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Genetics for the Pediatrician(Grand Rounds Episode for MOC credit) · Pediatrics Now: Cases Updates and Discussions for the Busy Pediatric Practitioner

• 0:00
  I'm Holly Wayment, and this is Pediatrics Now, cases, updates,
• 0:04
  and discussions for the busy pediatric practitioner.
• 0:07
  Today, I'm bringing you this fascinating talk from Grand Rounds.
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  This episode is eligible for MOC credit. Let's listen in.
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  Music.
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  So today, we're going to talk about genetics for the pediatrician.
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  I would love for this to be interactive.
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  I know it's Zoom. I wish I were there in the room with you. The goal is really
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  to make this fun and interactive and simple.
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  And the reason I have our zebras is we all cave into stereotypes.
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  All geneticists come with their zebras. But in medicine, we talk about a lot,
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  if you hear hoofbeats, think horses, not zebras.
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  And geneticists, of course, like to showcase their zebras.
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  But my main point is, You, as pediatricians, can see the difference between a horse and a zebra.
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  And a rare disease doesn't mean it's mysterious.
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  It just means that you have to have seen it before to know what it is and to
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  know the signs and symptoms associated with it.
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  And you can really make these diagnoses. disease.
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  So I don't have any disclosures and all of these cases are true cases,
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  but I did change the pictures for most of them just so to protect patient confidentialities
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  and minor, minor case details.
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  We're going to do some simple things. We're going to correctly identify top
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  scenarios, those top genetics consults that I see in my daily clinics.
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  We're going to understand basic categories of genetic disorders and tests.
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  And the way we're going to do that is we're going to know our genetics history.
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  It makes it so much easier to categorize these disorders as what category are
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  we in and what decade could I have diagnosed this if I were practicing?
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  When did genetics even start? When could you become a geneticist?
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  So by understanding the history and the decade where testing became available,
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  we'll in turn understand the broad genetic categories and how we place our patients
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  we see in clinic into those categories in order to know what to test when.
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  And we're going to also consider briefly the risk versus the benefits of genetic
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  testing so that we're not overwhelmed by these tests.
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  And we can really focus on what all of you do best, which is engaging,
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  interacting, and seeing your beautiful patient.
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  So it's going to be a rapid approach, but you don't have to remember the details.
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  It's more the philosophy that.
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  I've learned by being with these patients for almost 20 years.
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  So we're going to get objective one over with really fast.
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  What are some of the top 10 genetic consults that I see in my general genetics clinic?
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  I also do craniofacial vascular clinics as well. It's a lot of fun.
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  But in my general bread and butter genetics clinic, I see a lot of autism.
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  I see some patients with epilepsy, multiple congenital anomalies.
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  My mentor used to tell me a rule of threes, three differences,
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  such as a congenital heart disease, short stature, features that are different from the family.
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  And now we're thinking maybe there is a genetic condition that ties the pieces of the puzzle together.
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  Those neurocutaneous disorders, neurofibromatosis, tuberous sclerosis,
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  those patients with sensory neural hearing loss, our connective tissue disorders.
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  Does this patient have Marfan syndrome?
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  We get a lot of referrals for Erlos-Danlos, but good news, you can't make that
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  diagnosis unless somebody is post-puberty nowadays.
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  They've changed the criteria so we can really focus on our patients in a new, different way.
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  Skeletal dysplasia, movement disorders, newborn screening, metabolic disorders.
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  These are kind of our top 10 categories where you think of referring to a geneticist.
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  And most of the time, the patients I'm interacting with in clinic.
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  And we also, throughout this lecture, objective number two, we're really going
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  to think in terms of these broad genetic categories.
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  This is the slide I'm going to focus on for actually a couple of minutes and
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  kind of the work portion of this lecture, because it's so important to understand
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  the categories, but to really memorize those categories.
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  Were next to me to go through kind of genetics by the decade and put the categories
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  in context with the history.
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  But before I launch into the categories, I want to tell you a brief personal anecdote.
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  So when I first became a genetics attending and I got a new job,
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  my lovely, beautiful boss was so excited by my arrival and the extra help that
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  she immediately went to a conference and then vacation.
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  So I saw this baby who had microalpthalmia, deep set eyes, post-axial polydactyly.
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  And I sat there and I wrote the most beautiful note.
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  And I said, there was a differential and it included Smith-Lemley-Opeth syndrome and Joubert syndrome.
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  And I had a long lift. And then she came back, took one look at the baby and said, I'm dead.
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  You didn't send a karyotype for trisomy 13. This baby has trisomy 13.
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  And I thought, am I going to be fired today? Because I had never seen a baby
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  with trisomy 13 in my fellowship that didn't have a cleft palate or holoprosencephaly,
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  but she did fire me. She was lovely.
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  And then had me follow up with the patient where I told the patient,
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  you're having a lot of apnea.
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  I was was concerned because so many patients with trisomy 13 passed away,
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  but that patient, here I was wrong again, that patient was one of the 10% long-term survivors.
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  And that patient happened, the mother happened to take her to the playground
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  where my children played for the next six years that I lived in Rhode Island.
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  And it taught me, we became quite unfriendly terms,
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  but I've always remember two things from that encounter that the first thing
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  I want to do when I get to the bedside is I don't want to miss a major chromosomal category.
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  There are only five reasons we still send chromosomes for big disorders.
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  Trisomy 21, 18, 13, Turner, Klinefelter.
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  And we also send in mothers with recurrent miscarriages since they might have
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  a balanced translocation.
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  And otherwise, we rarely send our chromosomes, but I will never miss a trisomy
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  13 or major chromosomal abnormality again.
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  And I also learned how little I know about prognosis and to remember those 10%
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  of long-term survivors, even with complicated things like trisomy 13 and 18.
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  So none of my fellows or residents missed that category.
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  We start with And then we have the microdeletion duplication syndromes where
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  you're not missing a whole chromosome, but you're missing a small piece of chromosome,
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  maybe containing about 20, 23 genes.
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  It could be missing, it could be doubled. And those are your classic microdeletion
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  pediatric board syndromes.
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  You all know 22q11 deletion syndrome, Williams, Smith-Beginnis,
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  where they have the behavioral problems and trouble sleeping,
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  Kredischat, Wolf-Hirschhorn.
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  And now, of course, you have hundreds and hundreds of micro deletion duplication
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  syndromes. And you can go on rarechromo.org if there's a new one you haven't heard of.
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  But your main idea is that it's groups of genes missing or added.
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  So you really will be seeing...
