Pediatric cardiologist Emilio Quezada, MD, discusses signs that a young patient should be evaluated for genetic syndromes – such as Marfan syndrome – associated with thoracic aorta dilation and aneurysm. He presents family history and visual cues that should alert primary care providers to the need for potentially lifesaving evaluations, then lays out important guidelines on management, monitoring and referrals.
Refer to Fetal Treatment Center I'll be speaking to you about genetic or telepathy uh recently sort of new development in in pediatrics. And I'll try to explain why today. What I'm going to try to achieve is for you to be able to define what genetic or telepathy is. To be able to identify cardinal clinical features of the most common aorta Claffey syndromes. And I am going to do this. This park is specifically focused on clinical findings here and that the pediatrician is going to see patients like this frequently. I also want to want the attendees to know that there is significant overlap between syndromes. And this is just highlighting the importance of genetic testing and in some suggestions to know when to refer your patients. I'll follow this agenda and so we'll start with the definition. So in order to do that, we need to define or discuss the normal anatomy of the aorta. So as you most of you know, the orders divided in multiple parts, initially from the aortic annual list, we have the aortic root in the sino tubular junction or the place where the route joins the a sending aorta. That's the second portion. Typically we have the aortic arch bottled by the descending aorta. In pediatrics. Uh The diameter is dependent of both age and body size. Typically with the formula for B. S. A. How do we define if an aorta in its different portions is dilated. This will be as always in pediatrics with a cease course and typically will be defined as dilated with a C. Score greater than two. When do we go from agility or a toe and charisma. Typically this is the finding adults as greater equal or greater than 1.5 times this limit. There are a plethora of research papers of this problem, given the severity of the The mortality associated with. So they have determined in adults the normal growth rate of the Aorta, which is 1.5 mm per decade. And we're gonna use that the growth rate over our talk. So how does the neuropathy? What is the neuropathy? It's a disease that affects the portions of the order particularly can be divided into as the thoracic aortic portion and where you can develop aneurysms and the abdominal aortic portion, they tend to be too really too different diseases. It is the 18 causes of death in adults reported by the CBC CBC Pardon and 1-2% of all deaths reported in industrialized countries. Yeah, As I mentioned, an aneurysm is defined as dilation to a diameter of 50% above normal or 1.5 above the diameter. Briefly I wanna a remind the audience of La paz La Plazas law which is a formula where we can determine, we can calculate wall tension and wall stress. The upper formula shows wall stress and as you can see or a given a blood pressure, increasing the radius of cylinder leads to a linear increase in the wall tension. This would imply in a cylindrical structure that large arteries or wider arteries must have thicker walls in order to withstand the different levels of tension. Typically, what happens in new york aneurysms is as the wall diameter Ak radios increases, the wall tension is directly proportional to it, so it the pressure increases. But the problem is that the wall is not compensated and large but it remains thin and that's the significant risk for aneurism becoming dissections. This is what's called an aortic bled, which is the narrowest thinnest portion of the wall. Typically when sections occur. Mhm. Its relevance is that of significant healthcare burden their success, early mortality increase, incidents in in recent years due to improvements in diagnosis. And we continue to have in patients that have non syndrome. IQ Jurassic aneurysm significant under diagnosis. This is the typical patient that just has sudden death without other findings. In regards to all aneurysms. And I'm including here both abdominal and thoracic, the city, the c. d. c. reported approximately 10,000 deaths in 2018, most of which were men. This is an abdominal aneurysm and as I mentioned, a completely different disease than thoracic aortic aneurysms. So typically thoracic ones occur both equally in both genders. They tend to be more common as age increases. This is also associated to probability of the vascular wall. Typically the causes are the ones that we know hypertension and sought an injury and less often is what I'm talking about today, inherited connective tissue disorders that have syndrome IQ. Or genetic or telepathic, there's this familial form that I will speak briefly about and important to know this one and know some numbers They mentioned in the literature that dissection causes about 6% of southern cardiac death At a mean age of approximately 27 