocardiofacial syndrome (velo means palate or roof of the mouth, cardio stands for heart, and facial stands for the typical facial characteristics seen in their patients). In 1980, Dr. Shimizu, also of Japan, noticed that there were similarities between the patients who were diagnosed with CTAF and those with DiGeorge syndrome. Dr. Shimizu described one patient known to have findings of both DiGeorge syndrome and CTAF. In 1981, Dr. Shprintzen reviewed the patients reported to have CTAF and suggested that they had velocardiofacial syndrome.

Following Dr. Shprintzen's reports of patients with velocardiofacial syndrome (VCFS for short), Tony Lipson, M.D., a geneticist from Australia, emphasized the wide variability in findings between patients and even with the same family. Dr. Lipson also suggested that patients who had a palatal problem generally responded well to treatment. He noted that since many of the findings in the patients with VCFS were subtle, that pediatricians may not suspect the diagnosis at all - leading to delay in treatment for the hypernasal speech (speech that sounds like it is coming through the nose). He made a plea for diagnosis of this syndrome as early as possible so that treatment could begin. However, there was no good test available in the newborn period - until recently.

The story continues.

In 1990, C.A. Stevens, M.D., from Utah, reported a patient with DiGeorge syndrome whose father had a cleft palate, problems fighting infection, and facial features consistent with VCFS. He proposed that all previously reported patients with a parent and child affected with DiGeorge syndrome were examples of VCFS. This followed a report by Rosalie Goldberg, M.S., from New York, suggesting an overlap of findings between patients with DiGeorge syndrome and VCFS, such as calcium problems and problems with infection. When Dr. Lipson reviewed his patients with VCFS, 6 of 38 patients had features of both DiGeorge syndrome and VCFS. Recently Drs. Weyerts and Jones from San Diego found that the medical problems seen in older patients with DiGeorge syndrome and VCFS were indistinguishable. So, in 1992, Dr. Driscoll, again at the Children's Hospital of Philadelphia, demonstrated that the vast majority of patients with VCFS had a 22q11.2 deletion. In fact, she found that this deletion was no different from that seen in patients with DiGeorge syndrome. This finding explained the reason for the overlap in clinical findings between the two diagnoses, and therefore supported the idea that these were in fact the same syndromes.

The story enlarges even further.

Since Dr. Driscoll's discovery that DiGeorge syndrome and VCFS are in fact the same diagnosis, other "syndromes" have been added to the list of diagnoses which have the 22q11.2 deletion as the underlying cause of the patients' problems. These presently include CTAF, as described by the Japanese, and one type of Opitz G/BBB syndrome. Opitz G/BBB syndrome was first described by John Opitz, M.D., a physician in Montana. The hallmark features include: hypertelorism (widely-spaced eyes), hypospadias (the opening of the penis is not at the tip), swallowing problems, and noisy breathing. These findings were extremely variable, from severe to mild, in affected family members. In 1995, Donna McDonald-McGinn, M.S. and Elaine Zackai, M.D., at the Children's Hospital of Philadelphia, reported a patient with Opitz G/BBB syndrome, without overlapping features of DiGeorge syndrome or VCFS, in whom a 22q11.2 deletion was found. In addition, they reported patients with overlapping features of the three syndromes, including a father and child, all of whom were found to have a 22q11.2 deletion. Since their report, Julie Fryburg, M.D., a physician from Virginia, and Drs. Lacassie and Arriza from New Orleans, independently reported patients with features of both Opitz G/BBB syndrome and VCFS and a 22q11.2 deletion.

So, in summary, the 22q11.2 deletion is thought to be the underlying cause of the medical problems associated with the vast majority of patients with DiGeorge syndrome, velocardiofacial syndrome, conotruncal anomaly face syndrome, and some patients with Opitz G/BBB syndrome. Furthermore, the diagnostic name which is given to a particular patient's set of findings is generally determined by the subspecialist to whom the patient presents. For example, patients diagnosed with CTAF presented to cardiology because of their heart defect. The same is true for many patients with DiGeorge syndrome who often had problems with calcium and their thymus gland in addition to their heart problems. Patients diagnosed with VCFS were usually older, presenting to the cleft palate clinic for follow-up due to a cleft palate or VPI. And lastly, patients with Opitz G/BBB syndrome often presented to the ear, nose and throat doctors due to their noisy breathing. Thus, the perception that these diagnoses were really distinct entities may ultimately be explained by the bias of each medical group's area of expertise.

We at the Children's Hospital of Philadelphia, therefore, refer to all patients with a 22q11.2 deletion by their cytogenetic name, patients with a 22q11.2 deletion (as we do in other chromosomal disorders, i.e. 4p-, 18q+, trisomy 21, etc.) which allows all physicians involved to immediately understand the cause of the problem, the recurrence risk, and the variable prognosis. It also allows physicians to compare their patients to children in the literature with the exact same thing rather than possibly comparing "apples to oranges".

22q and You
"Decicated to Teaching, Learning, and Caring for patients with a 22q11.2 deletion"
Clinical Genetics Center - The Children's Hospital of Philadelphia
Wood Bldg Room 1080 - One Children's Center - 34th St & Civic Center Blvd - Phila, PA 19104
Phone (215) 590-2920 - Fax (215) 590-3298 - Email: mcginn@email.chop.edufile:///SLIDE%20CAMERA/Applications/Visual%20Page%201.0.2/22q&you/medicalneeds.html