An Approach to Fetal Syndromes - HD

Introduction to Diagnosing Fetal Syndromes by Ultrasound

I am Dr. Beryl Raff from Harvard Medical School, and I'm going to be talking about my approach to diagnosing fetal syndromes by ultrasound.

Today I'm going to be talking about my approach to detecting and identifying fetal syndromes, which is a very complex area since there are so many hundreds of syndromes that it's sometimes hard when you're doing an ultrasound, a prenatal ultrasound to decide which syndrome it is that you're really dealing with.

To do this, you really have to be a detective, sort of like Sherlock Holmes, because you have to do it as a stepwise method, and it's what I call the sentinel feature method.

And here is what I mean. Once you find a malformation sonographically, you form a list of possible syndromes in your mind, and then you look around for the one additional feature that I would call the sentinel feature that would really nail the diagnosis of any one of the syndromes that you have on your list.

And during this talk, we'll go through lots and lots of examples of how I do this. Then when you look at the pattern of the malformations that you've detected on the fetus, you are much more likely to arrive at the correct syndrome dealing with the sentinel one that led you to the syndrome to begin with.

So let's see some examples.

Facial Clefts

First of all, facial clefts. What are the possible syndromes that can be associated with facial clefts?

There are many more than the four that I have on the list here, and one of which is certainly familial. But let me just show these as examples.

First of all, you have to be sure that you're not dealing with trisomy 13, and that cleft is a very central cleft, which really makes a huge hole in the maxilla and disrupts the nose and the eyes are often close together.

But if you're dealing with Trisomy 13, the sentinel feature is going to be polydactyly and holoprosencephaly.

Vanderwood syndrome is an autosomal dominant syndrome of simply facial clefting. So in that case, you would have one of the parents or a very close relative that would have facial clefting.

Semi-facial microsomia Goldenhar syndrome is usually a very, very asymmetrical looking face. They tend to have unusual clefts, particularly lateral clefts and ear tags. We'll see examples of, and of course, amniotic bands is always included because amniotic bands can disrupt the face as it can any organ system, but it does so usually asymmetrically.

So looking at the 3D ultrasound, you can tell that there is a facial cleft here, and these are not hard to diagnose. This is a complete cleft lip and palate, and you can see that this is an incomplete cleft lip only, which is much less severe as you can see by the newborn picture next to it.

And these were unassociated with any other findings and were isolated.

This on the other hand, is a fetus with Trisomy 13, and you can tell that there is a large monoventricle in the center here with fused thalami, which is typical of holoprosencephaly. And if you look at the face, you'll find this big old central cleft with a big hole, no nose really, and the eyes are quite close together.

But if you look at the hands, and this is the feature that will nail the diagnosis, this is the polydactyly on both hands, and that's what I mean by a sentinel feature.

Here's another fetus. You can see that there's polyhydramnios. You can even see that there's a large fluid collection in the head. But what we're talking about here is facial clefting. And there is a very strange lateral cleft here that goes over to the side. And if you look at the 3D version of this, you can see this lateral cleft right here.

But what you do see here is a little ear tag, which we really actually hadn't seen without the 3D, and which turns out to be the sentinel feature for Goldenhar syndrome or semi-facial microsomia, which is what this fetus turned out to have.

Looking at this young fetus at about 12 weeks, you can see on the 3D that there are many, many abnormalities here. There is a cranial abnormality with the brain outside the head. You can see that there's a huge facial cleft here.

Now this facial cleft is right through the middle of the face, and this is a disruptive destructive cleft. This is a cleft, which is really not anatomic. It's really couldn't develop embryologically like this. This is more of a destruction of something that was already forming, which is the hallmark of amniotic bands.

This amniotic band fetus also has an anterior abdominal wall defect and all sorts of other abnormalities.

Micrognathia

So let's go on to the next feature we're going to talk about, which is micrognathia. If you see a fetus that has a small chin like this one here, these are some of the syndromes that you might think about.

