This Podcast Will Kill You - Ep 106 Turner Syndrome: Let's talk about X

Episode Date: September 27, 2022

Are you in the mood to chat chromosomes, specifically the X chromosome? If so, have we got the perfect episode for you! You may have come across the definition of Turner syndrome as a genetic condition resulting from the partial or complete loss of an X chromosome, but what does that actually mean? What is the X chromosome, what does it do, and why is it so important? We attempt to answer these questions with our exploration into the biology of Turner syndrome before setting our sights on the who’s and when’s of the X chromosome and Turner syndrome. Our path through the history of these bundled packets of genetic material wouldn’t be complete without some fascinating detours, such as an exploration into the inspiring life of Nettie Stevens and the beautiful variations in sex chromosomes found in the animal kingdom. Finally, we wrap up our episode by taking stock of how much progress we’ve made with Turner syndrome treatment and research but also how far we still have to go. Tune in for all this and more! See omnystudio.com/listener for privacy information.

This is exactly right. There are already enough things charging your card every month. Dinner should not be one of them, which is exactly why Blue Apron is now subscription-free. You heard that right, Blue Apron no longer requires a subscription. You can order meals when you want them and skip when you don't without adding another recurring charge. Blue Apron meals are designed by chefs and arrive with pre-portioned ingredients, so there's no meal planning and no extra grocery trip. Order now at Blue Apron.com. Get 50% off your first two orders plus free shipping with code this podcast 50.

Terms and Conditions Apply. Visit blueapron.com slash terms for more information. This is Bethany Frankel from Just Be with Bethany Frankel. Listen, I have a bone to pick with these dog food brands calling themselves fresh, natural, healthy. Sounds great, but a lot of these quote-unquote fresh dog foods in your fridge are not even 100% human grade, which is why feed your babies, just food for dogs. It's good enough for big and smalls, my precious babies, so it's good enough for your babies. 100% human grade, real ingredients, beef, sweet potatoes, green beans, delicious.

These are foods that you would want to eat. Not that the babies would ever share. Just Food for Dogs is the number one bet recommended fresh dog food back by over a decade of research. No marketing fluff. My dogs lose their minds at dinner. They run to the bowl, tags wagging, paws tapping, full Broadway performance every single night. So I do care about the food I feed big and smalls. So go to just food for dogs.com for 50% off your first box, no code, no gimmicks, just real fresh food.

You're listening to a podcast. So you're doing something else too, like maybe scrolling home listings on Redfin, saving places you like without thinking you'll get them. Because that's what house hunting has become. But Redfin isn't built for endless browsing. It's built to help you find and own a home. home. Redfin agents close twice as many deals as other agents, which means when you find a place you love, you've got a real shot at getting it. Redfin helps turn saved listings into real addresses. Get started at redfin.com. Own the dream. So I don't really remember being diagnosed because that

happened the day that I was born. The story goes that my parents got told by the doctor that they'd seen a swollen right foot on their new baby, and they wanted to check that out. So it's basically always been something that I knew was a part of my life that I understood was part of who I was. It didn't really register that not everybody spent that much time sitting in hospital waiting rooms or being weighed and measured. It didn't really mean very much to me, other than just that was what life was like. Of course, you'd go in and you get checked out for various things. As I got a bit bigger, I understood that it was genetic and I kind of understood

what that meant. But explaining that to other people was the bigger problem. I was wanted to try and explain it to other kids, but they for some reason just didn't have as much interest in what a gene was as I did. And that became clear as I got older that that was a bit weird. I missed quite a lot of school comparatively. In retrospect, I'm pretty sure it was very annoying for my family to have to schedule around on various medical appointments. But again, it was just something that happened. Of course, you go in and get your bloods taken, you go and get scanned for various things.

That was just the thing that always happened. But it was sometimes hard not to be a little bit self-conscious. I have one foot that's fairly swollen, and I felt quite aware of that and self-conscious of that. But other people sometimes didn't even really notice, to be honest. I sort of figured that out as I went along. Like my elbows don't go straight. They go off at an angle,

and nobody knows that at all, unless I deliberately point it out to them. So what scans were there exactly? I think it was mostly heart and kidneys. those are the big ones. Lots of hearing tests. My hearing is a bit dodgy. But the biggest thing was always about my growth pattern.

Every time I went in as a child, I would get put next to measuring tape on the wall. And the doctor would always sort of try and pull my head up a little bit to try and get a little bit of extra height on me and we'll make sure that I was standing up straight to the point where I occasionally had to yell that my feet were coming off the floor. It was actually one of the first.

of stranger things was that I would get my growth chart. And I could see that on the Turner's Syndrome growth chart, I was right at the top. I'm absolutely top 1% a giant among Turner's people. But then they do the same plot on a regular people graph. And suddenly I'm right down the bottom. I understood from that very early that my comparisons of looking around the Turner Syndrome clinic, waiting room where I'm very tall and almost everybody is shorter than me was very strange. Part of the reason for that is that as a child, I had growth hormone injections. So those are ones that you do every day. I think that started when I was about eight or nine. When I first started becoming notably smaller than my compatriots in my class at school.

Initially, my dad tried to do them for me while I was asleep. But apparently that didn't work And I was a complete brat about it. They have a lot of special kits that they use to try and make it more comfortable for children, especially people who aren't very keen on needles, which I want at that age. So they're like strange injector pens. And the one I had was almost like a gun. It was on a spring, and it made a huge noise whenever I pressed it. So that actually freaked me out more than just doing it myself.

So eventually, after a lot of annoyingness, I ended up doing my injections, which was a sort of single injection every day. And that was actually fine. I didn't really mind that so much in the end. It was more the logistics of it that were really irritating. So if ever you went away, then you had to take all your medication with you in a cooler bag and then putting it in the fridge. There was always a lot of staring when I had to go and put medication in the fridge

if I went on school trips as a child. I remember going on one where we was, I think we're in the Lake District somewhere and me having to do my injection at the end of the day, some of the kids were like staring around the door as I was trying to do it. That wasn't not great. When I got a bit older, the doctors started becoming very concerned about giving me what they call the normal experience of puberty. So they put me on HRT hormone replacement therapy,

a kind which includes giving you periods, which I could really have done without. Nobody needs that. But it was always, in retrospect, quite strange that nobody ever talked about that as an identity issue or even referred to it as an intersex condition. I actually figured that out as an adult.

Nobody said those words. It was quite strange in retrospect, especially because they were always very clear that I wouldn't have my own children, that that just simply wasn't a physical possibility for me. And you would have thought that there would be a little bit more about that, but apparently not. Then again, I guess it affects so many different potential things that it's quite difficult to explain that to children. And I do now as an adult really appreciate that.

So now my adult life is kind of, well, how many other things can it affect? Is this another thing that I need to worry about? Or do I need to get that checked out? Or do I need to consider this other thing? So currently I get scans of my heart and my kidneys regularly, but also bone scans because along with the lack of natural estrogen is problems with your bone density. And due to some other medical issues, I had to stop the HRT. I just recently had a bit of a concern that my parathyroid gland wasn't working right,

although apparently it's actually fine because I didn't know what a parathyroid gland was until then. And the other biggest things at the moment, I guess, are getting shoes that fit. foot and ankle is notably bigger than the other. So that's a bit of a pain. Though I'm very lucky and I can usually just about manage a pair that are officially the same size. But I do have to wear a support stocking, which is sort of a pressure sock. And that is a pain, especially when it's really hot. Because if I don't do that, then my ankle starts to swallow up and my foot swells up and it also sort of aches. So I do wear my sock. I guess

I'm almost certainly going to need a hearing aid at some point or another. If you go around a Turner Syndrome convention or a Turner Syndrome clinic waiting room, you will see lots of people with hearing aids. And I've sort of, I guess, accepted that. I guess that's most of my story. It's a strange one to think that your life is a story, because it really is absolutely everything to do with who I am and how I live. I don't know what it would be like to know.

not have that. And trying to explain that is a bit strange. But I hope that was helpful. There you go. That's the end of my story. Thank you so, so much, Katie, for taking the time to chat and for sharing your story with us and with everyone. Yeah, thank you. We really appreciate it. Hi, I'm Aaron Welsh. And I'm Aaron Allman Updike. And this is, this podcast will kill you. And today we're talking about Turner Syndrome. We are. I believe. believe that this is, it's not our first genetic foray. Nope. But I think it is of this season.

