[Dr. Bob Wildin] Okay, just a really quick rundown
on clinical diagnostic criteria,
an overview for this dysmorphology
and clinical assessment module.
So, clinical diagnostic criteria are basically developed
for disorders with significant overlap
so that some clarity can be had with regard to
what the specific disorder is, and whether it meets sort of,
a minimal threshold for being diagnosed
below that threshold.
The specificity of that diagnosis tends to fail.
So they're typically based on large groups
of collaborative data, different clinics,
different sites who come together and compare
their clinical data on physical features,
on ages of onset, behaviors, things like that.
And they come up with, basically a model
where the clinical diagnostic threshold is set,
such that it much more often
correctly diagnoses a patient than incorrectly,
and it may include some scoring systems.
An example that's used in joint hyper-mobility system
is the Beighton, B-E-I-G-H-T-O-N scoring system,
which is basically a standardized score
for generalized joint hyper-mobility.
These criteria tend not to be strictly exclusionary,
meaning that if you don't meet the criteria,
it doesn't necessarily exclude that diagnosis.
But you ought to think twice about relying totally
on that diagnosis because you may be missing something else.
Because the data and the support
and the delineation of individual subtypes of disorders
vary over time as we learn more and more about them,
and we see more patients with more variations of them,
the disease classification systems
and the diagnostic criteria tend to change every,
you know, five, 10, 15 years.
So you do want to kind of try to look for
the most recent version,
because those are the most authoritative
and the most supported by current evidence.
So examples of clinical diagnostic criteria
include those for Marfan syndrome,
for neurofibromatosis type one,
and for Ehlers-Danlos syndrome of multiple types.
I use those clinical diagnostic criteria
to help me decide who needs genetic testing,
and who will not benefit from genetic testing,
and who needs to be followed, prospectively,
with screening procedures.
So, for example, on Marfan syndrome,
most of the time I do a Marfan syndrome evaluation
plus an echocardiogram.
Two evaluations give me a pretty good idea
as to whether or not Marfan syndrome is present.
When things are unclear is when I resort to clinical,
genetic gene sequencing for Marfan syndrome.
The same is true of neurofibromatosis type one.
I often get children who are referred
for multiple cafe-au-lait spots on the skin,
which are themselves benign.
Often they're not present at birth,
they develop in the first couple years of life,
and then they may add more and more spots
or they may become more evident over time.
So having some criteria about what is
just a normal amount of hyperpigmented spots
and what constitutes an increased risk for neurofibromatosis
is an important distinction with respect to follow up.
So that's a system that I use frequently as well.
Ehlers Danlos syndrome,
as I mentioned in the previous lecture, has multiple types,
and the differentiation of those has changed over time.
So I try to use a classification system
and the diagnostic criteria therein
to help define who meets the baseline diagnosis
for Ehlers Danlos syndrome of any type,
much less specific, more concerning types,
such as the vascular ecchymotic type.
So that's a quick overview of clinical diagnostic criteria
and how they're used in the context
of dysmorphology and syndrome diagnosis.
Hi, it's Dr. Bob Wildin again.
I wanted to bring to light some excellent online resources
regarding dysmorphology and syndrome diagnosis.
These are just to supplement
the reading and lecture materials,
and these are resources that you can continue to use
well after the course has completed.
So the first one is a catalog of dysmorphic features,
called "The Elements of Morphology,"
and it is a compendium of standardized terminology
that was arrived at by consensus among dysmorphologists.
It contains an organization, basically by body part,
and has pictures of the features,
which are pretty hard to come by,
in electronic format anyway,
because most of the clinical pictures are in books
or are covered by copyrights.
So since this is something that was developed by NIH,
it should not have copyright protection.
So I'm gonna open this up really quick and,
show you what this looks like.
Maybe make it a little bit bigger.
So it's sponsored by
the National Human Genome Research Institute,
part of the NIH, and it has a little description
of how this was developed.
There's a body with little links for the different regions
that each of the areas is categorized into.
There's also a navigation menu over here on the left side,
which is essentially the same list of things.
So let's go to the lips, mouth, and oral region.
And there's a list here.
I'll kind of scroll down
and you can see the different things.
