Speaker 1: So I don't really remember being diagnosed, because that happened
Speaker 1: the day that I was born. The story goes that
Speaker 1: my parents got told by the doctor that they'd seen
Speaker 1: swollen right's foot on their new baby, and they wanted
Speaker 1: to check that out. So it's basically always been something
Speaker 1: that I knew was a part of my life, that
Speaker 1: I understood was part of who I was. It didn't
Speaker 1: really register that not everybody spent that much time sitting
Speaker 1: in hospital waiting rooms for being weigh and measured. It
Speaker 1: didn't really mean very much to me other than just
Speaker 1: that was what life was like. Of course, you go
Speaker 1: in and you get checked out for various things. As
Speaker 1: I got a bit bigger, I understood that it was
Speaker 1: genetic and I kind of understood what that meant, but
Speaker 1: explaining that to other people was the bigger problem. I
Speaker 1: was wanted to try and explain it to other kids,
Speaker 1: but they, for some reason just didn't have as much
Speaker 1: interest in what, you know, a gene was as I did,
Speaker 1: And that became clear as I got older that that
Speaker 1: was a bit weird. I missed quite a lot of
Speaker 1: school comparatively. In retrospect, I'm pretty sure it was very
Speaker 1: annoying for my family to have to schedule around on
Speaker 1: various medical appointments, but again it was just something that happened.
Speaker 1: Of course, you have you go in and get your
Speaker 1: bloods taken, you go and get scanned for various things.
Speaker 1: That was just the thing that always happened. But it
Speaker 1: was sometimes hard not to be a little bit self conscious.
Speaker 1: I have one thought that's fairly swollen, and I felt
Speaker 1: quite aware of that and self conscious of that, but
Speaker 1: other people sometimes didn't even really notice, to be honest,
Speaker 1: and I sort of figured that out as I went along,
Speaker 1: Like my elbows don't go straight, they go off at
Speaker 1: an angle. And knows that at all unless I deliberately
Speaker 1: point it out to them. So what scans were there exactly?
Speaker 2: I think it was.
Speaker 1: It was mostly heart and kidneys, those are the big ones,
Speaker 1: and lots of hearing tests. My hearing is a bit dodgy.
Speaker 1: But the biggest thing was always about my growth pattern.
Speaker 1: Every time I went in as a child, I would
Speaker 1: get put next to measuring tape on the wall and
Speaker 1: the doctor will sort of try and pull my head
Speaker 1: up a little bit to try and get a little
Speaker 1: bit of extra height on me, and we'll make sure
Speaker 1: that I was standing up straight, to the point where
Speaker 1: I occasionally had to yell that my feet were coming
Speaker 1: off the floor. It was. It was. Actually one of
Speaker 1: the stranger things was that I would get my growth
Speaker 1: chart and I could see that on the Turner Syndrome
Speaker 1: growth chart, I was right at the top. I'm absolutely
Speaker 1: top one percent, a giant among turn of people. But
Speaker 1: then they'd do the same plot on a regular people graph,
Speaker 1: and suddenly I'm right down the bottom. I understood from
Speaker 1: that very that my comparisons of looking around the Turner
Speaker 1: Syndrome clinic waiting room, where I'm very tall and almost
Speaker 1: everybody is shorter than me, was very strange. Part of
Speaker 1: the reason for that is that as a child, I
Speaker 1: had growth hormone injections, so those are ones that you
Speaker 1: do every day. I think that started when I was
Speaker 1: about eight or nine, when I first started becoming notably
Speaker 1: smaller than my compatriots in my class at school. Initially,
Speaker 1: my dad tried to do them for me while I
Speaker 1: was asleep, but apparently that didn't work very well, and
Speaker 1: I was a complete brat about it. They have a
Speaker 1: lot of special kit that they use to try and
Speaker 1: make it more comfortable for children, especially people who aren't
Speaker 1: very keen on needles, which I wann't at that age.
Speaker 1: So there's like strange injector pends, and one I had
Speaker 1: was almost like a gun. It was on a spring
Speaker 1: and it made a huge noise whenever I pressed it,
Speaker 1: so that actually freaked me out more than just doing
Speaker 1: it myself. So I eventually, after a lot of annoying this,
Speaker 1: I ended up doing my own injections, which was a
Speaker 1: sort of single injection every day, and that was actually fine.
Speaker 1: I don't really mind that so much in the end.
Speaker 1: It was more the logistics of it that were really irritating.
Speaker 1: So if ever you went away, then you had to
Speaker 1: take all your medication with you in a cooler bag
Speaker 1: and then putting it in the fridge. There was always
Speaker 1: a lot of staring when I had to go and
Speaker 1: put medication in the fridge. If I went on school
Speaker 1: trips as a child, I remember going on one where
Speaker 1: we was I think we're in the lake district somewhere,
Speaker 1: and me having to do my injection at the end
Speaker 1: of the day. Some of the kids were like staring
Speaker 1: around the door as I was trying to do it.
Speaker 1: That was not great. When I got a bit older,
Speaker 1: the doctors started becoming very concerned about giving me what
Speaker 1: they called the normal experience of puberty, so they put
Speaker 1: me on HRT homeown Replacement therapy, a kind which includes
Speaker 1: giving you periods, which I could really have done without.
Speaker 1: Nobody needs that. But it was always, in retrospect quite
Speaker 1: strange that nobody ever talked about that as an identity
Speaker 1: issue or even referred to it as an intersex condition.
Speaker 1: I actually figured that out as an adult. Nobody said
Speaker 1: those words. It was quite strange in respect, especially because
Speaker 1: they were always very clear that I wouldn't have my
Speaker 1: own children, that that just simply wasn't a physical possibility
Speaker 1: for me. And you would have thought that there would
Speaker 1: be a little bit more about that, but apparently not.
Speaker 1: Then again, I guess it affects so many different potential
Speaker 1: things that it's quite difficult to explain that to children,
Speaker 1: and I do now as an adult, really appreciate that.
Speaker 1: So now my adult life is kind of well, how
Speaker 1: many other things can it affect? Is this another thing
Speaker 1: that I need to worry about, or do I need
Speaker 1: to get check that checked out, or do I need
Speaker 1: to consider this other thing? So currently I get scans
Speaker 1: of my heart and my kidneys regularly, but also bone
Speaker 1: scans because along with the lack of natural estrogen is
Speaker 1: problems with your bone density. And due to some of
Speaker 1: the medical issues, I had to stop the HRT. I
Speaker 1: just recently had a bit of a concern that my
Speaker 1: parathyroid land wasn't working right, although apparently it's actually fine
Speaker 1: because I didn't know what a paradyeroid gland was until then.
Speaker 1: And the other biggest things at the moment, I guess
Speaker 1: are getting shoes that fit one foot. An ankle is
Speaker 1: notably bigger than the other, so that's a bit of
Speaker 1: a pain, though I'm very lucky and I can usually
Speaker 1: just about manage a pair that are officially the same size.
