Good morning. I see a lot of familiar faces, some new faces, and so we're happy you have joined us for, that's a loud mic, we're happy you've joined us for a discussion of congenital hand, what's new in understanding and treatment in 2022. I have nothing to disclose other than we have a great faculty. So I'm going to start off by talking a bit about classifications and what's new with how we think about classifying congenital anomalies. Don Bay will be next talking about registries and the impact they are having on our understanding of congenital anomalies. Michelle James is going to get a little sciencey but really cool stuff on PIK3CA pathways related to macrodactyly and treatment that is really remarkable. And then Anne Van Heese is going to talk a bit about some of the key new strategies for actual treatment. And then we should have time for questions in a few cases, so enjoy. So I believe most in the room are familiar with the OMT classification, which was designed to reflect our understanding of limb formation as well as dysmorphogenesis. It's based on the concept that there are malformations, deformations, dysplasias, and syndromes, and trying to understand how any particular anomaly fits into those categories. It's been around now for more than 10 years, and it's been updated a couple of times most recently in 2020. And for those of you who hadn't heard Kirby Obert talk about limb formation, it really is remarkable in trying to conceptualize limb formation and when things go wrong. We have come a long way. We have a long way to go, but we've really come a long way. Some of the newer updates emphasize that 20% of patients have more than one diagnosis, and so we need to record those as we're thinking about them. Trigger finger is no longer included in the OMT because it's not a congenital anomaly. It's an acquired anomaly. There's a number of good studies looking at huge numbers of patients, which suggests it's not present at birth. And then, I think most importantly, and as the OMT was designed, there have been reconsideration of certain diagnoses and where they fit in the classification. So the best example is cleft hand. So there are seven categories of cleft hand or split hand-foot malformation, and six of those have a known defined genetic basis, and all of these are related to the apical ectodermal ridge during limb formation. And so essentially that led to reclassification. Arthrogryposis has also been reclassified. Most forms of arthrogryposis have a genetic basis, and so it is thought to be a dysplasia rather than where it was previously classified as a malformation. Now, that's a little controversial, and the best place to put arthrogryposis is unclear. But what's interesting to me, at least, is that the initial limb patterning is normal, and then things go south based on spinal cord and nerve, signaling, and muscle development. So based on that understanding, it truly is a dysplasia. Perhaps the most controversial and frustrating aspect of considering limb formation and dysmorphogenesis is sembrachydactyly and transverse deficiency. Sembrachydactyly is classically thought of as a limitation in blood flow to a developing limb where the mesoderm is affected, and the ectoderm is maintained, thus the presence of nubbins, whereas transverse deficiency is more of a loss distal to a time point. And how we classify those is controversial. Eventually, we will understand this better, and there's lots of discussion around this challenge. And then the syndrome list continues to expand, as we all know. I would point you to two directions if you're unfamiliar with them. First is the website OMIM, O-M-I-M. If you've never been, it's remarkable. If you ever have a kid come into your clinic that has a few different things, go to OMIM and just type those in. It is awesome. It used to be a textbook. It's much easier in the online format. And then there's actually a reference that Wee Lam, who's a developmental biologist and hand surgeon in Edinburgh developed related to OMT, which there are examples, and it makes it easier to conceptualize congenital anomalies. This was a study that Lindley Wall led looking at difficult-to-classify congenital anomalies. And you'll hear more about different registries. But the take-home from this is that we do not have a full understanding of every child that walks in with a limb difference. We are making progress, but we still have a long way to go. And ultimately, genetics are the answer, I think. So I want to share a few new concepts, and then I'm going to move on to Don's talk. You know, classically, we all are familiar with the WASL, or more appropriately named the FLAT classification for radial polydactyly. The problem, of course, is that it doesn't really represent all of the kids that can come into your office, and it doesn't necessarily guide treatment. And so because of that, there have been a couple of other classifications which are relevant, at least to, you know, think about these things. First was Chung 10 years ago that described that described four different types, and perhaps most pertinent to treatment are the last two, the osteochondroma type and the hypoplastic type. And the concept of a hypoplastic type is in really all the new classifications. The Rotterdam classification is amazing. However, it's overwhelming, at least to me. And so I think it's great for a scientific, you know, discussion, but probably not for simplicity in evaluating congenital anomalies. And then most recently, Anne Van Heest and her group leveraged the CUD database and looked at 150 thumbs and assessed the reliability of three good classifications, the FLAT classification, the Rotterdam classification, and the Chung classification, and essentially came up with a simple answer, is use the FLAT classification, but add a hypoplastic type or really two types, proximal and distal, as well as, you know, how to think about triphalangeal thumbs. And so this is a little bit of dry stuff to start your morning. The exciting stuff is coming next. But you really, I don't think you can talk about congenital anomalies effectively without, you know, how do we discuss them? How do we think about treatment? How do we standardize the care that we provide? I think