Chapters Transcript FGFRS-opathies: ACH and HCH Catherine Gooch, MD, presents on achondroplasia and hypochondroplasia and bone formations. Well, good morning everyone, and welcome to Early Bird rounds today. We really appreciate you all joining us this morning. Um, Today we have um Doctor Katherine Gooch, and she is specialized in um genetics, and so um we'll look forward to her talk this morning, but before, I just wanted to let you all know to please remember to keep your cameras and your mics muted during the session. Um, there will be time at the end for questions and um you're welcome to type your questions in the chat during the lecture, and then at the end, um, she'll be able to answer those as well, the QR code will be put up at the end for you all to scan for credit. We'll go ahead and give her our attention and um don't forget to take control. Of your slides. All right, thanks, Madison. All right. Does that look correct on your end? Yes, that looks good. Great. OK. So I'm Catherine Gooch. Hey, everyone. I'm one of the medical geneticists here at WashU. Um, I'm the medical director of the skeletal dysplasia clinic, and a lot of my um clinical practice is related to skeletal dysplasia and other genetic disorders of bone. So today I'm gonna talk about two of the most common skeletal dysplasias, which most of you guys have probably seen at least once or twice in clinic, achondroplasia and hypochondroplasia. So from a disclosure standpoint, um, rare bone disease is an area of rapid orphan drug development. So I am an unpaid investigator for multiple different clinical trials related to genetic bone disease. We will discuss some of my trials. I think I can discuss them without any bias. Um, like I said, I'm unpaid and I have no other disclosures. So achondroplasia, um, is an ancient panethnic uh genetic condition. It's the most common form of short limb disproportionate dwarfism, um, and it's well documented throughout history from ancient times. Um, so on the left here, you can see this is a Mesoamerican pottery, um, depicting an individual with achondroplasia. In the middle, we have an ancient Egyptian. Um, relief of someone with achondroplasia. And then on the right side, um, we have someone in medieval England clearly displaying features of achondroplasia. Um, so it's something that history has been aware of for a long time and the medical community has too, and it is no risk factor of persons, places or things. It is an equal opportunity genetic condition. Um, so the actual meaning of achondroplasia, a meaning no chondrocartilage, plasia growth, so no cartilage growth. I'm sorry if you can hear my dogs. You must be getting a package, and I'm working from home today. Um, so then hypochondroplasia, on the other hand, hypo meaning below normal cartilage growth. So similar but they are different. So, um, starting with achondroplasia, um, the incidence of achondroplasia is approximately 1 in every 20,000 to 30,000 births. So we do expect multiple babies to be born with this condition in the state of Missouri every year. Um, and it is caused by a pathogenic single nucleotide change in the gene FGFR3, which sits right at the end of the p arm of chromosome 4. Um, there is one mutation, 1138 G to A, that, um, accounts for 98 to 99% of all cases of achondroplasia. Um, so it is one mutation that we see recurrently, and about 75 to 80% of these mutations are new mutations, um, in the baby, so either the egger sperm that made the baby, um, and 20 to 25% are inherited from a parent who is affected by achondroplasia. Um, and with other, um, The single gene disorders, there does seem to be an advanced paternal age effect. So fathers who are over the age of 50 or 55, um, definitely are at increased risk of having a child with this condition. Um, so the way we, oh, it is autosomal dominant, so you only need one copy that has a pathogenic change in it. Um, the other copy we assume would be working just fine. And the way we diagnose someone with achondroplasia is through a combination of physical exam findings and obviously through molecular sequencing that shows the, the common 1138 pathogenic variant. Hypochondroplasia is very similar, so it's caused by mutations in FGFR3 as well, um, but it's caused by different mutations. There's about at least 20 to 30 known mutations that can cause hypochondroplasia. So you do see some more phenotypic variability than with achondroplasia. It is also autosomal dominant, um, although some of the actual numbers are a little harder because some patients with achondroplasia with hypochondroplasia, sorry, are more mild and um maybe don't really come to medical attention. There are people who just view themselves as shorter than normal but never thought to actually get a diagnosis. Um, so some of the things like incidents and um proportion of inherited versus de novo mutations are much harder to prognosticate. So then going into the actual condition. So if we think back to embryology, which I know is