years old. So we might not see this in pediatrics, but it's a significant, very tragic problem. Right? How do we classify? How do we differentiate between thoracic and abdominal? Oh, this was described in in the past, based on the doctor's arterials. If you focus on the picture here, the doctor sartorius is right here, kind of like opposing the the left subclavian artery. And typically they were described either proximal or a sending aorta or this told to the doctor santa rosa's are descending. And if you go through the character characteristics of each, you can see that there are different diseases. The A sending or thoracic aneurysm is non atherosclerotic. It has smooth borders, there's no calcium, no debris and no traumas formation as as opposite for descending or abdominal aneurisms, they tend to be the opposite. So different different pathological findings. So thoracic aneurysms typically can occur at all ages. Typically tend to be associated to genetic problems which will focus on today. It tends to be less frequent as an isolated aberrations such as familiar. The thoracic aortic aneurysm and dissection as I mentioned, doesn't tend to be associated with the typical risk factors and it can happen sporadically. Abdominal aortic aneurysms tend to be more common. They typically are affecting adults. It's a progressive and degenerative disorder that has the typical risk factors of aging, smoking hypertension. Huh? Death toll, epidemiologists and it's thought to be that of the two hit theory as in many things in medicine of genetic versus environmental expect plus environmental exposure. So we continue to our syndrome. So we're gonna talk about syndromes now and I want to pause first and just present a case to make this a clinically uh pertinent. So I had a recently in my clinic, I had a patient that was sent to me because they, the chief complaint that the patient came to the pediatrician for was that the mother noted that the patient had street A in the middle of his back. He also noted that his fingers were very long and due to the family history, the mom asked the pediatrician to do a referral. This is a 14 year old male and it the pediatrician didn't know some findings that I mentioned next. But the important family history was that the mother mentioned that there was a first degree cousin. It was very tall. The mother humorously mentioned that they were from filipino background and they're all very short and uh, cousin was six ft two, which was very abnormal for the family and had similar fingers and facial features of the, of her son. The pediatrician documented in the physical exam, what the mom had reported. So had street located in the middle of the back sort of like in the uh Oprah thoracic vertebrae in. She did not know that there was flat feet, a hint foot deformity, which is of august of one of the foot. I'll show a picture of that. She reported back to 6 to bottom and that she went ahead and ordered uh, an echocardiogram, which by a report was normal. So my question is, would you refer or not? And I'll try to answer that by when we finish the talk. So genetic your telepathy syndromes. I will be talking about four of them. I'll be talking with the most common. Starting with Marfan syndrome here, we're going to focus a lot on clinical findings and I'll briefly mention at the end a management just for your knowledge. But my focus is on clinical. So this is a disorder of fibrous connective tissue that has a high clinical variability. It's also described a striking player trumpism, which means two or more apparently unrelated effects produced by a single gene. The cardinal features affect three systems, including the skeletal system, eyes and the cardiovascular system. Other systems including our the skin. As in our patient, there are features that overlap with this other specific syndrome called congenital contractual Iraq, not actively. And it has been described to be more aggressive in males. It's an awesome a dominant disorder In which there is a heterogeneous hetero sickos partner mutation in a federal in one encoding gene in chromosome 15 minutes long arm. What this leads to is for formation of abnormal febrile. In that leads to the typical finna type and its complications. It is the prevalence is one in every 5000 individuals with a range in between three and 10,000, so somewhere slightly more frequent and turner syndrome, It accounts for 3-5% of all cases of aortic dissection, so not trivial. Prior to the cardiac surgical era. The mortality is the mean age of death was about 45 years and that nearly has doubled since we started doing surgery and have improved diagnosis. Typically, I oric dilation is found in nearly all patients, or at least four out of five patients, and most commonly in March, and the dilation will start from the root and it can progressively extend a higher into the a senora. Its diagnosis is highly clinical. The clinical findings were very well described in the Ghent. No psychology, which was the latest revision of the clinical