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  What we call dysmorphic features are features different than the parents,
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  unless the parent is also affected with the same microdeletion duplication syndrome,
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  which happens all the time.
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  But you'll be seeing differences on their physical exam most of the time when
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  you have a chromosomal microdeletion syndrome.
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  Next, we have our single gene testing category.
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  Again, this slide is kind of the bulk of the work. But if you don't know your
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  categories, you're not going to know where to kind of put a patient. shift.
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  So single gene disorders, this is one gene at a time out of our 20,000 genes.
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  A patient comes and they have very tall stature and they have a pectus and they
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  have aortic dilation and they have a positive wrist sign and a thumb sign.
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  And you're thinking they might have Marfan syndrome, a change in just one fibrillin
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  gene out of the 20,000, like 90% of people who meet that Gantt score calculator do.
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  This is a single gene disorder.
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  Next, we have our repeat disorders. That is where, and there are only about
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  five of them for you all to remember for all of your boards,
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  but that is where, for example, you have a child with intellectual disability
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  and that child has a long face and you start thinking about fragile X and they
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  have CGG repeats greater than 200,
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  which affects the FMR1 gene and causes differences in brain development.
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  And you only have to know about five repeat disorders.
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  Then we have our next generation sequencing, where instead of testing one gene
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  at a time, like for epilepsy, we test based on their presentation.
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  So we'll put 100 genes for epilepsy, and we'll sequence all 100 at the same time.
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  Next, we have our methylation disorder category, where you have the same sequence
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  of DNA, but there's a change in expression, such as Angelman syndrome,
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  Prader-Willi syndrome, Beckwith-Wiedemann syndrome,
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  Russell-Silver syndrome, some types of diabetes.
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  There aren't that many of those either. there.
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  Next, we have our exome where we're going through all the 20,000 genes,
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  those exiting portions, and we're closely analyzing those exons that might fit
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  into the clinical phenotype that we write down for those labs because they really
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  can't focus on everything.
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  They're going to to analyze better the exons where there might be a clinical disorder.
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  And now we have genome as well, where it's like the exome plus the microarray. But guess what?
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  Many genomes do not pick up some of the repeat disorders and some of the methylation disorders.
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  So genome does not mean that you've done every genetic test.
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  So I know that's a very kind of hard slide, and I've talked a mile a minute,
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  but we're going to break this slide down and think in terms of categories,
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  which makes it a lot more fun and easy to remember.
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  So, if you think about the expansion of genetics over the last decade,
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  which is projected to continue, it really can be very overwhelming.
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  Which category am I in? What test do I order? Do I just genome everybody?
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  And by, again, looking at the history, we can make it less overwhelming and
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  we can think in context of the decades and how we can still be with our patients.
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  So I know there's this idea that Texans have a lot of pride.
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  I don't know if that's true or not.
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  I've only been to Texas twice, but I know you know that you became a state in in 1845.
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  And so does anybody know when Hawaii and Alaska became a state and why that's
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  important, why that was a very important year for geneticists?
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  They became a state in 1959.
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  And the 1950s were a very exciting year for geneticists because before the 1950s,
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  you could be a cardiologist, you could be a pediatrician, but you couldn't be a geneticist.
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  In 1953, that's when Watson and Crick resolved the DNA structure of the double helix. There they are.
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  In 1956, Tiho and Levin discovered that human cells contain 46 chromosomes.
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  And then Lejeune in Paris in 1959 discovered that patients with Down syndrome had trisomy 21,
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  the same year Alaska and Hawaii became states that I'm sure all of you have,
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  many of you have traveled to and enjoy.
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  And so here we are with our chromosomes, three copies.
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  They had trisomy 21. Unfortunately, in the 1950s, many of these patients were
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  institutionalized and marginalized.
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  However, now we know with great loving care, these kids are such a joy and can
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  grow up doing all sorts of things.
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  And it's a lot of fun to interact in my daily clinics with many of the kids
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  that have Abdown syndrome.
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  So in the 1950s, you can see the ads about starting soda early.
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  They say how soon is too soon and that drinking the soda can help you fit in.
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  So hopefully we've learned a lot in the 1950s and we're no longer giving our
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  babies the same baby bottles full of, you know, these soda drinks,
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  although we are giving them our smartphones now and I'm not sure what's better
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  or worse for brain development.
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  But in the 1950s, we could start diagnosing trisomy 21, 18, 13,
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  Klinefelter and Turner syndrome. And that was about it.
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  And through the 1960s, the techniques with banding became more elaborate.
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  And maybe all these kids that were growing up on all the candy,
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  one can argue that they pursued some other things in the 1970s.
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  But regardless, meanwhile, here was Singer sequencing DNA in the 1970s for the first time.
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  And then genomics began to amplify in the 1980s.
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  And you started to be able to discover by the end of the 1980s,
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  Francis Collins, there he is shaking somebody's Craig Ventures hand,
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  but he was kind of the rock hero of genetics.
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  And he actually plays genetic songs that everybody wants to go on YouTube.
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  He plays the guitar. He's sort of the rock star of our field because he was
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  the one in combination with Dr.
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  Chi that sequenced one of the biggest genes, the CFTR gene.
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  So remember when you were growing up or some of us, a lot of you are younger
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  than I am, but you were growing up with your speaking spells and your cabbage touch kids in the 1980s.
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  And this was happening at the same time, because if you could sequence the largest
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  gene, that means you could sequence all the genes.
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  So before Before late 1980s, early 1990s, you could not verify a diagnosis of
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  Marfan syndrome. It was all clinical.
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  And then in the 1990s, not that much happened with testing except,
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  remember the fish probes, is anybody as old as I am, where you could start to fish,
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  meaning that if you had a group Proof of genes missing, you could design a fluorescent
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  probe for something like 22q11 deletion syndrome,
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  Wolff-Hirschhorn, Creedish, Schatz, Smith-McGinnis, Williams,
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  and you could go after that one condition.
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  And just to break it up, because I know it's early in the mornings.
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  That was the top song in 1990
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  rock set when all this fish stuff was happening just to bring you kind of back
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  and wake you up in the morning but at that point i when i started training as
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  a fellow i was so happy i was the tourist trap version of genetics because they
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  were so academic They got to spend an hour with the patients.
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  They could only order chromosomes and fish. Can you imagine?
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  That was so much fun. So as the decades went forward, we got the Human Genome Project.
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  And here, if you remember, and this is not political, this is just about history,
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  but here's Clinton with Francis Collins and Craig Venture.
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  Francis Collins led the public effort for the sequencing of the Human Genome Project.