We talked in the lecture about
thin upper lip or vermilion border.
There's also an averted upper lip.
So there's different kinds of things.
And there's the picture over here.
If you wanna get a better picture of it, you can click on it
and it gives you a little bit bigger thing.
So this lip, this upper vermilion border
is a little bit out-turned, in a way, in this individual.
So they have ears and around the eyes,
head and face terminology, hands and feet, and references.
So this is really a pretty nice resource
for looking for pictures for dysmorphology features
and picking out the right terms
that are associated with them.
Okay.
So we're gonna continue on,
and just to give an example here
are prominent fingertip pads.
It gives a definition and descriptive comments
as well as synonyms and old terminology.
And this is a example.
So it's these little areas on the pads of the fingers
where they're sort of,
it's almost as if the skin is tinted up a little bit.
Those are what we used to call prominent,
fetal fingertip pads, and now they're just called
fingertip pads or prominent fingertip pads.
Okay, so here's another resource called the
"Atlas of Malformation Syndromes in Diverse Populations."
So this is actually a fairly recent resource
that was added when we realized
that most of the picture records we have
for teaching about dysmorphology
were in Northern European populations,
and those derived from them.
So we were missing a lot of ethnic variation and so forth.
And a group got together
and started collecting these images.
It's still a process in the works.
Not all features are represented,
not all syndromes are represented,
but there's a lot of information there.
And if you ever have some question about whether
a particular gestalt faces in an ethnic group
that you don't see very often
is related to the ethnic group, you know,
the features associated with that ethnicity
or is actually really a syndrome associated,
gestalt then this is a resource that you can mine for that.
So the disorders are organized by geographic region
or by syndrome name.
And this picture is of a Chinese girl
with Williams syndrome.
So if you know Williams syndrome,
if you look at the Caucasian pictures of William syndrome,
you can begin to sort of compare
the dysmorphic features that are quite similar.
Sometimes they really look similar and sometimes they don't.
So it's an interesting exercise
and I'll just click on that and open it up
and we'll see, again, it's housed at N-H-G-R-I
and you can, over here on the left,
browse by condition or browse by geography.
And I just clicked on geography.
So Asia, Malaysia, Noonan syndrome.
Since we covered that before, I'm gonna have to,
somehow I lost that opening.
So there's a couple of boys with Noonan syndrome,
in Malaysia.
So, and each of those will expand as well.
So that's a really fun, interesting, and useful resource.
Okay, this is one that everybody should know about.
It's basically a catalog of genetic disorders and genes.
That was really the first medical database
to be developed on a computer, back in the 1960s,
and it was started at Johns Hopkins University
as the Online Mendelian Inheritance in Man.
Before it was online,
it was available on little floppy disks.
And it came after the publication of books.
The online version came after the publication of books,
which were essentially printouts of these really original
electronic databases of Mendelian Inheritance in Man.
So that's kind of an interesting historical point.
The pattern of development of this
was basically that experts would read the literature
and they would add a summary of relevant articles
to an entry that they had created with a number
that made it a specific reference-able entity.
So there's an ID number associated with each entry in OMIM.
And over time, it's kept that basic structure,
but it's added a lot more things,
like a lot of links into other databases at NCBI.
And it has some really useful features,
like clinical synopsis, which is basically a feature list,
and something called phenotypic series is
here is a set of disorders which are either,
you know, identical and non distinguishable
or very overlapping, and what are the sets of genes
and that are associated with that phenotypic series.
And then as I mentioned,
the links to the clinical resources.
So just a really quick look here at OMIM.
And it often comes up with this donation request.
That's has to do with funding.
It's traditionally been funded by NIH,
in particular N-H-G-R-I, and there is some friction
about how much funding it should get.
So they're asking for donations.
You do not have to donate to use it.
So you can search for, let's see,
you can search for a syndrome like Williams syndrome.
All right, and you get a list of things
which have that in the name.
You can, as for most databases, put quotes around a phrase
and try to force it into a phrase.
That sometimes works better than other times.
And even at this level, William syndrome
is the same as William-Beuren syndrome.