Nager syndrome is a very rare autosomal recessive syndrome where there is also an absent radial ray, and that's the sentinel feature associated with the syndrome.

Treacher Collins syndrome is that autosomal dominant. So typically you'll have one of the parents who has the syndrome, and they typically have hypertelorism, and they also have ear abnormalities that are actually very similar to those ear tags that we looked at.

Goldenhar syndrome, we talked about these as asymmetric cleft and ear tags.

Pierre Robin basically is a group of syndromes, and this fetus had Pierre Robin, which where there is a small chin and there typically is a cleft palate, although not a cleft lip, those are much harder to see by ultrasound.

You can have chromosomal abnormalities or aneuploidy, and these would include trisomy 18 and 13, for example. That can give you a small chin. But then you would look for the features of trisomy 18, for example, clenched hands, a heart defect, choroid plexus cyst, anterior abdominal wall defect, and so forth.

Joubert syndrome is an autosomal recessive syndrome, where the other feature besides the micrognathia is a Dandy-Walker variant. It's a devastating abnormality, which results in fetuses that have severe mental retardation.

And the last one on the list is femoral hypoplasia unusual facies where you have a small chin, sometimes a cleft, but you also had abnormal femurs, sometimes both, sometimes just one.

So let's see some examples. How do you diagnose a cleft palate? For example, here we have a fetus that has Pierre Robin syndrome that might have a cleft palate. So how do you chase that down?

Well, you can use 3D and put your window right in the mouth here. The fetus is upside down, the chin is up here. We have the line of sight in the mouth, and we are actually looking up at the palate right here. So you can look up at the soft palate and see that.

And let's compare that with a fetus that had a cleft palate. So this is the normal palate, and this is looking up at the palate from inside the mouth. And you can see there's a big hole, a linear sort of hole in this palate. You can compare that to the actual path specimen.

Now, here's another fetus that had a small chin and had a normal lip, as you can see, and a normal incisor teeth buds. But as you go further back here, you can see that there is a hole in the maxilla.

And one other way in which you can look at cleft palates would be in looking at where the tongue is. And here the tongue is actually up in the nose because there is no palate to hold it down.

Now going on to the next syndrome, Treacher Collins syndrome. This is typically an autosomal dominant syndrome, so that you may have a parent that has it that comes in with a 50% chance of passing this on.

And what's interesting about these two fetuses is that they are two different families, and yet you can see how very similar those profiles look with a small chin and a fairly straight forehead.

The worst case of Treacher Collins syndrome I've ever seen is shown here, where you have the eyes are very, very far apart. There's a very small chin, which you'll see on the next slide, but you can see that the fetus was just terribly deformed when it came out. No chin, no nose, no ears, a very severe abnormality.

The mother had Treacher Collins syndrome here, but a very mild form of it. And this obviously was very, very severe.

Now going on to the femoral hypoplasia unusual facies. Here you have a fetus that has a small chin, but you can see that looking at the skeleton, the one bone that was abnormal is one of the femurs right here, which is severely bowed. The other femur is straight, and the rest of the skeleton was normal.

And Nager syndrome, which is actually the first one on the list that I started with, is the one that has the short radius. And you can see here the humerus and the hand, but the radius and forearm are very short, and these can have extremely small chins.

This chin should have been over here someplace, but in fact, it's almost non-existent. And when these fetuses are a little older, you can see how incredibly small the chin is in this particular fetus who had Nager syndrome.

Maxillary Hypoplasia

Now going on to maxillary hypoplasia, what happens if you have a fetus that has a very small midface or a very small sort of maxilla region?

Well, you know, that Down syndrome is associated with a flat face and an absent nasal bone, and some degree of maxillary hypoplasia.

Other syndromes such as Pfeiffer syndrome or Carpenter syndrome, or these syndromes that have craniosynostosis like this one, this is Pfeiffer syndrome, has a very small midface here, as you can see, likely due to the fusion of the sutures, some of the skeletal dysplasias can have a midface hypoplasia, achondrogenesis or other skeletal dysplasia.

