Prenatal Diagnosis of Skeletal Dysplasias - HD

Introduction

Hello, my name is Anne Kennedy.

I'm a professor of radiology
and imaging sciences at the University of Utah
and also an adjunct professor of obstetrics and gynecology.

And today I'm going to give you my spin
on skeletal dysplasias.

This talk is being recorded in October
and that's why I gave it the name.

An approach to skeletal dysplasias
that won't rattle your bones for a Halloween theme,
but it's more politically correct.

Title is Prenatal Diagnosis of Skeletal dysplasias.

And I brought this subject up
because it's something that I'm actually rather scared
of in my own clinical practice.

When I was thinking about how to approach it in a way
that wouldn't be intimidating, I decided
to focus on the bone that we all look at all the time.

We are not scared of the femur.

We measure it on every study that we do.

So think about the femur. Are there one or two?

And you might think, really,
but yes, you should check
that two lower extremities are there
and that the femurs are symmetrical and length.

And then you need to look at the length of the femur.

And when we talk about the length of the femur,
what do we really mean by that?

We mean whether it is appropriate
for gestational age or not.

So if the femur is the only thing we're thinking about,
first thing you look at is how does it relate
to the gestational age
and how well do you know the gestational age of fat fetus?

Then you compare the femur length to the BPD
to calculate a risk for trisomy 21.

We do this with both the femur and the humerus
and it's important to realize
that this is a mathematical calculation
of the bone length in relation to the biparietal diameter,
not just to the gestational age.

And then if you do think your femur is not normal,
look at the rest of the bones in that foot.

Look at the tibia and fibula and the foot itself.

If you have a single abnormality in a single extremity,
you can think about limb reduction defects
or amputation perhaps for something like amniotic bands
or in maternal diabetes, you can have a short femur.

You can have foot cordal regression syndrome,
specific entities that go along with that condition

If there's more than one bone involved.

So you've just looked at one extremity,
you've looked at the femur and the tibia
and fibula on that side seem to be small as well.

Then you really need to look at all
of the long bones in that fetus.

And we measure all of them diaphysis
to diaphysis just the same way as we do for the femur.

You should be aware that curved bones can appear
to have different lengths depending on the direction
that you take the measurement in.

Measurements and Ratios

Then you have to do the math.

And I love radiology because it's all about the pictures,
but every so often we do actually have
to do the mathematical slash sciencey stuff.

And one of the things we do is we do a ratio comparing the
femur length to the foot length.

Now femur length to foot length,
stop a minute and think about that.

If you look at your own femur length
and your own foot length, you're gonna go,
how does that help me?

But remember that fetuses become infants
and infants have very different proportionality
of their legs to the rest of their torsos.

And the femur to foot ratio is a useful measurement in a
fetus with short bones because if it's less than one,
it actually suggests there is a real
skeletal dysplasia going on.

And here is a picture of acute little baby to show
that there's the foot length
and roughly from bottom to knee is the femur length.

And you can see that these are actually much more in
proportion In an infant they would be in an adult.

So what about the math thing?

And everything that we measure,
we measure standard deviations as well.

So if you look at the length of the bone
and how many standard deviations below what it should be
for gestational age, its measurement is
that gives you an idea of whether you're dealing
with a skeletal dysplasia versus a sort
of familial short stature.

And if it is a skeletal dysplasia, how bad it may be.

So very oftentimes fetuses that have short long bones,
it's two to three standard deviations below the mean.

And that can be one of the many, many, many named non-lethal skeletal dysplasia
that are described may be an anatomic variant
or it may be familial.

For example, myself, I have a very large head.

My mom likes to remind me of this every time she gets
to talk about my delivery.

And I'm also relatively short, so I have a large head
and a short femur, but I'm considered normal.

If you go onto fetuses
where it's more than four standard deviations
below the mean, you're definitely into skeletal dysplasia
territory there but probably not into the lethal ones.

And the ones that are lethal are associated with very,
very short long bones,
often greater than six standard deviations below the mean.