guidelines. It has had multiple revisions and the last one was in 2013. The changes in the new guidelines include an emphasis on the cardiovascular malformations and it's Diagnosis relies on seven rules. I also want to add that. It's diagnosis is very much based on family history. So this is why the pediatrician is so important in identification or finding of this those cases. So the seven rules can be divided into groups in the absence of family history of someone with marvin. You have, you can have aortic root dilation determined by see scores that are greater than two and the present uh evidence of utopia lintas so are displaced a lens. So those patients will need enough thermal logic examination. The second rule is aortic root dilation again And the presence of a mutation in February in one gene, The 3rd 1 again, we have aortic root dilation And a systemic score of greater than seven points. And I'm going to spend some time in the systemic score. Lastly, in the absence of family history, Having a copy of lanterns length is and a mutation in February in one with associated routing aortic root dilation gives you the diagnosis. If you have those, the diagnosis is made now in patients with family history. So this is having a first degree relative with Marfan syndrome, having eric Topol entities and family history of Marfan is diagnostic. So Topia Lantus is quite important, Having a systemic score of greater than seven. And the family history is also diagnosis diagnostic. And again, if you are 20 years or older, If you have a nice aortic root dilation greater than two or if you're lower and if Greater than three below 20 years of age. So this is just on the size of the aura, in the setting of positive family history. So if you have a brother or sister with Marfan and your orders dilated, this is nearly diagnostic. So the systemic score calculation is very important and I love this diagnosis because it's highly, highly clinical, it's very time consuming. So I always think that for the pediatrician is very difficult having such short visits. But once with practice you can get good at this. So it's a point value system And you will need a height, arm span and lower segment measurements. If you see there's approximately 21-22 available points. And if you have anything above seven, your systemic score is positive. So we'll start with the wrist and thumb sign. If you noted, if you know on the left side of your screen, it's and and on the right side is or if you have both, you have a score of three which is uh highest point you can give for a finding. And if you have risked or thumb sign, it's going to be one, the wrist is positive the risk time. So it's positive when the tip of the thumb covers the entire fingernail of the fifth finger, when it's wrapped around the contra lateral wrist and the thumb sign is positive. When the distal phalanx of the abducted thumb extends beyond the ulnar border of the palm, proceeding to practice the formally any impact of the formally is suspicious in a tall individual. But there's a higher power point value for practice carrying adam. It gives to for practice excavatum. It's one and it's important here to note that practice, the formally quote unquote is also one point this I've seen a couple of times as having a mile, very, very subtle, mild unilateral practice excavatum or carrying out so that the asymmetry can be considered positive in terms to their feet we have here, the him foot deformity that gives two points. It's a combination of four ft abduction and lowering of the mid foot and it's kind of, it's called a media rotation of the medial Malala's Also one point for a flat feet. This diagnosis is most people will come saying that they have flat feet and a few thoroughly examine them. There's always a little bit of, typically there's a little bit of arch. Two points will be given to each of the following both of which will require additional studies. Right? So spontaneous new authorities, typically your patient will know about this and we'll bring it up. But it's always important to ask sometimes they just forget at the time of the visit. But if you have a history of spontaneous pneumothorax that will give you two points and derelict asia. If you have a suspicion of Marfan syndrome, it's probably good to think of a spine city or MRI to be able to diagnose this, continue with the producer seO as a tabula which is obtained by a pelvic X ray in which if you can see in the image on your left the the asset pabulum produced further than this line, it should not pass this. And that is a significant point value for the systemic score scoliosis or through oracle lumbar. Skyfall hostess gives only one point reduced elbow extension, which always it's kind of confusing. But this is part of the criteria you would think they have a joint laxity but this is one of the discriminating features for other diseases. Because you in typically another diseases like earliest and low so low it sees you have hyper extensible joints and Marfan doesn't. This is