And it's definitely our first chromosomal one. Oh yeah, that's a good point. We've only done like single gene. I think so. I think, right? I don't know. It's almost like we should keep a list or something, Aaron. Yeah, this is going to be a very interesting one.

I don't know really anything. anything at all about the biology. And so I can't wait to ask you a thousand genetics questions. Oh, gosh. I can't wait to be like, I don't know the answer. But I'll try. So maybe before we do that, I think it's quarantini time. I think it is. What are we drinking this week? We're drinking nothing but nettie. And I love that I don't actually know what that means yet because I know it's about a researcher, but I haven't gotten to hear about her yet. Well, you will definitely get to hear about her. We named our drink after Nettie Stevens, who was not as involved in Turner Syndrome research, but was involved in uncovering what the X and Y chromosomes do. And

also she just, like, her story is so interesting and so inspirational. And so we just kind of wanted to pay tribute to Nettie. And what is in nothing to? And what is in nothing to? But Nettie. In Nothing But Nettie is gin, basil, some lemon, and cucumber. It's like very refreshing and delicious. I love it. It sounds phenomenal. We'll post the full recipe for Nothing But Nettie, as well as our non-alcoholic Plissy Barita on our website. This podcast Will Kill You com and all of our social media channels. We sure will. On our website, you can find a whole lot of stuff. We're not going to go through everything again. But I also just want to say real quick, because we've not been mentioning it, that we are always happy to receive firsthand.

So if you are interested in sharing one of your stories on a podcast, please reach out to us, preferably either through the contact form on our website or by emailing us directly at this podcast will kill you at gmail.com. Well, Erin, should we get started? On the biology of Turner Syndrome? Let's do it right after this break. Dinner shows up every night, whether you're prepared for it or not. And with Blue Apron, you won't need to panic order takeout again. Blue Apron meals are designed by chefs and arrive with pre-portioned ingredients, so there's no meal planning and no extra grocery trip.

There, assemble and bake meals take about five minutes of hands-on prep. Just spread the pre-chopped ingredients on a sheet pan, put it in the oven, and that's it. And if there's truly no time to cook, dish by Blue Apron meals are fully prepared. Just heat them in the oven or microwave, and dinner is ready. And here's the exciting news. Blue Apron no longer requires a subscription. You can order meals when you want them and skip when you don't without adding another recurring charge. Order now at Blue Apron.com.

Get 50% off your first two orders plus free shipping with code this podcast 50. Terms and conditions apply. Visit blue apron.com slash turrets. Terms for more information. Anyone who works long hours knows the routine. Wash, sanitize, repeat. By the end of the day, your hands feel like they've been through something. That's why O'Keeffe's Working Hands hand cream is such a relief.

It's a concentrated hand cream that is specifically designed to relieve extremely dry, cracked hands caused by constant hand washing and harsh conditions. Working hands creates a protective layer on the skin that locks in moisture. It's non-greasy, unscented, and absorbs quickly. A little goes a long way. Moisturization that lasts up to 48 hours. It's made for people whose hands take a beating at work, from health care and food service to salon, lab, and caregiving environments.

It's been relied on for decades by people who wash their hands constantly or work in harsh conditions because it actually works. O'Keefs is my hand cream of choice in these dry Colorado winters when it feels like my skin is always on the verge of cracking. It keeps them soft and smooth, no matter how harsh it is. outside. We're offering our listeners 15% off their first order of O'Keefs. Just visit o'Keef's company.com slash this podcast and code this podcast at checkout. A timeless wardrobe starts with pieces that are built well from the beginning. From the fabrics to the fit,

everything needs to last beyond one season. And that's how Quince approaches design. Quince has all the staples covered, from 100% organic cotton sweaters to premium denim made with stretch for all-day comfort and luxe cotton cashmere blends perfect for the changing seasons. The quality shows in every detail, the stitching, the fit, the fabrics. Every piece is thoughtfully designed to be your new wardrobe essential, and each piece is made with premium materials in ethical trusted factories and priced far below what other luxury brands charge. I recently got a pair of Quince's Bella stretch wide-leg jeans, and they are now in constant rotation. They are so comfortable. The fit is amazing. And they come in a bunch of different washes, so I'm about to go order some more.

Refresh your wardrobe with Quince. Go to quince.com slash this podcast to get free shipping on your order and 365 day returns, now available in Canada too. That's Q-U-I-N-C-E.com slash this podcast to get free shipping and 365-day returns. Quince.com slash this podcast. So Turner Syndrome, like we said at the top, this is a genetic condition. And in this case, Turner syndrome is a condition that results from the partial or complete loss of one X chromosome. So before I get into any of what that means, I want to first set up some definitions of things that listeners probably are familiar with, at least from our high school biology classes.

But that might have been a long time. So we'll go over it, shall we? Mm-hmm. So our X chromosome is one of our sex chromosomes. So what on earth is a sex chromosome? We'll start there. Essentially, our chromosomes, chromosomes in general, are conglomerations of our DNA and the proteins that our DNA wraps itself around. Humans, us, we have a total of 46 chromosomes, and each of these are present in pairs.

So we have 23 pairs of chromosomes. 22 of these pairs are what are called autosomes, and one pair is our sex chromosomes. We get one of each of these pairs from our parents, one full set of 22 plus one sex chromosome from the egg, and one full set of 22 plus one sex chromosome from a sperm. Those come together and, ta-da, a zygote is formed. we can look at chromosomes in humans by looking at what's called a karyotype. And this is a way of taking DNA from ourselves and literally like laying it out so that you can see them. It's very cool. If you haven't seen images since high school bio, we'll post them or you can Google it also.

And sex chromosomes in humans are our X and Y chromosome. They are called sex chromosomes because they enlargemonism. because they in large part are responsible for the initiation of sex determination. What that means is that our X and Y chromosomes are those that contain genes that result in the formation of our gonads and other reproductive structures. Sex determination is then furthered along during development by the production of sex steroids like estrogen and testosterone, which often come from our gonads. and then the development of secondary sexual characteristics.

So in humans, you can kind of think of it as like a three-step process of sex determination. And sex chromosomes are integral to that first step of the process. And because they are then resulting in the formation of these gonads, which produce sex steroids, they affect later stages as well. Cool. Mm-hmm. And everyone probably learned in high school biology that when it comes to sex chromosomes, XY equals male, and X, X, X, X, equals female. And that might have been the last of what we all

learned about sex chromosomes. So today we get to start the process in all of our brains of flipping that script, because as we'll talk a lot about, it's not that simple. It's not that simple. It never is on this podcast. It really is not. So what is Turner Syndrome then? Turner syndrome is what happens when an individual ends up with either an entirely or a partially missing X chromosome. And it turns out that when it's just a part of that X chromosome, it's often the tip of the short arm of the X chromosome, which as I'll talk about later is where many of the very important genes happen to sit. That's very interesting. Okay. I have a question already. Okay. Shoot. Give it to me. When it's completely missing, does there tend to be a pattern?

in whether it's missing from the sperm X or from the egg X? Great question. I think from what I read, it's more common that it's from the sperm X. So more commonly what you see is that the X chromosome that is present is from maternal DNA. Interesting. Yeah. And I don't think that we have a great idea as to why that is, at least not from what I read. Okay.

And what's interesting, too, is that this can happen both part of the way. of the X chromosome and an entire X chromosome being kind of left behind during the process of meiosis, which is formation of gametes, eggs, and sperm, or it can happen during mitosis. And what's very interesting is that Turner syndrome can also happen due to something called mosaicism. And this is when a fetus that becomes a human has multiple cell lines in their body. body. And this happens when during very early cell division in like a forming zygote, there is abnormal mitosis that results to some cells having, say, only one X chromosome and some cells having two X chromosomes. And so if you looked at the karyotype of this person, some cells would

have two X's and some cells would have XO or like just one X. Yeah. So the way that they tend to write these when you are writing out the result of a karyotype is someone with complete monosomy of the X chromosome with Turner syndrome would have the karyotype 45 comma X or 45 comma X it's sometimes written someone who was a mosaic could have the karyotype 45x in some of their cells and 46xx or 46x Y in other cells. Okay. So already, how interesting. Yeah. And so Turner's syndrome is not just one X. It's not just the mosaicism of two X's in some cells, one X and other cells. It's also X Y in some cells and X in others. Yes, it absolutely can be. Interesting. Yes. And I'll get into a little bit more, too, about the intricacies that might arise. when somebody might have that karyotype of 45x and 46xY because as it turns out it results in some

different organ structure that can have different effects down the line. Ooh, we'll get there. Whoa. Okay. Okay. Yeah. And those are not the only chariotypes that can exist. This again can be just from a partially missing or a structurally abnormal X chromosome. So you could have someone that is 46xx but missing part of that X chromosome. So really the the crucially. thing is that that part of the X chromosome is gone. Yep. Okay. So there's a lot of possibilities there.