Speaker 1: But I do have to wear a support of stocking,
Speaker 1: which is sort of a pressure sock, and that is
Speaker 1: a pain, especially when it's really hot, because if I
Speaker 1: don't do that, then my ankle starts to swallow and
Speaker 1: my foot saws up and it also sort of aches,
Speaker 1: so I do wear my sock. I guess I'm almost
Speaker 1: certainly going to need a hearing aid at some point
Speaker 1: or another. If you go around a Turner syndrome convention
Speaker 1: or a Turner syndrome clinic waiting room, you will see
Speaker 1: lots of people with hearing aids, and I've sort of,
Speaker 1: I guess accepted that. I guess that's most of my story.
Speaker 1: It's a strange one to think that that your life
Speaker 1: is a story, because it really is absolutely everything to
Speaker 1: do with with who I am and how I live.
Speaker 1: I don't I don't know what it would be like
Speaker 1: to not have that, and trying to explain that is
Speaker 1: a bit strange.
Speaker 2: But I hope that was helpful. There you go. That's
Speaker 2: the end of my story.
Speaker 3: Thank you so so much, Katie for taking the time
Speaker 3: to chat and for sharing your story with us and
Speaker 3: with everyone.
Speaker 4: Yeah, thank you, we really appreciate it.
Speaker 5: Hi. I'm Aaron Welsh.
Speaker 4: And I'm Aaron Almond Updyke.
Speaker 5: And this is this podcast will Kill You.
Speaker 4: And today we're talking about Turner syndrome.
Speaker 1: We are.
Speaker 3: I believe that this is it's not our first genetic
Speaker 3: foray no, but I think it is of this season,
Speaker 3: and it's definitely our first chromosomal one.
Speaker 4: Oh yeah, that's a good point. We've only done like
Speaker 4: single gene I think, so, I think, right, I don't know,
Speaker 4: it's almost like we should keep a list or something.
Speaker 3: Eric, Oh, yeah, this is going to be a very
Speaker 3: interesting one. I don't know really anything at all about
Speaker 3: the biology, and so I can't wait to ask you
Speaker 3: a thousand genetics questions.
Speaker 4: Oh gosh, I can't wait to be like, I don't
Speaker 4: know the answer, but I'll try, so maybe before we
Speaker 4: do that. I think it's quarantin any time.
Speaker 5: I think it is. What are we drinking this week?
Speaker 4: We're drinking nothing but Nettie? And I love that. I
Speaker 4: don't actually know what that means yet, because I know
Speaker 4: it's about a researcher, but I haven't gotten to hear
Speaker 4: about her yet.
Speaker 3: Well you will definitely get to hear about her. We
Speaker 3: named our drink after Nettie Stevens, who was not as
Speaker 3: involved in Turner syndrome research, but was involved in uncovering
Speaker 3: what the X and.
Speaker 5: Y chrome is zomes do. And also she just.
Speaker 3: Like her story is so interesting and so inspirational, and
Speaker 3: so we just kind of wanted to pay tribute to Netti.
Speaker 4: And what is in nothing but Netti?
Speaker 3: In nothing but Netti is gin basil, some lemon, and cucumber.
Speaker 3: It's like very refreshing and delicious I love it.
Speaker 4: It sounds phenomen We'll post the full recipe for nothing
Speaker 4: but Netti, as well as our non alcoholic Plussy Burta
Speaker 4: on our website, This Podcast will Kill You dot Com
Speaker 4: and all of our social media channels.
Speaker 5: We sure will.
Speaker 3: On our website you can find a whole lot of stuff.
Speaker 3: We're not going to go through everything again. But I
Speaker 3: also just want to say real quick, because we've not
Speaker 3: been mentioning it that we are always happy to receive firsthand.
Speaker 3: So if you are interested in sharing one of your
Speaker 3: stories on the podcast, please reach out to us, preferably
Speaker 3: either through the content on our website or by emailing
Speaker 3: us directly at this Podcast will Kill You at gmail
Speaker 3: dot com.
Speaker 4: Well, Aaron, should we get started on the biology of
Speaker 4: Turner syndrome.
Speaker 3: Let's do it right after this break.
Speaker 4: So, Turner syndrome, like we said at the top, this
Speaker 4: is a genetic condition, and in this case, Turner syndrome
Speaker 4: is a condition that results from the partial or complete
Speaker 4: loss of one X chromosome. So before I get into
Speaker 4: any of what that means, I want to first set
Speaker 4: up some definitions of things that listeners probably are familiar with,
Speaker 4: at least from our high school biology classes, but that
Speaker 4: might have been a long time, so we'll go over it,
Speaker 4: shall we h. So our X chromosome is one of
Speaker 4: our sex chromosomes. So what on earth is a sex chromosome?
Speaker 4: We'll start there. Essentially, our chromosomes, chromosomes in general, our
Speaker 4: conglomerations of our DNA and the proteins that our DNA
Speaker 4: wraps itself around humans us we have a total of
Speaker 4: forty six chromosomes, and each of these are present in pairs,
Speaker 4: so we have twenty three pairs of chromosomes. Twenty two
Speaker 4: of these pairs are what are called autosomes, and one
Speaker 4: pair is our sex chromosomes. We get one of each
Speaker 4: of these pairs from our parents, one full set of
Speaker 4: twenty two plus one sex chromosome from the egg, and
Speaker 4: one full set of twenty two plus one sex chromosome
Speaker 4: from a sperm. Those come together and toda, a zygote
Speaker 4: is formed. We can look at chromosomes in humans by
Speaker 4: looking at what's called a karyotype, and this is a
Speaker 4: way of taking DNA from our cells and literally like
Speaker 4: laying it out so that you can see them. It's
Speaker 4: very cool. If you haven't seen images since high school
Speaker 4: bio will post them or you can google it also.
Speaker 4: And sex chromosomes in humans are our X and Y chromosome.
Speaker 4: They are called sex chromosomes because they, in large part
Speaker 4: are responsible for the initiation of sex determination. What that
Speaker 4: means is that our X and Y chromosomes are those
Speaker 4: that contain genes that result in the formation of our
Speaker 4: gonads and other reproductive structures. Sex determination is then furthered
Speaker 4: along during development by the production of sex steroids like
Speaker 4: estrogen and testosterone, which often come from our go ads,
Speaker 4: and then the development of secondary sexual characteristics. So in humans,
Speaker 4: you can kind of think of it as like a
Speaker 4: three step process of sex determination, and sex chromosomes are
Speaker 4: integral to that first step of the process, and because
Speaker 4: they are then resulting in the formation of these goads
Speaker 4: which produce sex steroids, they affect later stages as well.
Speaker 4: Cool mm hm. And everyone probably learned in high school
Speaker 4: biology that when it comes to sex chromosomes, X y
Speaker 4: equals male and xx equals female, and that might have
Speaker 4: been the last of what we all learned about sex chromosomes.
Speaker 4: So today we get to start the process in all
Speaker 4: of our brains of flipping that script because as we'll
Speaker 4: talk a lot about, It's not that simple.
Speaker 3: It's not that simple.
Speaker 4: It never is on this podcast.
Speaker 5: It really is not.
Speaker 4: So what is Turner syndrome? Then? Turner syndrome is what
Speaker 4: happens when an individual ends up with either an entirely
Speaker 4: or a partially missing X chromosome. And it turns out
Speaker 4: that when it's just a part of that X chromosome,
Speaker 4: it's often the tip of the short arm of the
Speaker 4: X chromosome, which, as I'll talk about later, is where
Speaker 4: many of the very important genes happen to sit.
