Mucopolysaccharidosis Misdiagnosis: A Cross-Disciplinary Approach

This transcript was produced by automatic speech recognition and edited for readability; it has not been fully verified word-for-word. It may contain errors — particularly with names, technical terms, and where English is a speaker's second language. This session has more than one presenter; the speaker attributions are our best reading of the audio and should be confirmed. It is provided as a convenience only. For anything clinical, please refer to the video recording to hear exactly what the expert said.

Skeletal and Orthopaedic Manifestations — Dr. Klane White

Dr. Klane White: Good morning and thanks Barbara for inviting me to be part of this webinar. It's obviously a stellar cast I'm joined by and always happy to see my old friends. We've been working together probably for 15 or 20 years, the four of us. So this is fantastic and a lot of fun. So hopefully today I can give some insights into the manifestations of MPS.

This is really focusing on diagnosis as opposed to treatment but certainly we'll have some opportunity afterwards to talk about treatment but being focused on pediatrics I think it's this is much more appropriate. So I do have some disclosures which are not relevant to this talk. So the Mucopolysaccharidosis, again you've probably seen this if you have attended previous webinars, are not clinically obvious at birth.

And infants, you know, I can look at these and kind of see some subtle findings but you know most, you know, pediatricians are not going to recognize this and that's no fault of their own. It's just these kids don't, you know, this is a progressive disorder and they look pretty normal at birth. And so it there are some things that, issues that pop up that make this a concern, maybe concerning for MPS.

And from an orthopedic standpoint, in children as they grow, they grow differently with MPS. They tend to have a short trunk, short stature as opposed to say achondroplasia which is a short limb long trunk disorder. The most common reason for referral for MPS to the orthopedic office is a kyphosis or a gibbous deformity which is a result of a vertebral body hypoplasia which I'll go over later in this talk.

And then oftentimes we'll have kids who come in, they present to their pediatrician for limping and they get an x- ray and the radiologist will read you this ilateral Perthes disease. And again, we'll go through these manifestations. But if you have to take anything home today, this is, these are the red flags you need to be aware of.

So, I do apologize, there's a little bit of delay here. When we're thinking about diagnosis, I think it's really helpful for any disproportionate short stature disorder to start with a skeletal survey. And I would have very few qualms about any primary care physician, any pediatrician starting with a skeletal survey. At a minimum, this includes a lateral skull X- ray, AP and lateral spine, AP pelvis, forearm hand view, and a lower extremity view.

If you really are sort of limited in how many films you can get, get a spine film and get an AP of both lower extremities. And here I show some manifestations that are very classic for MPS with the hips and the epiphyseal changes at the proximal femurs, the kyphosis, and vertebral body abnormalities of the spine. So, you will see there is a recurrent theme here with these X- rays, and I think even after a while, anyone should be able to recognize these.

Now, there are limitations to skeletal surveys because many disorders with skeletal displays have overlapping X- ray presentations, and I'll share with you some spine and hip X- rays that make this obvious. The other issue is that within even certain disorders, let's just say Morquio syndrome, some present with a very classic presentation where they're very short stature, pectus abnormalities, very clear spine abnormalities, while others have near normal growth, but they'll have these hip changes that I mentioned, the ilateral Perthes disease.

So there's a wide array of X- ray presentations that can present as MPS, and they don't necessarily look the same, even within specific MPS types. And 30% of the time, the skeletal survey just won't give you a diagnosis. Of course, that's talking about all skeletal displays just in general. Let's see if this comes along. Okay. So when we talk about MPS, there's a constellation of bony findings, which is called dysostosis multiplex.

Now, this is a diffuse skeletal disease. It's very specific to MPS. My apologies. The lag is— let me see if I can go back. Can someone go back for me here? Anyway, this is an inflammatory disorder. You see changes to the joints. You see changes to the bones. It results in progressive deformity in early life as children age and become adults.

And it can result in arthritic changes. So specifically, what are we looking for? In the spine, we're looking for flattening of the vertebral bodies, again, anterior body hypoplasia, usually at the thoracolumbar— junction, so— sorry, but that's— the spine— those are the classic spine changes. In the skull, you will see a long, narrow skull. You'll see shallow orbits.