Now, before we dive too deep into what this looks like or what this results in, I also want to make a quick disclaimer, especially for anyone who's going to go back and read some of the literature of Turner syndrome. And that is that in a lot of the literature, Turner syndrome is characterized as a condition of women and girls. And this characterization isn't entirely accurate, largely because gender is a social construct, and it's not the same thing as sex, which tends to be a biological characterization that is, in large part, as I said, driven by genetics and particular sex chromosomes. So the characterization of Turner syndrome as a condition of women and girls isn't accurate. On top of that,

I think that what conditions like Turner syndrome show us is that even this idea of sex as a binary of male and female isn't entirely accurate either. Our genetics are not nearly as black and white as what we learned in high school. And so some of the papers that I read referred to Turner syndrome rather as a condition that affects phenotypic females. That is individuals who have, especially at birth, a phenotype, a set of observable, often physical characteristics that make them be labeled as female. So just sort of throw in all that out there. Yeah. So what does Turner Syndrome look like or result in?

Unsurprisingly, given the variety of genotypes and karyotypes that I just discussed, there is a large amount of variation in what the phenotype can actually be. And what that means is that there's also a lot of variation in what the downstream affects or potential medical conditions that might come along with Turner syndrome are. And when you read back through a lot of the literature, especially as we get into what the epidemiology of Turner syndrome really is, there's also an important distinction to be made between people who might have a particular carotype, so a particular set of chromosomes, and whether people have any observable characteristics that are associated with Turner

Syndrome. So in more modern definitions, you have to have both the karyotype where you are missing part or all of an X chromosome in at least some proportion of your cells, as well as a couple in particular of characteristics that go along with Turner syndrome to actually meet the definition of Turner syndrome. Okay, so the number of individuals that might be missing that portion of the X could be higher than the number of individuals that are diagnosed with Turner syndrome. Absolutely, yes. Okay, do we know what that difference is?

It's a great question. I'll talk more about it in the current event section. The short answer is like, not really, no. Yeah, okay. That makes sense. Yeah. But we'll get there. But first, let's talk about what are those characteristics to add to this karyotype to then result in this diagnosis of Turner syndrome. The two main things that we see are short stature and gonadal insufficiency. So that means generally what's called primary amenorrhea, so not ever starting mencies or sometimes initiation of mencies that then over a couple of years

stops and results in what's called secondary amenorrhea, so no longer having periods after just a couple years. There are a lot of other things that can go along with this, like congenital heart defects and other heart conditions, kidney abnormalities, and a whole bunch of other things. And instead of just listing what they all are, what I want to do is kind of focus on those two in particular most common characteristics, the short stature and the gonadal insufficiency, what we know about why we see those characteristics, like as it relates to this missing X chromosome, and then in that process, we'll see what a lot of these other characteristic findings might be. Does that sound good? Mm-hmm. Yeah. Okay. Spoiler, we don't have all the answers to this. Like, by a long shot.

But the overall basis for a lot of the phenotypic characteristics, as well as some of the medical conditions that can arise with Turner's syndrome, is something called haplow insufficiency. What a great word. It basically just means there's not enough gene product being produced to preserve normal function. Okay. So we talked in some of our other genetics episodes like cystic fibrosis and sickle cell anemia about this idea of recessive genetic disorders. Like, you need two copies of an abnormal gene to actually have the disease because one copy that's normal gives you enough of whatever it is to, like, not have disease. So this is like, it's like that same idea except kind of different because it's L chromosome. It's like the same thing, but kind of different.

You know, I feel like it's a decent enough analogy. No, it is. It is. I'm with you. I get, but it's, I guess it's that it's dominant. Like you really do need two copies of some of these genes to not have problems arise. Yeah. So here's where it gets even more interesting because we're dealing with sex chromosomes.

In people who are 46XX, they obviously have two X chromosomes, which is twice as many as somebody who is 46xY would have. And as it turns out, the X chromosome is a gene-rich chromosome that has over a thousand genes on it, while the Y chromosome. has less than 200. So what happens in the bodies of people who are 46XX to prevent over expression too much of these 1,000 genes is that one of the X's is actually inactivated. It's turned off in the body cells, in the somatic cells, but not the gonadal cells in the ovaries, of people who have two copies of this X chromosome. This is a process that's called silencing or X inactivation.

But 15 to 25% of these 1,000 genes are not, in fact, silenced. And these genes are called escape genes because they escape inactivation or silencing. And these are the genes that we need and want to have two copies of in order to have enough gene product for normal function, in order to not have that. haplo insufficiency. And do you know where else many of these genes are located? On the Y, I'm assuming. On the Y chromosome. Isn't that so interesting? It is really interesting. So even though we don't necessarily know everything there is to know about these specific mechanisms of some of what we see in Turner syndrome, in general, it's these specific genes, many of which are located on the tip of the short arm of the X chromosome, that part that's often missing in

people with Turner syndrome. It's these escape genes that likely lead to many of the characteristics or conditions that we can see arise in Turner syndrome. That's fascinating. Okay, so what are these genes? Great questions. So glad you asked. Yeah. So out of all those genes, we actually only have one that we know for sure, that we have good evidence of the kind of exact effect that we see due to haploid insufficiency. That gene is called shocks, S-H-O-X, and this is a gene that is normally not inactivated on the X chromosome. It is present on both X and Y chromosomes, and it stands for short, stature, homeobox containing gene on the X chromosome. Shocks. Shocks. So this particular gene, shocks, is in a family of genes called homeobox genes,

which are really important genes, like a whole suite of them, that regulate really key developmental processes during embryogenesis, during the process of the formation of an eventual human. And in the case of shocks, this gene is expressed during embryonic development in very specific tissues, including on the first and second pharyngeal arches. Who cares what that is? But what those structures develop into in the fetus are the maxilla, which is the top part of your jaw, and the mandible, which is the bottom part of your jaw, as well as parts of your inner and outer and middle ear.

It also is involved in muscles that are involved in chewing and hearing. This gene is involved in your soft palate and a whole host of other skin. melitol areas, like in the legs, in the hands. So this is a big deal gene. And decreased expression of this one gene out of hundreds that are likely involved in particular is the most strongly and convincingly correlated with some of the characteristics that are often seen in Turner Syndrome. So we can talk about what some of those are. Yeah. They are things like developmental changes to the inner middle or outer ears. That can lead to things like having ears that are low set, so lower on the cranium than is typical, which can lead to things like chronic

ear infections, especially in childhood. Very commonly, either that process or other variability in the structure of the ear leads to some degree of hearing loss in people with Turner syndrome, which can manifest in a lot of different ways. It's usually not complete deafness, but varying degrees of different forms of hearing loss, interestingly. We also sometimes see things like scoliosis, as well as osteoporosis, though that one is multifactorial. And that's because of some of the effects of shocks on the development of the skeleton, as well as other variations in the growth of the feet or the ankles or the hands, many of which can be seen in Turner syndrome. It's so much. There are so many things. I know. There is also something that can be seen

quite commonly in developing fetuses that have Turner syndrome on ultrasound that's called a cystic hygroma. This is a collection of lymphatic fluid that often forms on the back of the neck and forms into this cyst. This process is likely due not only to shocks, but to potentially multiple genes that are related to lymphatic drainage. But in many cases, this cyst that's seen during fatal development resolves and can leave behind a more webbed-shaped neck. Okay.