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  And many of you might remember that Craig Venture featured in all these Time magazines of the year.
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  He led the private effort, but then he ended up making that private information
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  public to kind of validate the public genome.
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  And by the year 2000, there was the first rough draft where,
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  again, if you could sequence one gene, you can sequence all the genes.
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  And now we could start testing for those single gene disorders.
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  And, well, the year 2000, and let me just tell you what the top song was then.
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  Were any of you Faith Hill fans, that was the top song in the year 2000.
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  And while that was happening, something very interesting happened.
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  These genome companies started popping up. And I had a very good friend, mentor.
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  She was a lab director at Einstein, really good clinician. and her best friend
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  went to work for one of these genetic companies.
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  And they were kind of in their heyday. They were offering very expensive tests.
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  And so her friend got the, you know, million dollar mansion.
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  And I remember thinking, that's not why I went into medicine.
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  But I could see that a lot of people were going to these companies and those
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  tests were very expensive.
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  And suddenly suddenly we had a new test, which was the microarray,
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  where patients were getting these tests and figuring out diagnoses that they didn't know they had.
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  And we were learning so much. So we went from only being able to order chromosomes,
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  FISH, and a few single gene disorders like Marfan.
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  We could also do some fragile X testing to suddenly being able to offer this
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  to every child with major intellectual disability, delays, unusual family features,
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  multiple congenital anomalies.
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  And we started making a diagnosis of about 10 to 20% of kids in the year 2000.
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  And so you can see, this is by Dr. Ledbetter et al. He goes through as well.
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  Name your category. In the 1960s, those chromosomal disorders,
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  we get better and better with span techniques.
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  In the 1990s, we start recognizing microdeletion duplication syndromes.
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  And in the year 2000, we start going across the genome for big pieces missing or added.
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  And then something new happens. All these panels start coming out with single
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  gene disorders together.
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  And then Exome only emerged in 2005 or so as a major player.
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  And now they're saying, if you just take somebody with autism,
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  intellectual disability,
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  non-dysmorphic, you have more of a 30 to 40% chance of a diagnosis with Exome
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  versus your 10 to 20% chance with that SNP array looking for pieces missing.
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  Are added. So it's been really interesting to practice with this exome test available.
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  And then of course, in 2010, genome started emerging,
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  but it's really only starting to make its way into clinic right now,
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  where we're deciding, oh, do we order exome, which has a lot more data and analysis in it?
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  Or again, do we order that genome, which includes, it's basically like an exome
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  plus micro deletion and duplications, but it's not perfect either.
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  And it has a lot more variants of unknown significance.
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  So that's the framework where we are now.
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  And as all of this genetic testing expands, we are challenged.
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  And this has been a question since 2010.
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  It was very trendy for people to write articles, genotype first.
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  We just have a newborn screen. We genotype type everybody for everything.
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  But I want to tell you that I truly believe that we all became doctors.
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  We're pediatricians. I'm a geneticist because we like being with our patients.
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  And that is still a skill.
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  And AI isn't going to smile, interact with them, get to know what's special about them.
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  So I would argue it's more fun.
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  It's more interesting. And it's also more medically critically impactful,
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  especially because if you just order all these genetic tests,
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  you're going to get so many variants and you won't be able to explain any of
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  those variants if you haven't been with your patient to get to know them,
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  their natural history and what they have and place that into context with any result you get back.
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  So I want to say, let's continue on as long as we can enjoy the phenotype first model.
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  And then we'll use our genotypes in a smart, very thoughtful way that keeps
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  us engaged with our patients and having fun with them.
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  And so there's a three-step solution for people who would like to continue,
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  as long as we can ride this out, our phenotype first model.
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  We do a detailed clinical analysis.
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  Then we use our resources. You only need two as a pediatrician to be like a geneticist.
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  Go to OMIM and do the clinical synopsis button. That will tell you the features
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  of a particular disorder.
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  And you can also type gene reviews with an S for any disorder.
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  And it'll tell you everything any geneticist knows if you're suspecting a condition.
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  So let's take this beautiful child and let's think with a phenotype-first approach.
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  But there is one problem to it. You have to be there next to the patient.
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  You have to actually do the work as a doctor to have this model,
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  but it will save you so much time of unnecessary testing, and it'll also make life more fun.
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  So let's try it for the patient I just showed you.
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  So in the phenotype first approach, you think what condition might match.
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  You think about the history of their present illness. So this child came and
• 23:41
  she had a little bit of delay and she has a father who was a little delayed.
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  And when he was younger, he was obsessed with dinosaurs.
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  And she is kind of obsessed with a certain television show and only wants characters from that.
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  And she came in because she was a little bit small for her age.
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  And on physical exam, we noticed the hyper telurism, the wide space nipples,
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  and she was sent to the cardiologist and they had a little bit of pulmonic stenosis.
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  So of course, our clinical conclusion is Noonan syndrome.
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  And we ask ourselves, is genetic testing indicated in the first place? Well, sure.
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  And we are thinking of rasopathies, the most common being PTPN11,
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  which is a single gene autosomal dominant disorder. Of course,
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  we could have de novo people.
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  And so once we've done our clinical analysis, we suspected Noonan syndrome,
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  we sent a single gene, she has Noonan syndrome.
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  And 99% of the time, if we just fill in this box, we can make diagnoses quite
• 24:48
  easily in genetics, it's really not hard.
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  It just takes the right process.
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  And really, I try to get the fellows and the residents to just fill in the blanks.
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  And I try to do it on every patient, every time myself.
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  So if we think about it, we're going to practice doing this together,
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  because practice every patient, every time makes the right approach.
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  And so we see these lovely ladies and they might have a bit of a wide spaced.
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  Neck. They might've come because of short stature. They may have had swollen
• 25:28
  hands and feet in particular when they were younger.
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  They're doing well in school most of the time. They may be petite.
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  And so what category are we thinking?
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  We're thinking chromosomal. What decade could we have diagnosed them?
• 25:45
  We could have diagnosed them in 1960, right?
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  And what test? Our chromosomal test.
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  Please feel free in your chat to make a guess.
• 25:56
  Now, what about this? These lovely girls, they also have short stature.
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  One of them has a cleft palate.
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  One of them has tetralogy of fallot. They have hypocalcemia.
• 26:10
  One of them has immune problems. All of you are thinking, what category?
• 26:17
  Microdeletion duplication disorders. What decade could we have diagnosed them.
• 26:22
  We could have fished in the 1990s. Today, we send a chromosomal or microarray or snip array.
• 26:28
  Right? What about this one? What is our category? These patients have a little periorbital edema.
