Disorders of Sexual Develpment with Dr. Kathy Graziano

Disorders of sexual development is one of those topics that a lot of us just don't have a lot of experience with, so we thought it would be a great idea to do a podcast on disorders of sexual development. So today, Doctor Kathy Graziano from Phoenix Children's Hospital is gonna talk us through what we need to know about disorders of sexual development. We hope you enjoy the podcast. Stay Current is a multimedia publication designed to keep healthcare professionals up to date with standards of care and new emerging ideas. Stay Current is created and edited by Todd Ponsky, Nicholas Bruns, Ian Glenn, and Avi Schlager in partnership with Global Cat MD and is recorded and produced at Akron Children's Hospital in Akron, Ohio. Welcome to Stay Current in Pediatric Surgery. This is Todd Ponsky at Akron Children's Hospital. And today, we're gonna be talking about something that truthfully, I don't know much about. And I'm very excited to be doing this uh podcast recording on disorders of sexual development. And with us, we have Doctor Kathleen Graziano, who is assistant professor at University of Arizona College of Medicine, and also Mayo Clinic in Scottsdale. And she's in the division of pediatric surgery at Phoenix Children's Hospital and is the director of reproductive anomalies in DSD clinic at Phoenix Children's Hospital. Kathy, thank you for joining us. Well, thanks, Todd. I'm really excited to help out with this topic, and as you and I have discussed, I'd really like to have more pediatric surgeons get an interest in this field. Yeah, I think that you and I were talking before we did the podcast, and I think this is certainly something that Many of us are very afraid of, to be honest with, uh, honest with you, we don't do this very often, and it seems like something that's this big mystery, so I'm hoping we can dig down into some of the common things we may see even if we don't make this our primary practice. Sure, yeah, we can do that for sure. These, these questions are on the boards, and I know a lot of the. Uh, pediatric surgeons who are in training are afraid of this topic, and we'll just try to keep it simple and talk about some of the types of cases that are on the board. So I think that will be very helpful. Perfect. So let's, let's start off. So what is a disorder of sexual development and what, what are the diagnoses that fall under this category? So a disorder of sexual development is sometimes it's now also being called a difference of sex development, um, is a term that replaces old terms like hermaphrodite, um, even kind of replaces the term intersex. So these are patients who have some sort of mismatch between their genetic sex, so whether they're XX or XY chromosomes. Um, and their anatomic sex, and then, you know, in some cases there are associated anomalies. DSD is an umbrella term that was developed by some experts in 2005 in the endocrine community, and it's in order to replace some of those older terms. So diagnoses that fall under this category include congenital adrenal hyperplasia. Um, Meyerokotansky Kosterhauser syndrome, or what we just call MRKH or vaginal agenesis. So you can see already it runs a gamut from babies to teenagers. Um, other babies with DSDs would be babies with severe hypospadius. Um, any baby with ambiguous genitalia from, from, for any reason. And um you know babies that have more complex diagnoses, more complex chromosomes are really rare, but congenital adrenal adrenal hyperplasia is not rare. That's 1 in 16,000 kids. So these are the types of patients that most pediatric surgeons will see. And so how does it work at your hospital and how does it work at other hospitals? Who, who usually takes care of these patients and, and who gets called when they present to the NICU or, or to a gynecologist or whoever? Right, so as you know, it used to be kind of a social emergency. If a baby was born with ambiguous genitalia, a pediatric surgeon or pediatric neurologist would be called, and decisions would get made quickly as to, you know, is this a boy or a girl, and what can we do surgically to change the way the baby looks so that, you know, no one has to answer any questions. It's not done that way anymore. Most of the time now these babies are either have a prenatal diagnosis or they're diagnosed shortly after birth with ambiguous genitalia. At our hospital, the DSD team will get called. Any member of the team may get called first, but we also have a coordinator that does a great job of making sure that every other member of the team also gets involved. So the patients are seen usually in the neonatal ICU by, um, endocrinology. They're seen by genetics. They're seen by pediatric surgery, pediatric urology as needed, pediatric gynecology if needed, although usually the pediatric surgeons are playing that role as well. Um, probably most importantly they can be seen by psychology and social work. Our coordinator is also our social worker, and we really try to make sure that the focus is taken off of the patient's genitalia and back onto what else is going on with this patient. Are they sick? Do they have other anomalies, other issues? Right, I think that's a great point. All right, Cathy, so. You're on call and the NICU calls you and says we can't tell what we're looking at. This is a newborn with confusing genitalia, ambiguous genitalia. Where do you begin with this? So that's a great question. The first thing that we do is try to find out what else is going on with the baby, especially what kind of life threatening problems. Some of these babies can be premature. They can have cardiac disease. So we wanna make sure that we make, we don't allow them to make this an emergency. That being said, the families want to talk to you right away, so you do try to get to the NICU as soon as possible. It used to be the surgeon was. The baby first and then figure out what to do. We try to get the surgeons to see the child last, so we want the first people in the unit who see these kids to be endocrinology and genetics because they're going to guide that workup and you're going to come behind pediatric surgery, pediatric urology, and do the exam and follow up on the studies, and then you use an organized approach to, you know, what is a very extensive differential diagnosis. And you're going to stay organized, ask about a prenatal diagnosis, because in the past, in the past we didn't have as much information before the baby was born, but more and more now people are going to have a karyotype that was drawn, and they can give you information about, um, well, we have what looks like ambiguous genitalia of female, but they have XY chromosomes that were drawn prenatally, so you already have a hint. Um, the less common things you don't need to focus on ruling them out. Just let's rule out the most dangerous things and. So, so checking on a prenatal diagnosis and then going to the NICU and doing an exam. You're looking for symmetry on exam. You wanna know what is the genitalia look like? How many holes do you see on the bottom? You know, is this a cloaca? Do