So that's a feature that's associated with Turner Syndrome. It can also lead to a small mandible, so a slightly underdeveloped lower jaw, or an narrow palate on the roof of the mouth, which can sometimes lead to dental problems later in life. But probably the biggest and one of the singular defining features of Turner Syndrome that has been very strongly shown to be associated with insufficiency of this gene in particular is the short stature that we often see. In general, people with Turner Syndrome reach average adult heights that are about 20

centimeters shorter than average when compared, I should say, to people who are 46XX of their same ethnicity or race. Okay. And while there is obviously a very huge range of like full adult height, individuals with Turner syndrome often also show decreased growth trajectories, both during fetal development, as well as early childhood. So they can kind of fall off what we call their growth curves. but height, of course, is something that is multifactorial. It's not determined by this one specific

gene. So the other reason that people with Turner syndrome often don't attain as great of a height as would be predicted, like especially by their parental heights, is because of a lack of a puberal growth spurt. Why do we see the lack of a puberto growth spurt? Well, that's because of the effects of Turner syndrome on gonadal function. So let's get into that, shall we? Yeah, I'm excited about this. Me too. I love talking about gonads. So in the ovaries, X chromosomes are not turned off entirely. It's only in our somatic cells. It's not just certain genes in the ovaries. It's the entirety of the X chromosome. Both of them are supposed to remain active. So if someone has part or all of their X chromosome missing, even if it's only in the gonads, such as, for example, in the case of a

mosaicism, then there's going to be haploid insufficiency of genes involved in the function of the ovaries. We don't know in particular necessarily which genes these are, because it could be any of them. But what this leads to is the loss of oocytes or eggs in the ovaries at a much more rapid pace than is typical. And this, in turn, leads to changes in hormone secretions, specifically our sex steroids, because our ovaries are what is secreting those hormones that then talk to our brain, which secretes more hormones, to talk to various parts of our body to grow, especially during puberty. And also to do things like grow breasts, grow adult hair patterns, armpits, genitals, etc. and eventually begin ovulation and then menstruation in the case of ovaries.

So we first of all don't see this pubertal growth spurt. And most often we also don't see Menarch or the beginning of menstruation. Okay. So what about people who have a Y chromosome? How does this picture differ or how is it the same? Great, great question. So it can get fairly complicated. because there's a lot of potential ways that that karyotype can present where people might have part or all of a Y chromosome.

But what can often happen, especially if someone is a mosaic that is, say, 45x in some of their cells and 46xY in other cells, often will not form true ovaries, but will rather form testes that then remain in the abdominal cavity, rather than ending up in a scrotum because there generally is no scrotum. There is phenotypically female genitals. Okay, gotcha. And one of the big risk factors with this in particular is that when testicles remain in the abdomen, they're at higher risk of developing into certain types of gonadal cancers. Why is that? I think it in part has to do with temperature differences, but I'll be honest, I don't fully know.

It's very interesting. Okay. Yeah. And that's true across the board if testes are retained in the abdomen. It's not specific to Turner Syndrome. Okay. All right. But in all of these cases, when it comes to gonadal insufficiency, whether we're talking about ovaries that are not fully developed or we're talking about testes that might be retained or some combination thereof because that's also possible. One big potential consequence of this is infertility. And so then the need for assisted reproductive technologies if somebody

decides that they want to try and get pregnant later on. What would that consist of? Usually IVF and possibly with donor oocytes. It all just depends on what an individual's phenotype is and how much ovarian reserve they have, if any. Okay. Gotcha. Yeah. And I do want to emphasize that this is a condition that has a very wide spectrum of phenotype. So some people, about a third of people with Turner syndrome, do initiate menstruation spontaneously. But the majority of them do then enter the secondary amenorrhea at a much more rapid rate than is typical for menopause. Okay. I have a question about the proportions of different karyotypes. So like in terms of Turner syndrome and people with Turner syndrome, what proportion of them

are 45x, what proportion of them are, you know, have some mosaicism, what proportion of them have a Y chromosome? What does that breakdown look like? Love that you asked. In general, most papers that I read estimate 45 to 50 percent of people with Turner syndrome are 45X, that's their cariotype. About 20 to 30 percent of people have some kind of mosaicism, be that 45x with 46X or XX or XXY, 466.4.6.4.4.6. XXXY or et cetera, et cetera. There's a lot of possibility there. And then the rest have some other type of structural abnormality of one of those X chromosomes. Okay. So huge variation. Yeah. But wait, Aaron, there's more. Now, another very medically important condition that can

arise as a result of Turner syndrome. And I'll just preface saying we do not understand the exact gene underpinnings here are a variety of congenital heart defects. And this can really range. One of the most common is what's called a bicuspid aortic valve. This is the valve between your left ventricle and your aorta. And like all of your valves in your heart are pretty important, but this one's like very important. And it typically has three leaflets, but in a bicuspid valve, there's only two. That means that these two leaflets are under a lot more stress and that can lead to stiffness of these valves and then eventually insufficiency of this valve. Okay. Another condition that's even a little scarier is aortic root dilation, which means the root, the first part of the aorta as it comes

off of the heart. And as a reminder for all listeners, your aorta is what carries your blood to literally all the rest of your body. When this gets enlarged, And this enlargement makes it weaker. And this can then put you at risk for not only that aortic insufficiency where not enough blood is making it into your aorta to give blood to your body. But it also can put you at risk for aortic dissection, which is where the wall of the aorta comes apart. And that can be life-threatening. Yeah. Turner syndrome can also be associated with other abnormalities like co-archation of the aorta, which is where later on in the core.

the aorta kind of pinches in, like it's more narrow, which can lead to increased pressure in some spots and decreased pressure in others, so you're not getting like adequate blood flow to all of the body. And honestly, there's a lot of other potential congenital heart defects that can result as well. There's a few candidate genes that might be involved. And one paper that I read, which of course I will link to, really suggested that it's likely a two-step process, where there's likely genes that are involved, but then particular alleles that put you at higher risk for having these heart abnormalities. That makes sense. Yeah.

So it's not just a haploid insufficiency issue. But, yes, there's a lot of possibilities in terms of what the anomalies that we see in the heart can be. And so we don't have exact answers as to the cause. And that is true when it comes to a number of other phenotypic characteristics or medical conditions. that can be seen in people with Turner syndrome. I can go through what some of them are, but we really don't have as clear of an idea when it comes to these less common conditions or characteristics,

like what the genes are that are involved. Or largely, what kind of complex gene and hormonal interactions might lead to some of these. It's so incredibly complicated. It really, really is. It boggles the mind. So we can see things like, kidney abnormalities, and just like with heart anomalies, congenital heart anomalies, these

can really range in terms of what kinds of structural kidney changes that we can see. People with Turner syndrome often also tend to be at higher risk for autoimmune conditions, especially thyroid disease, but also inflammatory bowel disease and others. They tend to be at higher risk for hypertension, and there's some questions arising as to whether they are also at higher risk for diabetes. Seems clear that they are at higher risk for osteoporosis, which is largely hormonally as well as gene regulated, because estrogen is really important in healthy bone growth.

Yeah. And in some cases, individuals with Turner syndrome can have difficulties in visual and spatial processing or visual motor tasks that can make some aspects of academics harder in some cases. But in general, there's very rarely any kind of global developmental delay or global learning disabilities or anything like that, which is very interesting, especially when it compares to many of the other anniaploides or chromosomal genetic syndromes that we see. And I would say as well, there's a paucity of data on the potential psychosocial effects

of living with Turner syndrome. I'm sure the research has really only just begun. It barely exists. Okay, so I have a couple questions about treatment. Number one, gene therapy. Does it exist? Great question. I saw nothing in my research about gene therapy.

My guess is that it's largely because the shocks gene is the only one that we have pretty decent evidence of its effect. Whereas all of the rest of them, we're like, yes, we know that these like escape genes are potential targets, but we don't even know what they do yet. Right. Yeah. We don't want to just like throw a bunch in there and be like, maybe this is okay. Right. Exactly.

Okay. So then my other question is treatment in terms of timing. So a lot of the things you described happen during development while you're a fetus, while you're a fetus. Yeah. but not everything. And so how does treatment play into that? Such a great question. So when it comes to the things that might happen during development, like say cardiac anomalies, congenital heart anomalies, as of now, in general, we don't have much in the way of treatments. There may be some very rare times where people get heart surgeries in utero, but that's like very, very rare, right? So in general, the way that Turner syndrome, is dealt with in terms of treatment is twofold. There's two aspects of it that are often addressed during development if Turner

syndrome is diagnosed early enough. And that is the growth insufficiency, so short stature, as well as the gonadal insufficiency. And those are treated with initiation of growth hormone and then eventually addition of estrogen therapy. Okay. Now, the timing of those, very controversial. There are some societies that have like guidelines, but from what I read, we just don't have a ton of evidence as to like when really is the best time to initiate growth hormone and then add in estrogen, etc. Yeah.

