Donna McDonald-McGinn, MS, LCGC, Director of 22Q And You Center at the Children’s Hospital of Philadelphia, and Clinical Professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania talks about the benefits of early intervention of 22Q.
Interview conducted by Ivanhoe Broadcast News in May 2017.
How do parents ever get to the bottom of what it is? How do they figure it out?
Dr. McGinn: There are children who present with very classic features and there are very astute physicians all over the world who know to think about this. Those are the children who have congenital heart disease and there are certain types that are very specific to this although you can have any type of heart difference. Also those children generally present in the newborn period with low calcium and sometimes they have seizures as a result of that. That can be a big clue. What’s confusing and important about this condition is that it had many names before we knew the underlying cause was a piece of chromosome missing. One of them is DiGeorge Syndrome and Dr. DiGeorge was an endocrinologist across town who first described children with congenital heart disease, low calcium and problems fighting infection because they had immune troubles. That has borne his name all these years. DiGeorge syndrome and syndrome just means a collection of findings. So those are children who come to attention pretty quickly because most people know now about the association with this tiny piece of chromosome missing. It’s the children who don’t have a heart defect that often go undiagnosed for years and years. We have one patient here whose son actually saw 27 sub-specialists before coming up with a unifying diagnosis at age five. And his parents were quite relentless, mom is an OBGYN, dad is an ENT and they said there has to be something that unites his features. However, he didn’t have a heart defect and he didn’t have a palatal difference at that time, although he did have what we call nasal regurgitation so he had food coming out the nose. They were really relentless in trying to come up with this diagnosis and then relieved when they had it because they had a path in terms of how to follow him going forward. Also some sadness that perhaps he had low calcium in infancy and perhaps that could have affected his intellectual development you know, across his entire lifespan. That’s something we grapple with in trying to identify children early so that they can benefit from all the early interventions in medical sub-specialties that they really require.
Is this calcium a routine test for an infant or is that something new?
Dr. McGinn: It’s a routine test if a child is shaky or if they present seizures.
If they have a seizure, would that be right after birth?
Dr. McGinn: Well it could be right after birth or it could be anytime. We have another child whose eighteen now and he presented with a very typical heart defect at an outside hospital. Multiple differences with the way the heart was formed. He went home and he wasn’t acting right and he was shaky, jittery and mom had two older children. She said, I know this isn’t right. She took him to the emergency room and they thought he had a stroke or they thought it was something related to the heart. Then they checked his calcium and it was quite low and then that led to the diagnosis. Sort of the ah moment of oh, he has a heart defect and he has hypocalcemia. This is a child who has DiGeorge syndrome let’s send the test for 22q. And then that child has ended up having all kinds of other things, which have benefitted from knowing to look for them because of the diagnosis.
What are the benefits of really intervening earlier?
Dr. McGinn: Having the diagnosis gives you a checklist of what to look for. If we diagnose a child in the newborn period we know to look for the heart to make sure there’s not a difference that may not have been noticed already. There are some children who have a heart difference that don’t even have a murmur at birth. Then when the little hole in the heart that’s open prenatally to keep the blood flowing appropriately closes then those children have a devastating problem related to that heart defect and can actually die. So it’s very important that if we suspect the diagnosis that we look at the heart first. That we check the calcium and we treat it if there’s a difference. We then check the immune system because in those children with DiGeorge syndrome; way, way back many of them died because we didn’t have good antibiotics and things like that to help with infection. We’re much more aggressive in providing prophylactic antibiotics and things like that in children who have this. Some of them may even need intravenous immunoglobulins to help their immune system when they have this condition.
Define, if you will, what 22q actually is.
Dr. McGinn: 22q11.2 deletion syndrome means very specifically to everybody in genetics there’s a tiny, tiny piece of chromosome material missing on chromosome twenty two. So we have forty six chromosomes, twenty three pairs and they’re numbered from the largest which is number one to the smallest which is number twenty two. Then we have the sex chromosome. If you’re a woman you have two x’s and if you’re a man you have and x and a y. The twenty-second chromosome has a tiny little piece missing on the bottom half. Chromosomes were first defined by the French and they noticed that they had a top half and a bottom half. In French the top half was short or petite so we called the top half the P arm and the bottom half the Q arm because Q follows P in the alphabet. Everybody knows that if you say 22q you’re talking about the bottom half of chromosome twenty-two. 11.2 means that’s the spot on the chromosome is missing.
But this one tiny bottom of the totem pole so to speak can really have some devastating effects?