But of course, the sentinel feature here is the limb abnormalities. And in Pfeiffer syndrome, the sentinel feature is a great big, big toe or a double big toe.

If the fetus has a cleft lip and palate, then obviously the midface is going to be very small as it was in the image of Trisomy 13 that I showed you before. But of course then you would be dealing with lots of other findings of Trisomy 13, such as polydactyly and holoprosencephaly.

Let's see some examples. Here's a fetus with Down syndrome, and you can see the rather flat face, the small ear, and the rather fat sort of back of the neck area and round face that fetuses with Down syndrome have.

This is a third trimester fetus with Down syndrome showing again, the flat face, very small nose that these fetuses typically have.

Now going on to Pfeiffer syndrome, that's the one that's a craniosynostosis, and it's associated with fusion of the various sutures. And that's why they end up with a cloverleaf shaped skull as you see here. And here is what these look like in 3D. And what they tend to have along with the cloverleaf shaped skull, is a large, big toe and sometimes even a double big toe.

So this is a place to look for your sentinel feature in fetuses with Pfeiffer syndrome.

Now, these are two fetuses that had skeletal dysplasias, and this one has achondroplasia, and this one has achondrogenesis. Achondrogenesis is a very, very severe short limb dwarfism that is lethal. And you can see the small midface that these fetuses have.

Achondroplasia is diagnosed much later in pregnancy. They survive and do actually quite well as adults, although they are small individuals.

Now, here's a fetus that had no nose and no eyes, and you can see by the profile here how severely malformed this face was. And on the 3D, there are no orbits. This is anophthalmia and no nose at all, and you can see how this fetus looked after birth.

Polydactyly

Okay, going on to another feature that may lead to a syndrome is polydactyly. And there are a number of syndromes associated with polydactyly.

We already talked about trisomy 13 being associated with polydactyly, together with facial clefts, holoprosencephaly, heart defects and other multiple anomalies.

Meckel-Gruber syndrome is an autosomal recessive syndrome which is lethal and associated with post-axial polydactyly and also cystic kidneys that eventually don't work. So the fetus ends up being in an environment of oligohydramnios, which sometimes makes it difficult to see things, but they do typically have an obvious posterior occipital encephalocele, which will stand out.

And the this triad of findings is associated with Meckel-Gruber, short rib polydactyly syndromes. There are three of the short rib polydactyly syndromes, and these are skeletal dysplasias. They're short ribs indicate their skeletal dysplasia. They also have short long bones. They tend to be quite lethal due to the short ribs and the hypoplasia of the rib cage. And hence the lungs.

Now what the sentinel feature is there, not only do we have polydactyly, but we also have a skeletal syndrome. And in type two, you also have a cleft, a central cleft. And that really nails the diagnosis of type two short rib polydactyly syndrome, which is called Majewski syndrome.

The next one on the list is Carpenter syndrome, and that one is very similar to Pfeiffer's. It's a craniosynostosis and it has pre-axial polydactyly, which means it has an extra finger, but on the side of the thumb rather than the side of the pinky.

Oral-facial-digital syndrome. There are a whole bunch of those. There are about 12 of them, and they tend to have pre- or post-axial polydactyly and some facial clefting.

And of course, many patients with polydactyly have it as a familial trait. And so sometimes we don't find anything else wrong with the fetus.

So let's look at the difference between pre- and post-polydactyly. Post-axial polydactyly is next to the pinky, but these are examples of pre-axial, a double thumb. This is a duplicated thumb. This one has a little extra thumb tag as here. And you can see, you can compare the post-axial polydactyly here with the pre-axial. This is the thumb tag. This is a completely duplicated thumb to different patients here. And again, just to show you a post-axial polydactyly, that can be just like a little tag.