Speaker 3: That's very interesting. Okay, I have a question already.
Speaker 4: Okay, shoot, give it to time.
Speaker 3: When it's completely missing, does there tend to be a
Speaker 3: pattern in whether it's missing from the sperm X or
Speaker 3: from the egg X?
Speaker 4: Great question. I think from what I read, it's more
Speaker 4: common that it's from the sperm X. So more commonly
Speaker 4: what you see is that the X chromosome that is
Speaker 4: present is from maternal DNA. So interesting. Yeah, and I
Speaker 4: don't think that we have a great idea as to
Speaker 4: why that is, at least not from what I read.
Speaker 5: Okay.
Speaker 4: And what's interesting too is that this can happen both
Speaker 4: part of the X chromosome and an entire X chromosome
Speaker 4: being kind of left behind during the process of miosis,
Speaker 4: which is formation of gamates, eggs, and sperm, or it
Speaker 4: can happen during mitosis. And what's very interesting is that
Speaker 4: Turner syndrome can also happen due to something called mosaicism,
Speaker 4: and this is when a fetus that becomes a human
Speaker 4: has multiple cell lines in their body. And this happens
Speaker 4: when during very early cell division in like a forming zygote,
Speaker 4: there is abnormal mitosis that results to some cells having
Speaker 4: say only one X chromosome, and some cells having two
Speaker 4: X chromosomes.
Speaker 3: And so if you looked at the caryotype of this person,
Speaker 3: some cells would have two x's and some cells would
Speaker 3: have XO or like just one X.
Speaker 5: Yeah yeah.
Speaker 4: So the way that they tend to write these when
Speaker 4: you are writing out the result of a caryotype is
Speaker 4: someone with complete monosomey of the X chromosome with Turner
Speaker 4: syndrome would have the caryotype forty five comma X or
Speaker 4: forty five comma XO. It's sometimes written someone who was
Speaker 4: a mosaic could have the caryotype forty five X. In
Speaker 4: some of their cells and forty six xx or forty
Speaker 4: six x Y in other cells. Okay, so already how interesting.
Speaker 3: Yeah, And so Turner syndrome is not just one X.
Speaker 3: It's not just the mosaicism of two x's and some
Speaker 3: cells one x and other cells. It's also x y
Speaker 3: in some cells and X in others.
Speaker 4: Yes, it absolutely can be interesting. Yes, And I'll get
Speaker 4: into a little bit more too about the intricacies that
Speaker 4: might arise when somebody might have that carriotype of forty
Speaker 4: five X and forty six x Y, because, as it
Speaker 4: turns out, it results in some different organ structure that
Speaker 4: can have different effects down the line. Ooh, we'll get there.
Speaker 3: Whoa okay, okay, Yeah, And.
Speaker 4: Those are not the only caryotypes that can exist. This again,
Speaker 4: can be just from a partially missing or a structurally
Speaker 4: abnormal X chromosome. So you could have someone that is
Speaker 4: forty six xx but missing part of that X chromosome.
Speaker 3: So really the crucial thing is that that part of
Speaker 3: the X chromosome is gone.
Speaker 4: Yep. Okay, So there's a lot of possibilities there. Now,
Speaker 4: before we dive too deep into what this looks like
Speaker 4: or what this results in, I also want to make
Speaker 4: a quick disclaimer, especially for anyone who's going to go
Speaker 4: back and read some of the literature of Turner syndrome,
Speaker 4: and that is that in a lot of the literature,
Speaker 4: Turner syndrome is carearacterized as a condition of women and girls,
Speaker 4: and this characterization isn't entirely accurate, largely because gender is
Speaker 4: a social construct and it's not the same thing as sex,
Speaker 4: which tends to be a biological characterization that is in
Speaker 4: large part, as I said, driven by genetics and particular
Speaker 4: sex chromosomes. So the characterization of Turner syndrome as a
Speaker 4: condition of women and girls isn't accurate. On top of that,
Speaker 4: I think that what conditions like Turner syndrome show us
Speaker 4: is that even this idea of sex as a binary
Speaker 4: of male and female isn't entirely accurate either. Our genetics
Speaker 4: are not nearly as black and white as what we
Speaker 4: learned in high school, and so some of the papers
Speaker 4: that I read referred to Turner syndrome rather as a
Speaker 4: condition that affects phenotypic females, that is, individuals who have,
Speaker 4: especially at birth, a phenotype, a set of observable, often
Speaker 4: physical characteristics that make them be labeled as female. So
Speaker 4: just sort of throwing all that out there. Yeah, So
Speaker 4: what does Turner syndrome look like or result in? Unsurprisingly,
Speaker 4: given the variety of genotypes and caryotypes that I just discussed,
Speaker 4: there is a large amount of variation in what the
Speaker 4: phenotype can actually be. And what that means is that
Speaker 4: there's also a lot of variation in what the downstream
Speaker 4: effects or potential medical conditions that might come along with
Speaker 4: Turner syndrome are. And when you read back through a
Speaker 4: lot of the literature, especially as we get into what
Speaker 4: the epidemiology of Turner syndrome really is, there's also an
Speaker 4: important distinction to be made between people who might have
Speaker 4: a particular carriotype, so a particular set of chromosomes, and
Speaker 4: whether people have any observable characteristics that are associated with
Speaker 4: Turner syndrome. So, in more modern definitions, you have to
Speaker 4: have both the caryotype where you are missing part or
Speaker 4: all of an X chromosome in at least some proportion
Speaker 4: of your cells, as well as a couple in particular
Speaker 4: of characteristics that go along with Turner syndrome to actually
Speaker 4: meet the definition of Turner syndrome.
Speaker 3: Okay, so the number of individuals that might be missing
Speaker 3: that portion of the X could be higher than the
Speaker 3: number of individuals that are diagnosed with Turner syndrome. Absolutely, yes, Okay,
Speaker 3: do we know what that difference is.
Speaker 4: It's a great question. I'll talk more about it in
Speaker 4: the current event section. The short answer is like, not really.
Speaker 5: No, Yeah, okay, that makes sense.