The classic enlarged, shallow sella turcica, which is where the pituitary sits in some flattened faces. And then if we look at the trunk, you often see a pectus abnormality. You see broadening of the ribs, and then, again, a short trunk with— and you can see short, flattened clavicles. So my apologies on the animation here. So if we're looking at upper extremities, the hand— there are some classic hand findings which aren't totally reliable, especially in young children, but in certain MPS disorders, you see very short, broad metacarpals.

They have pointiness at the proximal ends, which we call tapered metacarpals or bullet- shaped metacarpals. You'll see a distal radius abnormality, which often is interpreted on an X- ray as a Madelung's deformity. If we look at their lower extremities, you can see acetabular dysplasia. You see epiphyseal changes, and you can see flaring of the iliac wings, knock knees, or genu valgum, and ankle valgus.

But what this results in is a large constellation of orthopedic problems that we have to deal with, and just know that this slide is not meant to be memorized. It's just to show that with each MPS disorder, there are multiple different finding problems that we run into. They can be cervical problems, scoliosis, hip dysplasia, knock knees, and carpal tunnel syndrome.

So that's why it's important to make these diagnoses from an orthopedic standpoint. Looking at the spine, this is a classic gibbous deformity. You see this thoracolumbar kyphosis, again, and I'll go through the x- rays next, but this is due to the vertebral body hypoplasia, which is classically manifested as an anterior superior deficiency of the bone, and that's a little child with her.

So these are four different skeletal dysplasia disorders, and to the sort of untrained eye, they can just say that there's kyphosis and a little bit of difference in the vertebral bodies, but when I look at this, I can pretty much tell you which ones of these are. The third one from the left, or the second one from the right, is Morquio syndrome.

Again, if you look at that focal kyphosis, you see that vertebral body hypoplasia. And just a little exercise, this is a 10- week- old with Hurler syndrome. You can see that, where that arrow's pointing, you see that anterior body deficiency. If we look at a 3- year- old with Morquio, this looks similar to the last x- ray, where the two x- rays we saw, or we saw two x- rays ago.

Again, same thing. And if we look at a 2- year- old with MPS6, again, that anterior body hypoplasia and kyphosis. So hopefully by looking at a few of these slides, you'll see, you'll recognize that pattern. If we move on to the hips, we see epiphyseal dysplasia. You can see the flattening of the proximal femoral epiphyses, often misinterpreted for osteonecrosis or Perthes disease.

This does progress into acetabular dysplasia and misshapen of the proximal femurs with progressive subluxation and deformity and pain in the hips. So these are different forms of skeletal dysplasia, and the one on the far left is Hurler syndrome. The middle one is multiple epiphyseal dysplasia, and the one on the right is type 2 collagenopathy. Type 2 collagenopathy and Morquio often look very similar and can be confused until you get testing.

And then, again, this is just a little pattern recognition. This is that same 4- month- old, I'm sorry, this is a different 4- month- old with Hurler syndrome. You see a little bit of kyphosis. You see some changes with the hands. You see acetabular dysplasia, and the skull film is probably not that revealing, maybe a little bit of shallowness of the sella turcica.

If we look at a 2- year- old with Hunter syndrome, again, you see the changes, particularly in the hands and the forearms. You see broadening of the ribs. You see a lot more coarsening in Hunter syndrome. You see a little bit of acetabular dysplasia. So these are just, again, this is just pattern recognition. This is a 3- year- old with Morquio.

Again, you see that kyphosis. You see the changes in the forearm. The Morquio, you see a really shallow sella turcica in the skull, and you see the acetabular and proximal femoral changes in the hips. All right, and then this is MPS6. Again, those spine changes and hip changes. So I think that, again, this is all about pattern recognition.

You may not be looking at your own x- rays, but if you do, hopefully this will help you. But if you get interpretation from your radiologist, I think it tells you you need to be looking down one of these roads. So physical findings in young children can be subtle. They do start developing disproportionate short stature. They can start developing symptoms from their spine and from their hips.