And the important thing to take home from the math issue is
that the more standard deviations below the mean,
the long bones are the worse the prognosis is for
that particular fetus.

And the earlier you see long bone shortening the worst it
is, I'm gonna show you a case later
where the long bone shortening only becomes apparent
later in pregnancy.

Also there's a lot
of information coming out now about femur length
and growth restriction.

And if you see short bones at a standard second trimester
scan, you can bring that patient back
and see what's happening in other bones getting
progressively shorter or are they staying about two
to three standard deviations below the mean consistently
and progressive shortening can be a clue to achondroplasia.

One of the things about this whole math thing is there's
an awful lot of busy work involved and my colleague Dr.
Winter, who is a math physics major
before he did his medical school training, wrote a program
that makes it very easy to do all
of this measurement and calculation.

And the link is on this journal article
and basically all you have
to do is enter your measurement into this program
and then it will calculate all the math for you
with the number of standard deviations below the mean
that all of the individual bones are.

Achondroplasia

So we mentioned achondroplasia
and not only are we doing the math thing with this
where we are getting outta protractor,
which is something I bet many
of you have not seen since your high school days.

Achondroplasia is the one
where you get progressive limb shortening
as gestation progresses.

So this is a graphic of femur length.

This is a graphic of abdominal circumference for example,
and the fetus grows perfectly normally
during pregnancy except
for the extremities which start out a little bit short
and become progressively shorter
than the standard measurement as the pregnancy progresses.

So if you're seeing this
and you're seeing short femur,
you can look at the femur in a slightly different way.

When we train, we're all very clear
that you must measure your bones from here to here
and not look at anything beyond the diaphysis.

But in fact, if you look at this little angle here,
it's called the proximal femoral drazil metaphyseal angle
and you can see you can measure that
and what's being demonstrated that in aach chol fetuses,
this angle is increased.

And in that study that was recently published, five
of six affected fetuses had an angle greater than
130 degrees.

So have that in mind is if you see short bones
and you're getting progressively shorter
as you follow up the infant
or the fetus, you can measure this angle
and if you see the increase in the femoral dia aile angle
beyond these numbers, that's further information
that you may be dealing with achondroplasia.

Another thing in ACH HydroDrop plastic fetuses is
that there is a persistent lumbar kyphosis
and this is a fetal spine turned
to look like the sagittal x-ray.

Here's the sagittal x-ray for comparison
and most fetuses will move and change their position,
but you'll notice this persistent sort of curve
to the lumbar spine.

And here's an a picture from the internet of a normal child
and his achl sibling
and you can see how the spine is so much shorter along
with the proximal limb shortening, which is quite marked.

Here's an example of frontal bossing,
which is another feature that you see in Achondroplasia.

You have a rounded protuberance of the frontal bone
and there's a characteristic appearance in the hand
where the fingers are short but they're equal and length
and there's a gap between the third and fourth fingers.

Now I'm a treche have been for years and Mr.
Spock is certainly not a chondroplasty,
but he does a lovely example of that gap
between the third and fourth fingers.

If that helps you to remember that sign.

Achondroplasia is compatible with a perfectly normal life.

There's normal intelligence
and I pull this picture from a British newspaper
to show this young lady who is actually an Olympic athlete
and won a medal for the freestyle swimming in the
Beijing Olympics.

Lethal Skeletal Dysplasias

The more important skeletal dysplasias to make a diagnosis
of in terms of pregnancy management are those
that are lethal
and there's really only five of those as opposed to many,
many, many named non-lethal skeletal dysplasias.

So if we think about the lethal ones,
thanatophoric osteogenesis imperfecta type two
and aach androgenesis are 100% lethal.

Therefore, it's very important to be aware
of those diagnoses
and try to make a prenatal diagnosis so
that you can discuss the
pregnancy management with the parents.

Short rib polydactyly group contains a number
of entities, not all of which are lethal, but many are.

So we quote about a 70% lethality risk for that one
and hypophosphatasia has several subtypes,
but there is a perinatal lethal form
and if you are aware of specific sonographic features,
you can come to a more specific
diagnosis with either of these.

