What Is Chromosome 22q11.2 Deletion Syndrome, and Why Do You Need to Know?

Donna McDonald-McGinn, MS, CGC


July 18, 2016

Editorial Collaboration

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I'm Donna McDonald-McGinn, a clinical professor of pediatrics at the Perelman School of Medicine at the University of Pennsylvania. I'm also director of the 22q and You Center, chief of the Section of Genetic Counseling, and associate director of Clinical Genetics here at The Children's Hospital of Philadelphia (CHOP). I'm delighted to speak about the 22q11.2 deletion syndrome today because it's something that's near and dear to my heart, as it is to many clinicians at CHOP.

Five Decades of Discovery

The chromosome 22q11.2 deletion is the most common microdeletion syndrome, which is actually quite perplexing because it's a condition that most clinicians have not heard about, partially due to the fact that it has had multiple names over the years. In the early 1960s, Dr Angelo DiGeorge first described patients with a constellation of findings that came to bear his name, including immunodeficiency, hypocalcemia due to hyperparathyroidism, and later, congenital heart disease. That triad came to be known as DiGeorge syndrome.

In 1982, Dr Elaine Zackai here at CHOP identified a patient who had features of DiGeorge syndrome. The patient had the typical heart disease, hyperparathyroidism, and immune deficiency, but she also had a cleft palate and a gastrointestinal abnormality, specifically a jejunal web. That child turned out to have a chromosome difference, including a piece of 22q and chromosome 10 missing. Multiple patients thereafter came to clinicians' attention with DiGeorge syndrome and a piece of 22q missing, leading to the idea that this was the cause of DiGeorge syndrome.

Thereafter, Dr Beverly Emanuel and her laboratory spent 10 years looking at patients with DiGeorge syndrome. She found that only 25% really had a piece of 22q missing[1] under the microscope. So the puzzle remained: What about the remaining 75%?

Dr Emanuel then discovered a way to look for smaller deletions, known as fluorescence in situ hybridization (FISH), which she did here at CHOP along with Debbie Driscoll and concurrently with Peter Scambler and his group in London. This allowed us to look for very tiny pieces of material that you couldn't see with your eye under the microscope. She went back to those patients with DiGeorge syndrome and found that the vast majority had the deletion.

Bringing Unity to Overlapping Diagnoses

Thereafter, we and others noted an overlap with a number of other diagnoses. Velocardiofacial syndrome was a condition described by speech pathologists that included cleft palate or velopharyngeal incompetence, the same heart defects as in DiGeorge syndrome, and some differences in facial features. We looked at those patients, and they all had the deletion.

Then we noticed that there was a cardiologist in Japan who described patients with conotruncal anomaly face syndrome, who had the same heart difference and some mild facial differences. We contacted the Japanese researchers and suggested that they test their patients with this FISH study. They found that most had the deletion. Subsequently, we described patients with Opitz G/BBB syndrome, who had cleft lip and palate and laryngotracheoesophageal abnormalities, and many of them had the deletion. Then the Italians described a group of patients with Cayler cardiofacial syndrome, also known as asymmetric crying facies, and the same heart defects, who also turned out to have the deletion.

So you can see why clinicians have struggled with this. They learned about DiGeorge syndrome in medical school, but they didn't really learn about all of these other conditions and didn't know they were actually all the same thing with the same etiology.

We now talk about this uniformly as the chromosome 22q11.2 deletion. That designation of 11.2 is important because it tells everybody in genetics exactly where the piece is missing on the chromosome, and therefore what genes are missing. By having that piece missing, about 50 genes are missing, many of which we know to be very important for development.

Presenting Symptoms

For example, there's a gene within 22q11.2 called TBX1, and another gene a little further down the chromosome within the same region called CRKL, both of which are associated with congenital heart disease. We're discovering every day what many of the other genes do as well.

In contrast, 22q13.3 is a condition way down on the bottom of the chromosome that is completely different; it's really like comparing apples to oranges. So it's important that when we say 22q, we specify the area that we're talking about, because the genes differ from one area of the chromosome to another.

What happens once this piece of chromosomal material goes missing? It sets up a blueprint for the body to form a certain way. Embryologically, it affects the neural crest cell migration, causing congenital heart disease, differences in the immune system because of the thymus and the parathyroid glands, and therefore the hypocalcemia and hypoparathyroidism.

We've seen more than 1300 patients here in the 22q and You Center at CHOP, which is the largest such clinic in the world. From looking at such a large group of patients, we've seen that about three quarters of patients have congenital heart disease, palatal differences, and immunodeficiency. Even if they don't have frank chronic infection, they can have differences in immunoglobulins and in their humoral response to vaccines that may require revaccination. We have to pay attention to the immune system.

About half have hypocalcemia—sometimes in the neonatal period and sometimes later after times of stress, such as perioperatively, during pregnancy, or during puberty. About a third have renal problems, and a third have significant feeding problems. This last piece of information is important because pediatricians often will erroneously attribute the feeding difficulties to the heart difference. We know that's not associated. We really need to look for things like dysmotility and reflux, which are treatable, as well as rarer things like intestinal malrotation or nonrotation.

Probably the other most important thing to know is that the vast majority of individuals with this have learning differences. If we look at I.Q., about a third are in the average range, a third in the borderline range with an I.Q. of approximately 70, and a third in the intellectual-deficit range. All of these children, therefore, benefit from early-intervention strategies. Most go to regular school with extra help. We have some adults who never knew that they had 22q11.2 deletion syndrome until they had an affected child, but typically they'll report that they, too, had learning differences.

Finally, there are behavioral differences associated with 22q. In childhood, these include attention-deficit/hyperactivity disorder (ADHD), autism, anxiety, obsessive-compulsive disorder, lots of perseverations. In adulthood, these include many of those same findings, but more important, about 25% develop frank psychosis—in particular, schizophrenia.

Ongoing Research Efforts

We currently operate the International Consortium on Brain and Behavior in 22q11.2 Deletion Syndrome, a very large group that is run out of CHOP and the University of Pennsylvania, led on one side by myself and by Dr Raquel Gur on the adult side. We're looking for genes that may predispose to schizophrenia, both in 22q and in the general population.

The 22q11.2 deletion syndrome is a condition important in and of itself, given its frequency. It's also important because it has such variability, even between family members, including identical twins. It provides a window into understanding common conditions such as schizophrenia, which is seen in 1 in 100 individuals, as well as ADHD and autism.

We're also looking at structural differences, such as congenital heart disease, through our work with the 22q11.2 International Modifier Gene Consortium. We're looking for genes that explain why patients differ from one another, why one sibling would have congenital heart disease and the other one would not.

This syndrome may provide a window into treatment. We know that there's a gene within the deletion that affects a pathway that in turn affects the brain. We're about to launch a clinical trial here at CHOP looking at a drug that we hope will circumvent that pathway in order to better treat ADHD, autism, and anxiety in this population. This may then perhaps even lead to treatment strategies for psychosis and other psychiatric illness.

If anybody out there would like to learn more about this important condition, feel free to give us a call at 215-590-2920, or email me directly.

Thanks so much for joining.