Radiographic changes in the spine, hips, and ribs are probably the most reliable, but also there can be changes to the skull, the forearm, and the hands, and I think if you have any questions at all, then if you're working someone up for a skeletal dysplasia, I would always start with a test for MPS, whether that's enzyme testing or, these days, molecular testing, and I'm not a geneticist, but you're certainly going to want to consult your genetics colleagues. So with that, I think that's my presentation, and I thank you for your time.

ENT Manifestations of MPS — Dr. David Molter

Dr David Molter: Thank you very much. Appreciate the opportunity to be with this good panel I have. My only disclosure is that I was part of the Hunter Outcome Survey committee and so some of my data comes from our final report that is in the process of being released, but it's not completely released. No financial interest. So why an otolaryngologist, or overview?

Why an otolaryngologist specifically looking at ears? I know this is a pediatric audience and so the overlap with peds is significant: swallowing speech, sleep apnea, sneaking a little bit of pulmonary and anesthesia consideration and then summary. So why otolaryngology? Well, we see these kids a lot, and so if you look on the left- hand side of your screen there, the things that are in orange of that, those first seven presentations were involved in five of them, and so it's not that we're going to say, hey, a kid has otitis media, better check for MPS.

But as you start adding these things up, then we start to consider that and in particular, if you can cross fields a bit, if the otolaryngologist also sees that they've been scheduled for a hernia repair, then that can increase your concerns and we we actually operate on them a bunch and we are the, the general surgeons, are the first folks to operate on them in the hernia repair region here.

But after that tympanostomy, adenoidectomy, tonsillectomy and later on some procedures such as tracheostomy. So we see them early, we see them often, and then if you look at treating specialties of those patients that require anesthesia, it turns out that otolaryngology leads the pack. Now, some of those times they the their actual surgical procedures that we're performing. Some of the times it's auditory brainstem responses that we're measuring and so we end up with that.

But we get credit in both of those. So, looking at your manifestations year- this is a picture you're very familiar- with the outer ear sound being carried down to the tympanic membrane. Children with otitis media. This is the area- the middle ear- that they are most affected, because with otitis media you get fluid that fills that space and the fluid is non compressible, so the sound is reflected back, just like when you're at a swimming pool and there's water in your ear.

But in the MPS considerations we also need to consider the snail- like organ that you see here. The cochlea is important. Losses in the middle ear are called conductive hearing loss. Losses after that in the cochlea or as it heads up to the brain, would be considered sensor neural hearing loss. Now some of those fluids would be just a normal inflammatory response, but some of them are called glycoaminoglycans or GAG particles.

Now mucopolysaccharides was the previous name that we used in that setting, and that's where the M of MPS comes from. So there are a bunch of vacuoles and pieces in this fluid. In this patient, they were younger. There was no involvement from a sensorineural standpoint, only the middle ear. This is a mouse slide, and here you can actually see those GAG collections, larger collection right here, smaller collection here.

But this continues. This is called the basement membrane, and this is the fundamental tool inside the cochlea that helps drive this, and you can see them even in this small section right here. And then there are some changes in the ear that are harder to explain just based on the GAG collections. This left slide, the arrow points to the three hair cells that the body uses when it's transducing sound.

The sound wave makes the fluid in that inner ear move. And going back one, I think mine's also advancing on its own occasionally. But looking on this left- hand side, you can see that the hair cells are gone. And so this person would have a nerve- style hearing loss. Move it back forward again. So this evolves. The orange bracket or orange bar that you see is a conductive hearing loss.

That's the hearing loss that you have in the middle ear. The light bluish thing is pure sensorineural hearing loss, and the green bars are a mixture of the two. So that you can see in the young child, the left- hand side is dominated by these orange bars. And as you age, the green bars start coming up, which is the mixed loss.

And then as you continue to age, it becomes a sensorineural hearing loss. So there's a transition between the three being purely the middle ear, being a combination of the two, and then being purely the nerve. When we looked at 500 patients in the Haas outcome survey, we were able to demonstrate a hearing loss that progressed over time, and that hearing loss often led to the use of hearing aids.