everyone's favorite, um, there's two different ways that bones grow, endochondral ossification versus intramembranous ossification. So intramembranous ossification takes care of the axial skeleton and endochondral, the long bones. So FGFR3 is expressed in the growth place of the lung bone, so it is involved with endochondral ossification, and that is the ultimate disorder here is a disorder of endochondral ossification. So here's our um beautiful bones throughout the age, just going to show that growth plate developing through time, and right here at the plate um is where we have the disorders of the FGFR3. So zooming in even more, bone people love histology because our slides are so pretty and purple. Um, but right here at the junction between the proliferating chondrocytes and hypertrophic chondrocytes, um, this is where FGFR3 is active and when, um, that mutation is in place, it serves as a break on the, um, chondrocyte proliferation pathway. So the chondrocytes do not have this lovely pattern of growth and development. It is a stunted pathway. Um, so from a molecular standpoint, when you have a pathogenic activating mutation in FTFR3, this leads to um activated MAPA signaling in the chondrocytes going through that pathway. So it suppresses proliferation and maturation of the chondrocytes, the growth plate. So that growth plate just does not work. Therefore, the bone does not grow. Um, and then I'm gonna make a small mention here, um, of a molecule called C-type natritic peptide, um, which works on the opposite end of the signaling pathway. So FGFR3 um is functioning as a brake, CNP can function as the gas pedal on this pathway, and we'll come back to that a little later in the talk too. And if you have extra CNP you have long bone overgrowths. So here's the pathway, FGFR3, the transmembrane protein right there, and then distal to that is all of the bone growth map pathways. And then over here is the CNP side of it. So, I tell my trainees, it's, you know, I'm not gonna get into the super nitty gritty molecular details, but I kind of view it as the brake pedal and the gas pedal of the pathway when we talk about therapies. So the natural history of these conditions. Um, it is possible to have prenatal diagnosis. Obviously, if one of the parents is affected, it would be a 50% chance for pregnancy that their offspring would have this. Um, but if not, um, the cases that are the 75 to 80% of de novo mutations, um, definitely. There are some signs that you can see on ultrasound. However, I have seen, um, many parents not know that the baby was affected with achondroplasia until the time of birth. Um, they can be a little more subtle or harder to see. But this is a, um, a sonogram of a baby with achondroplasia. And, um, you can see here that this forehead really looks enlarged, embossed. And a depressed nasal bridge. Um, I can see little dots that are probably the feet and I cannot see the arms, um, in this picture. So me looking at this, doing what I do in skeletal dysplasia, I would be quite concerned. We appear to have a significant macrocephaly with shortening of the long bones. So there definitely are things you can see on ultrasound. And then sometimes the birth history also um can give you some clues. Um, babies who have achondroplasia have macrocephaly. It's not just proportionate macrocephaly, it's also just total macrocephaly. So, um, a failed vaginal delivery is something I see in probably at least 80 to 90% of my moms who attempt a vaginal delivery. Um, it is a very hard delivery just because of cephalopelvic disproportion. And if the mother has achondroplasia and the baby does too, there is virtually a 0% chance of her having a natural delivery, and we do recommend a C-section for any mom who has achondroplasia. So as the child goes through development, um, one interesting thing I like to make sure general pediatricians know is that when these babies are born, um, they are often normal birth lengths. When you look at them, they're clearly Disproportionate. But their overall birth length can be well in the normal range. And some of that is because their heads can be so large, honestly, um, it kind of makes up some of the difference. But as the baby grows, that growth chart drops off very quickly. Um, and from a developmental standpoint, um, they do have some some different early developmental milestones. There's a wonderful paper, um, published in pediatrics on achondroplasia, all the milestones, it's, uh, Julie Hoover Fon did the most recent, um, Rendition of that and it's wonderful. So I drove this um milestone chart from that paper. Um, and it shows that children with achondroplasia tend to have a wider range of, especially physical milestones, and they often are delayed compared to kids without achondroplasia. Um, so it's important to use the developmental milestone chart for achondroplasia because they're normal is different, but as long as they are within the normal range for their condition, I'm fine with