Yeah. So, but those are the two things that like growth hormone has been shown to increase final adult height substantially. And the addition of estrogen reduces the risk of osteoporosis and can facilitate. the growth of secondary sexual characteristics, and importantly, does not seem to increase the risk of any cancers, which is always something we think about when it comes to estrogen. Right. Yeah. Now, the other thing that then we have to consider is the treatment of all of the other things

that might go along with Turner syndrome. And for those, it generally just comes down to whatever typical medical management of those would be. So if you have high blood pressure, you treat it like high blood pressure. Mm-hmm. Mm-hmm. But yeah. That's pretty much, I think, hopefully the biology of Turner syndrome.

There's a lot there. There really, really is, Erin. So I got to know, how did we find out about this? Like, how did we figure out that this was a condition when it can have such varied appearance? And then how did we figure out, like, what we know about it? Good questions. Good questions. I will do my best right after this break. Anyone who works long hours knows the routine. Wash, sanitize, repeat. By the end of the day, your hands feel like they've been through something. That's why O'Keefe's working hands hand cream is such a relief. It's a concentrated hand cream that is specifically designed to relieve extremely dry, cracked hands caused by constant hand washing and harsh conditions. Working hands creates a protective layer on the skin that locks in moisture. It's non-greasy, unscented, and absorbs quickly. A little goes a long way. moisturization that lasts up to 48 hours.

It's made for people whose hands take a beating at work, from health care and food service to salon, lab, and caregiving environments. It's been relied on for decades by people who wash their hands constantly or work in harsh conditions because it actually works. O'Keefs is my hand cream of choice in these dry Colorado winters when it feels like my skin is always on the verge of cracking. It keeps them soft and smooth, no matter how harsh it is outside. We're offering our listeners 15% off their first order of O'Keefs.

Just visit o'Keef's company.com slash this podcast and code this podcast at checkout. This is Bethany Frankel from Just Be with Bethany Frankel. Listen, I have a bone to pick with these dog food brands calling themselves fresh, natural, healthy. Sounds great, but a lot of these quote-unquote fresh dog foods in your fridge are not even 100% human grade, which is why feed your babies, just food for dogs. It's good enough for big and smalls, my precious babies, so it's good enough for your babies. 100% human grade, real ingredients, beef, sweet potatoes, green beans, delicious. These are foods that you would want to eat.

Not that the babies would ever share. Just Food for Dogs is the number one vet recommended fresh dog food back by over a decade of research. No marketing fluff. My dogs lose their minds at dinner. They run to the bowl, tags wagging, paws tapping, full Broadway performance every single night. So I do care about the food I feed big and smalls. So go to just food for dogs.com for 50% off your first box, no code, no gimmicks, just real fresh food. Texting privacy policy and terms and terms posted at textingterms.

Texting enrolls you for occurring automated text marketing messages. Message and data rates may apply or apply stop, opt out. Visit ISSA online for details. Excuse me, what do you do for a living? Weight tables? You like it? Not really. Do you work out?

Every day. Best part of my day. Would you like to get paid to work out? Are you kidding me? How? With ISSA, you could become a certified personal trainer in as little as six weeks. Once you're certified, you can start your own business. Work at a gym or just do it as a side hustle.

Some trainers are making as much as $100 an hour. A hundred bucks an hour. Yes, please. But how do I even find a job as a trainer? That's the best part. There's such a huge demand for personal trainers that ISSA guarantees you'll get a job. I'm in. How do I get started?

Just send them a text. Get your free personal training evaluation kit today. Just text, Jim, to 3232.32 right. now. Get certified in as little as six weeks and ISSA guarantees you'll get a job. Text Jim to 32 32 3232. Text Jim to 32 32 32 32 32 32 32 32. Jim to 32 32 32 32. At its core, the history of Turner syndrome is a story of chromosomes, specifically

the X chromosome. I mean, of course, there's more to it than that. There is Dr. Henry Turner, the Oklahoma physician that in 1938, first described some characteristics that were associated with the condition. There's the improvements in our understanding of genetics that allowed researchers to pinpoint the chromosomal cause in 1959, and there's the founding and growth of many Turner Syndrome organizations over the past 50 or so years that have done so very much in terms of education, access to treatment, and connecting affected individuals and families all over the world. But what I really want to dive into today is that

what came before all that, the story of this chromosome at the heart of Turner syndrome. Yeah. The X chromosome, like you said, Erin, is one half of the pair of chromosomes, the other being why, that we usually refer to as the sex chromosomes, because they're involved in the process that ultimately leads to the formation of sexual organs and other sexual characteristics. They're not the only things involved, of course, nor is sex determination the only thing they do, as we know. So how did we come to call these two chromosomes sex chromosomes? I don't know. How did the growing field of genetics uncover their functions and how has our understanding of sex chromosomes

changed since then? I want to dive into these questions about the history of sex chromosomes, and then I'll talk a bit about how Turner's syndrome was first discovered. People have always been obsessed with explaining why some people are born with testes and others are born with ovaries and all of the variation in between. And in the century leading up to the discovery of the X and Y chromosome, things like heat, the position of the fetus in the womb, and the types of food you ate were all contenders for what sex the infant would have, what venotypic sex the infant would have. There are countless other beliefs or explanations that emerged over the thousands of years since humans first thought to wonder about anatomical differences. And the vast majority

of these explanations tended to suggest that it was kind of these more external factors after conception that made all the difference. Sex was pliable. It could be influenced by things after conception. But humans only began to get a peek at the complex internal processes that go into determining what we call biological sex at the end of the 19th century beginning of the 20th, when the X and Y chromosomes were first discovered. And even then, it would take a bit of time before this explanation of chromosomal sex determination was widely accepted. This was the end of the Victorian era, which was a period marked by strict gender roles, both privately and publicly. And so it may be kind of surprising to learn that during that same time, scientists studying sex saw it as a spectrum, as extremely

complicated and not necessarily a discrete binary trait. And this view is reflected in how these researchers thought sex was determined, which was, like I said, largely through these sort of external factors affecting the embryo or fetus rather than something that was determined at fertilization. For instance, did the egg come from the left or the right ovary? How old was each parent? What time of day did fertilization happen and what was the temperature? What did you eat? Like all of these things. And the research that many early embryologists and physiologists were doing at the end of the 19th century supported this notion that sex was highly flexible. Sex ratios of certain insects varied under certain environmental conditions.

and studies of sex hormones in birds and rodents showed that sex or sex characteristics could be modified after fertilization occurred. I love talking about sex in other animals. I know. I think that we need to devote an episode to that somehow. Oh, it would be so fun. It would be so fun. And this idea that sex was a plastic, changeable trait influenced by both the internal and external

environments led to the, quote, metabolic theory of sex, put forth by Patrick Gettys and J. Arthur Thompson in their 1889 book, The Evolution of Sex. Essentially, the idea was that females of a species should have a higher metabolic rate due to the increased demands of producing large gametes, eggs, while males of a species would have lower metabolic demands because their gametes, sperm, weren't as energetically costly to produce. And this fed into the concept that during times of scarcity, more males would be produced, while during times of plenty, more females would be. And that actually is, at least in part, what seems to happen in some species, I think insect species, not what happens in humans necessarily, as far as I think we have

learned at this point in 2022. But the metabolic theory of sex predominated for a few decades from around when it was introduced in 1889 or so until the 1920s. What ended up dethroning it? Chromisms. Oh. Before we get into the how and why of when chromosomes were recognized to be major players in sex determination, let's take a step back to get some broader context in what was going on in the world of genetics or evolutionary biology at this time.

And this is fun because I don't think, like I've done a whole lot of context setting for like germ theory and antibiotics and all the infectious disease stuff we cover, that I don't think I've really done it as much for like evolution? I don't think so. Yeah. Okay. Well, if it's a repeat, apologies and hope it's okay. If it's a repeat, we don't remember, so like no one else does either. Yeah. Yeah. Good. So as we know, the 19th century was a tremendous time of change and progress in really all fields of science. We've talked on this podcast in depth about things like physics, about things like the revolution that was germ theory. Microscopes and medical measuring devices were changing the way that we saw both health and disease,

and natural historians were traveling all over the world and returning home to fill the halls and basements of museums and their own private collections with specimens from every continent. One of these natural historians, by the name of Charles Darwin, came back with more than just an outrageous number of plants and animals. He also brought back with him an idea that would change the way we looked not just at ourselves, but at all life on Earth. His idea, which took him a few years to write up and publish, was the theory of evolution by natural. selection. The individuals of a species that are more fit for their environment are more likely to survive and reproduce, and their offspring will inherit those traits that made their parents more fit.