You can open up this gene phenotype relationships
and see that this is the only disorder
that's associated with this particular gene
and its inheritance.
So you can go direct, this is its ID number,
and you can go direct and read about
the gene phenotype relationship.
There is a button here that'll take you to a new page
that has a clear description of the clinical features,
but you can also use this quick little dropdown button
to scroll through a summary of what those features are.
And these little blue marks are links
that bring you back into that elements of morphology
that we talked about a few minutes ago.
Okay, so there are links there
that will bring you to pictures of the features.
All right?
So one of the things about this disorder,
Williams syndrome is they have
a gregarious, friendly personality,
and there's this sort of classic phrase
is they have a cocktail party personality.
Well, I don't know whether people know anymore
what a cocktail party personality is,
but it's someone who is able to walk up to other people
and chat with them happily, and everybody has a good time.
That sometimes can compensate,
at least in a casual, social situation, for the fact that
there is mental retardation present in the majority,
but not all patients with Williams syndrome.
So that's the way you can do it.
You can also search for, for example,
let's see, I'm trying to think of something fairly specific.
We could search for
Chiari malformation, which is not gonna be very specific,
and we get a list of disorders that are
named Chiari malformation as well as others
that have Chiari as a common feature there.
So one really quick tip about OMIM
is that in the classification scheme,
the disorders are all given an ID number.
When it looks like it may be a real disorder,
but the gene hasn't been identified,
gene or genes hasn't been identified,
or it's maybe polygenic, it gets a percent sign symbol.
Okay?
So here if you go over that, it says phenotype description
or locus molecular basis unknown.
All right?
Once you find the first gene for it,
then it can convert into a pound sign phenotype description,
molecular basis known.
All right?
So those are ways that you can look and see,
well, you know, if there's no molecular basis known,
genetic testing isn't gonna be available for that.
That's a really quick point.
The other point is that you see some of the ID numbers
start with one, and some of them start with two,
and others yet start with three,
and still others start with six.
So what does that mean?
It turns out that in the original classification,
if it started with a one,
it meant that it was an autosomal dominant disorder.
If it started with a two,
it was an autosomal recessive disorder.
If it was started with a three,
it was an X-linked recessive disorder.
And then it became kind of complicated
because we realized that some of the disorders
had multiple modes of inheritance
or that the inheritance wasn't clear.
And we, the OMIM started classifying those
with a first number of six.
And genes were also classified with the first number of six.
So that system kind of broke down,
but for a lot of places in OMIM you can still utilize
the one, two, and three as a dominant,
recessive and X-linked, and that's still quite accurate
as a way of of finding that.
So when you go to one of these,
let's not pick that one, let's pick a different one.
Let's pick Noonan syndrome.
There's the clinical synopsis, and we've talked,
and it'll have those facial features
that we talked about in the dysmorphology lecture,
and then there's also this phenotypic series.
Now this is a really good example
because there are multiple forms of Noonan syndrome
that are due to mutations in different genes.
They all have clinical overlap, strong clinical overlap,
and it turns out if you are a biochemist
and you look at this, you can say, well almost all of these
are in the same biochemical pathway.
So there's KRAS and NRAS, so they're both RASs,
BRAF is downstream of KRAS, as is RAF1.
PTPN11 is an inhibitor of that pathway.
And so there are a bunch of different genes
which can produce more or less the same phenotype.
And this is a context where you might think, okay,
I am not gonna test for them one by one
because I have a gene panel where I can
look at all of these at once
and come down to the answer fairly efficiently.
I will also point out that there are,
the inheritance pattern is listed here
as autosomal dominant for most of them.
This one, NS2 is autosomal recessive.
There's another one that's autosomal dominant,
that's the same gene, right?
So, and that has this six number at the very beginning
of the gene number and the phenotype number.
So there's these situations where it gets kind of complex.
And then there's another one here,
Noonan syndrome two, autosomal recessive,
probably a case report that has not been mapped,
doesn't have, or does have a gene here,
but it says it hasn't been mapped, which is a bit odd.
In any case,
this resource can provide you a lot of information.
We're gonna close that little popup.
And the organization is pretty much the same
as a one line text summary.
There's a description of the disorder.