that. Um, and the reason for that honestly goes back to that big head. Their head, just to put it bluntly, is heavy. It's large, they're disproportionate, so things that require good head control, like sitting up, are very hard for these kiddos. Um, but by the time they are 5, they should be completely caught up. When they enter that kindergarten classroom, they should be doing everything that all of their peers should be doing. If they're not, that is cause for concern. Um, but there are wonderful guidelines that we can follow them with. And there's also some unique milestones, and again these are related to their head, um, but these are, you know, kiddos with average intelligence, so they're going to be curious, wanting to play and get into things, so they find their own ways to move, um. So they'll scoot along their backs with their heads still on the ground. It's called reverse snow plowing, or they will attempt to crawl, but their heads are so heavy they can't lift it up. So that's just called snow plowing. Um, there's actually some really detailed um Descriptions of physical milestones in kids with achondroplasia. If there's any questions, I'm happy to provide those. Um, so just know that these kiddos can do different things that they have, um, Kind of um adapted to, and it's really excellent. And again, here's a link to that healthcare management guidelines by Julie Hoover Fong. If you have a patient with achondroplasia or hypochondroplasia, I strongly recommend you have a look at that because it is just a wealth of information. So from a medical complication standpoint, um, there are some things that we really need to be on the lookout for. Um, number one is sleep disordered breathing. This most commonly presents as obstructive sleep apnea. Um, looking at the literature, the prevalence ranges from like 20% to 90%. I swear in my clinic population, I do early screenings. It is at least 80 to 90%. Um, it is a significant thing early on and it's something we really need to keep an eye on. It's also hard to treat because the treatment is normally extra oxygen. If you ever tried to keep an oxygen cannula on an otherwise healthy mobile baby, it's very hard. Um, but it is something that we definitely need to keep an eye on to preserve those neurons. And the reason they have this is just narrow airways, and they have significant mid-phase hypoplasia as well. Um, so this peaks during preschool years because at this stage, the tonsils and adenoids are at their biggest. They're getting all those delightful daycare preschool cruds, um, and there. Airways are just smaller than other people's, so I cannot find an image of achondroplastic airway. So this is an average stature airway, but it just shows if you have a large tonsil or enlarged adenoids, obviously it's gonna take up more room. So if you imagine that these airways are hypoplastic, they're more stenotic, um, There's just not much space left um to for air movement. So most of these kiddos snore, um, and most of them also do end up getting their tonsils and adenoids out at some time. So just keep that in the back of your mind. It is something we always have to screen for. Um, and all of my babies, I may get a sleep study ASAP. So there are some kiddos if we're maybe a high-risk social situation or a very rural area, I don't let leave the hospital without getting a sleep study. Um, and then this obstructive sleep apnea is something that is definitely retained throughout life. It can get better as the airways grow and the patients grow, but many adults with achondroplasia also have significant sleep apnea and need a CPAP. Pregnancy definitely worsens this. I've had numerous moms tell them that, tell me that their husband has told them like when they're pregnant, they're concerned um for their breathing, so they have to get re-evaluated. So, always something to keep an eye on, um, the body habits of adults with achondroplasia also just really predisposes to sleep apnea. So, the other major thing that we need to think about, especially in Littles is foramen magnum stenosis. Um, this leads to a high risk of central sleep apnea. So the foramen magnum, as we all know, is the large hole in the base of the skull where the spinal cord, um, comes out of the brain and the brain stem. So in kiddos with achondroplasia, the foramen magnum is synotic, it's smaller than it should be, um, and I'm not sure why, um, but it is. And very unfortunately, the area that gets pinched, if that becomes too stenotic is the medulla, right at the breathing and heart rate center. So if you look at the historic literature, um it's actually really sad. Before the, maybe the 80s, there was a really high rate of SIDS in patients with achondroplasia. Um, and then Rich Polly and the group up in Wisconsin in the 80s did um a really sad autopsy case series to try to determine why these kiddos died, and they found um This frame and magnum stenosis leading to central sleep apnea and about 100% of the cases that they