In this way, species change over time in relation to their environment, all components of it. As you probably already know, this idea met with a lot of resistance when it was first introduced, with critics calling it sacrilegious or just bad science. But over the next few decades, Research uncovered more and more evidence in support of Darwin's idea, and many scientists turned towards working out the details of how evolution actually happened, rather than trying to disprove it. And one of the key questions that remained about the process of evolution was how the information got passed from parent to offspring.

What was the information actually made of, and where was it located? Fortunately, microscope technology could step up to prevent. some tentative answers. I love this. Just like the intersection, the, yeah, the combining of these different fields. Love it. So while Darwin was looking across eons of change, other researchers were a bit more microscopically focused, literally, around the same time that Darwin was writing and rewriting and editing

and stressing out about On the Origin of Species, which was published in, 1859, another biological theory was gaining traction, the cell theory, which basically stated that the basis of all life is cells. All living things are composed of cells. Cells are the basic units of all living tissue, and all cells come from pre-existing cells. Of course, people had observed cells and used that name since around 1665, when Robert Hook first used that word to describe the little boxes he saw in a piece of magnified cork, since they reminded him of the rooms that monks stayed in, called cellular. Oh, my goodness. So that's where a cell comes from. I don't think I ever knew that. But over the next 200 years or so, microscope technology had advanced to the point where people could not only look at cells in a tremendous variety of organisms and tissues, but also within cells themselves.

identifying different components, making inferences about their functions, and observing the variety of processes involved in, like, day-to-day cellular activities, processes including cellular division via mitosis or meiosis. Researchers observed that the cells produced via meiosis were germ cells, so these sperm and eggs, and they were different from those produced during mitosis. And I'll get into that in a second. And in the 1890s, German physiologist August Weissman integrated Darwin's theory of evolution with cell theory, proposing that the recombination of the germ cells was how information from each parent was passed down to their offspring and that the recombination process introduced the variation that would allow for natural selection to act because there has to be variation for natural selection to act.

Oh, my goodness. It's beautiful. It's so beautiful. But still the question remained. Where is that information stored? Experiments in the 1880s demonstrated that it had to be in the nucleus, but in what form? How is it packaged? Chromosomes seemed a likely contender.

Okay. While early cell biologists were hunched over their microscopes watching these cells go through this beautiful dance of division, one in particular, German cytologist Walter Fleming noticed something happening in the nucleus. He wrote that he observed the separation and copying of, quote, threads in the nucleus during division. Ten years later, those threads would be designated chromosomes by Heinrich Waldier because they stained so easily. You could visualize them very well with staining. Wait, why does that mean chromosome? Chromo.

Oh, chromo. Oh, chromo. Yeah. Wow, I never got that. I never thought about it. Me neither. Okay, so chromosomes got the name because they were so easily stained. I love it.

And it turns out that mitosis and meiosis acted differently on these chromosomes. So mitosis is when a cell divides to produce two identical daughter cells, each containing two full sets of chromosomes. while meiosis produces four granddaughter cells, each with only one set of chromosomes. And so it stood to reason that these chromosomes contained in the nucleus with only one set present in germ cells could contain that hereditary information. And crucially, that information in the germ cells, those chromosomes would be passed down to offspring without the changes that would accumulate in the somatic cells. cells during an individual's lifetime. Basically making it actual evolution as we know it

rather than this Lamarckian passing down acquired traits during a lifetime type of thing. Yeah. Okay. Yeah. Okay. So it took some time for the role of chromosomes in genetics to be fully embraced, but in the meantime, plenty

of researchers had turned their efforts to learning more about these mysterious threads and the things they do, including, possibly, sex determination. We're finally here. We come full circle. I haven't even mentioned Turner Syndrome in this yet, and it's still going to be a while.

It's still, it's so good, though. Okay. In 1891, a researcher named Herman Henking observed a strange extra chromosome, question mark, in the sperm of the fire wasp. At least he thought it was a chromosome. He also thought it could be a, quote, peculiar chromatine, element or the quote X element. Ooh.

Mm-hmm. People debated what this X element might do, but generally the consensus was dismissal. It was a degenerate was the word they used, chromosome, that was at the end of its evolutionary history and had little to no function. Huh. And for a few years, that was the end of it. Until around 1902, when a PhD student at the University of Kansas named Clarence McCorme. clung, found a, quote, peculiar nuclear element that he ended up calling the accessory chromosome

in the sperm of some locusts. He commented on the similarity between what he found and what Henking had found and suggested that this was not some crumbling chromosome at the end of its life, but rather a fully functional chromosome that played a role in determining sex, since he observed its presence in some sperm but its absence in others. quote, a careful consideration will suggest that nothing but sexual characters thus divide the members of a species into two well-defined groups, and we are logically forced to the conclusion that the peculiar chromosome has some bearing upon this arrangement. Huh, interesting. At the time, this was a very bold claim.

Chromosomes were generally thought to be the heritable units in the germ cells, and that each one was probably responsible for some traits, but the metabolic theory of sex, where sex was more pliable and could be changed after fertilization, that's still predominated. McClung himself didn't really pursue the idea any further, but other researchers certainly did. Two, in particular, would be instrumental in demonstrating that these accessory chromosomes played a role in sex determination,

And it seems like it's only recently, really, that one has gotten the credit she deserves. The same year that McClung published his hypothesis, 1902, Nettie M. Stevens, who was at Brynmar College and Edmund Wilson at Columbia University, both began examining this accessory X chromosome, mostly using insects. I feel like insects were always being used. They're fascinating. There's just such variation. Yeah. Plus, they're so easy to raise. Yeah. Histories of the X chromosome or sex determination by chromosomes often credit Wilson or even Thomas Hunt Morgan, who was also at Bryn Mawr with Stevens, with making the connection between X and sex.

While Nettie Stevens is included often as a footnote, or maybe worse, as just providing supporting evidence of Wilson's claims. But closer examination of the timeline of events. shows that Stevens should not only be recognized for being the first to demonstrate chromosomal sex determination, but also for her many other important contributions to the field of genetics, such as, I don't know, discovering the Y chromosome. Kind of a big deal. Kind of a big deal. I think Nettie Stevens' story is fascinating, and so I just want to talk a bit about it

before getting back to this history of discovery. I love it. Can't wait. Nettie Stevens was born in Vermont in 1861 and went to school to become a teacher, which is what she did for a number of years. Somewhere along the way, though, she became fascinated with biology. And so she saved up money from her teaching jobs to go to Stanford University. Wow. She was 35 when she enrolled and 38 when she graduated with her bachelor's.

I love her already. I know. I mean, I'm 35. the thought of going back to school, it's difficult. Like, it's really hard to get that motivation and that, yeah. So it's amazing. I imagine in the 1800s, it would not have been easy either. No, exactly.

That's what is so, it's unbelievable. The next year, she got her master's also at Stanford, and then went on to Bryn Mahr for her Ph.D., which she got at the age of 41. Wow. It is so inspirational. So it was, yeah, like 1902 when that happened. Wow.

At Bryn-Mar, first as a PhD student, during which she published nine papers, by the way. And then as a researcher, Stevens became fascinated by the fields of embryology, genetics, and cytology. Her postdoctoral fellowship allowed her to pursue independent research at Bryn-Mar while not having to teach. Wow. And it was during that fellowship. that she did the bulk of her groundbreaking work on sex chromosomes. Okay. Let me read to you part of the concluding paragraph of her 1905 paper

where she presented her findings about the common mealworm and sex determination by chromosomes. Quote, Since the somatic cells of the female contain 20 large chromosomes, while those of the male contain 19 large ones and one small one, this seems to be a clear case of sex determination. not by an accessory chromosome, but by a definite difference in the character of the elements of one pair of chromosomes of the spermatocytes of the first order, the spermatozoa, which contain the small chromosome determining the male sex, while those that contain 10 chromosomes of equal size determine the female sex. Right out. Just boom.

Done. Yep. So that was very strong supporting evidence. And around the same time, Wilson, Edmund Wilson, also published results that mirrored the findings of Stevens. But his conclusions about sex determination by chromosomes were undoubtedly influenced by her work. So one paper I went through like traced the footnotes and like the revision process of the paper and how like the things that he changed after her paper came out. It's just like all this stuff. Oh, how interesting.