defined as elbow extension is reduced. If the angle between the upper and the lower arm measure 170 degrees or less. Mhm. The facial features you have to make sure that you get three out of five facial features in order to give one point. Those include the liko succesfully. Which is the typical very narrow and elongated head kind of like what we see with very premature infants downward slanting palpable fishers and of farmers restaurant in Asia and Mahler High population which is an underdevelopment or the mandible in ST like in our patient. This actually looks somewhat similar to what he had give you. Gives you one point severe myopia gives you another point. Lastly, you can have a micro valve prolapse which is determined by echo and Oprah to lower and arm span height abnormality. So typically if you see shaggy from Scooby doo here, he probably had more fun because the operative lord so many ratio if it's less than 0.85 in whites or 0.78 in blacks is considered positive and an arm span two height. It contributes to one point. There's a wonderful online research provided by the mar found foundation that can be found in the address that will be attached today with your hand out. And this is an online calculator that gives you the uh option of clicking the signs that you are finding. And it also provides the explanation. So it's it's very, very useful. You can email yourself or the patient the score. The differential diagnosis of Marfan is non specific connective tissue disorders in young patients or the quote unquote potential Marfan syndrome, which do not meet all the criteria. And in older patients seek topia lentils syndrome, A mass syndrome, which is an acronym for myopia micro valve prolapse, aortic root dilation, an aortic aneurysm with skeletal findings and my global prolapse. So that concludes Marvin. We're going to continue with Lloyd's deeds. Lloyd said syndrome is an autism, a dominant the aorta apathy in which aneurysms form. And it also has widespread systemic involvement. Typically the triad of arterial torture, atrocity and aneurysms anywhere. Hyper terrorism and a by fit you villa or cleft palate. A our diagnostic, the this is rare, but it has an aggressive arterial aneurism information and a high rate of pregnancy related complications. The incident is unknown and the prevalence is, it's much less than Marvin is less than one in 100,000. It does have alarming vascular related mortality and the there have been documented growth rates of the order 10 times as compared to Marfan Syndrome. The mean age of death in patients with this diagnosis is significantly younger. According to this very good article. Over 30 years, they describe that 2/3 of patients with Lloyds six were dying secondary thoracic aneurysms and dissections, 22% of abdominal aneurisms, I'd dance sections and cerebral bleeding. In seven, a third of them have some form of vascular event in their pediatric years. As I mentioned before, it has a wide spread arterial involvement. The types of Lloyd's this syndrome are many. It goes from 1-5, which is determined by the gene, which is mutated. In the past. They used the severity of craniofacial features as a star classifying as a Type one and 2. And the revised pathology Just data sequential numbering two in corresponding to the gene that was mutated. The common ones are Lloyd seats one and two particularly low. It's this one has crane of fresh facial defects and they include by fate you villa I left palette orbital hyper terrorism. So as you will see white distance between the eyes and cranial synthesis. This is an adult with some of the signs. This is very important because it's easy diagnosis, not that frequently seen in pediatrics, you have again many of the findings craniums anastomosis being one of them. So the pediatrician will see this relatively frequently. So it's important to have it present the second type of Lloyd's. This is the vascular type in sometimes described similar to earliest Danlos vascular type, in which the similarities are they. Those syndromes have easy bruising. They have a upper extremity joint laxity, multiple organ visceral rupture, including intestine and uterus, and a very thin and translucent skin. Again, an adult patient with the skin findings and a pediatric patient with joint laxity. Again, the biophilia Villa over here in all forms of Lloyd's deeds. There is an aggressive thoracic aortic aneurysm information. They have fast growth rates of the aneurysms and they can dissect. It is a positive diagnosis if you have an aneurysm and any of the associated mutations. And the interesting thing about Lloyd's deed is if you focus on this picture, the liberal in jeans somewhere here and in Lloyd's, these the genes that are affected are downstream. So they tend to be downstream of the receptor. Here are findings of the different clinical findings of the different types of Lloyd states. Here is the hyper if you see here there's type four and there's hyper extensible joints you see miller high population and the by fit