looked at as a cause of death. Um, so that article actually really was very important and ended up saving lives of probably countless kiddos with achondroplasia because now that we know that this is a thing, we screen for it to prevent complications. So, Um, all of my babies with achondroplasia, um, had better get an MRI ASAP, um, after they see me in clinic. Sometimes we do them in the hospital as well. So we'll do a screening MRI to look at the base of that skull. They're almost always smaller than normal, but if there's no cord impingement, that's OK. We know that the Freeman Magnum is gonna be smaller than normal. And then we have a wonderful multidisciplinary skeletal dysplasia clinic and then I um have these kids follow with neurosurgery to monitor that. Um. Especially during the early preschool years, very important to monitor because if we do see signs of impingement, the treatment is an emergency skull-based decompression, so it is a big thing, um, but it at the same time it saves lives, so we monitor very closely. Um, let's see. From an orthopedic concern, um, obviously, when we think of patients with skeletal dysplasia, we know that they're gonna spend lots of time in the orthopedic office. They can have bowing of the extremities. One thing that I do think is underappreciated is that bowing really does not happen until gravity becomes something that the body is exposed to. So really until these kiddos start standing and walking, they will not bow. Um, So I've had a lot of parents come in for their 1 year checkup and they're like, oh, we're so glad we're not seeing Boeing. Yeah, you shouldn't be seeing Boeing cause baby just learned how to walk a week ago, um, but normally by the time they've had 6 to 12 months of walking under their belt, gravity does start to take its toll and we do see outward bowing of the legs, um. So that's something to keep an eye on. Some of these kiddos do need osteotomies, um, although there's some evidence that if you good physical activity can really help prevent that. Um, but all of my kiddos follow with orthopedics to monitor that. Scoliosis is also a really interesting phenomenon in patients with achondroplasia because it changes through time. So babies and toddlers have thoraccal lumbar kyphosis. So the spine comes outward in the thoraccal lumbar area. You can see the picture on the slide of that infant. That is really exaggerated. That is worse than anything I've ever seen in clinic. And part of the reason for that is because we do a really good job teaching our parents about seeing. Um, babies with achondroplasia will get a spine like this if they are placed in a lot of soft baby carriers. Um, I loved baby wearing my kids, wearing them in slings. It was great. It's really not a good option for kids with achondroplasia. If their spines are allowed to go and kind of bow out, so they can stay there. Um, so baby wearing is not a great option, bouncer's not a good option. They need really, um, Hardack chairs with good support that's gonna keep that spine in alignment, so this car seat, I think is a great example of what kiddos need. bumbo chairs, pretty good option, high chairs good, um, but soft things are really gonna do these kiddos a disservice. So, like I said, this changes throughout their lifetime. So we have that thoraccal lumbar kyphosis when they're babies, we keep an eye on that between ortho and neurosurge, they monitor. Um, but then the spinal cord changes throughout life. So by the time they're about in kindergarten, they look really good. They look like they don't have much scoliosis. Um, that's kind of the sweet spot. And then with time, it changes and you get a lumbar loosis. If you think about an adult with achondroplasia, everyone kind of has that body habits where they have a sway back and then their pelvis is kind of tilted up, and that's just due to the typical scoliosis with the condition. Um, so that is what we expect with the natural history. It is something that we keep an eye on. These kiddos definitely um can have a higher incidence of early onset arthritis as they grow, especially in the hips and knees, especially if we are in poor alignment. Um, so again, orthopedics. Um, and physical medicine and rehab are in clinic. I'm sorry, is there a question or a little bit of. A little bit of uh. OK, thanks. So spinal stenosis is also something that's really important to think about. Spinal stenosis, um, does not happen really in early childhood or even mid-childhood. We start seeing some of the early cases in, um, the high school years. Certainly, many adults with achondroplasia have problems with spinal stenosis. Um, and it can be very painful. It can be disabling. Um, also, as I've said, you know, patients have a normal intelligence, normal cognition, so they also kind of have normal careers. I saw one patient who was a nurse, and she was telling us how it is so hard for her to get through a 12-hour shift on the floor, because by the end of it, she just had