in 2022, it's not really okay to kind of do one-offs. I think the more scientific we can be about thinking on these anomalies and thinking about the best treatment, the better. So my take-home points are that classification systems are evolving and they are better than ever. It really is a challenge to continue to update these classifications, but we have to do it. And hopefully, our classifications should remain simple and help guide treatment. Thank you. So I'm going to pull up Don's talk as he is coming up. Oh, it's fine. Okay, good morning, everybody. Chuck asked me to talk a little bit about registries and provide an update about what's happening specifically in the pediatric hand space. It's great to be in a room like this where so many friends and colleagues and collaborators, and so I hope I do justice to what I think is really collectively our work together. I have no disclosures related to this. So I think all of us recognize the challenges, particularly in the care of congenital differences of the hand. Depending on our practice or our geographic locations, these can be relatively uncommon. Most of the information that guides us is still based on retrospective single surgeon or single center case series. Most of the metrics that have been reported in the literature tend to be surgeon or provider centered and not necessarily focused on what may be important to our patients and their families. And like in everything in hand surgery or otherwise, getting long-term outcomes and meaningful long-term outcome information can be challenging. Everywhere within orthopedics, everywhere in medicine, I would argue everywhere in the world there is a cry and a need for better prospective longitudinally collected data, focusing not just on things that we think are important but more patient-centered outcome and patient-centered outcome measures. And increasingly, there's an emphasis not just on the hand or physical function but also things like participation, emotional well-being, social interactions, et cetera. And so for all these reasons, registries have been really called for. And hopefully, they'll allow us to elevate our levels of evidence so we can provide better treatment and also improve healthcare value. If you look at the landscape these days, I think generally speaking, there's been some work on administrative databases as well as condition-specific registries. My screen is working. So maybe I'll touch base. I'm just going to keep going. Maybe we'll touch base a little bit on some of those things. So in the current landscape, there seem to be administrative databases, condition-specific registries, but maybe not as much or historically not as much as the pediatric hand. One example of administrative database that I think many of you are aware of is the PHIS or Pediatric Hospital Information System Database. This is largely an administrative database. Currently, I think there are about 49 children's hospitals that contribute data. And the data is what you might expect from a hospital EMR or an administrator-type system. There's abstracts on patient demographics, codes relating to diagnoses and procedures, as well as some information about billing, charges, and resource utilization. And while things like PHIS can be very helpful, particularly for rare conditions or if you're looking at resource utilization, they're not always that helpful for us on the front lines as surgeons, and they may not be necessarily helpful for our patients and their families. We previously have taken some steps using administrative databases. For example, we did a study previously looking at the PHIS to look at politicizations, and we're able to compile information from over 450 politicizations that were performed in the United States. We got some information, but not really much to really help us with day-to-day management or treatment. Chuck, I'm just going to keep going unless you want me to stop. Yeah. Moderator, tell me what to do. I'm happy to keep going if this is working for all of you. Yeah. Yeah. Okay. If I'm not doing a good job or something's unclear, throw something at me, please. It's a short toss from the background. So, yes, there are administrative databases used by many of our colleagues, particularly our administrators and people in the C-suite. There are also, as I think we're all aware, a lot of condition-specific registries. And so, for example, as an example of that, I participate in a member of a longitudinal prospective cohort looking at osteochondritis dissecans of the elbow. We now have about six or seven centers in the United States who are enrolling patients who have OCD of the elbow. And we've learned a lot. But, and while those types of efforts are more focused, clearly very clinical, the impact on a broader scale tends not to be that much. And so, while administrative databases can help us with resource utilization and condition-specific databases can help us on a particular thing, there's got to be a better way. And for those of us who take care of pediatric hand and congenital hand differences, there's a real need, I think, to share information so we can all be better together. Back in about 2012 or 2013, Chuck and I actually shared a cab ride home from a meeting to the airport, and we were lamenting about how things could be better and how we felt like we needed to try to be better. And around that period of time, there was a confluence of certain things that were happening in the world that provided us with some opportunity. So example of what was going on at that time were things like validated and simplified patient-reported outcome measures. PROMIS was just starting. A lot of other outcome instruments were happening. And so, we had a lot of PROs that were coming to the forefront. REDCap was really starting to go mainstream. And so, now we have this wonderful ability on relatively low budget to enter and compile and collect data. And so, that was a huge opportunity for us. And the internet was really, really becoming a part of our world in an everyday, practical way. And so, the confluence of those three factors together and the recognized need for something in pediatrics allowed for a really great conversation. Here's a just as wise and perhaps a bit