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  They might have kind of loose joints. They may be delayed, but super social and interactive.
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  They'll run in your lap. They might be small for their age.
• 26:47
  They may have lips that look a little bit thick as they get older and gaps between
• 26:52
  their teeth. They might have hypercalcemia.
• 26:55
  And because this is a microdeletion duplication syndrome, we have Williams syndrome.
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  Again, FISH or microarray analysis, again, could have diagnosed them in 1990 or 2000.
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  And with Williams syndrome, it's important, a pearl to remember is that aside
• 27:13
  from the supravalvular aortic stenosis, renal artery stenosis due to the elastin changes.
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  Please remember to take care of these kids during anesthesia because there can
• 27:22
  be sudden death. So don't do unnecessary anesthesia with these children.
• 27:26
  And then what about this condition? Again, you're seeing facial features,
• 27:31
  the prominent forehead, the hyper telurism that are different.
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  And most of these kids have serious epilepsy and they're diagnosed and nobody
• 27:41
  reminds them to go to neurology and they come in in status.
• 27:45
  This is, again, microdeletion or duplication syndrome. Could have diagnosed them in 1990, 2000.
• 27:52
  We can send either our fish, which nobody ever does, or a micro-erase nip. This is Will Pershorn.
• 27:57
  And please remember that they really have epilepsy.
• 28:01
  So be proactive about getting them to a neurologist who's on board with treating
• 28:04
  them early and aggressively.
• 28:06
  And then we have these kids. Again, this was, there was an article in the New
• 28:11
  York Times in around 2004 talking about them.
• 28:14
  They have small palpebral fissures, a broad flat nose, autism.
• 28:20
  Because they have more facial features that are different from their parents,
• 28:26
  they would have been better candidates for microarray.
• 28:29
  They have 16p11.2 duplication, but microarray testing versus exome approach,
• 28:36
  which is better for those kids that are kind of non-dysmorphic severe autism.
• 28:42
  And so I already had mentioned, now we're in a new category.
• 28:46
  This is a child, we talked about this a little bit earlier.
• 28:51
  Say that a lot of my patients with connective tissue disorders,
• 28:54
  instead of the Leonardo da Vinci circle, they're ovals, right?
• 28:59
  Long, long arms, might have a pectus, might have a high arched palate,
• 29:04
  may have flat feet with hind foot deformity.
• 29:07
  This is Marfan fibrillin mutate variant, pathogenic variant.
• 29:12
  We would have been able to diagnose him by about 1991 or 1992.
• 29:17
  And this is another patient next who has, again, a single gene disorder, short stature.
• 29:25
  I'm sure you can recognize that the single gene change in FGFR3 causes over
• 29:32
  inhibition of the chondrocytes.
• 29:35
  But what's really exciting about achondroplasia is that there are new treatments
• 29:39
  that stimulate those chondrocytes.
• 29:44
  And the two clinical pearls as a pediatrician to remember for achondroplasia
• 29:48
  is that if they present with sudden vomiting when they're little or severe headaches,
• 29:56
  they might have compression of the foramen magnum. That's an emergency.
• 29:59
  And you really want to monitor the head circumferences because some of these
• 30:03
  kids have hydrocephalus. And again, the third pearl is the treatment.
• 30:08
  And we would have been able to diagnose, again, her disorder by the 1990s with
• 30:14
  our single gene testing.
• 30:15
  And you can still use the same single gene testing in those patients or a small panel.
• 30:20
  If you think they have Marfan syndrome, you don't have to order an exome.
• 30:24
  And now here's another patient.
• 30:28
  And I mentioned this already, but just to drag the point home,
• 30:31
  so very long face, big ears.
• 30:34
  The females tend to be very shy.
• 30:37
  They can have autism too. They tend to have more prominent foreheads, joint hypermobility.
• 30:44
  In the males, we see the testicular enlargement, but only when they're in puberty.
• 30:48
  It's not like you're seeing that on a baby.
• 30:51
  And many times now we're diagnosing this when the mothers in certain states
• 30:56
  have prenatal screening and are found to be pre-mutation carriers,
• 31:00
  and then the babies will actually come.
• 31:02
  But otherwise, it's diagnosed very, very late. And when you diagnose one person,
• 31:06
  you diagnose a whole family.
• 31:08
  We're in the category of repeat disorders, fragile X.
• 31:13
  By the late 1990s, early 2000, we could test for these repeat disorders.
• 31:17
  Disorders and then now we're
• 31:20
  into our methylation and
• 31:25
  so we have these kids these babies the first two that baby is adorable laughing
• 31:32
  all the time but a horrible sleeper these parents are so tired who come and
• 31:38
  as the baby gets older doesn't talk might have seizures and the gait in the
• 31:43
  older children is very ataxic.
• 31:46
  And so you're thinking about Angelman, which the most best test would be a methylation test.
• 31:54
  We won't go into the details. And you could also do methylation tests even as
• 31:59
  early as in limited scenarios, as early as the 1990s, 2000s for certain conditions.
• 32:11
  And maybe a nevus flammus, maybe you look behind the ears, it railroad tracks,
• 32:16
  and this is Beckwith-Wiedemann syndrome, another disorder where methylation
• 32:21
  and printing tests would be your category.
• 32:24
  But now that we've kind of thought about the decades, thought about our genetic
• 32:29
  categories, in the real world.
• 32:34
  Things are always a little more complicated. The doctor says,
• 32:38
  I'm not sure of the cause. I think it could be due to alcohol.
• 32:40
  And the patient says, that's okay. I'll come back when you're sober.
• 32:45
  So the idea is that in the real world, we all have these feelings.
• 32:50
  Many of us, of course, it's not alcohol. It's sleep deprivation.
• 32:54
  It's too many sources where we are overwhelmed with our EHRs,
• 32:59
  our pagers, our phones, our our emails, and we have time for everything but thinking.
• 33:05
  And so we really need to remind everybody, look,
• 33:10
  we need our time to think, to sit there for five minutes with the patient and
• 33:15
  forget everything else and do, as I mentioned,
• 33:18
  that detailed clinical analysis to use our resources and consider where were
• 33:24
  we in the past with all this testing and what can the future bring to use the
• 33:28
  best of the past for this patient again.
• 33:32
  And that is a daily struggle for all of us in practice with this so many paper
• 33:37
  reality demands of us today.
• 33:39
  But I encourage everybody and I try to make a commitment to that every day.
• 33:44
  I'm going to, just like I take time to eat or answer emails,
• 33:49
  I'm going to take at least five minutes with this patient and sit there and
• 33:52
  think. And I try to tell the fellows.