Shooting pain all down her leg. Her leg is going numb, um, and she was concerned about how long she was going to be able to work. She was only in her 30s. Um, so that's due to spinal stenosis. So and it's also it's a significant source of morbidity. So definitely something to keep an eye on and also something that your, the parents of these kiddos may be complaining about themselves. So hypochondroplasia is um like I said, Not as well characterized or understood as achondroplasia because it is much more phenotypically variable, um, with some people probably underrecognized. Um, so there is a natural history study going on right now to try to get some more information. Um, WasU is a site. Um, Patty Dixon and I, um, are the investigators for that. So if you have any patients, I would love to enroll more. So please reach out. Um. Also with hypochondroplasia, we'll get into more details as the lecture goes on, but there is initially reported an increased incidence of higher intellectual disability, some increased temporal lobe epilepsy, and abnormal MRIs. I would say that in general, as a skeletal dysplasia community, we're confused as to why this was reported. Um, we're not quite sure how accurate some of the literature is, which is why I think we're all really waiting to see what that natural history study shows. Um, orthopedics is definitely the main concern that I see in my patients with hypochondroplasia. They have that boeing that gets worse, um, with weight-bearing, um, chronic lower extremity pain due to poor alignment. They also can have the scoliosis with lumbar lowerdosis. They also have limited elbow extension, so that's something that you'll see normally 10 to 15 degrees limited extension. They also have that earlier onset of osteoarthritis. And in general for all of these conditions, um, I like to make sure everyone knows social support is so important, um. Most cases are de novo. Like I said, 75 to 80% are de novo, and many parents are completely unaware of the vibrant and massive, uh, amazing little person community that there is. Uh, many affected kiddos are the only person with short stature in their school, so they're not aware that there are thousands of kids out there with similar struggles, um. And then normally, this becomes more obvious as the child grows. Like I said, in kindergarten, it's not quite as obvious, um, but kiddos with achondroplasia do not have a purittal growth spurt. So that really makes things obvious. By the time middle school comes around, which as we know is a hard time anyways, it is really obvious that something is physically different with these kiddos. Um, so then there's a wonderful organization called LPA, which is Little People of America. If you're not aware of it, I encourage you to give their website a look. It is wonderful. There's also a lot of Um, at different levels of support. So there is a local Saint Louis chapter just for the Saint Louis area. There's also regional, um, so Missouri is in a different region than Illinois, um, it's just the way it is. So there's regionals, and then they'll hold regional meetings. Um, we went to the skeletal dysplasia clinic, went to the last regional meeting, which luckily for us was just in Chesterfield. Uh, met a lot of patients. We did a Q&A, um, it's an amazing support system. There's also national. LPA, which is so cool, and we try to go every year. It's a national convention. There's literally thousands of people who attend. Um, and it's just a wonderful experience for me too, to see what it's like to be a person of abnormal stature, because at that conference, my 5'7 self is very much the exception, not the rule. Um, so it's really great to just turn the tables and for me to see what that's like. Um, And so going into some of the physical features, uh, I think we're all familiar with what patients with achondroplasia look like, but, um, I tell all of my trainees that one of the PES board pearls is just to show um a picture of this hand and say what's the diagnosis. Patients with achondroplasia, hypochondroplasia, sometimes, um, have what we call a trident hand where the three middle fingers all look about the same. Um, and the extremity show rhizomelic shortening, so that's the upper part, so humerus and femur are more affected than lower. The axial skeleton appears disproportionately large, and like I said, we have macrocephaly, midface hypoplasia, frontal bossing, depressed nasal bridge, and the Trident hand. Hypochondroplasia, like I said, is much more subtle with wider phenotypic variability. So, um, I like to show this picture of three different kiddos with hypochondroplasia, because I think they show the spectrum really nicely. This little patient over here on the left hand side, I think if I saw him, I would probably be like, oh, I wonder if he has achondroplasia. He's got that long forehead, depressed nasal bridge, and you can definitely see that rise in me like shortening. Um So I think he's he's one that I was kind