Speaker 4: Yeah, but we'll get there. But first let's talk about
Speaker 4: what are those characteristics to add to this carriotype to
Speaker 4: then result in this diagnosis of Turner syndrome. The two
Speaker 4: main things that we see are short stature and gonadal insufficiency,
Speaker 4: So that means generally what's called primary amenorehea, so not
Speaker 4: ever starting mensis or sometimes initiation of mensis that then
Speaker 4: over a couple of years stops and results in what's
Speaker 4: called secondary amenarea, so no longer having periods after just
Speaker 4: a couple of years. There are a lot of other
Speaker 4: things that can go along with this, like congenital heart
Speaker 4: defects and other heart conditions, kidney abnormalities, and a whole
Speaker 4: bunch of other things. And instead of just listing what
Speaker 4: they all are, what I want to do is kind
Speaker 4: of focus on those two in particular, most common characteristics,
Speaker 4: the short stature and the gonatal insufficiency. What we know
Speaker 4: about why we see those characteristics, like as it relates
Speaker 4: to this missing X chromosome, and then in that process
Speaker 4: we'll see what a lot of these other characteristic findings
Speaker 4: might be. Does that sound good? Yeah? Okay, spoiler, We
Speaker 4: don't have all the answers to this, like by a
Speaker 4: long shot, but the overall basis for a lot of
Speaker 4: the phenotypic characteristics as well as some of the medical
Speaker 4: conditions that can arise with Turner syndrome is something called
Speaker 4: Haplow insufficiency. What a great word. It basically just means
Speaker 4: there's not enough gene product being produced to preserve normal function. Okay,
Speaker 4: So we talked in some of our other genetics episodes
Speaker 4: like cystic fibrosis and sickle celenemia about this idea of
Speaker 4: recessive genetic disorders, like you need two copies of an
Speaker 4: abnormal gene to actually have the disease, because one copy
Speaker 4: that's normal gives you enough of whatever it is to
Speaker 4: like not have disease. So this is like it's like
Speaker 4: that same idea, except kind of different because it's chromosome and.
Speaker 3: It's like the same thing but kind of different.
Speaker 4: You know, I feel like it's a decent enough analogy.
Speaker 4: No it is, I'm with you, I get, but it's
Speaker 4: I guess it's that it's dominant, Like you really do
Speaker 4: need two copies of some of these genes to not
Speaker 4: have problems arise. Yeah, So here's where it gets even
Speaker 4: more interesting. Because you're dealing with sex chromosomes. In people
Speaker 4: who are forty six XX. They obviously have two X chromosomes,
Speaker 4: which is twice as many as somebody who is forty
Speaker 4: six X Y would have. And as it turns out,
Speaker 4: the X chromosome is a gene rich chromosome that has
Speaker 4: over a thousand genes on it, while the Y chromosome
Speaker 4: has less than two hundred. So what happens in the
Speaker 4: bodies of people who are forty six XX to prevent
Speaker 4: over expression too much of these one thousand genes is
Speaker 4: that one of the xes is actually inactivated. It's turned
Speaker 4: off in body cells, in the somatic cells, but not
Speaker 4: the gonadal cells in the ovaries. Of people who have
Speaker 4: two copies of this X chromosome. This is a process
Speaker 4: that's called silencing or X inactivation. But fifteen to twenty
Speaker 4: five percent of these one thousand genes are not in
Speaker 4: fact silenced, right, And these genes are called escape genes
Speaker 4: because they escape in activation or silencing. And these are
Speaker 4: the genes that we need and want to have two
Speaker 4: copies of in order to have enough gene product for
Speaker 4: normal function, in order to not have that HAPLO insufficiency.
Speaker 4: And do you know where else many of these genes
Speaker 4: are located.
Speaker 3: On the why I'm assuming all the WA chromosome.
Speaker 4: Isn't that so interesting?
Speaker 5: It is? This is really interesting.
Speaker 4: So, even though we don't necessarily know everything there is
Speaker 4: to know about the specific mech chganisms of some of
Speaker 4: what we see in Turner syndrome, in general, it's these
Speaker 4: specific genes, many of which are located on the tip
Speaker 4: of the short arm of the X chromosome, that part
Speaker 4: that's often missing in people with Turner syndrome. It's these
Speaker 4: escape genes that likely lead to many of the characteristics
Speaker 4: or conditions that we can see arise in Turner syndrome.
Speaker 5: That's fascinating. Okay, so what are these genes?
Speaker 4: Great questions? So glad you asked, Yeah, So, out of
Speaker 4: all those genes, we actually have one that we know
Speaker 4: for sure that we have good evidence of the kind
Speaker 4: of exact effect that we see due to haplo insufficiency.
Speaker 4: That gene is called SHOCKS SHO X, and this is
Speaker 4: a gene that is normally not inactivated on the X chromosome.
Speaker 4: It is present on both X and Y chromosomes, and
Speaker 4: it stands for short stature homeobox containing gene on the
Speaker 4: X chromosome shocks SHOCKS. So this particular gene SHOCKS is
Speaker 4: in a family of genes called homabox genes, which are
Speaker 4: really important genes, like a whole suite of them that
Speaker 4: regulate really key developmental processes during embryo genesis, during the
Speaker 4: process of the formation of an eventual human and in
Speaker 4: the case of Shocks, this gene is expressed during embryonic
Speaker 4: development in very specific tissues, including on the first and
Speaker 4: second pharyngeal arches. Who cares what that is, but what
Speaker 4: those structures develop into in the fetus are the maxilla,
Speaker 4: which is the top part of your jaw, and the
Speaker 4: mandible which is the bottom part of your jaw, as
Speaker 4: well as parts of your inner and outer and middle ear.
Speaker 4: It also is involved in muscles that are involved in
Speaker 4: chewing and hearing. This gene is involved in your soft
Speaker 4: palate and a whole host of other skeletal areas in
Speaker 4: the legs, in the hands. So this is a big
Speaker 4: deal gene and decreased expression of this one gene out
Speaker 4: of hundreds that are likely involved in particular, is the
Speaker 4: most strongly and convincingly correlated with some of the characteristics
Speaker 4: that are often seen in Turner syndrome. So we can
Speaker 4: talk about what some of those are. Yeah, they are
Speaker 4: things like developmental changes to the inner, middle, or outer
Speaker 4: ears that can lead to things like having ears that
Speaker 4: are low set, so lower on the cranium than is typical,
Speaker 4: which can lead to things like chronic ear infections, especially
Speaker 4: in childhood. Very commonly, either that process or other variability
Speaker 4: in the structure of the ear leads to some degree
Speaker 4: of hearing loss in people with Turner syndrome, which can
Speaker 4: manifest in a lot of different ways. It's usually not
Speaker 4: completeess but varying degrees of different forms of hearing loss. Interestingly,
Speaker 4: we also sometimes see things like scoliosis as well as osteoporosis,
Speaker 4: though that one is multifactorial, and that's because of some
Speaker 4: of the effects of shocks on the development of the skeleton,
Speaker 4: as well as other variations in the growth of the feet,
Speaker 4: or the ankles or the hands, many of which can
Speaker 4: be seen in Turner syndrome.
Speaker 5: It's so much, I know.
Speaker 4: There is also something that can be seen quite commonly
Speaker 4: in developing fetuses that have Turner syndrome on ultrasound that's
Speaker 4: called acystic hygroma. This is a collection of lymphatic fluid
Speaker 4: that often forms on the back of the neck and
Speaker 4: forms into this cyst. This process is likely due not
Speaker 4: only to shocks, but to potentially multiple genes that are
Speaker 4: related to lymphatic drainage. But in many cases, this cyst
Speaker 4: that's seen during fetal development resolves and can leave behind
Speaker 4: a more web shaped neck.
Speaker 5: Okay, so that's.
Speaker 4: A feature that's associated with Turner syndrome. It can also
Speaker 4: lead to a small mandible, so a slightly underdeveloped lower jaw,
Speaker 4: or a narrow palette on the roof of the mouth,
Speaker 4: which can sometimes lead to dental problems later in life.