About 40% of patients with MPS2 will end up with a decision to proceed with hearing aids. And these are the various symptoms or intervention that we identified in that group. The important thing here is to say these are some of the interventions. We put in tubes. We used hearing aids. The hearing aids can be a bone- style hearing aid for the child that keeps fluid in their ear all the time, but you don't want tubes.

Or it could be a traditional aid, or it could even be a cochlear implant. So it's important to say that not only can we recognize problems, but we can intervene in those problems. Speech and swallow. Many children with MPS will have concerns with their speech and swallow. Some of these are going to be based on mechanical features of the airway.

You can see extrinsic compression from other things, or intrinsic, which is to say the tongue itself has the gag particles or gag collections, and even the esophagus can become more stiff based on these inclusion bodies. There's coordination issues and there's cognitive issues. And I do want to say that the substrate accumulation has been shown in all of these tissues, in the tonsils, in the adenoids, in the tongue, in the superglottic tissues, and in the trachea itself.

So it's not just that we see an association, we can actually prove that the particles exist in those spaces, and that the proportion of change in size is related to that particle. And then speech, we see, in addition to the coordination sort of concerns that you would see with somebody that has a large tongue or a stiff tongue, you may actually see changes in the larynx itself.

The vocal cords can become thickened, the joints, so there are joints at the back of the true vocal cords that shift back and forth, and they may become stiff, and again, coordination issues and cognitive issues. And then a bit on airway obstruction and sleep apnea. So if you use OSA as a measure of adenotonsillar hypertrophy, and if you look across the various MPS types, there are certainly some that are more severe than others, but the overall representation of sleep apnea is in this study of 42 patients.

Two of them didn't have sleep apnea, and the rest had varying degrees of mild, moderate, and severe apnea, often based on the MPS type. We also see the same thing from the standpoint of swallowing concerns that may be associated with enlarged tonsils, nasal breathing concerns that are associated with adenoid concerns. The midface is smaller in many of these patients as well, and so that can confuse things.

So adenotonsillectomy is common. Interestingly, success rates for adenotonsillectomy and MPS is rarely reported. So it's what we all do, but how effective is it, I think, is probably measured by whether or not the patients go on to consider other things like CPAP. Nobody likes to talk about tracheostomy, and tracheostomy is much less common than it was in the past, as we're better with CPAP and some other interventions.

The kind of interventions that you may see in the NICU are actually applied across ages, but the tracheostomy does let us pass the base of tongue and the mouth. It doesn't let us pass the trachea. The trachea is often quite distorted in patient with MPS disorders, and so we sometimes find it to be challenging. There's some old literature that said it was too challenging, and I think that we've been able to prove that that's no longer the case.

We are able to manage the granulation tissue that we sometimes see in patients with tracheostomy. We try not to use permanent stents, which are essentially small straws placed in the airway, because those do have longer- term concerns. And then I'm not an anesthesiologist, but anesthesia is very scary. And, you know, Klain's world, it's the cervical junction that is such a scary thing for anesthesia, and so if you can't extend the neck, it's much harder to intubate a patient.

And certainly nasal intubation can be a consideration, but we have some patients that even with nasal intubation, we need higher- level techniques. And unfortunately, there are reports of MPS patients dying during otherwise routine MPS surgeries. The risk with anesthesia are readily identified by otolaryngologists. The tongue base, the pharynx, limited motion of the mandible. Sometimes the mandible, really, you can't get past it, and so if you need to do emergency interventions, that's hard.

And then the cervical spine, which I mentioned. So the other thing is that it's really nice to have an otolaryngologist around if you have a patient who's decompensating because of their airway. And so there will be times that that comes into play. So, overall, otolaryngologists- we see them early and there was at one point actually a study when we were trying to say who should get tested, looking at patients who had hernia.

Now, in particular, it was hernia not in the newborn or not in the premature child, so it was hernia without prematurity. And then other otolaryngology interventions, such as pressure equalization tubes, adenotonsillectomy, recognizing sleep apnea. So that's something that, since we were so interested in early intervention, we're trying to look at things on the left- hand side of this chart as triggers to pursue, and then we see them often.