you have a single hole? Do you have multiple, um, openings? And I know I say holes as if it's, you know, so kind of, um, mundane, but. This is how we talk to the families too, um, all right, we're dealing with how many holes do you have any palpable gonads. I wanna hit on a couple things you said in a little more detail, can you go over first of all you get there, tell me again how do you do the exam? What are you looking for and, and what does it tell you? Yeah, so the first thing I do is I make sure there's not just a big crowd around when I do the exam. The families are stressed. People have already looked a lot at the genitalia. Do you have an enlarged, um, clitoris or phallic structure in the middle. And if you know the chromosomes already, you'll know a little bit about, OK, is this, uh, like a micro penis, severe hypospadius, or is this an enlarged clitoris? And depending on what the chromosomes are, you'll have more of a clue there. Um, then you look, um, at the labia themselves. Do they look like labia that are just swollen, or do they look more like a scrotum that's empty? Um, maybe it'll look like a scrotum that's asymmetrical, and if it is, that makes you think more like a mixed gonadal dysgenesis. You could have someone with kind of complicated chromosomes, or you could have someone with normal chromosomes, XX or XY, that has one gonad that's descended. That gonad might turn out to be a testicle. There might be something that looks like an ovary on the other side. So we do have one of those kids, I would say every other year, and those kids right off the bat, the asymmetrical kids, you know, you're dealing with something a little more complicated. So looking for symmetry, looking for the midline structure, is that a clitoris? Is it a phallic structure, and then trying to determine how many holes are in the enterroitus. Do you have a urethra and a separate vaginal opening, or does it look like a urogenital sinus? Um, to sort that out is a little bit difficult in a tiny baby because things are pretty swollen. There, there used to be all kinds of maneuvers to figure it out. We don't do them as much anymore because. Some of the maneuvers are a little bit shocking to families. If you did a rectal exam with your pinky, you might be able to feel for a uterus, but I can tell you families are not into that idea that you would do that at the bedside, especially if you're not going to do anything about that right now and you're going to get an ultrasound to look for Mullerian structures like a uterus anyway. So I just do a real quick exam. Sometimes I'll take a Q-tip or a hemostat and just see if I have a separate vaginal opening. Um, when you're in the operating room with these kids, you can pull the labia out and you can really see the holes and see if you're dealing with your genital sinus or not. People used to get a genitogram to help figure out if there were separate openings or your genital sinus. That's not as common as as much anymore either, and that's because all of these kids, since we're delaying surgery, all these kids will eventually get cystoscopy and vaginoscopy, and then you'll figure out if you have a urogenital sinus at that time. So I think the exam is really important. The exam with the lab and the imaging can help you, and then you don't need to do as many kind of invasive type procedures early on. And um from there you can follow up with labs and imaging to get some more details. All of these things take a little while, um, even getting a rapid fish to look for basic information such as XX or XY chromosomes. It's gonna take you in most hospitals, a good 24 to 48 hours. And God forbid, you send it on a Friday or on a holiday, you're not gonna get it back for 3 or 4 days. So you have to let people know that as long as the baby is, you know, able to void, able to eat and poop, We tell families the baby's number one job is just to eat and poop and grow and cry, and the genitalia are not important in all of those things. So we really want families to focus on those things. When would you order which tests and what's your process of going through this patient with ambiguous genitalia? XXDSD is the most common and so the other most common thing that we see, to be honest, is an XY DSD that looks like a girl. So you might be dealing with a partial androgen insensitivity. You might be dealing with a severe hypospadius, or you could have a mixed gonatal dysgenesis. All right, so let's take it this way XX. Ambiguous genitalia. What is my differential there? Um, the most common things are common, so you would be ruling out an XX chromosome, congenital adrenal hyperplasia before anything else, because kids with what looks like, you know, an enlarged clitoris, they can even look like they have a phallus in a scrotum, but they shouldn't have descended testes because they should have ovaries up inside the abdomen. So that would be the most common thing. And then again, ruling out congenital adrenal hyperplasia because a baby with salt wasting CAH, if they, if they're allowed to go home with no steroids, they can die. So it, neonatologists need to know that ambiguous genitalia is really kind of CAH until proven otherwise, and you need to make sure that the the baby doesn't have that before they get sent home. So the key lab there is an elevated 17 hydroxyprogesterone level. If that is. That's elevated and this what maybe looks like a baby boy has XX chromosomes, then they have CAH and they need to be started on a steroid regimen before they go home. So an endocrine doctor would see the baby sooner than the surgeon really. Going in to see the baby for someone who has no, you know, real knowledge of this, I want to dumb it down for me a little bit. So ambiguous genitalia, you've already mentioned a lot of them, but so if I go in and I don't know the karyotype. What are the common differentials if we were to take the, the more common things we see? So congenital adrenal hyperplasia, right, is the most common, and that's gonna be an XXDSD. And so the other most common thing that we see, to be honest, is an XY DSD that looks like a girl, and those you're going to see some of those as infants for sure. They definitely present more commonly in the teenage years when these kids have amenorrhea. So their genitalia, X Y DSD babies can look so female that no one would have any reason to worry and call you about ambiguous genitalia. So you might be called because more and more there is some sort of karyotype that was sent. To answer your question, if you don't know the karyotype that it's XY, then you might get called because there's a mild enlargement of the clitoris or the skin around the clitoris, and you might say. Uh, they might say we don't think this is anything, but we just want to make sure. In those cases, I'd look and if it doesn't look normal to me, I'd say, well, you might be dealing with a partial androgen insensitivity. You might be dealing with a severe hypospadius, and we should definitely send chromosomes. So I think in every case you do the exam, you remain in your own mind too. Neutral and vague, and you start with