Speaker 4: But probably the biggest and one of the singular defining
Speaker 4: features of Turner syndrome that has been very strongly shown
Speaker 4: to be associated with insufficiency of this gene in particular
Speaker 4: is the short stature that we often see in general.
Speaker 4: People with Turner syndrome reach average adult heights that are
Speaker 4: about twenty centimeters shorter than average when compared I should
Speaker 4: say to people who are forty six x x of
Speaker 4: their same ethnicity or race. Okay, And while there is
Speaker 4: obviously a very huge range of like full adult height,
Speaker 4: individuals with Turner syndrome often also show decreased growth trajectories
Speaker 4: both during fetal development as well as early childhood, so
Speaker 4: they can kind of fall off what we call their
Speaker 4: growth curves. But height, of course, is something that is multifactorial.
Speaker 4: It's not determined by this one specific gene. So the
Speaker 4: other reason that people with Turner syndrome often don't attain
Speaker 4: as great of a height as would be predicted, like
Speaker 4: especially by their parental heights, is because of a lack
Speaker 4: of a pubertal growth spurt. Why do we see the
Speaker 4: lack of a pubertal growth spurt. Well, that's because of
Speaker 4: the effects of Turner syndrome on gonadal function. So let's
Speaker 4: get into that, shall we.
Speaker 5: Yeah, I'm excited about this.
Speaker 4: Me too. I love talking about gonads. So in the ovaries,
Speaker 4: X chromosomes are not turned off entirely. It's only in
Speaker 4: our somatic cells. It's not just certain genes in the ovaries.
Speaker 4: It's the entirety of the X chromosome. Both of them
Speaker 4: are supposed to remain active. So if someone has part
Speaker 4: or all of their X chromosome missing, even if it's
Speaker 4: only in the gonads, such as, for example, in the
Speaker 4: case of a mosaicism, then there's going to be haplo
Speaker 4: insufficiency of genes involved in the function of the ovaries.
Speaker 4: We don't know in particular necessarily which genes these are,
Speaker 4: because could be any of them. But what this leads
Speaker 4: to is the loss of oocytes or eggs in the
Speaker 4: ovaries at a much more rapid pace than is typical,
Speaker 4: and this in turn leads to changes in hormone secretions,
Speaker 4: specifically our sex steroids, because our ovaries are what is
Speaker 4: secreting those hormones that then talk to our brain, which
Speaker 4: secretes more hormones to talk to various parts of our
Speaker 4: body to grow, especially during puberty, and also to do
Speaker 4: things like grow breasts, grow adult hair patterns, armpits, genitals,
Speaker 4: et cetera, and eventually begin ovulation and then menstruation. In
Speaker 4: the case of ovaries, so we first of all don't
Speaker 4: see this pubertal growth spurt, and most often we also
Speaker 4: don't see menarc or the beginning of menstruation.
Speaker 3: Okay, so what about people who have a Y chromosome?
Speaker 3: How does this picture differ or how is it the same?
Speaker 4: Great great question. So it can get fairly complicated because
Speaker 4: there's a lot of potential ways that that caryotype can
Speaker 4: present where people might have part or all of a
Speaker 4: Y chromosome. But what can often happen, especially if someone
Speaker 4: is a mosaic that is, say forty five x in
Speaker 4: some of their cells and forty six x Y in
Speaker 4: other cells, often will not form true ovaries, but will
Speaker 4: rather form testes that then remain in the abdominal cavity
Speaker 4: rather than ending up in a scrotum because there generally
Speaker 4: is no scrotum, there is phenotypically female genitals.
Speaker 5: Okay, gotcha.
Speaker 4: And one of the big risk factors with this in
Speaker 4: particular is that when testicles remain in the abdomen, they're
Speaker 4: at higher risk of developing into certain types of gonadal cancers.
Speaker 5: Why is that?
Speaker 4: I think it in part has to do with temperature differences,
Speaker 4: but I'll be honest, I don't fully know. It's very interesting, Okay, yeah,
Speaker 4: And that's true across the board. If testies are retained
Speaker 4: in the abdomen, it's not specific to Turner syndrome. Okay, yeah,
Speaker 4: all right, But in all of these cases when it
Speaker 4: comes to gonadal insufficiency, whether we're talking about ovaries that
Speaker 4: are not fully developed, or we're talking about testes that
Speaker 4: might be retained or some combination thereof, because that's also possible.
Speaker 4: One big potential consequence of this is infertility, and so
Speaker 4: then the need for assisted reproductive technologies. If somebody decides
Speaker 4: that they want to try and get pregnant later on,
Speaker 4: what would that consist of, usually IVF and possibly with
Speaker 4: donor oocytes. It all just depends on what an individual's
Speaker 4: phenotype is and how much ovarian reserve they have, if any. Okay, gotchyah,
Speaker 4: And I do want to emphasize that this is a
Speaker 4: condition that has a very wide spectrum of phenotype. So
Speaker 4: some people about a third of people with Turner syndrome
Speaker 4: do initiate menstruation spontaneously, but the majority of them do
Speaker 4: then enter this secondary amnareea at a much more rapid
Speaker 4: rate than is typical for menopause.
Speaker 3: Okay, I have a question about the proportions of different
Speaker 3: carrier types, So like, in terms of Turner syndrome and
Speaker 3: people with Turner syndrome, what proportion of them are forty
Speaker 3: five X, what proportion of them are you know, have
Speaker 3: some misaicism, What proportions of them have a Y chromosome?
Speaker 5: What does that breakdown look like?
Speaker 4: Love that you asked. In general, most papers that I
Speaker 4: read estimate forty five to fifty percent of people with
Speaker 4: Turner syndrome are forty five X. That's their carriotype. About
Speaker 4: twenty to thirty percent of people have some kind of mosaicism,
Speaker 4: be that forty five X with forty six xx or
Speaker 4: xx y, forty seven xx y or et cetera, et cetera.
Speaker 4: There's a lot of possibility there, and then the rest
Speaker 4: have some other type of structural abnormality of one of
Speaker 4: those X chromosomes. Okay, so huge variation. Yeah, but wait, Aaron,
Speaker 4: there's more. Now, another very medically important condition that can
Speaker 4: arise as a result of Turner syndrome. And I'll just
Speaker 4: treface saying we do not understand the exact gene underpinnings.
Speaker 4: Here are a variety of congenital heart defects, and this
Speaker 4: can really range. One of the most common is what's
Speaker 4: called a bicuspid aortic valve. This is the valve between
Speaker 4: your left ventricle and your aorta, and like all of
Speaker 4: your valves in your heart are pretty important, but this
Speaker 4: one's like very important and it typically has three leaflets,
Speaker 4: but in a bicuspid valve there's only two. That means
Speaker 4: that these two leaflets are under a lot more stress,
Speaker 4: and that can lead to stiffness of these valves and
Speaker 4: then eventually insufficiency of this valve.
Speaker 1: Okay.