So in this study from 2010,, about 80% of folks had procedures, but 50% of them had had tubes, 49% of them had had adenoidectomy, 35% of them had had tonsillectomy. Overall, if we look at enlarged tonsils, adenoids and things along this line, about 80% of patients will have an otolaryngologist because of that in some of the newer data.

So I've tried to make a case for recognizing that we see them early and so we should be able to help you with identification. I've tried to make a case that we see them often and that we really do have interventions. So it's not just that we recognize the problem, but we can offer you some assistance in management of it, but possibly we don't see them enough- which is trying to figure out the relationship with anesthesia. We are the difficult airway service folks and so our input can be valuable for them. Thank you very much.

Prof. Barbara K. Burton: All right, thank you so much, David. That was really an excellent and very comprehensive discussion. I have a couple of questions that came up as I was listening. I think you talked very clearly about the airway issues and the associated risk of anesthesia. That goes along with that. I know in my practice taking care of MPS patients, I always try to make sure if they need any sort of surgery- and sometimes it might just be they need dental extractions or dental work under anesthesia or other things that seem on the surface very simple, but I don't like to see them and really recommend them going into outpatient surgery centers or places like that to get this, where we would not have access to an ENT specialist.

You know, like you mentioned, if the patient were to get into trouble or may not even have a pediatric anesthesiologist if it's a young child. So first of all, do you agree with that? And then, secondly, if a patient is going for surgery, let's say at your home institution, your anesthesiologist- they're familiar with MPS disorders. We always note in Epic there's difficult airway, all of that.

When should the ENT surgeon really be involved from the beginning? Is this a situation where it would be good for both anesthesia and ENT to be there every time, or if the patient, only if the patient's had a problem? What do you think about that?

Dr David Molter: So your first suggestion: I do think MPS patients shouldn't be operated on outside of the hospital setting and we have our own surgery centers and we don't operate even though it's the same anesthesiologist and me at the surgery center. We don't have them go there for their ABRS. They come to the main campus for their ABRS or any other sedated procedure, even if it's not a surgical piece.

From a standpoint of when we should be there. There are some groups that do a flexible endoscopy before any procedure. The German group actually mentioned that years ago. I think we're doing that a little less often as the anesthesiologists have become more comfortable themselves with doing flexible endoscopy or flexible nasal interventions. We still do it. And we certainly want to be there in the patient that we know there is a concern.

There's some very fancy things we can do. We can try to place a wire in the airway through the neck and have it come out through the mouth. And then once you have that, then the anesthesiologist can get secure. So that's higher level airway interventions. I think the tricky part is for the patients, this is a progressive disorder.

And so anesthesiologists are really good about noting what has happened in the past and based on that, trying to evaluate the risk profile for the next step. But my concern there is when was the last intervention? If you have a tonsillectomy at five, that tells us very little about the child at 10 when they're undergoing an orthopedic procedure.

So I'm very interested in seeing that 10-year-old. But if I saw them when they were eight and they're okay, I'm less worried about that. So it's the child that has a past history of doing well with surgery, when do you no longer have the ability to use that to say, oh, this kid's safe. We're allowed to do it with routine techniques.

And even in the kids that are otherwise safe, our anesthesiologists know they, even if I'm not there on that day, we always have an otolaryngology room running and they'll come on in and say, I have an MPS kid. So if you get a call from room seven, come. And so I think that communication is important.

Prof. Barbara K. Burton: Yeah, I agree. That makes perfect sense.

Dr David Molter: Absolutely.

Prof. Barbara K. Burton: Okay. Well, thank you so much for that. And with that, I'm going to ask Liz to come to the podium and share with us her discussion of the cardiac issues related to the MPS disorders. And I think we're going to need to get the slides moved forward to her deck. Very good. All right. Liz, take it away.