That's important because there is a prenatal diagnosis panel
which is extremely broad and extremely expensive.

So if you can narrow it down
to say you really think this fetus is than a toric
dysplasia, you can do more efficient testing.

And again, once you have a confirmed diagnosis,
the management plan for the pregnancy becomes extremely
important because we want to help families deal
with the fact that they're going to have an infant
who won't be going home with them more likely than not.

And you also want to avoid doing a cesarean delivery
for a pregnancy that is not going
to result in a live child in the long term.

Osteogenesis Imperfecta and Achondrogenesis

So what do we think about? We've mentioned
that the femur is short and it's really short,
so we're worried about a bad skeletal dysplasia.

Your next step is to look for fractures
and this is an example of a transverse
image through the chest.

This is the fetal spine, this is anteriorly,
this is the cardiac apex.

And notice how your ribs have a very angulated contour.

This can only happen with fractures.

This is a neonatal chest x-ray
and you can see that the ribs are extremely irregular.

This is referred to as beading of the ribs
and you can see this on ultrasound as well.

And that is because of many, many, many small fractures all lined up
along the length of the rib.

If you see fractures,
there's only two things to think about.

Here's another example.

This is a femur
and far different than the usual nice straight
femoral bone that we see.

This is bent and irregular and angulated.

And here's a neonatal radiograph again showing a fracture
and angulation of the femur
and also decreased mineralization.

Another way to assess ossification, which is lack
of ossification being a cause for fractures, is
to look at the brain.

And I know in my career as a radiologist,
ultrasound resolution is now spectacularly different to
what it was when I started,
but never ever, ever do you see the near field of the brain.

This exquisitely on a transabdominal scan
unless you have under ossification of the skull vault.

If it's under ossified, you can compress the skull vault
and you can see that there's a flattening here.

And this is the video clip showing pressure applied
and the actual skull vault is deformable
with transducer pressure, which is not normal
and implies decreased ossification.

So we said two things
to think about When you have fractures,
that's osteogenesis imperfecta and agenesis type one A.

That is particularly important
because note that condition is autosomal recessive,
therefore that couple, if they have another pregnancy,
have a one in four recurrence risk, whereas osteogenesis
and perfecta does not come with that type of risk.

We said there are fractures in both.

How are you going to differentiate between one or the other?

Next thing you do is you look at the spine
and this is just a 15 week fetus
and this is a coronal image.

So this is the spine, this is the contour
of the outside of the ribs.

And you can see that the ribs are very irregular
in ossification.

But although irregularly ossified,
there is echogenic material within the spine
and that's the key observation.

You have a spine here of an infant born
with osteogenesis imperfecta with all
of those rib fractures, but the spine is ossified.

If you look at this fetus, you'll note
that the spine is a column of black.

It is entirely cartilaginous. There's no ossification here.

And this fetus is actually at 22 weeks, unlike the last one,
which was at 15 weeks only.

There's a little bit of attempted ossification in the
spinous processes, but not in the vertebral bodies.

This is an abdominal x-ray.

This was a fetal skeletal survey
and you can see that, you can see the skull vault.

This is something that we refer to in my own practice
as the floating head sign
because the only part of the fetus
that we could see any ossification in was in the skull.

We could not identify vertebral bodies or long bones.

Now look at those two cases side by side.

Here's a coronal 15 week scan
with definite ossification in the vertebral column.

Here's a sagittal spine view
with absolutely no ossification whatsoever
in the ral bodies,
in just a little bit in the spinous processes.

So that's how you differentiate
between osteogenesis imperfecta and a androgenesis.

Thanatophoric Dysplasia

So we had five, we're now down to three to think about.

The next one we're gonna talk about is
thanatophoric dysplasia.

And the way to think about that again is
to keep looking at that spine.

So here's a neonatal chest x-ray
and a neonatal spine on either side
of a coronal fetal ultrasound.

This is the fetal abdomen here from side to side.

And you can see that the chest is tiny
and the heart actually takes up the chest from
side wall to sidewall.