So we talked about trisomy 13 as being associated with polydactyly, but then you would be looking for the facial cleft, the major midline facial abnormalities, the holoprosencephaly, the orbital abnormalities, as well as of course, the heart defects and other findings that are associated with trisomy 13.

This is Meckel-Gruber syndrome. And as you remember, this is an autosomal recessive syndrome where you have not only polydactyly, but you have large echogenic kidneys. Here they are longitudinally, and here they are transverse. And the brain is quite abnormal with a large cyst in the posterior aspect of the brain with an encephalocele off the occipital aspect of the brain.

Now, this can be diagnosed very early. This is one of the earliest times I've diagnosed it. You can see that the picture of the head transversely shows a large cyst in the back of the brain with a posterior encephalocele. And once you see that, you have to wonder about Meckel-Gruber syndrome. And so you would look for the sentinel feature, what is going to nail your diagnosis.

So you go specifically looking at the hand and here's the extra fingers. And then you look at the kidneys and you find that they are in fact echogenic. In 3D you can see basically a bird's eye view of this with the encephalocele and the extra digits, both in the hand and in the feet.

Going on to Carpenter syndrome. That's the one that has the craniosynostosis. Hence, you can see the unusual shaped head, sort of pointy head. This one happens to have a Dandy-Walker abnormality as well. But this one has pre-axial polydactyly of the great toe, which is quite specific for these syndromes.

Carpenters and Pfeiffer, you remember, had more of a cloverleaf shaped skull. Carpenters has more of a pointy shaped skull, but they both have this unusual great toe, which will single out these syndromes.

Now this is the short rib poly syndromes. This is the Majewski syndrome type two. And what distinguishes type two from the others is the facial cleft, which is not shown on this view. But what is shown on this view is the extra digit and the short ribs and the very narrow chest, and of course, the abnormal long bones making this a severe skeletal dysplasia.

This is an image of an actual Majewski syndrome showing the facial cleft. You'll see here the very narrow chest. These fetuses do not survive because of the narrow chest. And you can see the extra digit here. But what nails this diagnosis to really the only thing it could be, which is Majewski syndrome, is this central cleft.

Short Radial Ray

Now going on to another feature, the short radial ray. We talked about Nager syndrome being the autosomal recessive syndrome where you have not only a short radial ray, but you have severe micrognathia. So that's the way you would nail that diagnosis.

We also talked about amniotic bands being responsible for a lot of asymmetry and asymmetrical destruction of different parts of the fetal body, including an arm. This is usually asymmetric when it's amniotic bands, and it tends to be symmetrical when it's some of the other features.

Other syndromes, trisomy 18. Typically you have a clenched hands with overlapping index finger, which I'll show you in a moment, but sometimes you can have a short radial ray like this in a fetus with trisomy 18, and that will usually be bilateral. Of course, these fetuses will also have multiple other anomalies, choroid plexus cyst, heart defects, and all sorts of other things that will indicate Trisomy 18.

VACTERL Association is a series of abnormalities, including vertebral abnormalities, anal atresia, tracheoesophageal fistula, renal, and radial abnormalities. And that's hence why it's called VACTERL.

And so the features of that to look for are exactly those that are in its name.

TAR association, which is thrombocytopenia absent radius, you won't really see much else other than the absent radius because the other abnormalities are hematologic and are not going to show up on an ultrasound.

Holt-Oram syndrome is an autosomal dominant syndrome. So there you may see a patient who herself or the father has that syndrome, and they will be looking for a 50% rate of passing this on to an offspring. And these typically have the abnormal forearm, but they also have heart defects, and that's how you find them.

Fanconi anemia typically will have no thumb, just like this one. No thumb. And that's what really makes this different from some of the other syndromes that we've seen.

So let's see some examples of these. This is VACTERL Association. They have vertebral body abnormalities. They have a hydronephrosis, they have a short radius, which is why the hand is coming forward at a 90 degree angle instead of at the end of the forearm.