you villa here. The hand findings. So very very variable clinical presentation. I'm going to ask you to focus on the right side of our table here and this. They will I'll present a couple of times and it shows the symptom overlap with Marfan syndrome. So of course the area group enlargement can happen in both as the many skeletal findings. It can they can both have their elect asia and stretch marks. And I decided just to choose a couple of the important ones that differentiate Lloyd states which include craniums, anastomosis, gi problems such as rupture left you will and left palette, pardon. And basically the U. Villa. And let's this location is not found. Moving on vascular earliest Danlos. This earliest animals is a Complex the these with multiple genes and many types. We are going to focus on type four, which is the vascular type for obvious reasons. The syndrome is characterized by many problems that lead to higher morbidity, mostly secondary to bleeding or organ rupture. As you can see there can be arterial power, rope, rupture or uterine rupture as does in Lloyd's deeds. As I mentioned, the clinical features that are very remarkable are easy bruising thing. Skin with easily visible veins, the characteristic facial features and hypermobility of joints. The prevalence is slightly more frequent than Lloyd's the affecting one in every 9 90,000 individuals. The plastic hyper mobile type is way more frequent and one in every 20,000. The latest classification described 13 different types that are caused by 19 different gene mutations. The median survival in patients was earliest and most is 48 years. Typically four out of five dying because of arterial rupture and the other one out of five down secondary to other organ rupture as the others. It is also a somo dominant. It has a header psychos mutation in the gene called three A one. This is located in chromosome too, in the long arm locus three. And there are other mutations with two. Aaliyah was being mutated that can cost something similar cost. Policymaker Ajira with or without vascular Ehlers Danlos. Outside the genetic things that are known, I'm not gonna read through all of the criteria, but they're the international classification of earliest downloads. Basically the guidelines of diagnosis have created major and minor criteria and those are available online. Typically, again, just with connective tissue disorders that cause neuropathy. The family history is key. Right? So here again, the role of the pediatrician is very important because family history is a very, very important. That if you have a history of vascular and diagnosed in the family with any documented mutation, of course you're going to have the diagnosis. If you have any arterial rupture at any age of life. If you have rupture of your culinary intestines, that should be suspicious in women uterine rupture typically at the end of the pregnancy and fistulas of the carotid arteries. The rest. I'm just gonna live here, sorry, uh stating them and you can just can through them. But those are available online again our table that it differentiates the similarities. Sorry. Our includes skeletal findings, the valve prolapse that can remind about prolapse in marvin and of course again, aortic enlargement. Sometimes I section that happens early with the vascular type. As I mentioned, you have the the visceral and the arterial from fragility and rupture the facial features, the skin, distraught, fix cars that differentiated from the martin. I cannot highlight the importance of gene testing and I just put this, I cannot highlight the importance of knowing the difficult clinical diagnosis and uh similar findings for which genetic testing is key. Right? We are starting an aorta patty clinic in at UCSF and we are lucky enough to have uh big cardiovascular genetic counselors specialists on this. So, the choosing of diagnostic tests is much easier having that. Lastly, I'm going to talk about genetic, sorry about familial thoracic aortic aneurysm and dissection. This disease is heterogeneous disease of non syndrome. IQ thoracic aortic aneurysm disorders. So this is a patient that mainly is going to be picked up either by a catastrophic event or family history in your clinic. Edit an auto samel dominant inherited disorder with variable expression, incomplete penetrates the Yeah, discovery of isolated, a thorough security aneurysms happens in about one in five of these patients that a first the first degree relative that is affected. So again, family history is key. Right? If you have recently just had a family that came to me for a fetal echo and I just asked for history of congenital heart disease. And the father just mentioned that many of his male family members had this family of form of aneurysms, right? Nothing for the fetus but a future for the baby. It is by definition an isolated finding of thoracic aneurysm but there are described a characteristic identifiable features in some The causative mutations include the ones that are listed there. I'm going to