a rapid fish for chromosomes that will narrow down your diagnosis faster than anything else. So XX DSD, the most common thing is going to be congenital adrenal hyperplasia. So that's when you consult endocrine, draw your labs, especially the 17 hydroxyprogesterone level, and then. to, you know, support the baby, let the baby eat, but the baby will be on IV fluids. You don't necessarily need to start steroids until you get the answer back on that lab. That lab will come back faster than the chromosomes. They'll come back within 24 hours. Um, so that's the, that's always the most towards answer is rule out CAH. The other things that can present with XX, um, DSD in the infancy period, it's not very common to see, um. To see this, but you can see, um, an XX, um, ovotesticular DSD, and those are those kids who have XX chromosomes, but they've got half of both parts, and those kids have the asymmetry that we talked about. So I've seen that it's extremely rare, but I have seen it, and you, um, you think you're gonna be dealing with something else like a mixed gonatal disgener. Genesis or something really fancy, but it turns out they just end up having XX. A lot of them just have XX chromosomes, so they're probably meant to be girls, but they ended up half of their Mullerian structures are preserved and the other half aren't. So you go see the patient, you evaluate as you described the elements of the physical exam. You check their karyotype. If it is XX, which you probably have known before you even got there, you check for the 17 hydroxyprogesterone is correct. OK. And you can get an ultrasound. Everyone will get an ultrasound, and an ultrasound at every hospital has a variable amount of, uh, specificity, sensitivity, um, you know, it's user, it's user variable. So they might tell you we have what we, what looks like ovaries and a uterus on the inside. And which a CAH baby should have, and we have XX chromosomes and we have an enlarged phalex slash clitoris in the front. So and maybe a single opening that we can see, so you're a genital sinus if they tell me all that this baby has CAH, I can't imagine what else it would be. But sometimes what they'll tell you is that the ultrasound failed to show a uterus or it only shows one gonad, and now everyone's upset because nothing matches up. And what I tell the units and I tell the parents is that these structures are so small that the ultrasound can be unreliable and it takes a while to get people to kind of let go of that confusing information, but I tell them at some point if we need to, we'll get an MRI. It's not urgent. And the ultrasound doesn't matter because we're not going to do anything differently, but ultrasounds don't always match up with everything else just because that's not as reliable as everything else, OK? And I'm just going to keep repeating to clarify, to make it simple for me. XX, you're going to do the exam. You're going to maybe get the ultrasound. You're going to check the 17 hydroxyprogesterone. And pretty much that would solidify your diagnosis of congenital adrenal hyperplasia. You got to make sure then about their salt wasting and their cortisol levels and all that stuff and uh make sure that's taken care of. And then they go home. They go home, yeah, and they come back to see you, and, but they, the, the team has now told the family you have an XXDSD congenital adrenal hyperplasia baby girl, and in no matter how enlarged that clitoris is, in most cases we're going to tell them that your baby will most likely identify as gender female. Kathy, let me ask you, in the setting of prenatal diagnosis of congenital adrenal hyperplasia. Is there any role for prenatal maternal steroid administration to prevent the androgenizing effects? There is one center in the US that treats with steroids to try to decrease the virilization of the next baby girl if affected. Internationally and nationally, it's clear that that is not indicated. In fact, treatment with steroids can cause cognitive delay in the child, so you wouldn't want to trade the appearance of their genitalia for them having cognitive delay. So it's no longer indicated to do prenatal therapy, prenatal dexamethasone for families that have another CAH baby on the way, and that's just clear. After the baby's born, families may seek out surgery to Um, do a clitoral recession to make things look a little bit what's called normalizing surgery, and then they also at some point probably need that urogenital sinus addressed because the vaginal opening is hooked into the urethra. So when the, when the child, when the teenager goes through puberty, they're going to have an outflow obstruction to their menses. Some people will say you could buy even more time if you just shut down their puberty for a while, which you can do. But um right now very few babies are being raised without fixing at least that urogenital climate, but the timing of that is, is now controversial. I can say that families in general seek it out and they will seek out um surgeons who are not involved in these uh networks surgeons who are involved in the networks will still offer the surgery, but we'll spend a lot more time making sure people understand early versus late, so baby versus teenager. What are the pros and cons and how can we sort out for your child what's the best thing to do, knowing that there's no clear data on the answer yet. Got it. Now let's take the baby is XY. So now our differential is things like androgen insensitivity syndrome. You might be dealing with a. androgen insensitivity, you might be dealing with a severe hypospadias. So say for example, I'll give you a case we had a patient who had a prenatal diagnosis of ambiguous genitalia for a variety of reasons, they ended up getting chromosomes before the baby was born, so they knew they had XY chromosomes. Baby comes out, she's got a lot of other anomalies, but the, the genitalia externally look like female. They look very female. Um, so they already knew there was a mismatch and they called us. So what we did is when we went to examine her, we looked at, we looked at her perineum, but we didn't see anything shocking. There wasn't anything strange really, so we didn't need to do much as far as looking for your genital sinus. She had other reasons to be sick, other medical issues, um, so what we could do is start sending labs and you. In that case she's she's what we call an XYDSD. So she's now fallen into the category of I know her chromosomes, she's XY DSD, disorder of sex development. What are the different things that could cause that? So now our differential is things like androgen insensitivity syndrome. What exactly is androgen insensitivity syndrome? So that's something. Where incomplete androgen insensitivity syndrome, the body is making testosterone. There are gonads present that are making testosterone, but the tissues just don't recognize the testosterone. So you're looking for the androgen receptor in those cases. So you can do a genetic workup looking for the known genetic. You know, mishaps in, in androgen insensitivity, but like I said, you also need some, so if you