It talks about the genetic heterogeneity
that we just just mentioned
and has links to a bunch of other forms of the disorder
and talks about some other disorders
that you might also wanna look at.
A sort of a historical article summary,
a literature summary of the patient descriptions.
Now Noonan is known to be really pretty common.
So we're not gonna get every article
ever written about Noonan syndrome,
but basically how that syndrome
was historically developed through time.
Other features that you might see,
giant cell lesions, hematologic abnormalities and leukemia,
and inheritance patterns, population genetics,
how the gene was mapped,
and chromosome studies that may have been done
early on in trying to find out,
before we had molecular methods, and clinical management.
Mostly OMIM doesn't have a lot on clinical management.
I would go to gene reviews for that,
we're gonna talk about that in a moment.
But it does have a great deal of information
about the disorder, and particularly historically,
and has some of the original references.
Some OMIM entries also have a set of mutant allele.
So before ClinVar and other databases were developed
and we started sequencing genes and coming up with variants
that seemed to be pathogenic,
OMIM was the natural place to record those.
So a number of those are recorded in OMIM,
during a particular time span,
and then other databases kind of took that over.
But that's sort of a legacy feature
that you'll see in many OMIM disorder entries.
Over here in the clinical resources,
you can link to gene reviews,
which we're about to talk about Genetics Home Reference,
which you guys know about.
And GTR, which is Genetic Testing Registry,
we'll talk about that in the testing module,
and other kinds of of resources.
So there's just a navigation panel here on the left.
So OMIM was a really old, a venerable workhorse,
that can be very helpful.
All right, so gonna move on to...
And this was just a picture of Van Der Woude syndrome,
which we saw some lip pictures of,
or in the dysmorphology lecture.
But let's move on to GeneReviews.org.
It's part of the NCBI books,
but most easily reached when you're, you know,
in a browser and some random machine
by typing in GeneReviews.org into your browser address bar,
and it will pull up the gene reviews in NCBI Books.
It is authoritative, curated, updated,
and consistently organized, which really takes it way beyond
most other resources in terms of usability and reliability.
It contains diagnostic and management recommendations,
one of the few places where management recommendations
are clearly laid out.
And it includes genetic information
and genetic counseling overview.
So here's an example of the Williams syndrome area
and rather than open it up,
I'm just gonna sort of point out some areas of value.
Here, so this is the search box you wanna search in,
here, not here.
If you search up here, you get everything in NCBI books.
This one will come up,
but it's much more efficient to search in this box here.
It gives you a summary, which it can be
a couple of paragraphs, three, four paragraphs,
and always has clinical characteristics,
diagnosis, management summary,
and genetic counseling down here at the bottom.
After that is really, essentially,
a full book chapter on this disorder.
And you can jump through the book chapter quite easily
by using this navigation thing over here on the right.
So I'll often go to diagnosis or clinical characteristics,
or differential diagnosis, so I'll say,
it looks kind of like Williams syndrome,
but I don't think it is.
So let me see what other people think
overlaps with Williams syndrome.
What are things that look like it that you need to consider?
And you can just click on that link
and move down in the article to that segment.
The other area I use a lot is the management.
What are the management recommendations
for when a new diagnosis is made?
What are the management recommendations
for annual surveillance or periodic surveillance
for issues that may come up in this disorder.
Molecular genetics may help you understand
the types of testing that may be helpful
for confirming the diagnosis.
And then the genetic counseling section
will tell more in detail about the mode of inheritance,
the genetic counseling issues,
and have resources for that as well.
There is a resource section here,
which is sort of organizations
that focus on that particular disorder
that you may wanna refer your patient's family to
for more support and more information.
So those are all really, really good.
There are links here
which links out to other kinds of things.
It links to the specific tests in genetic testing resource,
which we'll also cover later.
And tests in genetic testing, resource by condition.
And then other related information, OMIM,
PubMed Central, and places like that.
So it's really a very,
it's like having a free book that's updated all the time,
or every year or so, at your fingertips in the clinic.
Quite wonderful.
All right, so I'm gonna quit there
and move off of this lecture topic.
I appreciate your listening and learning
and I think that's the end of my lecture.