Looking at your x-ray, again, you have
that small chest appearance,
but look at these vertebral bodies.

There's only a little bit of calcified vertebral body
and a whole lot of intervertebral disc space.

Same on the lateral. The vertebral body is very flat.

The intervertebral disc space is large
and this is described
as platy spon meaning flattened vertebral bodies.

So what does that look like on ultrasound?

The ossified vertebral body is echogenic.

The intervertebral disc is hypoechoic.

So I've turned this ultrasound around
to mirror the appearance in this radiograph
and you can see there's your flattened vertebral body just
as you see here and your increased intervertebral disc space
just as you see here on the radiograph.

Here's another example. There's a sagittal of the spine.

Here's a TAL of a normal spine.

The vertebral body is quite flat.

The intervertebral disc space is increased vertebral body
much bigger and actually less distinct at its margins than
the intervertebral disc space in the normal case.

Here's a paper from quite some time ago actually
1990, published by Dr.
Philly's group. And they described a mathematical way
of evaluating plati Bondi
and they said to measure the vertebral interspace
and the vertebral body height
and create a ratio, the ratio is the height of the body
over the height of the body plus the interra space.

And they have lots of nice data in here.

Here's an example of how we look at that.

Here's a al image of the spine
in an abnormal case superimposed on a normal case.

Now you look at your vertebral body, vertebral body,
then you look at your interspace size here and here
and you can do the math and measure the ratio,
but actually you can also do what I call the eyeball scan.

And just look at this.

And you can see here
that the intervertebral space is much bigger than the ible
body height and that is clearly abnormal.

And that is what leads you to making a diagnosis
of platy spon, which then takes you
to consider thanatophoric dysplasia.

TD is associated with some other findings.

TD two is famously associated
with the blat shadel skull deformity,
which is also known as a clover leaf.

And in my attempt to find cloverleaf examples,
I found cloverleaf rolls on the internet
and you can see again very prominent frontal appearance
with an upturn nasal tip.

And then here is your clover leaf
appearance right here due
to the craniosynostosis associated with this diagnosis.

Here's a 3D reconstruction.

Again, you can show the mark bulging of the frontal bones
and you could do a 3D surface reconstruction
and axial image if you wanted to bring out that shamrock
or clover leaf appearance.

TD one is associated
with a very characteristic appearance of the femur.

It is very shortened and curved.

Here's a 2D, here's a 3D,
and here's a radiograph
of this typical appearance which was described
as the telephone receiver femur.

Now unfortunately for the generation of sonographers
and medical students coming up,
a telephone receiver looks nothing like that.

It's now a smartphone
and it's shortly going to be just a piece
of tape you stick on your forearm.

But it was originally described to illustrate the fact
that it was short with curved end just
as you would pick up an old fashioned telephone.

Short Rib Polydactyly Group

All right, we mentioned two of those guys that went away.

We mentioned three of those guys that went away.

So now we're left with the short rib polydactyly group
and hypophosphatasia
and the short rib polydactyly group, like I say,
is not uniformly lethal,
but there is a characteristic appearance.

If the ribs are short, then your chest is going to be small.

And anytime you see a fetus that you think has cardiomegaly,
you need to ask yourself the question, is the heart big
or is the chest small?

And there's normative data out there for chest circumference
and chest height for gestational age,
but also if you do a coronal image through your fetus,
if the chest appears pinched in relation to the abdomen,
that is described as a bell-shaped thorax.

And this is a radiograph of this child when,
after delivery and you can see the chest is very straight
sided and then flares at the bottom.

Ossification is normal.

There aren't any fractures, but the chest is small
and the ribs are short.

They don't curve around in a normal way.

This, again, is from the daily male in the uk
and this is one of the cases of a short rib poly
syndrome infant that did not die,
but this baby is facing a lot of surgeries in his lifetime
to try and widen his thoracic cavity so
that he can oxygenate appropriately.

Hypophosphatasia

All right, we got rid of those guys,
we got rid of those guys.

What are we left with hypophosphatasia.