younger Dr. Goldfarb as I knew him in 2012. And so, that prompted our creation of C.U.D. So, what is C.U.D.? C.U.D. is an acronym that stands for the Congenital Upper Limb Differences Registry. And the objectives or goals for C.U.D. are to assess the upper extremity function and health status of children with congenital upper limb differences and try to quantify or characterize results of both surgical and non-operative treatment. Those were our simple stated goals and continue to be our goals today. This is a prospective longitudinal cohort study, a registry. And the patients that we currently enroll are patients anywhere between birth to 18 years of age who have not had surgery on the affected limb that we're following. And we tend to use both the PODC and particularly the PROMIS outcome instruments, not just for upper extremity function, but also looking at other domains including pain, anxiety, depression, and peer relationships. The database as constructed is pretty straightforward. We collect clinical data that we get from the office visits. Every patient gets an x-ray. Every patient gets a clinical photo. We use the OMT classification that Chuck talked about in the last slide. So, every patient gets an appropriate OMT classification. And serially at interval times throughout life, these patients get outcome measures assessed according to the PROMIS. Data is entered online through REDCap. As we've grown, we've also evolved into having a more robust governance. And so now we have multiple committees that help us operationalize CUD. We have groups of individuals involved in classification questions, research efforts, onboarding and data cleaning of our centers. And hopefully we'll expand to even more international work in the future. I'm super fortunate and really so happy to have so many amazing collaborators. And currently these are the institutions that are part of CUD concentrated in the United States and North America. Really lucky to have all these folks as collaborators. Where is CUD now? So here's where we are as of about last month. So currently in the CUD registry, we have about 4,500 patients enrolled, of which just under 4,000 are being followed prospectively and have been consented in that way. The average age of the patient is about 4.1 years, though the median is indeed a bit lower. And it's roughly 45% female or self-identified female. As we look kind of at who our patients are, about a quarter of them have a family history of a congenital hand difference. Almost 20% knew about their hand difference even before birth based on pre-dental screening. As would be expected, about a quarter of these patients have associated musculoskeletal conditions, for example, of the spine or differences of the lower extremities. And about a little under a third have associated medical comorbidities or syndromic associations. And going back again to the OMT, the majority but not all of these patients have hand plate or isolated hand differences. Smaller font, I apologize for that, but here's a laundry list currently of our top 10 diagnoses, kind of giving you a snapshot of some of the patients that are in our CUD registry. As is probably typical for a more orthopedic-based US cohort, we see a lot of radial polydactyly, honor polydactyly, and thumb deficiency with some of the other diagnoses represented here. And so CUD has been up and going since 2014. We now have 11 centers that are actively enrolling and we're starting to create a very robust database. And this is where it's really starting to get fun. As we thought a little bit about research as it comes for registries, and I'm looking forward to the discussion afterwards to learn more. In general, we have approached research and research productivity in kind of three phases or three ways. In the beginning, as the database was just starting out, we wanted to make sure we were collecting information accurately and reliably. And we had the opportunity to do some initial cross-sectional or snapshot-type studies on the patients enrolled. As the registry matures and the patients mature, we hope to enter a new phase or a second phase, looking at early results of treatment, perhaps early complications. And then the holy grail and the long-term goal is to really, in the longer-term future, be able to report back some longer-term outcomes and even longer-term unexpected outcomes and need for revision treatment. So I'll just provide a brief survey now on about some of the things that we've been able to accomplish in the past eight years or so with QUD. One of the first papers that we published on our database was this one, in which we had four raters from our multicenter effort, assessed 60 patients, entered in the QUD database to confirm that we had good reliability and we were accurately capturing the information into this online REDCap database. And we were pleased to find out that, indeed, the platform and the infrastructure worked. Looking at some more phase one studies, classification, epidemiology, et cetera, one of the earlier studies looked at a cross-section of 586 patients, looking at PROMIS and POTSI scores, and, indeed, as you would expect, the patients had lower upper extremity function. But interestingly, the patients in our cohort scored higher than population norms as it relates to peer relationships and actually reported lower pain, depression, anxiety than their peers, something that I think we've all probably observed in our clinical practices and has been corroborated by studies from other centers. Chuck mentioned this paper looking at classification systems of specific entities. And so this is the paper by Caroline Hu and others looking at how best to classify radiopolydactyly. This is an example of how a registry can get larger numbers of patients so we can look more critically at the existing classification systems and create common vernacular and vocabulary. And then there are times where we got to pool patients who had relatively rare conditions, some that surgeons or centers might see a handful of here and a handful there, but together we can make more definitive statements. This is a paper that came out recently in the Journal of Hand Surgery looking at patients with ulnar dysplasia. Eighty-nine