Ep 106 Turner Syndrome: Let's talk about X

in hospital waiting rooms for being weigh and measured. It didn't really mean very much to me other than just that was what life was like. Of course, you 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, you know, 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 have 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 thought 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, and I sort of figured that out as I went along, Like my elbows don't go straight, they go off at

an angle. And knows that at all unless I deliberately point it out to them. So what scans were there exactly?

off the floor. It was. It was. Actually one of the stranger things was that I would get my growth chart and I could see that on the Turner Syndrome growth chart, I was right at the top. I'm absolutely top one percent, a giant among turn of people. But then they'd do the same plot on a regular people graph, and suddenly I'm right down the bottom. I understood from that very 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 very well, and

I was a complete brat about it. They have a lot of special kit that they use to try and make it more comfortable for children, especially people who aren't very keen on needles, which I wann't at that age. So there's like strange injector pends, and 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 I eventually, after a lot of annoying this, I ended up doing my own injections, which was a sort of single injection every day, and that was actually fine. I don'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 was not great. When I got a bit older, the doctors started becoming very concerned about giving me what they called the normal experience of puberty, so they put me on HRT homeown 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 respect, 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 check 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 of the medical issues, I had to stop the HRT. I just recently had a bit of a concern that my parathyroid land wasn't working right, although apparently it's actually fine because I didn't know what a paradyeroid gland was until then. And the other biggest things at the moment, I guess

are getting shoes that fit one foot. An 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 of 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 and my foot saws 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 that your life is a story, because it really is absolutely everything to do with with who I am and how I live.

I don't I don't know what it would be like to not have that, and trying to explain that is a bit strange.

our sex chromosomes. So what on earth is a sex chromosome? We'll start there. Essentially, our chromosomes, chromosomes in general, our conglomerations of our DNA and the proteins that our DNA wraps itself around humans us we have a total of forty six chromosomes, and each of these are present in pairs, so we have twenty three pairs of chromosomes. Twenty two 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 twenty two plus one sex chromosome from the egg, and one full set of twenty two plus one sex chromosome from a sperm. Those come together and toda, 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 our cells 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 will 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, 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 go ads,

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 goads which produce sex steroids, they affect later stages as well.

Cool mm hm. And everyone probably learned in high school biology that when it comes to sex chromosomes, X y equals male and xx 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.

has multiple cell lines in their 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.

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 throwing all that out there. Yeah, So

what does Turner syndrome look like or result in? Unsurprisingly, given the variety of genotypes and caryotypes 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 effects 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 carriotype, 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 caryotype 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.

a couple of 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 gonatal 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? 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 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 celenemia 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 chromosome and.

six X Y 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 two hundred. So what happens in the bodies of people who are forty six XX to prevent over expression too much of these one thousand genes is that one of the xes is actually inactivated. It's turned off in 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 fifteen to twenty five percent of these one thousand genes are not in fact silenced, right, And these genes are called escape genes because they escape in activation 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.

X chromosome shocks SHOCKS. So this particular gene SHOCKS is in a family of genes called homabox genes, which are really important genes, like a whole suite of them that regulate really key developmental processes during embryo genesis, 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 skeletal areas 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 completeess 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.

People with Turner syndrome reach average adult heights that are about twenty centimeters shorter than average when compared I should say to people who are forty six x x 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 pubertal growth spurt. Why do we see the lack of a pubertal growth spurt. Well, that's because of the effects of Turner syndrome on gonadal function. So let's get into that, shall we.

We don't know in particular necessarily which genes these are, because 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, et cetera, 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 menarc or the beginning of menstruation.

Y chromosome. But what can often happen, especially if someone is a mosaic that is, say forty five x in some of their cells and forty six x Y 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.

in the abdomen, it's not specific to Turner syndrome. Okay, yeah, 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, gotchyah, 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 this secondary amnareea at a much more rapid rate than is typical for menopause.

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 treface 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.

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 aorda 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.

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. Like not just yeah, so it's not just a Haflo 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.

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 annuploides 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.