Speaker 4: Another condition that's even a little scarier is aortic root dilation,
Speaker 4: which means the root the first part of the aorta
Speaker 4: as it comes off of the heart. And as a
Speaker 4: reminder for all listeners, your aorta is what carries your
Speaker 4: blood to literally all the rest of your body. When
Speaker 4: this gets enlarged, and this enlargement makes it weaker, and
Speaker 4: this can then put you at risk for not only
Speaker 4: that aortic insufficiency where not enough blood is making it
Speaker 4: into your aorda to give blood to your body, but
Speaker 4: it also can put you at risk for aortic dissection,
Speaker 4: which is where the wall of the aorta comes apart,
Speaker 4: and that can be life threatening.
Speaker 5: Yeah.
Speaker 4: Turner syndrome can also be associated with other abnormalities like
Speaker 4: coorctation of the aorda, which is where later on in
Speaker 4: the course, the aorta kind of pinches in like gets
Speaker 4: more narrow, which can lead to increased pressure in some
Speaker 4: spots and decreased pressure in others. So you're not getting
Speaker 4: adequate blood flow to all of the body. And honestly,
Speaker 4: there's a lot of other potential congenital heart defects that
Speaker 4: can result as well. There's a few candidate genes that
Speaker 4: might be involved, and one paper that I read, which
Speaker 4: of course I will link to, really suggested that it's
Speaker 4: likely a two step process where there's likely genes that
Speaker 4: are involved, but then particular alleles that put you at
Speaker 4: higher risk for having these heart abnormalities. Like not just yeah,
Speaker 4: so it's not just a Haflo insufficiency issue, but yes,
Speaker 4: there's a lot of possibilities in terms of what the
Speaker 4: anomalies that we see in the heart can be, and
Speaker 4: so we don't have exact answers as to the cause.
Speaker 4: And that is true when it comes to a number
Speaker 4: of other phenotypic characteristics or medical conditions that can be
Speaker 4: seen in people with Turner syndrome. I can go through
Speaker 4: what some of them are, but we really don't have
Speaker 4: as clear of an idea when it comes to these
Speaker 4: less common conditions or characteristics, like what the genes are
Speaker 4: that are involved, or largely what kind of complex gene
Speaker 4: and hormonal interactions might lead to some of these.
Speaker 3: It's so incredibly complicated, it's it really really boggles the mind.
Speaker 4: So we can see things like kidney abnormalities, and just
Speaker 4: like with heart anomalies, can general heart anomalies, these can
Speaker 4: really range in terms of what kinds of structural kidney
Speaker 4: changes that we can see. People with Turner syndrome often
Speaker 4: also tend to be at higher risk for autoimmune conditions,
Speaker 4: especially thyroid disease, but also inflammatory bowel disease and others.
Speaker 4: They tend to be at higher risk for hypertension, and
Speaker 4: there's some questions arising as to whether they are also
Speaker 4: at higher risk for diabetes. Seems clear that they are
Speaker 4: at higher risk for osteoporosis, which is largely hormonally as
Speaker 4: well as gene regulated. Because estrogen is really important in
Speaker 4: healthy bone growth. Yeah, and in some cases, individuals with
Speaker 4: Turner syndrome can have difficulties in visual and spatial processing
Speaker 4: or visual motor tasks that can make some aspects of
Speaker 4: academics harder in some cases. But in general, there's very
Speaker 4: rarely any kind of global developmental delay or global learning
Speaker 4: disabilities or anything like that, which is very interesting, especially
Speaker 4: when it compares to many of the other annuploides or
Speaker 4: chromosomal genetic syndromes that we see. And I would say
Speaker 4: as well, there's a paucity of data on the potential
Speaker 4: psychosocial effects of living with Turner syndrome.
Speaker 3: I'm sure the research has really only just begun.
Speaker 4: It barely exists.
Speaker 3: Okay, So I have a couple questions about treatment number one,
Speaker 3: gene therapy.
Speaker 5: Does it exist?
Speaker 4: Great question? I saw nothing in my research about gene therapy.
Speaker 4: My guess is that it's largely because the shocks gene
Speaker 4: is the only one that we have like pretty decent
Speaker 4: evidence of its effect, whereas all of the rest of them,
Speaker 4: we're like, yes, we know that these like escape genes
Speaker 4: are potential targets, but we don't even know what they
Speaker 4: do yet, right, Yeah, we.
Speaker 5: Don't want to just like throw a bunch in there
Speaker 5: and be like, eh, then maybe this is okay, right
Speaker 5: exactly Okay.
Speaker 3: So then my other question is treatment in terms of timing.
Speaker 3: So a lot of the things you described happen during
Speaker 3: development while you're a fetus, while you're an embryo, while
Speaker 3: you're a fetus, Yeah, but not everything, and so how
Speaker 3: does treatment play into that?
Speaker 4: Such a great question. So when it comes to the
Speaker 4: things that might happen during development, like say cardiac anomalies,
Speaker 4: can genital heart anomalies. As of now, in general, we
Speaker 4: don't have much in the way of treatments. There may
Speaker 4: be some very rare times where people get heart surgeries
Speaker 4: in utero, but that's like very very rare, right. So
Speaker 4: in general, the way that Turns syndrome is dealt with
Speaker 4: in terms of treatment is twofold. There's two aspects of
Speaker 4: it that are often addressed during development if Turner syndrome
Speaker 4: is diagnosed early enough, and that is the growth insufficiency
Speaker 4: so short stature as well as the gonadal insufficiency, and
Speaker 4: those are treated with initiation of growth hormone and then
Speaker 4: eventually addition of estrogen therapy. Now, the timing of those
Speaker 4: very controversial. There are some societies that have like guidelines,
Speaker 4: but from what I read, we just don't have a
Speaker 4: ton of evidence as to like, win really is the
Speaker 4: best time to initiate growth hormone and then add in estrogen,
Speaker 4: et cetera. Yeah, yeah, so, but those are the two
Speaker 4: things that growth hormone has been shown to increase final
Speaker 4: adult height substantially, and the addition of estrogen reduces the
Speaker 4: risk of osteoporosis and can facilitate the growth of secondary
Speaker 4: sexual characteristics, and importantly does not seem to increase the
Speaker 4: risk of any cancers, which is always something we think
Speaker 4: about when it comes to estrogen. Right. Yeah, Now, the
Speaker 4: other thing that then we have to consider is the
Speaker 4: treatment of all of the other things that might go
Speaker 4: along with Turner syndrome, And for those, it generally just
Speaker 4: comes down to whatever typical medical management of those would be.
Speaker 4: So if you have high blood pressure, you treat it
Speaker 4: like high blood pressure. But yeah, that's pretty much I think,
Speaker 4: hopefully the biology of Turner syndrome.
Speaker 3: There's a lot there there, really really is.
Speaker 4: Aaron, So, I gotta know, how did we find out
Speaker 4: about this, Like, how did we figure out that this
Speaker 4: was a condition when it can have such varied appearance,
Speaker 4: and then how did we figure out like what we
Speaker 4: know about it?
Speaker 3: Good questions, Good questions. I will do my best right
Speaker 3: after this break. At its core, the history of Turner
Speaker 3: syndrome is a story of chromosomes, specifically the X chromosome.
Speaker 3: I mean, of course, there's more to it than that.