have X, Y, DSD, that's your category, now I want to know, is there testosterone present in an abnormal amount in this baby? Now the problem is babies have this mini puberty. Of infancy, so they will have a certain number of abnormal labs or what's considered abnormal labs in the beginning, um, you know, 8 to 12 weeks. So what I do, and this is because pediatric surgeons surgeons do not need to know all the details of all the hormone levels in a baby. What you need to do is grab your. Endocrine colleague, they probably have seen the baby before you, but if they haven't, you say I've got what I think is an XY DSD prenatal diagnosis involving XY chromosomes, but female genitalia, looking, you know, it looks like female genitalia. Help me decide what labs to order. And again, they're going to order testosterone, they're going to order FSH, LH levels, and they look at ratios of FSH and LH and testosterone. Um, those labs have to be drawn. They'll look at cortisol levels. They often will look for, you know, the steroid synthesis itself. Is this an issue of just not making, being able to make steroids, so they'll look for cortisol levels. They will add these things all up, and it takes a while to draw some of these labs because some of these babies are so small you can't just like take all their blood and send it off to the lab. So we've had. Babies that it takes, especially in the preemies, it can take a few weeks to months to get everything you need in order to narrow down the diagnosis. Tell me a little bit more about the severe urologic complications that can mimic X Y DSD. Yeah, so definitely it gets a little bit more complicated because now you're probably dealing with a urologic diagnosis, something for the urology colleagues that has to do with Um, the phallus itself and where the hole on the phallus turned out to be, because if you have piano scrotal transposition, um, and that's where the, there's just kind of the, the scrotum itself is kind of high riding and the opening on the phallus can be very, very low at the base of the scrotum. Then it can look very confusing to people. It, the chromosomes will come back as X, Y, and then the family wants to know, well, OK, what do we do from here? And they just want to know what surgery are we gonna do. So we have to let them know that there's some time needs to pass. The babies need to get bigger because the more complicated, the more severe the hypopa is, the more difficult the surgeries are, and I'm kind of speaking for my urology colleagues right now, but. These babies, these XY severe hypospadius babies can be what are called um hypospadius cripples, and these are people who've had many, many surgeries throughout their lifetime, never achieving the result that they hoped for. So in those cases, they may end up with more surgery and a worse result than even the baby girls. So it's even more important to let the families know, um, you know, we need to, you know, educate. About this and help you decide what to do. That's where the advocates can really help. So xy with severe ambiguous genitalia is probably going to be a year like they, they just have anatomical only issues. It, it's just the hole is in the wrong spot. The thallus is too small. The scrotum and the and the um phallus ended up, you know, upside down. So these are just basic rare but severe. Your problems that don't, aren't really have anything to do with your chromosome or with your, um, hormone levels. So the hormone levels will be normal in these kids. You can, um, supplement them with testosterone and most endocrinologists and urologists will do that. So in this newborn period while they're getting ready for surgery, they're going to be placed on testosterone, which, you know, may or may not help with growth. So when it's time for surgery, Surgery, they'll have something more to work with. But again, I'm sort of speaking outside of my realm. These are definitely things we talk about in my clinic, but XY severe anatomical ambiguous genitalia is probably going to be something like that and not something related to the hormones. Now correct me if I'm wrong, complete androgen insensitivity syndrome will have normal appearing female genitalia despite having XY chromosomes. Is that correct? In most cases they will if they're partial, they may not. So partial antigen and sensitivity may have an enlargement of that structure. The completes shouldn't, so they should be pretty normal. They used to say that they had a short vagina, that it was just supposed to be only the lower third formed and the um and the upper 2/3 didn't. The truth is these girls mostly have a normal depth of a vagina, and if you tested that at birth with a little hemostat or a ebaki or something, I think you'd be fooled and you know you'd think of this is normal. You're not gonna necessarily look for a cervix or do a vaginoscopy, but in some cases, you know the chromosomes and you have what looks like a normal external genitalia. So the investigation on that girl is going to wait. Um, you're going to send your labs, send your, you know, repeat your chromosomes and send your labs for 17 hydroxy hydroxyprogesterone, but if the testosterone level comes back high and you have XY chromosomes, then you're probably dealing with a, dealing with a complete, and like you said, their, their bottom probably looks pretty normal. So how does a mixed gonadal dysgenesis present? So a mixed gonadal. Genesis looks like a lot of times they're asymmetrical, but if they are symmetrical, then we think, OK, this is probably a CAH, but you just get the sense that it's a little different than your regular CAH. Now what the way they look different is they usually like the middle structure looks a little smaller, a little more abnormal than just an enlarged thus. The CAH girls can look like a boy. Um, but the, but the mixed goads sometimes don't, it just looks a little bit different. We're still ruling out CAH, and then in the process of ruling out CAH, we'll find out that they have. You know, 45 X X 40, you know, 46 xy they're they're like a mix they can be XXY they can be all kinds of different, um, different things. We just had a patient who was X X X Y, um, and had what just looked like actually just looks like hypophagia looks like severe hyposphia, so they will look a little bit different than the regular, you know, CEH that you think of and then you almost get surprised when you get. The chromosomes back. So in those cases we really don't tell the family much before we find out. Then when you go investigating with your ultrasound and later maybe a diagnostic laparoscopy, you can find any variety of structures a hemi vagina with a regular looking fallopian tube and an ovary on one side, a full scrotum with a descended testicle on the other side. When you biopsy these structures or remove them in the in the process of doing a reconstructive surgery, you'll find out they're not. As normal as they look. A lot of them are kind of like a mosaic ovo testis, um, but it's important to get everybody involved. These are the cases where you're having family meetings, you're getting 2 or 