And this area here, this is dilated loop of bowel with intraluminal calcifications, and those are pathognomonic for a mixture of meconium and urine, which occurs when there's a fistula between the rectal sigmoid and the bladder. And that invariably is a sign of anal atresia.

So this can be construed as a very good sign of anal atresia in this case, which would make this compatible with VACTERL Association.

Here's a fetus that had Holt-Oram syndrome. The one parent had it, and sure enough, the hand is very abnormal. There is no thumb here, although there is an extra digit. But these are all digitalized. They're not, there's no thumb that opposes any of these.

The heart is abnormal. There's a large VSD and a small aorta. And if you look at the hands of this fetus, and this is one hand, this is the other hand, you'll see that all the fingers are in the same plane. So this fetus won't be able to oppose, won't be able to pick anything up with it with its thumb because all of its fingers are in a row.

And the treatment here is to make one of the fingers a thumb so that it can actually grasp something. And this one here has a fused first and second digit on that hand.

Now, here's a fetus with trisomy 18, and you can see that both forearms are abnormal short. The ulna is foreshortened, the radius is not there, and that's why the hands are clubbed and coming back forward, the fetus also has micrognathia and had a number of other abnormalities associated with trisomy 18.

Clenched Hands and Hand Abnormalities

Now going on to clenched hands or syndactyly basically hand abnormalities. There are many more syndromes that have hand abnormalities than those that I've listed here, but these are just an example of how to sort through what you might be dealing with.

A lot of times when the fetus has a clenched hand or has contractures of the hands, it indicates a fetus that is not moving. So these are really contractures. And you will see this in arthrogryposis. There are many different types of arthrogryposis. These fetuses don't move.

They can have arthrogryposis based on central nervous system problems or what they call distal arthrogryposis based on muscle abnormalities. But for whatever reason, there is no movement.

Peniscrotal transposition syndrome is also a severe abnormality where there's very little activity. The way to nail this diagnosis is the fact that there's quite severe hypertelorism. The eyes are too far apart, but this is known as akinesia dyskinesia syndrome also, which means the fetus is really not moving.

Trisomy 18 we've talked about, and the main position of the hand for trisomy 18 is clenched with overlapping index finger, as well as all of the other findings that we know of as associated with trisomy 18, including rocker bottom feet, heart defects, and so forth.

Cerebral ocular dysgenesis syndrome is a very severe syndrome where you have microcephaly and intracranial abnormalities, such as agenesis of the corpus callosum. You can have microphthalmia and cataracts, and they tend to have club feet, and they tend not to move very much.

Smith-Lemli-Opitz syndrome has genital abnormalities in a male, for example. The outer genitalia will look more like a female and or will look ambiguous. So they have hypospadias, cryptorchidism, and they have syndactyly of the second and third toes, which is very specific for this syndrome.

Triploidy is a syndrome where you have three sets of the same chromosomes. All of the chromosomes are a triploid. And so the abnormalities are vast in fetuses with triploidy, there are very many abnormalities. But I guess the best way to spot a fetus with triploidy is the severe early onset intrauterine growth restriction that they have. IUGR, this is very easy to spot in the first trimester. And quite dramatic.

Apert syndrome is another one of the craniosynostosis syndromes, sort of like Carpenters and like Pfeiffer that we talked about. But this one is associated with a mitten hand. The hand is got a thumb, and then all the other fingers are fused together like a mitten.

Amniotic bands, as you know, can be associated with any number of abnormalities, including clenched hands. And EEC, ectrodactyly ectodermal dysplasia clefting, this is a claw hand or foot. They're usually bilateral, and it also has a cleft syndrome.

So let's look at some examples here. You have trisomy 18, and this is a fetus with trisomy 18 with the typical clenched hand with overlapping index finger, like a little knuckle that is over the top of the other fingers. And you can see right here, and if you see this fetus, you would want to look for intracranial abnormalities associated with trisomy 18, such as a Dandy-Walker abnormality, choroid plexus cyst.