focus on back to two and the NYH- 11 mutations because they take up like 1/5 of them. So are more frequent. And the diagram there just shows the different mutations in red. So actor took, we found here, the second most frequent as can be found here. And what mutations in those two genes do is that they result in an improper assembly of the acting and the myosin filaments. So this results in a in a defect in fiber connecting genesis and incorrect by Brylin one Assembly. So again we end up with this problem in February. In one, its features Again focusing on the two most common. The two most common gene mutations acted to an M. I. N. Y. Age 11 show that most patients with familial thoracic, aneurysm and dissection have lived a theoretical Aris which is this translucent skin with vascular charity. In when discoloration of the skin that we see sometimes in our clinics, most pediatricians will know that there's a scene in Down syndrome. So we know what the sign is. Also. We can have irish flock eli. So floaters there cardiac wise they can have a patent doctors, arterial Asus or non thoracic and aneurysms such as uh in the brain, premature coronary artery disease, presence of ischemic strokes. Like seeing here in letter C. And and and a similarly appearing vascular path you of the karate. It's a similar to moya moya disease, which is a very rare vasculitis. And the number two cause is the M. Y. H. 11 mutation which leads to those with an associated P. D. A. Again, I'm going to focus on this one. The overlapping or common symptoms, aortic enlargement and discriminating features are lack of Marfa annoyed features that I findings which are both listed there in the absence of this location of lenses and absence of derelict asia. So that was a lot of clinical stuff. So now I want to talk briefly about the management. I want to make the pediatrician aware that we do have guidelines for this tinkle published in 2013 health supervision guidelines for Children with Marvin, which is geared for the clinical provider. It's a very nice paper to have as a resource Here. We in this paper we get an anticipatory guidance table for Marfan Syndrome. So it's very nice similar to what we have for trisomy 21 but marvin being significantly less frequent, so we forget. But you have all your checklist over here and different in frequencies of visits that you need to do. Of course if you see here, echocardiogram is key because of your ventilation, but you do have this available to you online. I will share a link to this article cardiac wise. Typically those patients that have suspected genetic aorta posse will require an initial echocardiogram and typically I recommend getting a second visit with an echocardiogram within six months. The reason why I do this is to determine the growth rate. If there is a significant change in that six month period of course the follow up is going to be sooner. And if there is no significant change we can go to yearly follow ups. If the second line more frequently Uh imaging is indicated of course. If the aortic root is very very large greater than 4.5 If the rate of aortic growth is greater than five per year. And if there's progressive worsening of the aortic valve intermittently you can do other demographic modalities and young adults even difficulty of imaging with echocardiogram. But echocardiogram is highly reliable. It is definitely recommended that yearly at least we do a C. T. And an M. R. If there's any history of dissection and or root replacement of course. So then moving on to medical management. I think this is a very important for the pediatrician. Right? I think here is again the valuable role of the pediatrician in risk factor reduction. Of course there's always if you have any sort of a neuropathy or aneurysm or anything concerning you should always try to reduce risk factors such as hypertension, abnormal lipid smoking. If you have a clinical suspicion on your patients. My recommendation would be sometimes those patients that have some form of mixed connective tissues or tend to be athletes and it's very difficult for the pediatrician but I think very important to restrict them from strenuous exercise is particularly isometric exercises like weight lifting pull ups, push ups because of the high risk of increasing intravascular pressure and causing the aneurysm to dissect. Of course. Good for anybody discouraging cocaine. Another admin ergic agents managing stress and important again, highlighting the role of the pediatrician. Close multidisciplinary monitoring during pregnancy and I would say add to during a pediatric years. Right, So the pediatrician is the one that coordinates the care from many different specialties. Briefly, I want to mention pharmacologic therapy which includes a beta blocker therapy. This is a mainstay of therapy for Mark and particularly and other genetic air to open these. There is uh base on why we treat and why we choose the this type of medication. If you see here there's a cascade of angiotensin and the aneurysm