extremities, which I would argue is a lot, particularly if you can think about what any single surgeon or any single center might be able to accrue. In this particular cohort, 20% of patients had associated medical morbidities or musculoskeletal differences. And a very interesting finding for me and I think the authors as well is that 8% of these patients had cardiac, structural cardiac differences, and maybe these are patients that we need to have see our cardiology colleagues when we see them in the beginning as well. We also learned a lot about the process. So Dr. Villeman's here in the room and so we learned a lot about how to do registry work and how to think about registry work. So Carly described in this paper from Journal of Hand Surgery about the so-called inception effect. As you begin a registry, particularly a surgical one, many of the patients that enrolled early are going to be very young patients or the older patients that probably weren't going to need surgery anyway. And so understanding what the makeup of is a registry, particularly in the first three years, is very important as you formulate research questions and make statements. I think we're probably starting to enter phase two where we can look a little bit more at results of treatment, surgical treatment, early complications. Previously at the Hand Society meeting, we presented a series of 62 patients, for example, with radial ulnar synostosis. We found that these patients indeed had lower upper extremity scores as measured by our functional outcomes, but the kids were equally happy and equally participatory. One thing that we found very interesting is that if you had a patient with bilateral involvement with more than 45 degrees of pronation or unilateral involvement with a fixed 90 degree pronation or 60 degree pronation, it seemed that their functional scores in a self-reported way dropped off. And so maybe this is giving us more detailed information about the patients we should consider for surgical treatment. And then the world is different now, and the things we think about now are different than in 2012 or 2014, and the nice thing about the database is we've also been able to pivot to other interesting questions. Lindley Wall and others have published this paper looking at social deprivation. 375 good patients, average age in this cohort was about 11 years. Overall, if you look at the entire group, functional scores were pretty normal, but if you look at patients who came from areas of greater social deprivation, there was actually more pain, anxiety, and worse peer relations, something that, again, I think perhaps we observe and is serving as a foundation for future work. To date, we've had 16 completed projects from CUD and 18 projects underway, and so I think the vision of trying to create more research, ask better questions, come up with perhaps improved information, I think, is so far being successful. And we've been really lucky to collaborate with a lot of our international colleagues as well. There's been great alignment between investigators and surgeons from all over the world. So if we look at contributors to the Australian Hand Difference Registry, our colleagues in Sweden, folks that are creating similar efforts in the UK or Northern Europe, a lot of synergy, a lot of opportunity for collaboration, and hopefully together we can get better. I'll finish perhaps with some final thoughts. For those of you who are involved in this work or thinking about doing work similar to this, some of these lessons were hard learned. In terms of data collection, we made a very conscious effort to be very streamlined. It would be easy to try to collect 200 or 300 pieces of information about every patient. This is still a little bit of a mom and pop show, and so it just wasn't reasonable, and I think that was a wise decision in retrospect, trying to keep it clean and simple, and leveraging technology as much as we can in the absence of lots of free time or people hours. We purposely made a decision to expand QUD slowly. So we have an onboarding process now where one center comes online every three to six months at most, trying to ensure that we maintain quality of data entry and not rush to expand beyond our capacity. We've tried as best we can to have a research process that involves some formal vetting and conversation and thought, and make sure that the people who contribute, patients who contribute energy and effort, who contribute intellectual contributions, are appropriately recognized in any of the publications that come from QUD. I think that's very important for all of us. We've tried, as with every volunteeristic effort, to make the governance as inclusive and transparent as possible, distributing roles and responsibilities throughout our investigators. And funding's been really hard to get. If any of you want to support our efforts, we'd appreciate that. But this has not been a highly funded project. What I really learned, though, is that if you take really amazing friends and colleagues, and you engage in a worthy cause, you can really do some pretty inspiring work. And so this has reaffirmed my convictions that what we do together is really, really worthwhile. And I continue to be inspired by my collaborators. So thank you very much. If you want some more information, you can take a picture of this QR code. This will take you to our webpage. Thanks. So I brought, just as an incentive to stay to the very end, not that hopefully you need an incentive to stay to the very end. That didn't come out right. One of our therapists made cookies. We had a hand camp recently and made cookies for our hand camp. So I have really good, really cool cookies with hand differences. So we got to stay to the end to get those. My wife said, don't leave them in our house. So I brought them with us. I'm sure we're the only ICL with cookies. So I'm going to talk about an update on treatment of PIC3CA-related overgrowth spectrums. And I'm sure that you guys have all heard about this. I want to focus on the contribution of hand surgeons to this effort and then tell you about where it is going or probably going. So the stimulus for talking about this was a press release that came out in April of this year that the