3 endocrine recommendations. You have your ethicist there because the families will want a reconstruction to kind of determine how to raise this child. That is, that's a difficult child to convince everybody to just wait and see, even though that's almost the best person, the best baby to wait and see. Um, it's usually people will want you to assign a gender, and then you have to take everything into account, make a recommendation, look at the literature, and then also make people understand and, and say the words. What if we're wrong? If we're assigning a gender female and we end up removing this testicle, what if we're wrong? What are we going to say about that later? Um, they used to make determinations on those babies just based on whether the chances this baby can have, um, you know, function as far as reproductive function. We want to have the best function and we want to preserve either the phallus and the testicle or we want to preserve the hemi uterus and the ovary and. And historically they were raised as girls because they were thought that you could it'd be easier to preserve that hemming uterus on the one side. There's no follow up data on those babies, so it becomes a real issue when you're talking to families. Luckily, these are extremely rare cases. Because it's very difficult, they need to be raised in your clinic. They have to be followed up, uh, yearly, and then you'll see, you see as they come in what they kind of act like in your clinic and you get a certain sense of that. OK, let's switch gears now. How do the teenagers usually present? So the teenagers are an extremely common group of patients that I think are very well served by a pediatric surgeons and helping decide what to do with them because pediatric surgeons can think outside of the box and Um, kind of understand all the different reconstructive surgeries that might be necessary, uh, because we're, we're operating on cloacas, we're operating on, um, in perforated anus. We're, we're in the pelvis all the time, so we, we get it. So these patients present usually to their pediatrician. Because around age 1415, 16, they have not gotten their period. The average age to get your period is age 12, but around age 1415, people start to worry. We're taught that you really shouldn't worry until they're 16, but I can tell you that most patients presented about 15, um, to us because their pediatrician decides to go ahead and just run some labs. So the first thing the pediatrician will do is do an exam. As well, but some of the girls, like a, a, a complete androgen insensitivity is not gonna have an abnormal exam in the office. Even MRKH usually is not picked up by a pediatrician, and MRKH is um Meyer Rootansky Koster-hauser syndrome or vaginal agenesis. And these girls have a normal appearing inroitis, but they don't have an opening, but they have what looks like should be an opening. There's hymenal tissue there. It's just, there's no actual opening, so pediatricians miss it all the time, and families get very mad. Some families just fire their pediatrician, but it, I can see why they wouldn't, they wouldn't notice that there's No actual hole there and the kids don't know either. They don't get their period so they get chromosomes sent the chromosomes come back as XY, and we get an emergency call to the office. Um, can you see this family? I just gave the results to them or I haven't given the results to them and I need somebody to see them right now to explain what's going on. So that's probably the most common thing that we see is X um is is Maya Roatansky. So My Roatansky is XX chromosome and then the congenital adrenal or the sorry, the, the complete androgen insensitivity is the XY um, the XY's are very confusing to families, and these are the girls that, um, have a normal vagina, so they're not really in most cases gonna need surgery, but they have. Gonads inside, then someone needs to talk to them about that. So if you want to divide these two categories of patients and go one at a time, I would say the, the first one to talk about is the most common, which is XX MRKH or vaginal agenesis. So these, their, their chromosomes have been sent, they're XX. They come to you because they've just gotten the diagnosis that they have no vagina. And it's usually the mom and the and the daughter in your office, and pretty much everyone's freaking out because they usually have had some sort of imaging that also shows that they have ovaries but no uterus or a rudimentary tiny uterus or a little, you know, little piece of uterus so it's not going to carry a baby. They've looked it up or someone's told them that they're probably not going to be able to carry a child because they don't have a uterus. Um, they're upset because no one ever told them this happened. It came out of nowhere. And so our job is to first um get to know the family and kind of calm everything down. So this girl is just they, they have ovaries. They're just as much a girl as they ever were. There's no confusion on their gender, um, so we let them know that you're just, you're the same person you were before we found this out. Um, we talked to them about what they like to do, how, what kind of sports they do, what their goals are, most of these kids are in high school. Um, we want to let them know that in general in this country and in most countries, vaginal dilations are the first thing that is offered in order to create a vaginal canal in order to be sexually active, that they don't need to think about all their surgical options right away, that they need to try vaginal dilations first. If they're seeing a surgeon, they may have already tried that, so they may have been kind of seeing a variety of gynecologists and trying the dilation. There are some good studies on dilation, and the truth is dilations work when that child is ready to become older and sexually active. The problem is when the anatomy isn't OK for dilators, which happens. And they're hurting their urethra. Do they need a surgical reconstruction? And the answer is probably yes, although most gynecologists in this country will tell you probably no. So, going back to the beginning, she's got amenorrhea, um, just to, to restate what you said. So the, the first step would be, usually the pediatrician, um, would get, um, an ultrasound. Um, they, they do get an ultrasound and they get, they send labs. They get chromosomes. And chromosomes. And, and where in this, and then the next would be an exam under anesthesia. So I, we do, I love an examiner anesthesia, but I usually meet them first, and I tell them the one thing about the examiner anesthesia, they'll get you a lot of information. Um, they don't really like the exams in the office because they're pretty young, so it's not like an older woman going to a gynecologist. It's a very uncomfortable thing. And we can tell them the other thing is we really need to look, it's not just like a regular exam. We might take a, we, we're probably gonna do a cystoscopy, we might even do a diagnostic laparoscopy, so we may not do an exam in the office at all. We may go straight to, to EUA. They are always