Cardiac Manifestations of MPS — Dr. Elizabeth Braunlin

Dr Elizabeth Braunlin: Well, thank you for inviting me to this meeting. So the objectives of my talk are to describe the best method to establish cardiac... define the three major cardiac findings in MPS, describe age- related differences in cardiac findings, and then recognize the importance of these age- related differences. The cardiac findings are best determined by echo. Physical exam is usually unrewarding.

They don't have murmurs. And because of their airway issues, it's often difficult to hear murmurs even when they are present. Chest X- ray and EKG don't demonstrate the anatomy or the function of the heart. And a chest CT or an MRI is expensive and requires sedation. So cardiac echo usually doesn't require sedation. And you can define the anatomy and the function.

What you can't define is the involvement of the coronary arteries by cardiac ultrasound. You can have some fairly serious coronary artery disease with MPS that is not detected by echo. So cardiac finding number one of the three, anatomy is normal and function is usually normal. So you have normal anatomy, meaning you have two atria, you have two ventricles, you have four cardiac valves, and you have normal cardiac function usually.

So what do I mean by normal cardiac function? When we talk about function, we talk about an ejection fraction and we can actually measure that on cardiac echo. On the left-hand panel is a trace of the left ventricle in diastole when the heart is filling with blood. And on the right-hand panel, they've scrolled a few pixels further and they're doing the systolic dimension.

When the heart is empty, it's ejected all of its blood. And the difference between the area in diastole and the area in systole as a percentage is what we call the ejection fraction. And we're happy if anyone has an ejection fraction of more than 50%. Cardiac findings two and three are that the cardiac valves are thickened and oftentimes they leak or are stenotic.

We can tell that on cardiac ultrasound by looking at the valves. On the left-hand panel here is a normal mitral valve open to receive blood and this is a two-dimensional image. On the right-hand picture is a mitral valve from someone with MPS and I think you can appreciate that the valve is thicker and that is increased because of the presence of glycosaminoglycans.

The bottom left-hand panel is an aortic valve and you just can barely see the leaflets in the open position here, whereas on the right is an MPS aortic valve and you see how easy it is to see these thickened valve leaflets. They too have MPS material in them. The cardiac finding number three is that you can have dilation of what we call the aortic root, which is composed of the beginnings of the ascending aorta, the sinus, the sinotubular ridge.

Here we're measuring aortic sinus in an 11-year-old and it measures out to be 2.33 centimeters. Well, here is a two-year-old with an aortic sinus that's just about the same diameter, 2.13 centimeters. So in this case, we use something called the Z-score to compare how far from normal it is. So a Z-score is kind of like a standard deviation and this patient at 11 years of age has a normal Z-score, so a Z-score would be zero.

But because there's the same size of the aortic root in a two-year-old, this Z-score would be greater than two. And sometimes it can even be more like three and four for Z-scores. So it's an important thing that we follow on echo. So also notable is that the MPS phenotype, you've already learned this, develops over time. Here's a baby.

It looks pretty cute, a little baby. Now you're starting to see some of the phenotype that you associate with MPS in the younger child, the older child, and here's an adult. The same picture over the course of time and you can tell the progression because of the deposition of glycosaminoglycans. So just as the somatic cells and the facial phenotype develop over time, the cardiac findings increase over time in MPS.

So cardiac signs in young infants can often be absent and they're often mild. But the important thing about infants is that with MPS, cardiac function, that ejection fraction can be decreased. That turns out to be a very important fact when you care for young infants because they oftentimes don't have good enough function to undergo bone marrow transplant or anesthesia until you do something to fix the function.

And so here is a picture, first of all, if I get it to go back, of normal ejection fraction like we talked about before. And here is a child who presented at about a month of age where the difference between the diastolic area and the systolic area is very small. And this patient showed up with an ejection fraction of 29%.

And so at that point, wouldn't have been able to undergo anything like bone marrow transplant and would have been at higher risk to undergo anesthesia. Valve thickening can be fairly minimal in early infancy. This is a picture of a mitral valve with the arrow, and also the left ventricle like you've seen before. Even though the valve thickening can be fairly minimal, you can see mitral regurgitation.