They typically have heart defects. They may have omphalocele. They may have clubfoot or rocker bottom feet. They may have neural tube defects. They have a lot of abnormalities, including IUGR as well.

Now this fetus and the next one have arthrogryposis. And you can see by these images that the arms and legs are really fixed. There's a lot of contractures. These arms and legs are not moving. And the hands are all together in a very unusual stance.

And sometimes when the fetus hasn't moved for a very long time, then you see this severe extension of the lower extremities, which is very typical of a fetus that's just absolutely contractured. Just like some old people in nursing homes might be if they haven't been moved for a very long time, they have the same type of contractures from lack of moving.

Here's an example of cerebral ocular dysgenesis syndrome, where you have club feet and you typically have microcephaly and other intracranial abnormalities. But what helps you distinguish this one is the eye abnormalities. They sometimes have anophthalmia, but in this case, there was a cataract right here, that echogenic area.

Now going on to triploidy this is the one where you have three sets of chromosomes and it has abnormalities throughout the entire fetus, all organ systems, but it has syndactyly in particular of the third and fourth digits.

Now, the way you spot this abnormality is a severe growth restriction, asymmetric growth restriction that is shown here. You can see the head is of a certain size, but the body is much, much smaller. And it's really a visual thing. And you can see here that the fetus is very, very skinny and looks like it's terribly emaciated, which is really unusual at this early stage in the first trimester. There's almost nothing else that will do this.

And if you look in detail at fetuses with triploidy, you find lots of abnormalities, as in this case, an intracranial brain abnormality. But also this very small fetus or small body for a normal sized head. But if you look at the hand, you'll see the syndactyly, which is almost always there between the third and fourth digits.

Now, here is a fetus with amniotic band syndrome, and this was a very unfortunate fetus at about 26 weeks. And if you look at this image here, you'll see the face, the lips and the nose. And you'll see this veil of bands that is really traversing right in front of the fetus, sort of like the fetus is wearing a veil.

And if you look at the hand here, it has really got all the fingers together where you can't sort them out. And in 3D it was much easier to sort them out, because you could see that the middle three digits were actually tied together by this band.

Now the thing about amniotic bands is it's typically unilateral because it will affect wherever the band is, and it won't typically affect both sides in exactly the same way.

Now, these two fetuses have Apert syndrome. The upper one, these are two different fetuses. The upper one is about 20 weeks. You can see the high forehead, the macrocephaly associated with Apert syndrome, due to the fusion of the sutures. And here is the mitten hand. This is the fingers are all tied together or stuck together, I should say.

And in this older fetus, you can see that all these digits are all together. And the thumb is separate. And again, here you have the macrocephaly or the high forehead and the small maxillary region associated with these syndromes.

Now, EEC ectrodactyly ectodermal dysplasia clefting is a syndrome where you have clefting here, big cleft in the middle of the hand and the feet as well. And you can see it in 3D here. And then they also have clefting, bilateral clefts of the face. And that is quite characteristic of the syndrome.

Spine and Hemi-Vertebrae

Going on to other parts of the skeleton, we can talk about the spine hemi vertebrae. This is not neural tube defects. This is vertebral body abnormalities.

And in this list of syndromes, you have sirenomelia or caudal regression, which is the most severe of these syndromes. And this is when you're missing part of the lower spine, certainly missing the sacrum. And in the sirenomelia syndrome, the legs are fused together into sort of a mermaid-like appearance. And these typically do not have any kidney development. So they typically, ultimately have oligohydramnios and is lethal due to the lack of renal function.

Caudal regression is similar, may not be quite as severe, but there is no sacrum and the legs usually do not have any movement. They have contractures, and they may or may not have variable kidney abnormalities associated with that.

Dyssegmental dwarfism is a syndrome that is associated with a Puerto Rican population mostly. And it is a syndrome where the spine is very short due to the multitude of vertebral body abnormalities throughout the entire spine. This is very severe. And so these people tend to have difficulties breathing 'cause their chest is smaller as their ribs are pushed together quite significantly.