very hopeful with the EUA that you'll find structures and that the diagnosis is wrong, so we have to let them know that that's not what we're trying to set out to do, um, so I think, I think not at this point, not everybody even needs an EUA. If you can do. And if you know the labs are XX and you have reliable imaging showing no uterus, normal ovaries, and you can do enough of an exam in the office that you see how they're set up and whether or not they'd be OK for dilators, you might be able to get everybody to just kind of calm down and wait a while and then try dilators. You may not have to put them to sleep because if you put them to sleep, it becomes a real focus on their anatomy and do I need surgery, right? But the, but then there's, you know, the for an imperfect hymen. You would, that's where the imaging helps. You would see a very enlarged, you'd see hydroculpos. Correct. So the imaging, the ultrasound may help you. If the ultrasound isn't clear, an MRI is very helpful. So an MRI will tell you, do I have a vaginal, um, structure that's full, and in that case, yes, then you have, uh, hydrometrocculpos or you have a bulging membrane on the perineum. Sometimes you don't. Sometimes, and, and again, these girls have amenorrhea and they're asymptomatic. If a girl. 15 or 16 year old with amenorrhea has pain. You're gonna think, OK, this is not just vaginal agenesis MRKH. This is an obstructed, um, uterus and vagina. This girl has either a long vaginal septum or a distal vaginal agenesis. We see those kids a lot too. I can tell you those kids usually present to the ER because they're in pain. So they're getting more. They're getting an MRI that shows, OK, we've got a problem, and if they have a bulging membrane on their bottom, then it's a, it's just. Awesome because then you know you're gonna make them better with the hymenectomy and they're gonna be good to go. It's the ones that don't have a bulging membrane that have more of a problem that's gonna need um surgery and and unfortunately they need surgery that's fairly urgent because they're in pain and they're obstructed but that's good that you brought that up because most of them are going to be asymptomatic though most of the MRKHs are asymptomatic. There are forms of MRKH and Eulerian obstruction that are very symptomatic and you're gonna see those too. So what about, so talk to me how a child with androgen insensitivity would present and then how do you treat them? Yep, so androgen and sensitivity girls are also, um, have amenorrhea, so they present at age 1516. The pediatricians will send chromosomes and they come back XY. In this case, they, everyone panics, um, we send them to us and we explain again there's nothing different about your child just because we have a new lab back they're still female and we ask them, you feel like a girl, right? Yes, so you are a girl, there's nothing that's different. The only thing we found out is that, you know, because of the way you were set up when you were born, your gonads are not ovaries, they are more like testicles, and they're making testosterone and because your body cannot see testosterone. All that extra testosterone gets converted to sort of like a girl hormone and your body can see that and that's why you look so much like a girl. So in a way you're kind of like a supergirl because you have more girl hormones than anyone else and you have no. hormones you cannot respond to them. So that's why your skin is perfect and you don't have a lot of extra hair in these sort of puberty areas. And when they hear that, they just have this sort of light bulb go off that says, oh, OK, now it all makes sense to me. They're a very interesting group of patients, extremely smart, extremely sweet. They're sort of a personality phenotype that goes with androgen sensitivity girls, so. They're pretty easy to take care of because they don't need a lot of surgery, but you do have to make decisions about these donuts. And because they more and more understand that if you remove their gonads, you're going to kind of change how they feel because you're changing their hormonal setup. So more sophisticated CAIS patients are, are electing to keep their gonads for as long as they can so that they don't have to take estrogen replacement therapy after you do their gonadectomy, and those patients are enrolled in prospective studies in order to assess their cancer risk and make sure that we're following those gonads. But what these groups of patients have told us is, you guys want to take these gonads out because you're worried about the cancer risk. What's the difference between anybody's, any female's cancer risk for ovarian cancer? How is it any, any more or less than your risk doctor for ovarian cancer? And we had to say, OK, that makes a lot of sense because someone has to follow a, a normal female's ovaries, especially if they're at risk for ovarian cancer for any. a number of reasons. And so why don't we develop protocols that can follow these patients the way we follow those patients and it made perfect sense. I can tell you all of this is brand new and it may even change again in the next 10 years, but it's a, it's a good example of providers listening to patients and coming up with what I wouldn't even say is a compromise, just a new way of treating them that really takes everything into account, and I'm happy to be a part of that actually. Um, it makes, it always makes life a little easier when you don't have to do something complicated by yourself, and if it's your colleagues that are helping you or if it's the patients themselves who are helping you, it, it's just an ideal situation. So, so X Y DSD, complete androgen insensitivity or CAIS, is um a patient that may or may not need a gonadectomy depending on. You know, their education level on how, you know, what they wanna do, um, if they do not elect for a gonadectomy, they have to be followed closely for, for, uh, screening for malignancy of those gonads, um, and they should not need any reconstructive surgery. Um, they can present in the infant years with a hernia. So these are those kids that are a female presents to your clinic with a lump in the groin, and you think it's probably an ovary, maybe an incarcerated ovary, so you schedule them for surgery relatively quickly, and that structure doesn't exactly look like an ovary. So you wonder, do I, am I dealing with a complete. insensitivity female, you know, that has, and this is a testicle. So it used to be that the board's answer was that you'd probably leave the testicle in, maybe biopsy it, go talk to the family and let them know what you're dealing with because you want to confirm the diagnosis before you remove any of these donuts. So you're going to send chromosomes, find out if you're, if you're right, if this is XY and not XX. Um, that's still a good answer. It's still a good answer to biopsy the testicle. It doesn't hurt it to do that, um, but this time you're going to tell the family we're going to confirm the diagnosis, and we may elect to keep those gonads for a long time. Uh, it is, it would be good for and, and normal and