of surprised to learn that that he had um hypocon. And this girl in the middle, I think her facial features are more subtle. She doesn't have that really strong achoroplasia gestalt, but at the same time, she has a long bossed forehead and she definitely has some shortening of her long bones. And then this little boy here, um, I included this picture because you can see he's in a little swimsuit, so you can see the extra little rolls that he has on his arms and legs. It's a pretty common physical feature, and that can show that the long bones aren't catching up with the soft tissue growth. It's kind of how I view it. Um, so these babies, they are stinking cute. They have all these little extra fat rolls, and they're just adorable to work with. Um, but I thought the series of pictures really showed that patients with hypochondroplasia do not always look exactly like each other, not like patients with achondroplasia. Um, let's see what else. Slow growth. So in general, hypochondroplasia, we're still working on getting growth charts that I think are really super accurate, but in general, their growth is going to be below average, but higher than achondroplasia. Um, I know that's super general, that's the best I got right now. They have some bowing, facial features can be much more subtle, Trident hands are really not as much of a thing, but they do have that limited elbow extension. Um, that's more specific. Also, assortative mating is something that I think we all need to be aware of when we take care of patients in the little person community, um. People who are a little person are more likely to marry another little person, uh, which is great, but there does come with that genetic caveats, right? Because we have genetic disorders in both mom and dad in that situation. So this couple over here, um, obviously quite famous for those of you who watched TLC in the 2000s, Matt and Amy roll off. So Amy has achondroplasia, a dominant condition. And Matt is diastrophic, a recessive condition. So when they went to have a child, all of their children would be carriers for Matt's diastrophic. And then it would be a 50% chance for pregnancy that they would get Amy's achondroplasia variant. So there's a lot to think about when you have two parents affected with a genetic skeletal dysplasia, especially as sometimes you can have different mutations that are in similar or neighboring pathways. Um, and one of the more common, because achondroplasia is ovarian, is so common, it is common for both parents to have achondroplasia. So when we look at their reproductive outcomes, here's a pun of square for two parents with achondroplasia. Um, 25% of their kiddos, we would expect to have normal stature, not to inherit those achondroplasia variants. 50%, we would expect to have achondroplasia. And 25%, we would expect to inherit both parents, a contropla variance, and this is really important to know and to counsel about um on my end because this is normally considered a lethal genotype. Um, there have been some kiddos who are more long-term survivors, but they are pretty Medically complex. Um, so this is a really complex thing to think about. Um, and in the LP community, there's many couples where if both of them have a form of dwarfism, they just choose to adopt. Um, it's really sweet and very common in the community because they know that this is, um, a significant risk and not something that they're really wanting to deal with. So, you know, personal decision there, but definitely something we need to be aware of. All right, so I'm sure you guys wanted to talk about a hot topic in the little person community, which is vasorreide. Um, so if no one has heard of this before, um, I'm not sure, it is a strong topic of interest in my world, but I think pretty limited there. So vasorretide is CMP. So remember, going back to this at the beginning, FGFR3, when we have that activating mutation, it functions as a break in the pathway so we don't get bony elongation. But at the other end of the cell membrane, we have um a receptor for something called CNP and CMP acts as a promoter of bony elongation. So CNP, this little molecule that binds, um, has a really short half-life. So a drug company decided to bioengineer a CNP analog that had a longer half-life. So, in patients with achondroplasia, if we have this receptor always on, pushing that brake on all the time on bone growth, well, what if we also jammed down on the gas pedal? What would that do to the, to the patients? And that became a drug called vasorittide. Um, an analogous CMP. Um, So it has been engineered for a longer half-life to hopefully increase endochondral ossification to lead to more um chondrocyte proliferation and and differentiation, um. This has been a super, super complex um topic in the LP community. Um, there was huge backlash initially, and there still is some, I think a lot of that is due to um You know, historically, little persons were considered, you know, circus sideshows. It