And this is a picture, this blue jet is a picture of mitral regurgitation. And we look at the thickness of the jet and the length of the jet. So this is a fairly thin, narrow jet. And this would be classified as trivial to mild mitral insufficiency. This is also from a three-week-old child to show you that even though the valves are not very thick, there can be regurgitation present.

What's not present in infants is valve stenosis, either mitral or aortic. But finally, like we mentioned before, you can see aortic root dilation even in young infants. We've had some infants show up with C scores of 4 in infancy. In older infants and in children, it's very uncommon to see decreased function. You see normal function. You have a normal ejection fraction.

Here is someone who has a normal ejection fraction, but also has developed clear-cut mitral valve thickening. You can see how thick and bulbous this valve is compared to the one in infancy. And here is a picture of mitral insufficiency. The jet is now clearly a little bit wider, and it goes all the way back in the left atrium and almost reaches the pulmonary veins.

Again, mitral stenosis and aortic stenosis are uncommon findings in children. With any luck, I'll be able to pull up an echo showing that there's normal flow without any turbulence or sparkles in it across the aortic valve here. And this is in a one-year-old. So regurgitation is quite common in older infants and children. Mitral is more common than aortic.

Valve thickening is present, but valve stenosis is absent. In older adolescents and adults, continue to have normal function. You continue to have valve thickening. You continue to have valve regurgitation, as is seen in this picture here. But now you've developed valve stenosis. This seems to happen in adolescence and adulthood. And it turns out that even though mitral regurgitation is seen very commonly in children, when you hear about who is getting surgery, it's almost always for valve stenosis.

And then we also have aortic stenosis. Remember how that signal was all blue before with no turbulence? Here is the same image, but now there's turbulent flow as the blood grows across the aortic valve. So that is aortic stenosis. So adolescents and adults, valve thickening, regurgitation, and now you see stenosis. So here they are in a little table.

Important thing to remember, decreased function in infants, valve regurgitation in older infants and kids, regurgitation and stenosis in adults. The implications of this are that cardiac function needs to be improved before you can have bone marrow transplant. And the best thing to improve cardiac function in young infants is actually enzyme replacement therapy. It's kind of precision therapy for decreased function.

It's been reported from several centers, including ours, that kids who show up, about a third of the newborns who show up will have decreased function and enzyme replacement therapy will improve that function, normalizing it and allowing them to go on to bone marrow transplant or whatever is in line for them. Valve problems such as the thickness regurgitation and stenosis, as well as aortic dilation on the other hand, don't reverse with any current therapies and they may progress despite all of our current therapies.

So early treatment, when we have valve problems that are less, like in the infants, may delay the onset of more serious valve problems requiring cardiac surgery. And finally, cardiac echo is the most reliable way to find and follow cardiac issues in MPS. There are major age-related differences in the findings. Less than six months may have absent or mild valve findings and about a third of them will have decreased ejection fraction.

Infants greater than six months and children will usually have normal cardiac function. They'll have valve thickening and regurgitation. And in adolescents and adults, valve stenosis develops. Early recognition and treatment of these cardiac echo findings will reverse decreased function and may delay more serious cardiac valve problems. Thank you very much.

Panel Discussion and Audience Questions

Prof. Barbara K. Burton: Thank you, Liz. That was just a great and very clear discussion, I think, of the cardiac issues and the evolution of those. In the U.S., as you know, we now are in a situation where we have almost universal newborn screening for MPS 1 and we are getting into MPS 2 newborn screening with more and more states coming online.

And we have one state that does MPS 4A. And I think hopefully over time, other MPS disorders will also find their way into newborn screening. So I'm wondering what you think we should be doing with these babies that come in from newborn screening where we get a very early diagnosis or we're involved in the diagnostic process. Do you feel like we should get an echo right from the beginning, you know, wait until six months, wait until a year? What's your recommendation there?

Dr Elizabeth Braunlin: That's a great question. And given that the babies who have been diagnosed as MPS by newborn screening will undergo procedures under anesthesia, sometimes fairly lengthy ones, I believe that each child should have a cardiac ultrasound. As soon as the diagnosis is established, in order to make sure that you're not dealing with one of those kids that has decreased function that's going to need to have enzyme replacement given perhaps for a couple of weeks, up to a month or more through peripheral IV before you would risk having them undergo general anesthesia for permanent line placement.