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. 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, win really is the best time to initiate growth hormone and then add in estrogen,

et cetera. Yeah, yeah, so, but those are the two things that 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. But yeah, that's pretty much I think, hopefully the biology of Turner syndrome.

with the condition. There's the improvements in our understanding of genetics that allowed researchers to pinpoint the chromosomal cause in nineteen fifty nine. And there's the founding and growth of many Turner Syndrome organizations over the past fifty 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 what came before all that, the story

of this chromosome at the heart of Turner syndrome. Yeah, the X chromosome, like you said, Aaron is one half of the pair of chromosomes, the other being why that we usually referred 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?

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 externsnal 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 peak at the complex internal processes that go into determining what we call biological sex at the end of the nineteenth century beginning of the twentieth 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.

or fetus, rather than something that was determined at fertilization, for instance, did the egg come from the.

seems to happen in some species, I think insect species, not what happens in humans necessarily, as far as as far as I think we have learned at this point in twenty twenty two, but the metabolic theory of sex predominated for a few decades from around when it was introduced in eighteen eighty nine or so until the nineteen twenties.

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 provide some tentative answers.

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 use that name since around sixteen sixty five, 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 cellula.

cells produced vamosis were germ cells. So these spur and eggs, and they were different from those produced during mitosis. And

I'll get into that in a second. And in the eighteen nineties, German physiologist August Weismann 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 act.

in the nucleus during division. Ten years later, those threads would be designated chromosomes by Heinrich Waldyer because they stained so easily you could visualize them very well with staining.

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 during an individual's lifetime, basically making it actual evolution as we know it, rather than this Lamarchian 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. I know we're finally here, we come full circle. I haven't even mentioned Turner syndrome in this yet, and it's still gonna be a while. But still it's

still good though, Okay. In eighteen ninety one, a researcher named Hermann 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 chromatin element or the quote X element. 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, and for a few years. That was the end of it until around nineteen oh two, when a PhD student at the University of Kansas named Clarence McClung 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 Hanking 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.

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 nineteen oh two, Nettie M. Stevens, who was at Brinmar 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.

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 Stephens' story is fascinating, and so I just want to talk a bit about it before getting back to this history of discovery.

her groundbreaking work on sex chromosomes. Okay, let me read to you part of the concluding paragraph of her nineteen oh five paper where she presented her findings about the common meal worm and sex determination by chromosomes.

size determined the female sex.

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 twelve years, I have had no one that was as capable and independent and research work as miss Stevens. I was in one letter of recommendation, I think from Thomas Hunt Morgan.

have gotten all the credit, and her name would have been forgotten entirely.

even if they maybe didn't play the biggest role in it. So, 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 fifty, only nine years after finishing her PhD.

variation there is across the animal kingdom. Geneticists looking for a universal answer as to what determined sex, such as XX produces females and xy produces males, were continually thwarted by exceptions to that narrow rule some bird, sea, urchin, and insects species where females were x y or ZW and males were xx or zz, or insect species where males were either xo or x y.

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 turned 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 Ulric Turner syndrome. M Perhaps the first half of the twentieth century saw continued interest in sex chromosomes and genetics as well.

that you mentioned aaron, estrogen and testosterone right. Henry Turner, an Oklahoma physician, was one of these early endochronologists, 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 nineteen thirties, 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 extra angling of the forearm at the elbow and under development of sexual organs and secondary sexual characteristics.

And in nineteen thirty eight 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 gnatotropic hormone to some avail. I don't know what that hormone actually was that was in the paper.

enticingly simple binary picture of sex. XX 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 discreete. 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 the thisxxy system that we're familiar with, some birds and other organisms have a ZZZW system where zz develops as males zws female. There are also systems that don't just use this master switch on the distinct chromosome like the SRY on the Y chromosome to kick off the sex determination process, but also use genes on autosomes, the non sex chromosomes that are involved in this process.

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 births 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 adolescents 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.

be expected m hm, so underdiagnosis 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, Aaron on just how interesting sex chromosomes are, is that it's actually very rare to be born with

Turner syndrome, especially with a forty five X caryotype. So those numbers that I just cited, one in twenty five hundred not that rare, and forty five to fifty percent of those people are forty five X. But it's estimated that up to ninety nine percent of fetuses with a kareotype of forty five X actually result in spontaneous abortion, i e. Miscarriage or early pregnancy loss.

a number of which are compatible with life. But forty five XO 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 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 syndrome.

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