Speaker 3: There is doctor Henry Turner, the Oklahoma physician that in
Speaker 3: nineteen thirty eight first described some characteristics that were associated
Speaker 3: with the condition. There's the improvements in our understanding of
Speaker 3: genetics that allowed researchers to pinpoint the chromosomal cause in
Speaker 3: nineteen fifty nine. And there's the founding and growth of
Speaker 3: many Turner Syndrome organizations over the past fifty or so
Speaker 3: years that have done so very much in terms of education,
Speaker 3: access to treatment, and connecting affected individuals and families all
Speaker 3: over the world. But what I really want to dive
Speaker 3: into today is what came before all that, the story
Speaker 3: of this chromosome at the heart of Turner syndrome. Yeah,
Speaker 3: the X chromosome, like you said, Aaron is one half
Speaker 3: of the pair of chromosomes, the other being why that
Speaker 3: we usually referred to as the sex chromosomes because they're
Speaker 3: involved in the process that ultimately leads to the formation
Speaker 3: of sexual organs and other sexual characteristics. They're not the
Speaker 3: only things involved, of course, nor is sex determination the
Speaker 3: only thing they do as we know. So how did
Speaker 3: we come to call these two chromosomes sex chromosomes?
Speaker 4: I don't know.
Speaker 3: How did the growing field of medics uncover their functions,
Speaker 3: and how has our understanding of sex chromosomes changed since then?
Speaker 3: I want to dive into these questions about the history
Speaker 3: of sex chromosomes, and then I'll talk a bit about
Speaker 3: how Turner syndrome was first discovered. People have always been
Speaker 3: obsessed with explaining why some people are born with testes
Speaker 3: and others are born with ovaries, and all of the
Speaker 3: variation in between. And in the century leading up to
Speaker 3: the discovery of the X and Y chromosome, things like heat,
Speaker 3: the position of the fetus in the womb, and the
Speaker 3: types of food you ate were all contenders for what
Speaker 3: sex the infant would have, what venotypic sex the infant
Speaker 3: would have. There are countless other beliefs or explanations that
Speaker 3: emerged over the thousands of years since humans first thought
Speaker 3: to wonder about anatomical differences, and the vast majority of
Speaker 3: these explanations tended to suggest that it was kind of
Speaker 3: these more externsnal factors after conception that made all the difference.
Speaker 3: Sex was pliable, it could be influenced by things after conception,
Speaker 3: but humans only began to get a peak at the
Speaker 3: complex internal processes that go into determining what we call
Speaker 3: biological sex at the end of the nineteenth century beginning
Speaker 3: of the twentieth when the X and Y chromosomes were
Speaker 3: first discovered, and even then it would take a bit
Speaker 3: of time before this explanation of chromosomal sex determination.
Speaker 5: Was widely accepted.
Speaker 3: This was the end of the Victorian era, which was
Speaker 3: a period marked by strict gender roles both privately and publicly,
Speaker 3: and so it may be kind of surprising to learn
Speaker 3: that during that same time, scientists studying sex saw it
Speaker 3: as a spectrum, as extremely complicated and not necessarily a
Speaker 3: discrete binary trait, and this view is reflected in how
Speaker 3: these researchers thought sex was determined, which was, like I said,
Speaker 3: largely through these sort of external factors affecting the embryo
Speaker 3: or fetus, rather than something that was determined at fertilization,
Speaker 3: for instance, did the egg come from the.
Speaker 5: Left or the right ovary?
Speaker 3: How old was each parent, what time of day did
Speaker 3: fertilization happen, and what was the temperature?
Speaker 5: What did you eat like? All of these.
Speaker 3: Things and the research that many early embryologists and physiologists
Speaker 3: were doing at the end of the nineteenth century supported
Speaker 3: this notion that sex was highly flexible. Sex ratios of
Speaker 3: certain insects varied under certain environmental conditions, and studies of
Speaker 3: sex hormones in birds and rodents showed that sex or
Speaker 3: sex characteristics could be modified after fertilization occurred.
Speaker 4: I love talking about sex in other animals. I know.
Speaker 3: I think that we need to devote an episode to
Speaker 3: that somehow.
Speaker 4: Oh, it would be so fun.
Speaker 5: It would be so fun.
Speaker 3: And this idea that sex was a plastic, changeable trait
Speaker 3: influenced by both the internal and external environments led to
Speaker 3: the quote metabolic theory of sex put forth by Patrick
Speaker 3: Getty's and J. Arthur Thompson in their eighteen eighty nine.
Speaker 5: Book The Evolution of Sex.
Speaker 3: Essentially, the idea was that females of a species should
Speaker 3: have a higher metabolic rate due to the increased demands
Speaker 3: of producing large game meats eggs, while males of a
Speaker 3: species would have lower metabolic demands because they're gametes, sperm
Speaker 3: weren't as energetically costly to produce, and this fed into
Speaker 3: the concept that during times of scarcity, more males would
Speaker 3: be produced, while during times of plenty more females would
Speaker 3: be And that actually is, at least in part, what
Speaker 3: seems to happen in some species, I think insect species,
Speaker 3: not what happens in humans necessarily, as far as as
Speaker 3: far as I think we have learned at this point
Speaker 3: in twenty twenty two, but the metabolic theory of sex
Speaker 3: predominated for a few decades from around when it was
Speaker 3: introduced in eighteen eighty nine or so until the nineteen twenties.
Speaker 5: What ended up dethroning it chromosomes.
Speaker 3: Ooh, Before we get into the how and why of
Speaker 3: when chromosomes were recognized to be major players in sex determination,
Speaker 3: let's take a step back to get some broader context
Speaker 3: in what was going on in the world of genetics
Speaker 3: or evolutionary biology at this time. And this is fun
Speaker 3: because I don't think like I've done a whole lot
Speaker 3: of context setting for like germ theory and antibiotics and
Speaker 3: all the infectious disease stuff we cover that, I don't
Speaker 3: think I've really done it as much for like evolution.
Speaker 4: I don't think so.
Speaker 3: Yeah. Okay, Well, if it's a repeat, apologies and hope,
Speaker 3: hope it's okay.
Speaker 4: If it's a repeat, we don't remember, so like no
Speaker 4: one else does either.
Speaker 5: Yeah.
Speaker 3: Yeah, So, as we know, the nineteenth century was a
Speaker 3: tremendous time of change and progress in really all fields
Speaker 3: of science. We've talked on this podcast in depth about
Speaker 3: things like physics, about things like the revolution that was
Speaker 3: germ theory. Microscopes and medical measuring devices were changing the
Speaker 3: way that we saw both health and disease. And natural
Speaker 3: historians were traveling all over the world and returning home
Speaker 3: to fill the halls and basements of museums and their
Speaker 3: own private collections with specimens from every continent. One of
Speaker 3: these natural historians, by the name of Charles Darwin, came
Speaker 3: back with more than just an outrageous number of plants
Speaker 3: and animals. He also brought back with him an idea
Speaker 3: that would change the way we looked not just at ourselves,
Speaker 3: but at all life on Earth. His idea, which took
Speaker 3: him a few years to write up and publish was
Speaker 3: the theory of evolution by natural selection. The individuals of
Speaker 3: a species that are more fit for their environment are
Speaker 3: more likely to survive and reproduce, and their offspring will
Speaker 3: inherit those traits that made their parents more fit. In
Speaker 3: this way, species change over time in relation to their environment,
Speaker 3: all components of it. As you probably already know, this
Speaker 3: idea met with a lot of resistance when it was
Speaker 3: first introduced, with critics calling it sacrilegious or just bad science.