was a really poor quality of life, um, but recently there have been wonderful, um, pushes, especially through LPA to normalize dwarfism, say we are just like other people, we are intelligent, we, you know, are fully functioning, we're just smaller than normal. Um, so they call it dwarf pride, it's wonderful. Um, so there was a lot of backlash when this drug came out, and the only, um, thing that the initial drug study was looking at was annualized growth velocity. It wasn't looking at if these patients were healthier on the whole. It was only looking at if they were taller than average or if their growth was increased. Um, so that made a lot of people very upset that we're trying to treat these patients with cosmetic medicine just to make them, trying to make little people look more like average stature individuals with no concern for this actually going to help health problems, um. So it is a huge um area of controversy in my world. Um, I have some patients who are on this treatment. I have some patients who are not. There's a wide range of um viewpoints and honestly, it, the drug does help, but it's a complicated thing. So it's a daily injection. Um, a subcutaneous like growth hormone, and I have a lot of patients who are interested until I tell them it's a daily injection. They're like, absolutely not, Dr. Gooch. I'm not gonna poke my child every day to make him or her a little taller. Um, so the kiddos do still, they do have extra growth. Boys grow on average an extra 2.5 centimeters a year, and girls grow on average an extra 1.5 centimeters per year when they're on this. Um, but at the end of the day, that is still not a normal growth velocity, quote unquote. Um, so these patients are still going to be little people on the drug. Um, so it's not going to totally normalize growth, but they will be taller than if they were not on the treatment. Um, this only was approved, FDA approved a few years ago, and I think the longest patient who's been on it it's probably only been 9 or 10 years. So I have a lot of patients asking me about long-term data to tell them there's just not that much. And most of the long-term data that we have was just looking at height velocity. Um, so we know there's a lot of medical complications like we just spent the last half hour talking about, right? Um, and there's been very limited data about this. There's some evidence that there might be more upper airway volume, maybe more foramen magnum volume. The studies have been small, um, and it hasn't been super, um, obvious, I would say from the data that we have so far. Um, I will say one thing that I have seen though consistently, which I don't have data on, but just my seeing patients on the drug and not on the drug, their bones tend to be straighter. Um, I don't see the Boeing nearly as bad, um, in patients on vasorittide. So I think that's something that I imagine the data will eventually show, but because this is a newly approved drug, we're just not there yet with the data. So, um, if any of you guys have patients, you know, interested in it or wanna talk more about concerns or implications, um, please reach out. It is something that we are well versed in in dysplasia clinic. Um, oh yeah, sorry. Here's some of that, that data, um, that I had just the extra growth per year. And then the study from under fives, um, showed that there was an increase in facial volume, sinus volume, and some foramen magnum volume increase. So, um, we'll see. But at the end of the day, as many questions are left unanswered. There are a lot more clinical trials going on in this area than I ever thought there would be. One really cool thing about um bone is that it's a easily accessible organ that is always turning over. So we're always getting new bone growths and You know, unlike a lot of genetic disorders that affect the brain, our big problem with um neurodevelopmental genetic disorders is getting a drug that can penetrate the blood-brain barrier. There's no blood bone barrier really, so it is a really, um, it's a much easier organ to treat. And because of that, there's amazing um clinical trials out there right now. So this is just a screenshot that I compiled of multiple different trials um that are ongoing. So there's vasoratti is the only approved treatment for achotroplasia, but there are multiple other injection and oral medications that are in clinical trial. Um, we also, um, I just got approved to be a clinical trial site for an oral FGFR3. Receptor analog. So that's something that we're looking at starting in 2025. Um, there's hypochondroplasia trials out as well. We're a trial site for hypochondroplasia, vasorretide, I wash you. So there's lots of things in the future which make my job really exciting. Um, and also really complicated when we think about views and wanting to treat our patients' medical conditions and not just give them cosmetic medicine. So it's a really, uh, dynamic landscape out there right now. Um, and here's some references. Uh, that's