FDA had approved Alpelicib for PIC3CA-related growth spectrum. And I'll explain why this is especially interesting. As most of you know, there's been mTOR inhibitors used for these types of conditions for many years. But the Alpelicib, I'll give away the message at the end, actually intervenes at a point in the pathway that is most relevant to the patients we take care of. And so this is getting close to being something that we will actually be probably not prescribing but recommending for our patients. So I'll explain the background of that. So PIC3, I'm going to define a lot of terms here because I realized when I put this talk together I had no idea what all these things stood for and, you know, how they connected with each other. I just knew there was a general idea about this. And I'll disclose, some of you may have been there, that when Mary Beth Izzaki first presented some of this work about 10 years ago, she was introduced and then moderated by Lisa Litanza who after Dr. Izzaki's talk said, I have no idea what Mary Beth just said but I think she's about to cure cancer. So you'll see where we're going with this. PIC3CA is a gene that regulates cell growth pathways and the pathways are complex but they basically include this P13K, AKT and mTOR pathway. So just hold on to those three, those three terms. And probably the other most important thing to understand which I'm sure most of you do is the concept of post-zygotic gain of function mutations. This has been around for a long time but it's very key to these disorders that I'm going to be talking about. This is when a mosaic, when a mutational event is mosaic, it occurs post-zygotic stages so that it affects only certain parts of the developing fetus. So this is the P13K, AKT signaling pathway. This is sort of the heart of what we're going to talk about. I've put next to the various things as many of the names I could find that actually went with them, whether that's meaningful or not, mammalian target of rapamycin is mTOR, things like that. I don't know how people came up with these and some of them I can't even figure out how they got AKT out of protein kinase B but we don't need to know that. But they do all have names and these are the abbreviations. And I'm going to come back to this slide a couple of times, adding on additional information to build on this. So basically the concept here is that this gene, the PIK3CA gene, gets inappropriately activated and upregulated more or less in the different parts of those pathways. And this creates a number of different phenotypes that previously we hadn't necessarily even put together under one general group. And these include some things that we see as pediatric hand surgeons, macrodactyly being the probably most common one, even though it's incredibly uncommon, and then a bunch of vascular malformation syndromes, Clove syndrome and clipal trunony are probably some that you may be familiar with. And then some conditions that are more neurological or don't really show up in hand surgeons offices, tuberous sclerosis and hemimegalencephaly. There are also some of the pathways that in the PIK3CA from the PIK3CA gene are related to certain cancers. So these are just examples of the tissue overgrowth type problems, the lipofibromatous hematoma, the clipal trunony syndrome on the right, and then the muscular hemihypertrophy and vascular malformations. So to me, one of the most interesting and really cool things about this is a lot of the development of this understanding came from Dr. Izaki at Texas Scottish Rite and her colleagues. And this paper published in 2013, I believe, talked about type 1 microdactyly and the lipofibromatous hematoma. They did a series of whole exome sequencing that showed a novel mutation in this gene that affected the nerve tissue and proposed that isolated microdactyly is caused by a somatic activation of this pathway. So really out of hand surgery came one of the earliest understandings of this pathway. And there have been several articles since then that have further developed these ideas and probably are what the people who've developed the drugs have built upon. This was a workshop sponsored by the NIH five or six years later that came up with the term PROS, PIK3CA-related overgrowth syndromes, to connote all of the conditions that we're talking about. And then they made some preliminary recommendations for both assessment, diagnosis, and testing of possible pharmacologic therapies. So this is that same pathway, and this is what the NIH group sort of filled out the details of what was known at the time. So if you see on the left are the PROS spectrum, the conditions that we may end up treating. And they seem to be most related to an interruption or some type of effect on the growth or an upregulation of the growth pathway at P13K. There are also mTOR-related conditions. There are P10-related conditions, and there are AKT-related conditions. And that's relevant, as you'll see, when I wrap this up in a few minutes. So moving back to hand surgery, the next step was a publication that described the entire treatment of macrodactyly, but put the potential medical treatment in the mix, because that hadn't been before. And to me, this is one of the most potentially exciting developments in the last 30 years of Pete's hand surgery. But, you know, this article pointed out surgical treatment is still used. It's not curative. And basically, it would be nice to have another alternative. Also, the fact that excessive scarring may occur. The next work on this came from our colleagues in Great Britain, and they were looking at an mTOR inhibitor. So mTOR is one of those pathways. Seralimus or tacralimus has been used to treat some of these conditions, and they looked at 11 articles and found that this showed improvement in symptoms in the majority of kids in the various series, and the recommendation was out for prospective trials. And this was published, I think, in 2021. So what's going on with these prospective trials? Well, this is a seminal article published in Nature in 2018. The lead author is a guy named Kanaud from France, and he took a PIK3CA inhibitor, which later turned out to be alpelisib, which actually works on that P13K level, and first treated