• 33:55
  So this was a 12-year-old. Previously, this is a true story,
• 34:00
  my patient, previously healthy boy who presented with increased clumsiness.
• 34:07
  The dad said he acted drunk sometimes.
• 34:10
  He had grades and concentration. His handwriting was getting worse.
• 34:14
  He wrestled as a sport and had some decreased performance and shortness of breath.
• 34:19
  And the cardiology evaluation showed some question of cardiac hypertrophy.
• 34:25
  And so the question was, what was the best genetic test? How do we diagnose
• 34:30
  them? And he went to neuromuscular clinic.
• 34:33
  And the question is, what would you have done? A neuromuscular panel,
• 34:37
  an exome, repeat disorder testing, chromosomal microarray, or methylation study?
• 34:43
  I can't see the chat, but I can tell you what
• 34:46
  the neuromuscular guess what the neuromuscular specialist did a neuromuscular
• 34:51
  panel right so it was negative then he came to genetics six months later with
• 34:56
  worsening symptoms sometimes requiring a walker so what do we do now we do our
• 35:02
  handy dandy approach we fill out the table.
• 35:07
  So we do the clinical work. He's had some ataxia, some slurred speech.
• 35:12
  He was falling while playing lacrosse and also in wrestling.
• 35:15
  He was 10, previously healthy. The exam showed decreased reflexive and a murmur.
• 35:21
  His echo, there was that concern about hypertrophic cardiomyopathy.
• 35:25
  People say never to use Google. I disagree.
• 35:28
  If you know what to Google, what to put in your chat GPT, these things can be useful.
• 35:35
  And a simple Google search would reveal that there is nothing else that causes
• 35:39
  ataxia, progressive degeneration, and hypertrophic cardiomyopathy except Friedrich's ataxia.
• 35:46
  But that's not on a neuromuscular panel. That is a repeat disorder.
• 35:51
  And that is what he had. So this table, just doing the table,
• 35:56
  could have prevented six months of an extra diagnostic odyssey.
• 36:00
  It's an autosomal recessive disorder.
• 36:02
  Each parent was a carrier. It's on two different alleles. It's Friedreich's
• 36:06
  ataxia. And time is of the essence.
• 36:09
  So you want to do the tables and the right testing because now there's a new
• 36:14
  FDA-approved treatment that we are getting him on, which is an activator of nuclear factor.
• 36:21
  So the excitement of the Genome Project is all these new treatments.
• 36:25
  But if you miscategorize them and do the wrong thing, you waste time.
• 36:30
  And that is time away from treatment. So now, case two, to test or not to test.
• 36:39
  So because of my work in the Ray Helfer Society, it's a nonprofit for child
• 36:43
  protection, it's academic, and that's a whole saga in my life.
• 36:46
  But because of it, I do always like to present the other side of cases where
• 36:51
  we might think about, do we need to test this baby with genetic testing?
• 36:56
  So we have a two-month baby, also a true case of mine, reported apnea.
• 37:02
  Parents report previous difficult feeding and colic, otherwise healthy.
• 37:06
  Parents are first cousins.
• 37:08
  Ophthalmological exam reveals bilateral retinal hemorrhages diffusely located.
• 37:13
  The imaging shows subdural hematoma, many rib fractures, and the parents are
• 37:19
  described as very caring and nice by the bedside.
• 37:23
  So he's not supporting the head while on exam.
• 37:26
  We don't see bruising. There's hypotonia. The head is on the large side,
• 37:32
  and the pediatric resident who does take a history said, oh,
• 37:35
  oh, there's consanguinity.
• 37:37
  Consanguinity says this must be metabolic. And when you re-go take the history,
• 37:42
  the parents say, oh, maybe there was a little delay in motor skills.
• 37:46
  This is a tiny baby. Maybe he wasn't rolling over that well.
• 37:49
  He wasn't smiling that much.
• 37:52
  And so what do you do next? Do you follow up on the newborn screen results?
• 37:57
  Do you send metabolic testing, including something called a urine for C5DC.
• 38:04
  I'll explain what that is. Do you do a personalized sequencing panel for every metabolic disorder?
• 38:10
  Do you do exome testing or do you do genome testing?
• 38:15
  So the disorder that the resident was rightfully concerned about was glutaric acidemia type 1.
• 38:22
  It has an incidence of 1 in 30,000. This family was not Amish,
• 38:26
  by the way, where the incidence is higher.
• 38:28
  And it often presents with dystonia after viral illnesses.
• 38:33
  In this disorder, we see retinal hemorrhages in the posterior pole, not diffuse. use.
• 38:39
  And macrocephaly is defined as 98%, but this baby's head circumference is 90%.
• 38:46
  So it does have a generous head, but so do the parents when you measure their
• 38:50
  heads and not true macrocephaly.
• 38:53
  And the MRI in this disorder shows widening of the sylvan fissures,
• 38:58
  expansion of the CSF spaces, but this baby's MRI only shows the subdural, no other issues.
• 39:05
  So actually in doing the deep probe, This child's findings do not match glutaric acidemia type 1 at all.
• 39:17
  The retinal hemorrhages are different
• 39:19
  once you compare in your clinical synopsis and your gene reviews.
• 39:23
  The MRI findings are different.
• 39:27
  And in glutaric acidemia, babies don't fracture. So unfortunately,
• 39:32
  the multidisciplinary team believes that this is child abuse.
• 39:38
  But we send the testing, and the testing shows in glutaric acidemia,
• 39:44
  almost 100% of patients, even the low excretors, have abnormal elevated C5DC.
• 39:53
  And in this patient, that lab comes back normal, ruling out biochemically glutaric
• 40:00
  acidemia, and it is repeated three times.
• 40:03
  So should genetic testing be indicated in the first place?
• 40:07
  If you're going to do the genetic testing and variants return,
• 40:10
  that might be difficult to interpret.
• 40:13
  And there is when there's yet another handy dandy table.
• 40:17
  And I ask people as an exercise, let's think about the benefits versus the risks
• 40:22
  of genetic testing if we're testing for disorders where we have clinically and
• 40:27
  biochemically, for example, no suspicion whatsoever.
• 40:32
  And so on the one hand, if there's a diagnosis present, that's wonderful.
• 40:37
  Fault. That's knowledge.
• 40:38
  But on the other hand, if there's a misdiagnosis based on a variant or confusion,
• 40:43
  that can cause a lot of anxiety.
• 40:46
  And it can cause us to focus on the wrong things.