And that is, as I say, there are multiple subtypes of
that condition, but there is a perinatal lethal form.

The key characteristic of hypophosphatasia is
that the bones are severely demineralized.

So it's not like in the osteogenesis imperfecta
where there was almost no ossification of the skull vault so
that it was easily deformable
and it's not, typically associated
with dramatic fractures like osteogenesis imperfecta is,
it's more what we call moth eaten, ratty appearing bones.

They just are not normally mineralized.

So you can see through them better than you expect to,
but they still do show some echogenicity indicating some
ossification and mineralization.

Here's a chest radiograph of an infant recently born with
that diagnosis and you can see how incredibly thin
and grass the ribs are.

The virtual bodies are ossified
but not heavily calcified for an almost term infant.

And the scapula are small and moth eaten.

The humeral head and neck is very poorly mineralized.

Here's an example of
that moth eaten appearance of the bones.

You can see that it's not a nice white,
sharp linear interface with shadowing from it
and there is some angulation and distortion of the bones.

But in comparison to an osteogenesis imperfecta for example,
there will not be that ribbed beaded appearance
and the marked, marked intensity of fractures in every bone.

And here's an example of the angulation of the femur
and tib fib in a radiograph
of this case when the infant was born.

Overall Approach to Skeletal Dysplasia

Alright, we mentioned the math
and I keep going back to that.

So microme really is tiny limbs.

The smaller the limbs you have, the more likely you are
to have a severe skeletal dysplasia.

And remember we said if the standard deviations are greater
than six below the mean,
the final diagnosis may not be apparent,
but the prognosis is always bad.

There are other things that we measure.

We mention the foot length
because you can do the foot femur ratio
to identify if you have a skeletal dysplasia.

And we always measure the abdominal circumference as part
of our normal biometry
and we can measure the chest circumference
to confirm the visual compression that the chest is small.

A foot femur ratio less than one suggests a skeletal
dysplasia, a femur
to abdominal circumference less than 1.6 suggests
that the dysphagia looking at is one
of the lethal varieties.

And a chest to abdomen circumference ratio of less than 0.8
also suggests lethality.

What's the overall approach to a skeletal dysplasia?

First of all, do you have one?

Are you dealing with just a familial short stature?

You use your standard deviations for that
and you also use your foot to femur ratio.

If the bones are short, which ones are they all short
or is it a, rhic bone shortening alone
because that changes the differential.

When was the bone shortening seen?

The earlier you see shorten
and long bones, the more likely you are to be dealing
with a bad versus lethal skeletal dysplasia.

What size is the chest?

The small chest is the thing
that makes these children unable to breathe
and to oxygenate.

So the small chest size, again associated
with lethal conditions.

Look at your head shape and ossification.

If you see that typical cloverleaf shape skull
that goes along with euphoric dysplasia.

If the mineralization is very poor, go back
and look again for fractures.

And you're probably going to go down the,
osteogenesis imp perfector, differential.

If the spine is completely lacking in ossification,
that's agenesis.

And always, always, in any case of any fetus
with abnormalities, look at the hands and feet
because you may get clues to a specific diagnosis such as
that characteristic three four finger gap
that you see in achondroplasia.

The lethal skeletal dysplasias are early and onset.

The chest is small.

There can be fractures
or marked bowing clover leaf associated with,
thanatophoric dysplasia type two.

And the presence of hydro drops is always bad.

Remember your measurements that suggest lethality.

The bad guys involve multiple bones,
and it's really, really important to try
to arrive at a diagnosis of lethal versus non-lethal so
that you can have a discussion about delivery
planning with the parents.

It's also very important to try
and establish a specific diagnosis in all cases.

So when you're having that discussion about the delivery
plan, you also need to broach the subject of
how you're going to make a specific diagnosis, whether it be
by a full formal autopsy
or whether it be something like just for example,
a bone biopsy depending on the family's wishes.

The importance of the specific diagnosis is
that in autosomal recessive conditions,
there's a recurrence risk
of one in four in future pregnancies,
which may change family's reproductive plans.

Thank you.