mice with a mouse version of Clove's syndrome, and then went on to treat 19 people with Clove's. And this was really sort of a phase one study to show that there weren't substantial side effects, but he did see some early positive effects of the drug. And he has gone on to recently publish the treatment of two infants with a life-threatening version of one of these conditions with this medication and showed that at one year they had reduced size. Now, the leg sure looks better on the top. I can't say for sure that that macrodactyly looks better one year later, but I guess we can be hopeful about that. Maybe it's just that it doesn't look worse. So these are the early results of two infants, and this was published earlier this year. And then the same authors have tried to look at the bigger picture of where can we influence this pathway at every level where these different diseases occur. And they've laid out both the diseases that came from that NIH study that belonged to the different parts of the pathway, and then the treatments that are available at those various parts. And basically the take-home message here on the right, the pharmacologic treatment, there are now mTOR, AKT, and P13K inhibitors, and the results are promising so far. So back to our pathway, and there are, as I mentioned, three areas where we can see effects of various drugs intervening. So alpelicib is the one at the P13K level, and this is where macrodactyly is. So this is probably of the most relevance to us. Seralimus is an mTOR inhibitor, and the conditions that follow that pathway are now being treated with seralimus. And then over here by AKT, there's another drug that can interfere and possibly treat proteus syndrome. So where do we go with this? This is another article that was published recently to kind of lay out a consensus for where are we going with this. And the consensus statement is that there's huge clinical heterogenicity, which we know. This is going to be a patient-specific treatment, and in my opinion, is going to be prescribed by hematologists and oncologists. At least that's what's happening at my institution, not by hand surgeons. But of course, we're going to be the people that these kids present to, so we need to know about this. There are now prospective phase two multicenter randomized double-blinded placebo-controlled studies of some of these drugs. But their take-home message for us is that there are still some important issues where there aren't any consensus. And one of these is surgical management of overgrowth tissue, including orthopedic. So I can't tell you yet that every child you see with one of these conditions needs to be medically treated based on the consensus in the literature, but I can say that this is on the horizon, and we need to be aware of it. And that's pretty important, I think, to our patients. And most of this take, most of us take this pretty seriously. This is a cartoon from Gary Larson, and the sense of humor is Dr. Izaki. Can you guys see that? So that's all I have on this. Thanks very much. So hopefully everyone is aware that there's a, in May, in Minneapolis, Ann is hosting the World Congenital Symposium on Congenital Anomalies of the Upper Extremity. And it'll be three and a half days of amazing speakers and discussion. So hopefully, and Dr. Connaught is coming, who was just referenced as a guest speaker. And hopefully, I can get this talk to go before May of 2023. Maybe not. I think what's really new is that at a hand surgery conference, our first three talks are about classification by embryology, databases, national databases, and medical management with things that I haven't seen since biochemistry. So I thought I would give a little bit of clinical situations and an update in that regard. Again, I don't have any specific financial disclosures, so I'm going to just talk a little bit about syndactyly and hypoplastic thumb to give a clinical aspect to our ICL. And I think, you know, as you know, syndactyly is a very common condition, one in 2,005 births. We have classifications that are primarily simple, partial or complete, or complex or complicated. I think we have a fairly good consensus about doing surgical releases between 6 and 18 months of age. If they are border digits, then we tend to do them at a younger age. If they are simple incomplete syndactyly, we tend to do them at a little bit older age. Certainly the one on the left with no digits, you want to liberate those digits fairly early, whereas the one on the right is a simple incomplete syndactyly and could be done any time. I usually tell families before kindergarten, but certainly doesn't need to be. Generally we think of these as being done as staged procedures, oftentimes the first and third, and then a second stage is the second and fourth, just so we aren't releasing adjacent webs and don't worry about the vascular compromise. I think the big question has been the skin graft source, and if I just looked at pertinent articles in the last five years, and all of these are surgical techniques for the flaps. So it's one of those things where there's just pictures upon pictures of variations of different flaps, and we continue to search for the holy grail and try to kind of find the flap that works for you. And I know I modify my flaps, I don't do them exactly the same every time, I'm continuously trying to look for something. One of the things is that we have gotten more information about Sharif's original dorsal metacarpal advancement flap. These pictures come from Doug Hutchinson's article, and he wrote an article about comparison of skin graft and graftless techniques in the same patient. And although it takes a lesser tourniquet time to not graft, you do have these dorsal hand scars, so generally I think that the current thought is that that's out of favor. And I think from the patient and the parent point of view, that those scars are very visible, and so that has been, I guess, more fallen out of favor than the traditional techniques that would include skin grafting. I think the other newer technique that bears mention is the use of synthetic dermal substitutes. Dr. Gold, Farber, and Wall have written about that, and use, again, I don't have any specific financial