safe for this child, for this infant, to keep those gonads through puberty. But at this point we may even keep them beyond puberty. So it used to be maybe take them out because they need to be taken out someday anyway, and I definitely take care of older CAIS patients who had gonadectomies in their young years. Now you wouldn't take those out. When you do a biopsy, what are you looking for? So you're looking for just normal um structures for the testicle itself, so the tubules that make the, the sperm, they're gonna be visible under um. Under the microscope you're not looking for malignancy at that stage, um, and that's something that it's very difficult to sort out how we're gonna follow these patients who elect to keep their gonads. It's gonna be imaging and labs, and over time we'll have more data on what to look for that looks abnormal, um, because again it's how, how do you pick something up that's abnormal? It's just like the ovaries. You gotta be looking a lot and frequently. As far as assigning a gender, we let everybody know that that's something we used to do. Now we're a lot, we, it, it is good to assign, assign a gender to the child, so everyone will get together and say, I think you can raise this child as a boy or raise this child as a girl. Pick a girl name, pick a boy name. In very rare cases, we recommend picking more of a neutral name, but we really slow down the train and we let families know that sometimes we won't have an answer for you for a couple of months depending on how many labs need to get drawn. If the baby's premature, very premature, which happens sometimes. We need even more time to let this baby grow and kind of sort out the anatomy and the and the um labs. So in our hospital, all of those people I mentioned are part of the DSD clinic, and then we kind of go from there. That's great. I'm curious about what it's like for someone to be. Not gender assigned and go through early years of their life. In general, if the DSC team sees a patient in the in the hospital where it's not really clear, you know, what would be their gender of rearing, and this can be a baby, you know, that is highly virulized congenital adrenal hyperplasia or it can be a severe hypospadius, and there are still a lot of advocates out there that say. You know this baby may not be clearly identifying as male or female later, and so it's maybe not a great idea to have the family clearly assign a gender at birth. What we will do is we will explain those controversies to the family. We'll tell them that all of the advocacy groups agree that it's OK to assign a gender. And so they can go ahead and do that with our recommendations and we'll tell them we think your child's going to feel like a male or we think your child's going to feel like a female and then if they want to slow things down they have then they they can and we can raise the child as gender neutral and let them know that we can just see, you know, how things go in the first couple of years. It's usually pretty clear within a couple of years. Life, what kind of gender you have. Although in the case of highly virulized congenital adrenal hyperplasia, you may have someone who's going to identify as gender female but is more of a tomboy. And so then you wouldn't want to think that you made a mistake. The truth is it's a new concept to raise a child as gender neutral, but it's not a concept that is very far off from happening more and more. And it's gonna start internationally and it's going to be done more and more in the US. I wouldn't say it is gonna happen overnight, but I would say inevitably less surgery is going to happen on babies over the next decade. And more and more you're going to see choices being made in the teenage years on these kids, which is why they all have to be in a very strong follow-up clinic with support so that we can explain to them that everybody's different. And when moms raise, and I specifically say moms because this is, these are the only ones I've talked to that have raised gender neutral CAH babies, for example, what they say they do is when their children ask why do I look different, their answer is everybody's different. And they really keep the focus off of their genitalia and they really keep um exams and things like that private. So these kids aren't, you know, showing everybody their genitalia every time they go into the clinic and it's a unique thing to be able to do and with the right team of people, you can do it and because we don't know whether the outcomes are better with early surgery or late surgery. We cannot tell families that they're making a mistake if they decide to delay surgery. In fact, we need to let them know, uh, we need to let them understand that we don't know, um, and I think that's, it's, it's being studied. We will know. I hope 20 years from now you can do this podcast with me and I can tell you the answer. So that's your, that's your long answer to how do you raise a gender neutral child. It's not common now. It will be more common, and there are ways to do it. I probably would need another hour because I know that's always a question I've had is if we don't assign, you know, what bathroom do they go to and those kind of things, and I know that that's a much more complicated thing than we can get into right now. It is, it is. The truth is that kids. Kids are going to do better with this than we are because of all these changes that are going right now with with gender. Kids themselves are probably going to wonder someday why we had such a problem. Now we can kind of stop it at that because then the controversies after that about how female they feel gets really confusing to families. So you don't need to predict the rest of their life or what toys they'll play with. You can just let them go home. Let them identify, you know, identify the baby as a girl, and then when they come back to clinic, you can start to explain more about how 3AH women are because otherwise they'll fixate and they will come to your clinic with pink clothes only and bows everywhere or they'll do the opposite. They got a prenatal diagnosis of boys, so they bought everything that was boy and it turns out they actually have a girl, but they won't stop using the boy name. There's a boy clothes, and many CAH girls have to have a boy name already assigned by the family because that's what they thought they were going to get. So those mismatches take more time to get over. Obviously our DSC clinic is part of a 10 center collaboration called the DSDTRN or Translational Research Network. It's headed up by the DSD Centers at Michigan and UCLA. Phoenix Children's is part of it. And every patient gets enrolled in a long term follow-up study that over time measures their gender identity and their body self image, their sexual satisfaction later after any kind of reconstructive surgeries, although that's way down the line. All of that gets tracked and built into an anonymous database where every patient enrolled, all, all of the studies get all the answers to these questions get put into that database. So then you can match up their chromosomes. What