Klippel-Feil is a syndrome where you have mostly neck abnormalities. So you have vertebral abnormalities that deal with the head and neck.

MURCS Association. You have müllerian duct abnormalities, including renal anomalies, and you also have vertebral body abnormalities, again, of the neck. In particular, we talked about VACTERL, Poland syndrome as again, the upper spine, not the lower spine, but most commonly when we see a vertebral body abnormality like that, it's an isolated vertebral body abnormality. And the prognosis is good, although they will have a scoliosis of some kind.

Now, in this case, there was also a rib missing, which is interesting to see.

Now, here's a hemi vertebra. You can now with 3D skeletal mode, really see that hemi vertebra very, very well. And in this case, this was an isolated finding with a very good prognosis.

Here is another fetus that had multiple vertebral abnormalities. Now, in this case here, the chest is starting to get a little bit small because of the stacking of the ribs due to the so many of these vertebral abnormalities altogether. So this fetus may end up having some more respiratory problems than the other one.

Now, dyssegmental dwarfism is the syndrome in the Puerto Rican population where you have so many vertebral abnormalities that the ribs are just bunched really close together, and it looks more like a crab in a sense. So they have severe respiratory problems due to that.

And here's a 3D example of such a syndrome where every single vertebral body is abnormal.

Now, sacral agenesis is basically when you're dealing with a complete disappearance of the or non-development of the lower lumbar spine and sacrum. And some oftentimes you have renal abnormalities with it, and you oftentimes have contractures of lower extremities that don't move. Similar to what we see in arthrogryposis.

Very severe is the sirenomelia syndrome, which is lethal because it is invariably associated with absence of both kidneys. And we see it well here because it's in the first trimester where the oligohydramnios is not dependent on renal function. But eventually there will be no amniotic fluid, and it would be very hard to make this diagnosis later due to low visibility. But you can see the single lower extremity.

Short Limbs and Skeletal Dysplasias

Now going on to the short limbs, there are a number of dwarf or skeletal abnormalities that are sort of daunting when you think about them. And you might think are hard to diagnose, but they're really not that hard to diagnose if you think of it from a systematic point of view where you just take one step after the other.

So let's look at some of the most common ones and certainly the most common one is thanatophoric dysplasia. By far, the most common skeletal dysplasia is this one, and this is associated with the old fashioned telephone receiver, S-shaped femur, S-shaped lower extremities, platyspondyly, and very, very narrow chest and short ribs.

And this is by far the most common, probably the next common is osteogenesis imperfecta type two or the congenital. And again, the bones are very abnormal and all broken, but sometimes they're hard to distinguish from the bowed bones, because sometimes when bones are broken, they can heal in a sort of a bowed position so that it may look like thanatophoric.

But what will nail this diagnosis is the decreased ossification of the skull, which is very dramatic and gives you a look inside the brain that is much better than we otherwise see.

Achondrogenesis is the one where I showed you an image of the face. It's the one with extremely short limbs. And that one, the particular feature is decreased ossification of the spine, which is very specific. This one has the shortest limbs that we see.

Diastrophic dysplasia is one that has a hitchhiker thumb. The thumb really stands out because it comes off the wrist rather than the hand.

And last but not least, campomelic dysplasia is a syndrome where you have severely bowed bones of the lower extremity. In fact, you often have absent fibula and very bowed tibia and femur, but virtually normal looking upper extremities, very different looking upper extremities than lower extremities. They also tend to have small scapula.

So let's look at some examples. Thanatophoric dysplasia, this is the s shape appearance of the legs. The legs look like an s on both sides. The femurs look like a telephone receiver, and the chest is very narrow due to their short ribs. And you can see here how narrow the chest is compared to the abdomen.