It's really this paper was great. Yeah. And also his study system was one in which the male of the species has one fewer chromosome than the female. And so initially he was thinking it was more about dose rather than dominant recessive characteristics. Interesting. Yeah. And not to mention that even in that paper, he said, yeah, chromosomes probably play a role in sex, but it's more about metabolism. Yeah. I know. I mean, ultimately, the question of who guys. that's priority for a certain discovery is always a bit of a sticky one. And maybe it's more important not to say this person is first. No, this person is first. But to take a closer look at why there's discrepancy or why one person is given credit over the other. And I think it's safe to say that in Nettie Stevens case, her gender played a role. Despite her incredible accomplishments,

She was never given a faculty position. And while her colleagues recognized her brilliance, quote, of the graduate students that I have had during the last 12 years, I have had no one that was as capable and independent in research work as Ms. Stevens. I was in one letter of recommendation, I think, from Thomas Hunt Morgan. You mean Dr. Stevens. Dr. Stevens. Yeah, she's pretty sure a doctor at that point.

But a lot of these accolades, a lot of this praise was almost, almost always qualified by for a woman. Quote, I consider her not only the best of the women investigators, but one whose work will hold its own with that of any of the men of the same degree of advancement. I mean, tried but missed the mark. Yeah, it's, that's, I mean, it's like, that sucks, but that's the way it was. And so, but I think it is really important to acknowledge that. Yeah. Yeah. But I don't know. Also, in one paper I read about Nettie Stevens, the author pointed out that it was probably for the best that Thomas Hunt Morgan, who was also at Bryn Mawr and like a huge name in genetics, was initially so resistant to Stevens' ideas about the role of chromosomes in sex determination because if he had been more on board, his name would have been on all her papers and he probably would have gotten all the credit and her name would have been forgotten in time.

entirely. Wow. Interesting to think about. Yeah. Well, and then I think there's the trend that happens where if someone is very highly accomplished in a number of different fields, they tend to be given credit for things, even if they maybe didn't play the biggest role in it. In any case, I just wanted to spend a bit of time on this brilliant scientist who made so many incredible accomplishments in the field of genetics in such a short amount of time and during a time when, so many things were working against her. And she probably would have made many more if her life was not cut short, sadly, by breast cancer. She died at the age of 50, only nine years after finishing her PhD. Oh, my goodness. I know, I know. But the work by Stevens and Wilson greatly advanced our understanding of how chromosomes are involved in sex determination. But it would take a number of years before that idea was why.

accepted, due in part to just how much variation there is across the animal kingdom. Geneticists looking for a universal answer as to what determines sex, such as X, X, X, produces females and X, Y produces males, were continually thwarted by exceptions to that narrow rule. Some bird, sea urchin, and insect species, where females were X, Y, or ZW, and males were X, X, X, or Z, or insect species, where males were either XO or XY. I mean, the variation in these systems kept researchers from concluding definitively that these chromosomes were involved in sex determination. Huh.

And this is reflected by it taking until the 1920s for these chromosomes to be widely referred to as sex chromosomes. Interesting. Yeah. Up until then, they were known by a variety of names, including heterochromosomes and accessory chromosomes, idio chromosomes. Even when it became clear that sex determination was part of what these chromosomes did, some researchers rejected these labels partly because they weren't quite convinced that that was how it worked, partly because they felt that too much was still unknown about other processes of sex determination and the function of these chromosomes, and partly because

they felt that it was too simplistic and didn't capture the full spectrum of sex. It terms of sex into a binary. And I'm going to come back to this aspect of sex and sex chromosomes in a bit, but for now I want to turn briefly towards the actual topic of today's episode, Turner Syndrome. Or should I say Ulrich Turner Syndrome? Perhaps. The first half of the 20th century saw continued interest in sex chromosomes and genetics, as well as another rapidly growing field, that of endocrinology. So around the same time that people were debating what to call the X and Y chromosomes, other researchers were busy characterizing hormones, particularly the ones that seem to play a role in the development of secondary sexual characters.

For example, these hormones that you mention air in estrogen and testosterone, right? Henry Turner, an Oklahoma physician, was one of these early endocrinologists, and he would frequently be asked to consult on cases where people were suspected to have different hormone levels or a different hormone functionality. Throughout the 1930s, he noticed in seven of his patients that were assigned female at birth what he thought might be a previously undescribed hormonal condition that led to a suite of physical characteristics, including short stature, cubitus valgus is like one thing that he pointed out, which is that that extra angling of the forearm at the elbow, and underdevelopment of sexual organs and secondary sexual characteristics. And in 1938, he published case summaries of these seven individuals and suggested that this was a newly described condition that was likely caused by a hormonal imbalance. He tried pituitary growth hormones to no avail and anterior pituitary gonadotropic hormone to some avail.

I don't know what that hormone actually was. I don't know. It might have just been growth hormone. Yeah. Yeah. He was right that it was a condition with one specific cause, which is what ultimately ended up making him the namesake of Turner's syndrome, and that hormones were involved. But he was wrong about it never having been described before. Remember how I called it Ulrich Turner Syndrome?

You might have seen that places? Sure did. Turns out, a German pediatrician named Otto Ulrich had actually published a case study of an eight-year-old with the same suite of characteristics that Turner had described, but eight years before Turner's paper came out. Oh. Mm-hmm. With Ulrich and especially Turner's work, there was now a clinical description of this condition. But the ultimate cause remained a mystery for a couple of decades. Was it hormones?

Was it something else? Like where did this? How did this happen? And it was only in 1959 that genetic technology and imaging had advanced to the point where researchers Ford at all were able to link cases of Turner syndrome with the presence of only one X. Wow. That's a long time. It's a long time. I mean, it makes sense, I guess, in terms of,

of technology and our understanding of chromosomes and how everything worked and being able to actually work with them. Right. And like karyotype enough people or individuals and things like that. Yeah, exactly. Side note. Remember the person that Ulrich described in his case report, the eight-year-old? Yeah.

So a couple of researchers followed up in the 1970s and confirmed just one X. Wow. That's kind of cool. Isn't that cool? Yeah. In the year since the 1959 paper showing that a single X was at the root of Turner syndrome, we've learned so much more about it, including the fact that it isn't always a whole X missing, right?

You talked about Aaron. Which specific genes might be involved and what types of treatments seem to be helpful. And right alongside that, we've been expanding our view of sex overall. The X and Y for humans, I think, provides this enticingly. simple binary picture of sex. X, X, X means female, X, Y means male. But obviously there's much more to it than that. And I think it's important to remember that there are so many different ways you can categorize sex. And some categories might be discrete. Others are continuous. And none are binary. Yeah. Chromosomal sex, gonadal sex, hormonal sex, genital sex, sexual identity, to name just a few.

The diversity of sex in humans alone is amazing, and I didn't even talk about other animals. For instance, like I mentioned earlier, instead of this XXXY system that we're familiar with, some birds and other organisms have a ZZZZW system, where ZZ develops as male, ZW is female. There are also systems that don't just use this master switch on the distinct chromosome, like the SRI on the Y chromosome to kick off the sex determination process, but also use genes on autosomes. Yeah. The non-sex chromosomes that are involved in this process. And then there's so many animals, too, that can switch sex during their lifetime, like well after development.

Like, what? And for some, like, environmental factors play a huge role, temperature, stuff like that. It's like it's not ridiculous. Like the metabolic theory of sex works. It's just there is, is there an overarching theory of sex and how sex determination works? I don't think there is. Does there need to be? Isn't that sort of the beauty of it all?

But it's fascinating. I mean, there's like I am going to link to some papers because don't you want to know more about species that have lost the Y chromosome entirely or those that have. have evolved to have another type of X. Yep. Read about the African pygmy mouse with the XYW system. What? What? What?