Prof. Barbara K. Burton: That's a great comment because I've been thinking, well, certainly it seems like it's important for the severe form of MPS 1 where we'd be sending the patient for transplant. But as you said, even kids who may not be going for transplant because they have other diagnoses or are going to be getting other modes of treatment would be getting procedures like you said.

So that's a great, I think that's a great comment and certainly influences my thinking about it for sure. Yeah. Good. Any of you, either of you other guys have any questions for one another or any issues we haven't touched on that you'd like to bring up at this point? I'm looking in the chat and I don't see any questions from the audience.

Oh wait, one just came in. I have what ongoing cardiac monitoring is recommended for MPS patients, especially those on enzyme replacement therapy? Liz, that's for you.

Dr Elizabeth Braunlin: Yeah. So I see the patients who are on enzyme replacement therapy about once a year and we. Do vital signs, listen, like I said, it's very unusual to hear even mitral regurgitation in patients with MPS, and we get echoes annually. We look at the valves, we look at the function, we look at the aortic root, we measure Z-scores, and then the other thing I do is we get an EKG every year to look at the PR interval because there are reports out there about gag deposition in the conduction system, and patients who have progressively prolonged PR intervals are at risk, especially when they undergo anesthesia.

Take away their sympathetic drive with anesthesia and you have a prolonged PR interval, it may end up being advanced heart block with a very slow heart rate. There are papers in the literature about unsuspecting dentists giving anesthesia in an MPS patient and ending up with a patient dying from heart block.

Prof. Barbara K. Burton: Yeah, okay, yeah, very good, good to know for sure, and of course some of our older patients get arrhythmias and things too, so yeah, I think that cardiac follow-up is very critical for all of them. I have a question for you, David, from again the audience. How can obstructive sleep apnea in MPS be effectively managed?

Dr David Molter: So it's a tree. We almost always start with adenotonsillectomy. The turbinates, which is... the adenoids may be hypertrophied, and so that's something that is commonly done in adults, but most of the time in kids we leave that alone, but not in the MPS kids. So I'm willing to try to do a turbinate reduction to try to improve the airway there.

I don't know of many people using mandible advance as a therapy for this because the mandible has some other concerns. There are plenty of folks that use tongue-based procedures where you actually excise the central portion of the posterior tongue to essentially make a groove there. And then I think CPAP and BiPAP, that technology has just really improved so much in the last 15 years that I think there are plenty of patients now who are treated with CPAP, BiPAP who would have needed surgical intervention, not counting the TNA, before.

So I think that's the piece. And then finally, you know, a tracheostomy is a potential procedure, but fortunately it's relatively rare. It's in the 5% sort of range where the other things from an ENT standpoint are in the 50% sort of range.

Prof. Barbara K. Burton: Okay, great. Thanks. Klane, we have a question here. How does dysostosis multiplex specifically manifest in the spine of MPS patients?

Dr. Klane White: I think I alluded to this, but clinically it manifests as a gibbous deformity. So, you know, parents will notice a bump in the back, and that's usually one of the earliest signs of MPS that families and, you know, primary care providers can see. Now radiographically, this manifests as underdevelopment of the vertebral bodies, usually in the front, which then results in that forward bend in the spine.

Later in life, this can progress and require surgery for thoracolumbar kyphosis, again usually between T12 and L2. And in some cases, the spine can spin off and then result in scoliosis. I think it's important to note that kyphosis is really a concern with neurologic disease, and scoliosis is more of a pulmonary disease. So I think that's, in a nutshell, what providers should expect.

Prof. Barbara K. Burton: Okay, great. Thank you so much, and thank you also to our audience. Unfortunately, we're coming up against the end of our allotted time, so we're going to need to close down the webinar, but I'd like to thank all of the speakers for such a fantastic discussion and also thank you to the audience for participating with us here today. Everyone, have a good day.

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