• 40:51
  If there's a real diagnosis, there's potential for early and improved treatment. That's wonderful.
• 40:56
  But if there's misdiagnosis, we might blame everything on the misdiagnosis.
• 41:01
  Or if there's a genetic disorder like Down syndrome, we might do diagnostic
• 41:07
  overshadowing where every single symptom, they have fractures,
• 41:10
  which we don't see in Down syndrome, but we say it must be their Down syndrome.
• 41:14
  We don't want to do that either.
• 41:16
  For relatives, it can give them prenatal risk counseling, but when a diagnosis,
• 41:20
  a misdiagnosis is believed, there could be fear of sudden catastrophic events,
• 41:26
  metabolic episodes like dystonia that aren't going to actually happen in this baby.
• 41:30
  We want the potential to confirm a genetic diagnosis and as an explanation,
• 41:35
  but on the other hand, we don't wanna use an erroneous diagnosis if it's not true.
• 41:40
  We wanna advocate for patients using these diagnoses, but if they have a diagnosis
• 41:46
  that's not real, they may be considered more medically fragile,
• 41:50
  which could affect their adoption, home placement, future life insurance.
• 41:55
  Incidental finding can lead to medically actionable plans later in life.
• 42:00
  But again, if you find a BRCA mutation in a baby, what is the implication or
• 42:05
  a cardiac arrhythmia gene for their future military service?
• 42:09
  So we want to provide all of our latest technology and resources,
• 42:14
  but we also don't want to erroneously deprive vulnerable or any other children
• 42:19
  of their choices in genetic testing.
• 42:22
  So it's a hard balance. There's no easy solution, but at least let's think before
• 42:27
  we reflexively order exome and genome on everybody.
• 42:30
  So in this particular case, biochemical testing over and over again,
• 42:36
  the clinical findings ruled out glutaric acidemia, but another colleague before
• 42:42
  I arrived to this case had ordered an exome.
• 42:45
  And it came back with a likely pathogenic variant in glutaric acidemia,
• 42:51
  as well as a variant of unknown significance.
• 42:54
  So now she said, I was correct. I ordered the exome. I'm very good friends with
• 42:58
  this colleague, which has had a different of opinion.
• 43:02
  Then there was a likely pathogenic change in an osteogenesis imperfecta gene.
• 43:07
  And there was an incidental finding of hereditary hemochromatosis.
• 43:12
  So what do we do? We have to think about the pretest probability,
• 43:17
  the database and literature review, the inheritance pattern.
• 43:21
  We do not have to think so much about paternity and consanguinity,
• 43:25
  and we have to think about the phasing with these variants.
• 43:29
  And so what we do is we do a very simple process, just like we do simple clinical work.
• 43:36
  We do the same thing with variants every time. The biggest thing is our pretest
• 43:41
  probability, the clinical work that came first.
• 43:44
  Do we think this is glutaric acidemia?
• 43:46
  As I've told you, we do not. Then we search our databases like ClinVar,
• 43:52
  Franklin, Decipher for variants that have been reported.
• 43:56
  And how likely is this variant to be real? We think about our inheritance pattern.
• 44:01
  If there is one variant in an autosomal recessive disorder, that is not enough
• 44:05
  to call it a disorder. You need two.
• 44:08
  We classified the variants after that using the American College of Medical
• 44:12
  Genetics guidelines and pathogenic, it really causes it, likely pathogenic,
• 44:18
  a variant benign or likely benign.
• 44:22
  So we use that same genetic approach that we used for clinical approaches every
• 44:28
  single case, we get a variant.
• 44:30
  So like I said, if you have an autosomal recessive disorder,
• 44:36
  you need two variants, one on each allele.
• 44:39
  But if you look at this, there could be a situation where somebody has two variants on the same allele.
• 44:46
  So one gene is affected, but in autosomal recessive disorders,
• 44:52
  usually if you have one gene that's working, you don't have the disorder.
• 44:55
  So you could also be very confused and see two variants and assume the patient has a disease.
• 45:01
  And unless you've done phasing and you know that the variants are on opposite
• 45:06
  alleles, they may not have that disease.
• 45:08
  And so, again, I know all of this seems kind of overwhelming,
• 45:12
  but that's why we don't want to order genetic tests.
• 45:16
  And risk variants if we're not ready to do the work when they return.
• 45:20
  So the true outcome was that the child was a carrier for the disorder,
• 45:25
  but not affected for GA1.
• 45:27
  Both of these variants, when the parental testing was done, were found on one allele.
• 45:34
  Yes, it's a coincidence that the child was a carrier for glutaric acidemia,
• 45:37
  but the child was unaffected. It came from one parent.
• 45:42
  The C5DC, like I'm saying, was normal. The serpent app was autosomal recessive,
• 45:49
  and there was only one variant, and you need two in this rare form of autosomal
• 45:54
  recessive osteogenesis imperfecta.
• 45:57
  So the child did not have osteogenesis imperfecta as an explanation for the rib fractures.
• 46:02
  And the child was affected with hereditary hemochromatosis,
• 46:07
  a mild form, where later in life, if you're male, you might want to give blood
• 46:11
  transfusion, donate blood so that your blood does not, your iron is not too
• 46:17
  high in your liver and so forth, but really didn't cause a problem for this baby.
• 46:21
  But because of this genetic testing in the civil proceedings,
• 46:25
  the diagnosis was made of glutaric acidemia type 1, osteogenesis type 6.
• 46:33
  They said that the hereditary hemochromatosis caused the child's liver injury,
• 46:38
  which we we believe was unfortunately from abuse and the criminal proceedings
• 46:43
  were dropped and the child was returned to the home. So again.
• 46:49
  I have kind of hoped to show you through that kind of sad case that we really
• 46:55
  want to think before we just reflexively send genetic testing for everybody,
• 47:00
  because particularly in vulnerable children,
• 47:02
  genetic testing is not always of benefit.
• 47:06
  Now on to kind of our last case in the real world.
• 47:10
  And this is, again, just to practice using our handy dandy tables and systematic process.
• 47:15
  So, this is a case that I think is a little bit more uplifting than the one
• 47:20
  I presented a minute ago, where there's an otherwise healthy boy with appropriate
• 47:25
  development and first evaluated for gait abnormalities at 11.
• 47:29
  He reportedly always carried his right arm at an abnormal angle when running
• 47:34
  and increased his gait disturbance over the right side in the preceding two years.
• 47:39
  And initially, orthopedic evaluation raised concern for a tethered cord,
• 47:44
  but a neurological concern raised concern for right hemiparesis with a gait
• 47:51
  characterized by kind of the circumduction of his elbow when walking. It was really unusual.