I know. The variety in this is it's just, it's beautiful. It's breathtaking. And I'll link to a few papers on our website that go into these examples so you can read more and get hyped also about the diversity of sex. I especially recommend Moore and Roberts from 2013 titled Polygenic Sex Determin. nation. It's a really well-written, accessible, fascinating paper. And there's so much more that we could talk about in terms of sex and sex chromosomes. But I have to stop somewhere because otherwise I will

never stop ever. So what I want to do is I want to ask listeners to send in your favorite sex chromosome trivia in all the different animals and then hand it off to you, Aaron. So tell me where do we stand with Turner Syndrome today? Oh, I can't wait to. But also, Aaron, that's how we make our whole episode about sex chromosomes as we just share listener facts. I love it. Actually, I love that a lot. But I'll get into the what we know about Turner Syndrome today right after this break. Most of the papers that I read cited relatively similar statistics, which is interesting, especially in the context, as we'll learn that like, we don't know. These are estimates. We never know. We never know. That's the theme of this section. But in general, the estimate is about one in 2000 phenotypically female live births result in Turner syndrome.

Another way to enumerate that, although it's looking at the literature a little bit more problematic, is that about 50 to 60 of every 100,000 adult, the literature says, adult women, have Turner syndrome. Okay. Right? So rare, but not that rare, really. It's like one of the most common, if not the most common of sex chromosome anomalies, right? Absolutely, 100% yes. Okay. Now, we don't have information on what the variation is globally in different populations and different regions, largely because we just don't have data for most of the world to be able to say, like, these regions have higher or lower incidence of Turner syndrome.

But what's interesting about Turner Syndrome is looking at the time frame of diagnoses, I think, because there are three main peaks of when people are diagnosed. It can be diagnosed prenatally via genetic testing, amniocentesis, things like that. And so some percentage of people, and I don't have an exact number on this, are diagnosed very early, like before birth even, potentially. And then there's usually a second peak of, people being diagnosed not until young childhood when they fall off their growth curves. And then pediatricians are like, hmm, let me think, look at these other characteristics, perhaps we should get

a karyotype. Okay. And especially through adolescence, when people perhaps have primary amenorrhea and present, you know, in teen years having no period and then get worked up. And then the last peak might not come until adulthood when someone might be diagnosed because they're struggling with infertility. Interesting. Okay. And it's estimated that potentially up to 20% of people may never be diagnosed. And the reason that this is important is because it kind of gets back to like what is the definition of Turner syndrome. Yeah. Right. If you are never diagnosed with Turner syndrome, do you have Turner syndrome and are just undiagnosed? Or do you not actually have any of these phenotypic characteristics of Turner syndrome. Therefore, you might have this

karyotype, but you don't actually have Turner syndrome. And that's kind of like a, I don't know, a philosophical question. Right. Well, but I think it's also a clinical question, too. It is a clinical question, definitely. Where we get this 20% number is from some studies that have been done like in Great Britain and a few other countries that have looked at karyotypes of people across the board and found a much higher prevalence of Turner syndrome than would be expected. Mm-hmm. So under diagnosis, essentially. Now, another thing that I think is important to note because it's really fascinating and gets to a lot of what you were talking about, Erin, on just how interesting sex chromosomes are, is that it's actually very rare to be born with Turner syndrome, especially with a 45x chariotype. So those numbers that I just cited, one in 2,500, not that rare. And 45 to 50% of those people are 45X. But it's estimated that up to 99% of fetuses with a carriotype of 45X actually result in spontaneous abortion, i.e. miscarriage or early pregnancy loss.

That's very interesting because, yeah, you're right. It's common, but also extremely rare. Right? And it's also important to note, because fascinating, that I am fairly positive. positive that Turner syndrome, especially as 45X, is the only known survivable monosomy, where you have a complete absence of one chromosome. The complete absence of any of the other sets of chromosomes results in a non-viable fetus. Wow. There are partial monosomies like Cretus shot, there's 17Q12 microdilations, there's other types of chromosomal anomalies, and of course there are various

is a number of which are compatible with life. But 45XO is the only one with an entirely missing chromosome that's compatible with life, which is pretty incredible. And there is actually some suggestion that perhaps those fetuses that do survive might have some degree of mosaicism that we're just not detecting. But so far, there's not a lot of evidence to actually like confirm that hypothesis. Right. So, Suffice to say, there are a lot of areas that are ripe for research. So many. There are a few really great papers that I will direct to that have a lot more detail on kind of what,

especially the medical community thinks are the greatest needs when it comes to research on Turner Syndrome. But a lot of it is, like, we need to understand the true genetic mechanisms underpinning a lot of the conditions that we see. We don't have all that information. We need better evidence-based guidelines for care because, like I said earlier, we have guidelines, but we need more evidence to support those, of course. And I think that we also need a much better understanding of how people living with Turner Syndrome are doing, psychosocially, emotionally, physically. Like, there's a lot to be said, and we've talked about this in a lot of our genetics episodes about involving people. living with these conditions in the research, not merely as subjects of research. So, yeah, that is Turner's syndrome.

There's a lot. I think I've already said this, but there's just so much there. It really does. One of the things that really excites me about this is just talking about the variety inherent in sex chromosomes and sex determination, because it is so much more interesting than the black and white that we learned in school. Right. I mean, the black and white, we learned that way because it's convenient, right? It's not accurate. Right. And you're missing out if that's how you're looking at sex. Is this irreversible constant thing. Like, there are so many different ways to define it. It's really cool. It's really cool. And yeah, I think it also makes us think that there is one thing that is normal and the rest of everything outside of that is abnormal,

which isn't the case. There's a lot of variation in what can happen during the process of development, during the process of cell replication and division. Like, it's awesome. It is. So. So, sources? So, so everyone can read some more. Let's do it. I have several. I'm going to shout out a couple that I found super helpful. One is by Abbott at all from 2017 about the history of sex chromosome discovery. A paper by Brush 1978 about that was the one about Nettie Stevens. It's a great paper. And then also I got some info from a book by Sarah Richardson and called Sex Itself. And then finally, I just want to shout out again that great paper by Moore and Roberts from 2013 called polygenic sex determination. I had a number of papers a couple of my favorites that are more

recent. One was Turner Syndrome mechanisms and management from Nature Reviews Endocrinology 2019. And another was the changing face of Turner Syndrome from Endocrine Reviews 2022. Both of those have a lot on like where we stand with Turner Syndrome, what we know and what we need to know. But we'll post the list of all of our sources from this episode and every episode. one of our episodes on our website. This podcast will kill you.com. Go check it out. I want to give a special thank you to Emily Moore, who helped me talk through this part of my history for this episode. You're the best. Thank you. And thank you again to Katie, the provider of our firsthand account. Thank you so much for sharing your story with us and all of our listeners.

I mean, we can't thank you enough. Thank you to Bloodmobile for providing the music. for this episode and all of our episodes. Thank you as always to the Exactly Right Network. And thank you to you, listeners. We hope that you liked this and that we did okay. Yeah, let us know one way or the other. Yeah. But I had a lot of fun.

I did too. And a special thank you to our patrons. Thank you so much for your support. It means the world to us. It really does. Okay, well, until next time, wash your hands. You filthy animals. This is Bethany Frankel from Just Be with Bethany Frankel.

Listen, I have a bone to pick with these dog food brands calling themselves fresh, natural, healthy. Sounds great, but a lot of these quote-unquote fresh dog foods in your fridge are not even 100% human-grade, which is why feed your babies just food for dogs. It's good enough for big and smalls, my precious babies, so it's good enough for your babies. 100% human-grade, real ingredients, beef, sweet potatoes, green beans, delicious. These are foods that you would want to eat. Not that the babies would ever share. Just Food for Dogs is the number one

vet recommended fresh dog food back by over a decade of research. No marketing fluff. My dogs lose their minds at dinner. They run to the bowl, tags wagging, paws tapping, full Broadway performance every single night. So I do care about the food I feed big and smalls. So go to justfoodfor dogs.com for 50% off your first box. No code, no gimmicks.

Just real fresh. Why have I asked my age-fat guy I found on Angie.com to change my grandpa's trachea tube? Because I was so amazed by how quickly he replaced our air ducts. I knew I could trust him to change Pop-Pub's tube while I was on vacation. Make a quick, young man. Aw, see, Pop-P trusts you. I think we should call it doctor. Connecting homeowners with skilled pros for over 30 years.

Angie, the one you trust, to find the ones you trust. Find pros for all your home projects at Angie.com. Success starts with your drive, and American Public University is here to fuel it. With affordable tuition and over 200 flexible online programs, APU helps you gain the skills and confidence to move forward. Whether you're changing careers, starting fresh, or pursuing a lifelong passion,

our programs are designed for people who never stop. You bring the fire, APU will fuel the journey. Learn more at APU. U.S.edu.