And you can look in 3D and find also the very short ribs. And what you see here in 3D is the platyspondyly. So the very, very small vertebral bodies. These are the vertebral bodies here. Look at how small they are. And very, very typical of this abnormality.

And yet again, another fetus with the same syndrome, thanatophoric dysplasia, showing that s-shaped appearance of the lower extremity, which is so typical. This one has more of a clover shaped skull, which we see in thanatophoric dysplasia type two.

And yet another example of thanatophoric dysplasia, showing you, again, the telephone receiver femur, the short ribs, and again, the s shape of the lower extremities, which are so typical.

Now, going on to campomelic dysplasia, campomelic dysplasia is associated with marked bowing of the femur and the tibia, and often absence of the fibula. On the other hand, the upper extremities tend to be relatively straight compared to look at how incredibly bowed and short the femur is.

Now the scapula tends to be a little short. There are some measurements that you can look up for scapula measurements, but that's not quite as visual as the difference between a relatively normal upper extremity and a very, very bowed short and almost pretzel like lower extremities that's associated with campomelic dysplasia in this third trimester fetus. You can see that quite dramatically.

And you can see the faces are rather unusual, but what you can see here is how small the scapula is. And if you were to measure it, it would measure under the fifth percentile.

Now, achondrogenesis is the one that has the very, very short limbs. And in fact, those limbs are so short that they can't even come together in front of the fetus. But what nails this diagnosis is the absence of the ossification of the spine. You can see the spine is not ossified like the other bones are at this stage.

And you can see even an older fetus, this is in the third trimester. You lose the ossification of the spine here, almost completely. This was the third trimester fetus with this abnormality, where you can see that small midface that we talked about early in the talk, but also the incredibly short almost flipper like appearance of the long bones of the extremities.

And you can see the very short, very narrow chest due to the very short ribs and how incredibly short the entire upper extremity is.

Now going on to diastrophic dysplasia, this is the skeletal dysplasia that has a hitchhiker thumb, and you can see that the thumb sticks out no matter what position the hand is in. So this is not hard to spot. These tend to also have club feet and short limbs.

And the last one that I'll go into is osteogenesis imperfecta congenital, which is the type two. Now, what's remarkable here is how similar this femur looks to the thanatophoric dysplasia. It looks bowed, and if the reason that it's bowed is because it's been broken many times, and here is the tibia in two different planes, but you can see the beading of the ribs because the ribs have been broken many times.

And what nails this diagnosis is that you see the brain much too well here because the ossification of the calvarium is decreased. So you see the surface of the brain of the near side, which is almost never, which is never seen under normal circumstances, including the lateral ventricle of the near hemisphere.

Now, you can also see this in 3D where you can see the beading of the ribs and the irregularity of the surface of the ribs due to multiple fractures.

Now we have seen these also in the first trimester, this one happened to have micrognathia as well, but you can see the very narrow chest here and all of the very abnormal extremities and bones. But note that there's almost no ossification of the skull here, which is very specific for the syndrome.

Now there are four, at least four types of osteogenesis imperfecta, and only type two is really lethal at birth. Type one is another an example of an autosomal dominant one where you have people getting pregnant with this syndrome. This was an affected mother, and because it's autosomal dominant, she had a 50% chance of passing that on to a child. And sure enough, in looking carefully at all the bones, in the third trimester, we found a fracture of the femur. In this particular case, just one fracture. So this is how we made the diagnosis that this fetus also had the abnormality.

Conclusion

So to conclude here, I've shown you the approach to diagnosing syndromes using the sentinel feature, and we are all fetal ultrasound specialists and therefore dysmorphology and detectives. So we must look for dysmorphology like a detective.

Once you see an abnormality, you make a list of the possible syndromes, and then for each syndrome, you think of one sentinel or distinctive feature that is going to be characteristic enough to help you narrow that list down to a very few syndromes or maybe even one. And then you use the pattern of all the malformations that you've seen to arrive at that particular diagnosis. And most of the time you will be right.

Thank you so much for your attention.