• 47:58
  And so we did the clinical work.
• 48:02
  This was my colleague, Dr. Seth Berger, who did this case. And the child had
• 48:07
  an atypical gait. It was getting worse over time.
• 48:09
  Otherwise, a completely unremarkable examination. He was smart, doing well in school.
• 48:15
  And the clinical conclusion, there wasn't a lot of laboratory data, was we just don't know.
• 48:21
  And this is where, because exome does have, with these really neuroatypical
• 48:27
  disorders, a 30% to 40% diagnostic yield, he sent the testing. Okay.
• 48:33
  And when the testing came back, there were two variants in a gene called GCH1,
• 48:40
  guanosine triphosphate cyclohydroxylase.
• 48:43
  And because he had a really good clinical picture of an unusual gait,
• 48:48
  he went back and looked at those variants.
• 48:50
  And it turns out that they've been reported with hyperphenylalanemia in some cases.
• 48:55
  But in rare cases, they don't lead to what we call hyperfi.
• 48:59
  But rather there's a central tetrahydrobioptrin deficiency, decreasing tyrosine
• 49:06
  hydroxylase, and that tetrahydrobioptrin deficiency is responsible for dopamine.
• 49:13
  And when he looked through the literature, even though the lab had classified
• 49:17
  these variants as variants of uncertain significance, there were two of them.
• 49:21
  He did parental phasing.
• 49:23
  It was on opposite alleles, and it fit with the potential clinical.
• 49:28
  So he did more testing and he hadn't ordered a chromosomal test.
• 49:34
  This patient didn't have Down syndrome.
• 49:36
  He didn't look like a microdeletion syndrome. He didn't look like Fragile X or anything.
• 49:40
  The neuromuscular panel at that point was not gonna be any higher yield than
• 49:44
  the exome because if you have a differential of more than 25 genes,
• 49:49
  they're encouraging exome right now.
• 49:50
  Again, not on everybody, but on cases where you think that something neuroatypical
• 49:55
  and truly unusual is going on, it might be a reasonable approach.
• 50:01
  And so this is the outcome of his walk before and after.
• 50:07
  So you can see that before dopamine treatment, and let me play it again,
• 50:13
  it's much more of a subtle circular gait and his walk is a a lot better after dopamine treatment.
• 50:21
  So this is just to show that when you follow a clinical approach,
• 50:27
  even if you don't know, but you've tried your best to kind of categorize the
• 50:31
  patient, and then you do order a broader test like Exome because you've carefully
• 50:37
  thought about its use, its implications, the risks versus benefits,
• 50:41
  and you get variants of unknown significance back when you've really thought
• 50:46
  about your clinical, you can then spend some time interpreting those variants
• 50:50
  and you can make a difference.
• 50:53
  And about out of all the people that get exomes, maybe three to 5% will come
• 50:57
  back with something actually treatable, like in this case.
• 51:01
  And that's why we're really there for these patients to interact,
• 51:05
  engage, and always think, are we ordering something where we will identify a
• 51:09
  treatable condition that will have impact?
• 51:16
  And So just to summarize, let's all encourage a phenotype first approach.
• 51:22
  It's a lot more fun to engage with these beautiful patients and try to make
• 51:26
  a guess, even if we fail forward, even if we're wrong.
• 51:31
  We're really, Dr. Kamat and I were talking about how it's still better to make
• 51:36
  a guess of your top three because that distinguishes you as a doctor from any
• 51:41
  other service professional or nurse practitioner,
• 51:45
  physician assistant, whatever you are that brings so much joy and care for kids.
• 51:50
  It distinguishes you as an expert in your field.
• 51:53
  Then after we've named our category, thought about what decade could we have
• 51:57
  diagnosed them? And if we could have diagnosed them in the 1990s or year 2000s
• 52:02
  with a more simple test, maybe we should still use that simple test approach.
• 52:07
  We don't need all these extra layers of variants and a more modern approach.
• 52:12
  The simple test and solution works and is faster and cheaper.
• 52:17
  We're going to consider the benefits versus risks of ordering our tests.
• 52:21
  And we're going to be with our patients. And my daughter, who's about to go
• 52:25
  to college, was so funny. She does a lot with Best Buddies and Special Olympics.
• 52:30
  She's considering being a special education teacher.
• 52:33
  It's kind of cute. And she lectured me the other day and said.
• 52:36
  Mom, I bet you're not talking directly enough to your nonverbal patients because
• 52:41
  nonverbal patients can interact and talk too.
• 52:45
  They may not speak, but they can still engage.
• 52:47
  So following my daughter's advice, I made extra special care in my clinic last
• 52:52
  week to really talk to these kids.
• 52:55
  And it was so rewarding because they did talk back to me in their own ways,
• 53:01
  whether pointing or engaging.
• 53:03
  And that was just such a joy. So let's be with our patients and take time to think about them.
• 53:09
  Every patient will have a lot more fun, despite all the pressures of medicine.
• 53:13
  And I want to thank Dr. Kamat, who is just such a star and amazing contributor
• 53:18
  to the pediatric field, and all of you, my colleagues, both in the Rare Disease
• 53:23
  Institute and Child Protection colleagues.
• 53:25
  And please come visit us in D.C.
• 53:29
  Thank you. And I would love to take any questions.
• 53:33
  Yeah, I'm just...
• 53:35
  Curious, you mentioned things in your presentation.
• 53:40
  Anyway, thanks for a wonderful presentation and a joyous one.
• 53:45
  Where we're having to deal with relatively common tetradogenic events that occur
• 53:53
  as prenatal exposures but are not genetics.
• 53:56
  And about the sort of total ecology of running every possible genetic test and the cost of doing that.
• 54:05
  Financial cost as well as the clinical and emotional cost of doing all of that.
• 54:12
  When the child was gestated and born in a toxic environment,
• 54:21
  on the peninsula, organic toxins for agriculture are the most obvious one,
• 54:28
  which you mentioned, which is prenatal exposure to alcohol.
• 54:31
  Or maybe it's the mom who's on phenobarb.
• 54:35
  Feature disorder and how far what
• 54:38
  exactly how to balance this ecology in terms
• 54:42
  of resets the time and assets that
• 54:45
  we have available when we're trying to differentiate between
• 54:48
  let's say some rare satellite amplification syndrome
• 54:52
  versus prenatal exposure to alcohol i mean yeah i know a lot of people for example
• 54:58
  that have done a lot of research really high level research on autism and there's
• 55:04
  about a third of those kids that have small heads and eventually you start to think.