Dr. McGinn: By having that piece missing you’re missing about fifty genes. Genes are the blueprint for the body they determine everything about us. How tall we are, our hair color, our eye color and they also determine how our organs form. With those genes missing they send out a signal, I want the heart to form a certain way, the thymus, which controls the immunity, the parathyroid glands which control calcium and parathyroid hormone. They really set things up to go in a certain direction. What’s interesting about 22q is that not everybody has the same things. Only three quarters of patients have an immune system difference, a heart difference, a palate difference, so the roof of the mouth. Only about half have hypocalcemia and then others have really significant feeding and swallowing problems. For a parent that’s the most difficult thing. Every mother wants to be able to feed their child and when they can’t its devastating. This is something again early diagnosis to say the feeding issue is not because of the heart difference, which it can be in many children with heart differences. It’s because of the chromosome 22q differences, and it would be useful to see a gastroenterologist or a feeding specialist who knows about how to feed children with this condition.
What is 22q and You?
Dr. McGinn: 22q and You is our center here at the Children’s Hospital of Philadelphia. We happen to be the group that first found the deletion and association with DiGeorge syndrome. Doctor Elaine Zackai who is the head of Clinical Genetics here and the medical director of the 22q and You Center saw a child back in 1982 who had symptoms of DiGeorge syndrome. The heart difference, the immune, the hypocalcemia but she also had a cleft palate and difference in the way her GI tract was formed. She said, you know, I want to send chromosomes on this child. We actually found in the laboratory of Dr. Emanuel who was the head of the psychogenetic lab that there was a switch in chromosome. There was a piece missing on chromosome 22 and a piece missing on chromosome ten. They called Dr. DiGeorge and said, have you seen any other children with a piece of any chromosome missing. He said, well we have a couple and the chromosome in common was 22. They made the leap and they wrote a very similar paper in 1982 that said DiGeorge syndrome is due to a piece of chromosome 22 missing. From 1982 to 1992 the puzzle remained what about all these other children where we’re not seeing the piece missing. It turned out that we couldn’t see it under the microscope. Dr. Emanuel developed a test that came out in 1992 that we could see what’s called sub-microscopic deletion. Even smaller than something you can see with your eye under a microscope. That allowed us to see that in fact almost all the patients with DiGeorge syndrome had that piece missing. Then we actually found that many other conditions that had been described clinically were actually due to that piece missing. We thought this was very rare and it turned out its not rare at all it’s just something that we didn’t understand because we didn’t have a test.
So let’s say somebody is at home watching this piece and maybe they looked at their child and thought something, but really haven’t gotten to the bottom of it. Kind of a laundry list of what some of the symptoms you mentioned, you mentioned autism earlier that parents might notice?
Dr. McGinn: So most children with 22q speak late. They generally walk on time or a little bit late, they hit their other milestones on time but speech is almost always delayed. So the mean age of speaking is about two and a half. We have some non-speakers as old as five, six, and seven and then speech comes in and it becomes strength. In addition, children have a learning disability and it’s an atypical learning disability most of the time. Usually they’re really good at reading, memorization and spelling but have relative difficulty with math and abstract reasoning; in particular word problems and things like that. We have adults who never knew that they had this until they had a child with a heart difference but when you probe a little bit about their history they say, well you know my sibling is a physician, my other sibling’s an attorney, I was the one who needed the tutor. I was the one who struggled and had to work much harder. I was the one that had scoliosis. Therefore, things that we think are very common in the general population we see more frequently in this. Then I think the thing that’s most worrisome for families besides as you mentioned some of the behavioral difference like autism, ADHD, anxiety we see in sixty percent of people who have this condition. Sadly twenty-five percent of individuals with this tiny piece missing develop schizophrenia. On the one hand, although it’s frightening, the greatest likelihood seventy-five percent is that the child won’t develop schizophrenia. This provides a window into understanding that condition which is very common in the general population. Right now we’re looking for genes within this tiny piece of chromosome missing that may shed light on what causes schizophrenia in these patients as well as in the general population. The hope is that we’ll develop better drugs or translational work to help schizophrenia related to this and understanding the pathways associated with these genes. Additionally, drugs for ADHD, anxiety and hopefully autism. On the one hand although it seems somewhat overwhelming to families, on the other hand it’s really a window into helping their children and to helping children likely worldwide with these related conditions.
The diagnosis has to be through genetic testing?
Dr. McGinn: Through a blood test, yes. Actually I should say through a blood test but now we’re even able to do it through saliva. We don’t typically do this test clinically using saliva but we could and that’s something that’s coming in the future.
If there is somebody at home watching and they kind of suspect they should go to their physician and…?
Dr. McGinn: They should go to their physician and say, you know I’ve always been concerned about my child and I saw this piece and I’m thinking about 22q11.2 deletion syndrome as a possible diagnosis. Is there a way that you could send the test, is there a way that you could speak to the genetics folks that you work with or could you refer me to genetics for an evaluation.
END OF INTERVIEW
This information is intended for additional research purposes only. It is not to be used as a prescription or advice from Ivanhoe Broadcast News, Inc. or any medical professional interviewed. Ivanhoe Broadcast News, Inc. assumes no responsibility for the depth or accuracy of physician statements. Procedures or medicines apply to different people and medical factors; always consult your physician on medical matters.
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Donna M. McDonald-McGinn
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