their, you know, gender of rearing was, what their attitude is about their own body, and kind of hopefully over time improve their care. So we're very robust about getting all of our patients into that follow up, um, registry. Got it. So let me ask you, as our time's ending here, um, are there any other things that we didn't address that you wanted to talk about? So I think we talked about the infants with ambiguous genitalia, the important thing to look for, how important it is for you to rely on your colleagues, the expertise of the endocrinologists and the urologists at your institution. But again, seeing as many patients as you can to really get a sense of what looks like a regular CAH, what looks different. Um, I think we talked about the delay, the new real interest in delaying surgery and how we would take care of patients who elect to delay any reconstructive, uh, surgery. We talked about the teenagers and how to take good care of them and how to understand what their goals are before we rush into any um surgeries and how to kind of calm everybody down. And then the biggest controversies in care for pediatric surgeons to know, this is the last part is just keep, we'll, we'll keep you posted on the timing of surgery to make sure nobody gets into any trouble with removing gonads that should stay in or doing reconstructions that should be delayed. And then this idea that informed consent might be something that um is a little tricky. Whenever surgeons are in the room, people want to do what we say because we seem very confident and they want a plan and they want closure. So it's very easy to spin someone towards surgery and you don't even know you're doing it. So listening to your biases and understanding that informed consent involves people repeating back to you things like This surgery will not be the last surgery your child has. This surgery is most likely the first step to what will include other revision surgeries later, and having me repeat back to you, I understand there will be revisions that will be required later in life and kind of checking that box that they're saying that out loud. I understand that follow-up may include dilators. If they're trying to avoid dilators and the surgery you're performing on them involves dilators, they have to say, I understand that, and And I'm willing to do the dilators so that I have a good outcome. So managing those outcome expectations in the beginning is more complicated than than we used to do. And then the last thing is the advocates who I know very well. are wonderful people who help me with my patients every day. They also in certain cases are going to be looking to the legal world to solve some of these problems. So we have to be careful about assigning gender and then later if we're wrong, if someone wants to come back and sue the institution or sue the doctors, of course that would be, that's, that's a problem. There's a very high profile case right now that is happening this year. And I'm looking at the implications of that, and the pediatric surgery community will be updated on that as soon as I know what's going on. In the meantime, I would say. To really think in terms of your team and what are the legal aspects of these procedures because families will may seek them out and if you don't offer them they may seek them out from someone else so it may be best to just have a better, more robust way of doing informed consent using shared decision making. All of those tools are on our website at the pediatric surgeons of Phoenix. Some of the shared decision. Making tools are being studied. Anyone who has a question is welcome to contact me. I can be reached at K Graziano@ Phoenixchildren's.com. And let me just spell that. That's K G R A Z I A N O at Phoenix Children's.com. So it's P H O E N I X C H I. L D R E N S dot com. So there's no apostrophe in Phoenix Children's and it's dot com dot com, yeah and so I can be reached at that email address. I can also be reached. Our office is 602-254-5561. And they can uh put patients or put people through to me um we're happy to hear from patients or from people who have questions about uh the procedures that we do one of the most common reconstructive procedures we're doing more and more of is called a buccal mucosa graft for uh strictures. The vagina or for um vaginal septums and also for just a vaginalplasty for someone who doesn't have one that is an awesome procedure I'm really excited about it but it doesn't have a lot of follow up so people have questions about that uh can definitely call us at Phoenix Children's. We're happy to answer any questions and, and like I said, my commitment is to update the pediatric surgeons on what's going on and hopefully recruit more younger surgeons to take this on as a as a niche because it's something that's so confusing that once you get it, it feels so much more comforting to get it and actually the patients love it that you get it. They love that about you that you understand what they have because it's so confusing. We give them a break and we tell them. You don't need to understand it. Most of your doctors don't understand it, so when you get it, that'll be great, but don't make it your focus and don't be so stressed that you, you know, don't understand it. They're a wonderful kid. It's a wonderful population of patients to take care of too, and it's, it's fun. It's, and it's a whole, that whole age group, which is great, like young and older, so I've been blessed. Um, Dr. Corin trained me initially at University of Michigan and got me started in this, and then Dr. Teitelbaum. Who's there and is sick, um, he told me, um. Cathy, you can really make a name for yourself in ambiguous genitalia, and I thought what a strange thing to say to somebody, but it is so true you can, um, and again, the more pediatric surgeons I can find, especially I just need a handful of people out there who wanna do this. I'd be happy to get their institutions kind of up and running on this. Just Akron. Yeah, I think, uh, I think people are definitely gonna contact you. I also wanna tell people that, um, we'll try to get, um. Any videos we can find um from around the web or whatever uh or Cathy's videos we'll put on here and also um feel free to, to leave comments on the app um for Cathy or for anyone about the particular patients you have or questions you have about the uh podcast. Cathy, I really appreciate you uh taking the time with us today. This has been very informative and very helpful and a topic that's normally very challenging for most of us. So thank you so much and, uh, I, uh, I hope you have a good rest of your day today. Yeah, thanks, Todd. I'm really happy what you're doing with the podcast. I think it's, um, it's really comprehensive, and I know I'm gonna download the app right now. I'm excited. Awesome. All right, Cathy, thank you so much. We hope you enjoyed this episode of Stay Current in Pediatric Surgery. You can listen, watch, or read all content by downloading the Stay Current and Surgery app. Please send questions or comments to us at staycurrent podcast@gmail.com. We'll see you next time.