interest, but Hylamatrix is one of those synthetic dermal substitutes. So the gold standard still tends to be the full thickness skin graft. I think the most common site for that remains the antecubital fossa, with the groin as the second site, with the caveat that secondary pubic hair growth can occur during the adolescent period. So this is an enticement to come to the World Symposium in May, but from my point of view, we have been doing an intra-patient randomized controlled trial where they get Hylamatrix on one side of the graft and a full thickness skin graft on the other side, and we will have a two-year reveal so that the patients are blinded as to which side it is, and so we'll have that final on 24 patients at the World Symposium. But it looks something like this, where they have a skin graft on one side, and they have the Hylamatrix on the other side, and so if you look back at that, the Hylamatrix is on the ring finger, so you can see here the Hylamatrix is on the ring finger, the skin graft is on the other finger, and here's the 24-month reveal for example 1. And then example 2 is Hylamatrix on the long finger, skin graft on the ring finger, and here they are at their 24-month reveal. So example 1, both the provider and the parent chose the skin graft side. Example 2, both the provider and the parent chose the Hylamatrix side. And then after they choose their side and do their rankings, we tell them which side is which at two years. So I think this is going to be a fairly mixed result. There are always pluses and minuses with every technique, so I think more than anything it's trying to learn what the pluses and minuses of that technique are. The pluses of the Hylamatrix is shorter tourniquet time, less donor site morbidity. The negatives are it's not a proven higher, better scar formation, and it does have an open area early on, and in our hands a little bit higher infection rate. So I think we're still searching for the perfect scar, and that is something that we have a guest lecturer at the symposium in May as well speaking to us about scar formation and maybe eventually medical management of the scar formation will be part of what makes our syndactyly most successful. But we're all continuing to search for that fountain of youth. So then the next thing I was going to just chat about was updates in the treatment of the hypoplastic thumb. So this was a survey of 74 pediatric hand surgeons, both national and international, talking about two different controversies. One was in the type 2 and maybe 3A thumb, whether to use, if you're doing an opponent's plasty, whether to use the FDS opponent's plasty or abductor digiti minimi Huber opponent's plasty, and I think the favor has gone a little bit more towards the FDS opponent's plasty. I think it provides you a little bit more options regarding the reconstruction, mostly because of the length of the tendon, and that can be used as part of the MCP stabilization and the ulnar collateral ligament reconstruction. And then the other controversy that continues to be battered about is with polycysation surgeries and treatment of the type 3B and 4, and the positioning of that, again, in this particular survey, it was, do you do tip-to-tip positioning or do you do more of a key-pinch type positioning? And again, in this particular group, favoring a little more towards the tip-to-tip positioning. And so just talking about thumb hypoplasia, again, we're looking at the first web contracture, the ulnar collateral ligament and MCP joint instability, and then the lack of thenar muscles with resultant lack of strength. So Dr. James helped us understand that in type 3A and less, that it is the CMC presence that allows us to do a thumb reconstruction, whereas when the CMC is absent on this spectrum of disease, that polycysation is most commonly recommended. So for the 2s and 3As, the most common reconstruction would remain Z-plasty of the first web, MP with a possible reconstruction of the ulnar collateral ligament, and then the opponent's plasty of your choice. So again, as you're thinking about opponent's plasties and trying to decide what type of opponent's plasty to do, you want to think about the vector of the transfer and be able to set that either through the FCU, around the pisiform, or more distal if you want more of an adduction moment arm, and then your source of the muscle with the most common being abductor digiti minimi or flexor digitorum superficialis. So just to show a couple cases, I'll start actually first with this one, is an older male, 13, who this was actually his dominant hand, and as he got into junior high and high school had to do more writing. And so this was an FDS opponent's plasty, first web Z-plasty, so this would be harvesting of the FDS tendon, and the FCU was used as a pulley, and it was placed under the skin and onto a radial-sided incision in the thumb to provide opposition. Whereas in a younger child, this is a 3A as well, but in that child, a Huber opponent's plasty was done, and I think the advantages there are that it does provide this aesthetic contour of giving a thenar-type looking muscle, but the disadvantage there is that it doesn't have the length, and you don't have the ability to reconstruct the ulnar collateral ligament concomitantly. So again, as I said, I would say that in 2022, the favor has gone a little bit more towards the FDS opponent's plasty just because of the function and the ability to reconstruct the ulnar collateral ligament. I think polycyzations remain the gold standard. It's an excellent operation. Again, I think we continue to fiddle with the incisions and fiddle with exactly how much rotation we use, but again, I think this remains the gold standard and is a very functional operation. Some of our international colleagues continue to look for other ways to reconstruct and maintain five digits on the hand. The two methods that have been published within the last year are use of a non-vascularized toe phalanx, as you can see here, where the non-vascularized toe phalanx is placed at the base of the thumb, if you can see that one right there, and then here are the results. So again, a smaller bony portion to the thumb, but again, for cultures where five digits on the hand