most of what I had. I also did want to make you guys just aware that we have our multidisciplinary skillstal dysplasia clinic, and in the few minutes we have before questions, just give you some information about that. Um, so we have multiple medical specialties there. So I'm one of 3 geneticists. There's also Gary Goddesman and Marwan Shenai, um, who function as geneticists and dysplasia clinic. We have Zach Meyer in orthopedic surgery. Aaron Husser is a new addition. He came from the Paley Institute in Florida. Um, he's a really big deal. We're very lucky to have him. He has, you know, a decade of experience in, um, helping little person patients surgically. We also 2 years ago, got Blake Montgomery. He was another huge wham. He is a pediatric ortho spine guy, and his main area of interest is dysplastic spines. Um, so he was so eager to join dysplasia clinic and just jumped in feet first. Um, we, he came to LPA with me last year. He's a wonderful addition for our spinal problems. We have Cherie Smith in physical medicine and rehab and her nurse practitioner Satira. They also have their orthotist with them in clinic. So we can do things like wheelchair prescriptions, molding of whatever they want to mold and make braces for in clinic. So that's really fantastic. Um. Let's see. Oh, neurosurgery, um, Doctor Jen Straley, she's the head of Pete's neurosurgery. Um, she is the neurosurgeon for our clinic and she and her nurse practitioners do an excellent job, um, keeping track of our patients. We also have two amazing nurse coordinators, Dawn Easterland and Angie Meninger, who came to us from Shriners with years and years of experience with genetic bone disease. So if you have any questions, Dawn and Angie, they know everything. They heard all the cats that are the medical, uh, staff. I don't know what I would do without them. They're just really fantastic and wonderful. So, um, I think that was most of what I had. Oh, dysplasia clinic is one Friday a month at Slitch Downtown. And if there's any questions in the chat or if anyone wants to unmute, um, I am happy to talk about this all day. Well, thank you so much. That was a great presentation. Um, we do have 2 questions in the chat, and while you answer those, I'll pull up the QR code for everyone to scan. OK, let's see. Uh, the cause of the macrocephaly, that's a great question. Um, I'm not super aware of what the actual underlying cause is. I'm not sure it's been well studied, um. What ICD 10 code can you use that achotroplasia? Oh, for the MRI I tried to get one on a baby that was 2 weeks old and was denied. Oh, that's really concerning, um, that you couldn't get an MRI using the choroplasia diagnosis code. Um. I wonder if you could use like a um congenital malformation of the skull or something like that, ICD 10 code because we do expect them to have abnormally shaped foramen magnum, uh, maybe something getting at that, but that is really concerning that insurance would not let a baby with achondroplasia get an MRI. Um, I don't like that at all. And um, you know, if you are having that concern, also I will put my email in the chat, please reach out. We can definitely um work things out to try to um bully insurance around. So, There's my email. Yeah, please reach out with questions or concerns. We'll leave a few more minutes here for questions, um. Like I mentioned before, please feel free to unmute if you have any questions, if you'd rather do that than type them in the chat. Yeah. And uh while we wait for any other questions to roll in, I wanted to, um, first of all, thank you, Doctor Gooch. You are our last um early bird round speaker for 2024, so this was a great way to end it. Um, I'm gonna put in the chat what we can expect for next year of early bird rounds, um, for that first session back. It'll be on, uh, February or February, January 10th, um, so I'll put that here. How long is the wait time to get in to see genetics? Oh, what a good question. OK. Um, so the party line is I'm currently booking into July and we have 1700 unscheduled referrals. However, if you have a patient with a genetic bone disease or a patient, you want to get in to see genetics sooner. Uh, if you're really concerned, shoot me an email. I will always overbook myself in skeletal dysplasia clinic. Um, so those patients, especially, I'll We'll work in absolutely, do not worry about that. Um, for general genetics, if it's not urgent though, there is quite a bit of a wait. Um, we do have a cancellation list and I would strongly encourage any patients to get on that cause we know it is a problem that we are trying to fix, but it is a supply and demand. Yeah. Anything else? Well, if there are no, no further questions, thank you all for joining and um we look forward to resuming early bird rounds and hope you all have a great weekend. Thanks guys. Thank you. Created by Presenters Catherine F. Gooch, MD Assistant Professor of Pediatrics, Division of Genetics and Genomic Medicine View full profile