information and all of them are geared for different specific goals. Inhibiting the reigning angiotensin al dust Arone cascade is very important particularly and more effective. Are angiotensin receptor blockers. Those in adults have been proven many many times to be extremely beneficial. So I likely will start patients if we get to a diagnosis less effective in our ace inhibitors. And this is just because it goes a slightly deeper down into the angiotensin, august alone. Uh cascade. Other and interesting newer medications are the use of statins. Again, reducing risk factors, doxy cycling and tetracyclines. If you see here, they have a specific place which is just interesting randomizing which is an empty, you're basically an immuno suppressor that has been used in abdel McComas is now being studied in aorta passes to and cox inhibitors. So interesting research and as I mentioned, there's a plethora of in publications on this. Briefly, I want to talk about the surgery that can be done with patients with this. And when do we do this? I'm going to start with the timing for referral for repair. So I'm going to focus, ask you to focus on the red in the general population. If you have an aorta that measures 55 mm, you're going to get an aortic replacement. If The growth of your aorta is greater than five per year, you're also gonna get a root replacement. Typically here, it's important to remember that we can forget the aneurysm or dilation associated to bicuspid aortic valve. Right? This is what those numbers come in handy. In terms of what we're talking about today, Marfan Syndrome, you have a greater than five without risk factors. Those are 5cm dilation of the Aorta. The number is going to be less at 5.5. If you have the risk factors, most of them, we talked about Low, it's seats, the number comes even down to greater than 4.2 cm. Again, as I mentioned, a more aggressive and catastrophic disease. So the numbers are less. So your 4.2 cm you're getting an aortic root replaced. And if you measure differently with demographic imaging such as C. T. O. R. M. R. The number is measured from outside the vessel and it's slightly larger but definitely smaller than morphine. In that in vascular, earliest Danlos and familiar thoracic, aortic aneurysm and dissection. There's no specific recommendation and the role for prophylaxis surgery has not been established. But those tend to be aggressive and it depends on family history. Briefly, there's many surgical procedures, all of them with the surgical name in which you can replace the valve and replace the A sending areas is the mental procedure. Then you can have valve sparing procedures in different forms and shapes. Finally, I'm going to bring you back to our case. So if you guys recall, we had the physical exam findings of ST a flat feet, the hint foot deformity, um very mild practice and Iraq not actively. And the echo was normal with family history. So I thought the pediatrician did very well in referring this patient. My recommendation is if you have three clinical findings and you are suspicious, just refer your patient in this patient specifically with a family history. I thought the Referral was appropriate. The my findings were similar, had some differences. But you can see here that the systemic score was four. So didn't truly qualified. I did send the patient for genetic counseling because given the family history. So we shall see it though. I do think the role of the pediatrician is very important. So what can you do to manage this in your office? The management in pediatrics is not gonna be anything acute. So basically exporting and coordinating the initial that gnostic studies. And I wouldn't be shy. I would go ahead and order your pelvic x ray. If you want to follow the marvin guidelines you can order a spinal city to rule out the oral act asIA and this pediatrician did do an echo and I don't disagree with that because you're doing all the studies. If you just you guys are very busy with short times with your patients, we would be happy to take care of this once they're referred to the clinic. And of course very important to request family history. Even if you don't get that much in your clinic, you can request that they go through a family history and provide you with that later. So when do we refer a patient? I think this hopefully I made this clear if you have positive family history and if you have two or three suggestive clinical findings of all of those syndrome, it forms of york apathy. What can I the pediatrician due to manage the patient while they're waiting? Let's say the waiting time is a lot again cannot highlight enough. The risk factor reduction counseling. More importantly on the third one down this list, restriction Australians, physical activities. I think that's very important that the pediatrician recommend to their patient and just ensure that there's multiple specialty consultations and those will include an ophthalmologist, tests, genetic counseling, cardiology and more depending on your criteria.