is important, this remains a viable option. And also described has been composite tissue transfers. So this is a group that has done metatarsal composite toe transfers, so taking off the second metatarsal head and part of the MTP joint for reconstruction. So this is a metatarsal right here, which is replacing the previous metacarpal. So just to give an update, I think in syndactyly, we continue to discuss the manifestations of the scars that we produce during syndactyly releases, and we continue to look for alternatives, although I personally believe that full thickness skin graft from the antecubital fossa remains our gold standard. In thumb reconstruction, particularly in radial longitudinal deficiency, we continue to explore further the Huber versus FDS transfer, the role of polycyzation, and other options, particularly for the type IV thumb. But again, polycyzation remains the gold standard with excellent functional results. Thank you very much. Questions? Yes, please. I think we should not call this Huber transfer, because this was done by Lexer. Lexer is the first German surgeon who did a latissimus dorsi, who did a, you know, oponosplasty. Huber was his assistant, you know, young guy, who after Lexer died, described it. So really, credit should be, if we are talking about whom should be given credit, should be given to Lexer. Kind of like the Wassel classification. Yes. Likewise. Thank you. Don has a question. First of all, great comment. Thanks so much. Michelle, can I ask you a question about your presentation? Yes, but I don't know if I can answer it or not. I'm sure you can. You now know everything I know about that. So, really exciting that the pathway is being differentiated, and we're understanding different parts of the pathway. And it seems like we have more targeted pharmacologic treatments for different parts of the pathway. Has this information changed how you image, look at imaging, or think about what tissue to send to pathologists to help parse out, you know, is this going to be more of a lymphatic problem, and I should think about this particular enzyme and that pharmacologic treatment versus a vascular thing, and I should be going in this direction. Does my question make sense? No, your question makes sense. I guess I would know that from a gross point of view. The way it's changed my treatment so far is in April, literally a day after I saw the email about the new drug, I saw a young woman who my senior partner did a ray resection for macrodactyly 20 years ago. She's 21 now. And she has a massive lipofibromatous hematoma in her palm. And I've been following it by MRIs, and I really had no good, you know, no good idea about what to do with it. And I called the young Hemonc people and told them about the drug, because they hadn't heard about it yet. And now she's seeing them in consultation. And I don't know if at this stage of her growth if that will be helpful, but I wish it had been about 10 years earlier. You know, and we saw this thing start to grow, and maybe we could have done something about it, because now removing it I don't think is an option. So that's the only way it's changed so far. But even after surgical treatment, if you're doing a ray, there's still a role for subsequent medical therapy for the other subclinical disease. Yes. I would send every kid with macrodactyly to the Hemonc people at this point just to get a consultation. I think I don't want to miss anything like this, just like I wouldn't want to miss the Fanconi's. Yeah. Thank you. Philip Stockmans from Belgium. I mean, are we already at a point where we are going to give these drugs to non-vital threatening conditions? We are very close. I mean, in my perception, it's, you know, some of the kids that you're showing where, like a protease, for example, who has the coagulation problems and everything like that, it's clear. I mean, it's this or you don't do anything and you're running into trouble. But for an isolated macrodactyly? I think we're close. And I guess the reason I would say that is, so far, they have not found the side effects from the Alpelicid that they found from Seralimus. Seralimus has a lot of side effects. So that's one. But it's a small number of kids. But the other reason is, I mean, I had sort of thought early in my career that you do a ray resection, the hand looks fine, you know, with an isolated macrodactyly and you're good. But the 20-year follow-up, not so good. I mean, go and see the doctor next door. He's specialized in this. I mean, it's that, I mean, you don't want to see these kids because it's a difficult consultation and it's, you know, it's not an easy sell, so to speak. But, I mean, the drugs are given lifelong. Possibly. I don't know. Is that true? I mean, if you want to inhibit it. But I don't know that the growth occurs lifelong. I mean, in my experience, the growth occurs more like growth occurs with puberty. So they'll, at their pubertal growth spurt, they'll get a big spurt. This girl I was following, and it's a single case, but I was following with MRI. She had a big spurt. But I don't know that the growth occurs lifelong. I mean, it's a little bit like denosumab that we give for gigantic giant cell tumors. They're also, we started giving it, we gave it, had a good result. Then we start stopping it. Then we saw it reoccur. So I would be very surprised if this pathway is not going to behave biologically a little bit in the same direction. Maybe low dose or something like that. Yeah, I don't know that yet. I don't know if anybody knows the answer to that yet. I don't. It's a good question, though. It's a really good question. Nina? Did you, so you're, I'm sorry, I can repeat your question or you can come to the microphone, whatever's easier. Okay. That's exactly my question you answered. Okay. That we don't know what happens. It's the growth spurt, you know. Yeah. What is influencing this pathway? Yeah. That's not, that's normal. Yeah. Yes. Anybody else have any thoughts on that? I think that's the key question here, probably.

congenital hand anomalies

OMT classification system

genetics

registries

upper extremity function

PIK3CA-related overgrowth spectrum disorders

pharmacologic treatments

surgical techniques

syndactyly