• 55:11
  Maybe this is not genetic. Absolutely.
• 55:15
  And it is a hard balance, but I think what you're getting at,
• 55:20
  and I completely agree, is that, for example, if you're thinking fetal alcohol
• 55:24
  syndrome, there is diagnostic criteria.
• 55:27
  And what I do is I just put the checklist, and then I put this patient has microcephaly,
• 55:34
  the small help ebrile fissures, the flattening of the bridge,
• 55:38
  the hockey hockey stick hand.
• 55:40
  This patient has the neurotypical behaviors.
• 55:43
  And then I tell the families that it depends on the state, but sometimes having
• 55:48
  the diagnosis of fetal alcohol syndrome actually helps with services.
• 55:52
  And sometimes that's enough. And so there are times when it might behoove them
• 55:58
  to hold off on further testing.
• 56:02
  And really instead I say to them, I think we could always do genetic testing,
• 56:07
  but maybe we really want to focus on this diagnosis, the services for this right
• 56:12
  now, and then see them back, do the developmental evaluation.
• 56:17
  Get their early intervention and see them back later.
• 56:20
  And so by really, again, spending time and thinking about what would have the
• 56:26
  most impact for this child,
• 56:28
  many families will avoid testing and are quite reasonable when you refocus them
• 56:36
  and say what the benefit might be of holding off and focusing on something else for a while.
• 56:42
  And I always tell people, if it is a teratogen, like if it's,
• 56:48
  I had a baby with a very, very severe cloacal abnormality and many, many other things.
• 56:56
  And they said, oh, this is maternal diabetes. But the mom really only had one.
• 57:01
  A little bit of diabetes. It was not enough to explain the severity of the disease.
• 57:05
  So I do think that when there is a teratogen present that has a known disease,
• 57:12
  you can also use those clinical, like valproic acetatexase, that you can use
• 57:17
  those clinical features to try to categorize them.
• 57:20
  And then your discussion can follow based on how suspicious you are that it's
• 57:25
  fetal alcohol versus something else.
• 57:27
  Thank you, Dr. Natasha. There is a question from Dr. Buesgenwald.
• 57:30
  Can you share your favorite website resource again for looking up syndromes?
• 57:36
  Yes. So I use two sites. When you go to OMA, which is, you know,
• 57:41
  free, it's very overwhelming if you do a disorder like Noonan syndrome,
• 57:45
  but you have to go to the clinical synopsis section, touch clinical synopsis.
• 57:51
  That gives you all the little things that you want to look for at the bedside.
• 57:54
  And then the other one is gene reviews with an S. So if you type Noonan syndrome
• 57:59
  gene reviews, it's going to give you everything a geneticist would tell you.
• 58:03
  And so, in fact, when I make a diagnosis, I literally pull it up because I like
• 58:08
  to be systematic and I don't want to forget things.
• 58:10
  And I just go through and then I cut and paste it into my note half the time.
• 58:14
  I do the same thing. If there's a variant in somebody for a gene like in a Noonan,
• 58:18
  I literally take the clinical synopsis and then I paste it and I highlight in
• 58:22
  bold what the patient has.
• 58:24
  And if they have the diagnosis, a lot of it is going to be in bold.
• 58:27
  Otherwise, it's not it, usually.
• 58:30
  There is a comment by Dr. Williams, very helpful approach, and thank you for
• 58:33
  reminding us all about the joy and importance of being with the patient.
• 58:38
  Thank you, Dr. Williams. And there's a question by Dr. Perlman,
• 58:41
  are methylation disorders and repeat disorders included in current microarray panels?
• 58:48
  No, they are not. There are rare, so in the SNP array, which has single nucleotide
• 58:54
  polymorphisms, they They do not always have the methylation included.
• 59:01
  However, in cases, for example, Angelman or Prader-Willi, where it's because
• 59:06
  they got two copies from one parent,
• 59:09
  then you will see the same single nucleotide polymorphisms and you'll think
• 59:14
  that they have two of the same chromosome.
• 59:17
  So some of it can inadvertently show it, but not if there's just one methylation
• 59:22
  difference or something. thing.
• 59:24
  So that is why on your boards and in real life, if you suspect Angelman,
• 59:28
  Prader-Willi, Russell-Silver, Beckwith-Wiedemann syndrome,
• 59:32
  certain diabetes things, you really want to go for the methylation test because
• 59:36
  that will show you every type of methylation abnormality and it won't miss them.
• 59:43
  But there are some cases of Angelman or Prader-Willi that are caused by microdeletion.
• 59:47
  There are some cases where you would see uniparental diastomy that SNP can detect,
• 59:51
  but your highest yield is still the methylation category, methylation test.
• 59:56
  That's always on your boards.
• 59:58
  Any other questions, comments for Dr. Schur? This is Ryan Van Ramstorst,
• 1:00:04
  Chief Medical Director for Medicaid CHIP Services in Texas.
• 1:00:07
  Dr. Schur, thank you so much. Just a public service announcement for the group.
• 1:00:11
  Because of legislation from the last legislative session, Senate Bill 989,
• 1:00:16
  which is what we call the biomarker legislation,
• 1:00:18
  the draft clinical policy for Texas Medicaid coverage of things such as whole
• 1:00:23
  genome sequencing will soon be posted to our website for public comment.
• 1:00:28
  I highly encourage all of you to take a look at that and submit a comment if you're so interested.
• 1:00:33
  Your comments help us sculpt the policy and make sure it's in line with clinical
• 1:00:39
  best practice guidelines.
• 1:00:40
  And so just wanted to make that announcement. We anticipate it's going to be
• 1:00:43
  posted within the next week or so.
• 1:00:45
  I'll put a link in the chat to the website where it's going to be posted.
• 1:00:48
  So just wanted to make that announcement because of this wonderful presentation
• 1:00:51
  this morning. Thanks, y'all.
• 1:00:53
  I'm so jealous. I wish that our Medicaid would come to some of of our genetics lectures.
• 1:00:58
  I'm so jealous of how things are being done in your area.
• 1:01:03
  That's wonderful that you're working together on this. That's amazing.
• 1:01:07
  See, we can learn from other states.
• 1:01:11
  I'm going to tell them that.
• 1:01:16
  Music.
• 1:01:18
  Thank you for listening to that
• 1:01:20
  wonderful talk. Click on the link in this podcast for free credit. it.
• 1:01:25
  I'm Holly Wayment, and you're listening to Pediatrics Now. I'll see you next time.