Speaker 3: But over the next few decades, research uncovered more and
Speaker 3: more evidence in support of Darwin's idea, and many scientists
Speaker 3: turned towards working out the details of how evolution actually
Speaker 3: happened rather than trying to disprove it. And one of
Speaker 3: the key questions that remained about the process of evolution
Speaker 3: was how the information got passed from parent to offspring,
Speaker 3: what was the information actually made of and where was
Speaker 3: it located. Fortunately, microscope technology could step up to provide
Speaker 3: some tentative answers.
Speaker 4: I love this.
Speaker 3: I just like the intersection that the Yeah, the combining
Speaker 3: of these different fields. So while Darwin was looking across
Speaker 3: eons of change, other researchers were a bit more microscopically focused. Literally,
Speaker 3: around the same time that Darwin was writing and rewriting,
Speaker 3: and editing and stressing out about On the Origin of Species,
Speaker 3: which was published in eighteen fifty nine, another biological theory
Speaker 3: was gaining traction, the cell theory, which basically stated that
Speaker 3: the basis of all life is cells. All living things
Speaker 3: are composed of cells. Cells are the basic units of
Speaker 3: all living tissue, and all cells come from pre existing cells.
Speaker 3: Of course, people had observed cells and use that name
Speaker 3: since around sixteen sixty five, when Robert Hook first used
Speaker 3: that word to describe the little boxes he saw in
Speaker 3: a piece of magnified cork, since they reminded him of
Speaker 3: the rooms that monks stayed in called cellula.
Speaker 4: Oh my goodness.
Speaker 5: So that's where cell comes from.
Speaker 4: I don't think I ever knew that.
Speaker 3: But over the next two hundred years or so, microscope
Speaker 3: technology had advanced to the point where people could not
Speaker 3: only look at cells in a tremendous variety of organisms
Speaker 3: and tissues, but also within cells themselves, identifying different components,
Speaker 3: making inferences about their functions, and observing the variety of
Speaker 3: processes involved in day to day cellular activities processes including
Speaker 3: cellular division via mitosis or myosis. Researchers observed that the
Speaker 3: cells produced vamosis were germ cells. So these spur and eggs,
Speaker 3: and they were different from those produced during mitosis. And
Speaker 3: I'll get into that in a second. And in the
Speaker 3: eighteen nineties, German physiologist August Weismann integrated Darwin's theory of
Speaker 3: evolution with cell theory, proposing that the recombination of the
Speaker 3: germ cells was how information from each parent was passed
Speaker 3: down to their offspring, and that the recombination process introduced
Speaker 3: the variation that would allow for natural selection to act,
Speaker 3: because there has to be variation for natural selection act.
Speaker 4: Oh my goodness, it's beautiful, It's so beautiful.
Speaker 3: But still the question remained, where is that information stored?
Speaker 3: Experiments in the eighteen eighties demonstrated that it had to
Speaker 3: be in.
Speaker 5: The nucleus, but in what form?
Speaker 3: How is it?
Speaker 5: Packaged?
Speaker 3: Chromosomes seemed a likely contender. Okay, While early cell biologists
Speaker 3: were hunched over their microscopes watching these cells go through
Speaker 3: this beautiful dance of division. One in particular, German cytologist
Speaker 3: Walter Fleming noticed something happening in the nucleus. He wrote
Speaker 3: that he observed the separation and copying of quote threads
Speaker 3: in the nucleus during division. Ten years later, those threads
Speaker 3: would be designated chromosomes by Heinrich Waldyer because they stained
Speaker 3: so easily you could visualize them very well with staining.
Speaker 4: Wait, why does that mean chromosome? Chromo chromo? Yeah, wow,
Speaker 4: I never got that.
Speaker 5: I never thought about it.
Speaker 4: Yeah, me neither.
Speaker 3: Okay, So chromosomes got the name because they were so
Speaker 3: easily stained.
Speaker 4: I love it.
Speaker 3: And it turns out that mitosis and myosis acted differently
Speaker 3: on these chromosomes.
Speaker 5: So mitosis is.
Speaker 3: When a cell divides to produce two identical daughter cells,
Speaker 3: each containing two full sets of chromosomes, while myosis produces
Speaker 3: four granddaughter cells, each with only one set of chromosomes.
Speaker 3: And so it stood to reason that these chromosomes contained
Speaker 3: in the nucleus with only one set present in germ
Speaker 3: cells could contain that hereditary information, and crucially that information
Speaker 3: in the germ cells, those chromosomes would be passed down
Speaker 3: to offspring without the changes that would accumulate in the
Speaker 3: somatic cells during an individual's lifetime, basically making it actual
Speaker 3: evolution as we know it, rather than this Lamarchian passing
Speaker 3: down acquired traits during a lifetime type of thing. Yeah, okay, yeah, okay.
Speaker 3: So it took some time for the role of chromosomes
Speaker 3: in genetics to be fully embraced, but in the meantime,
Speaker 3: plenty of researchers had turned their efforts to learning more
Speaker 3: about these mysterious threads and the things they do, including
Speaker 3: possibly sex determination. I know we're finally here, we come
Speaker 3: full circle. I haven't even mentioned Turner syndrome in this yet,
Speaker 3: and it's still gonna be a while. But still it's
Speaker 3: still good though, Okay. In eighteen ninety one, a researcher
Speaker 3: named Hermann Henking observed a strange extra chromosome question mark
Speaker 3: in the sperm of the fire wasp. At least he
Speaker 3: thought it was a chromosome. He also thought it could
Speaker 3: be a quote peculiar chromatin element or the quote X element.
Speaker 3: People debated what this X element might do, but generally
Speaker 3: the consensus was dismissal. It was a degenerate was the
Speaker 3: word they used. Chromosome that was at the end of
Speaker 3: its evolutionary history and had little to no function, and
Speaker 3: for a few years. That was the end of it
Speaker 3: until around nineteen oh two, when a PhD student at
Speaker 3: the University of Kansas named Clarence McClung found a quote
Speaker 3: peculiar nuclear element that he ended up calling the accessory
Speaker 3: chromosome in the sperm of some locusts. He commented on
Speaker 3: the similarity between what he found and what Hanking had
Speaker 3: found and suggested that this was not some crumbling chromosome
Speaker 3: at the end of its life, but rather a fully
Speaker 3: functional chromosome that played a role in determining sex, since
Speaker 3: he observed its presence in some sperm but its absence
Speaker 3: in others. Quote, A careful consideration will suggest that nothing
Speaker 3: but sexual characters thus divide the members of a species
Speaker 3: into two well defined groups, and we are logically forced
Speaker 3: to the conclusion that the peculiar chromosome has some bearing
Speaker 3: upon this arrangement.
Speaker 5: Huh.
Speaker 4: Interesting.
Speaker 3: At the time, this was a very bold claim. Chromosomes
Speaker 3: were generally thought to be the heritable units in the
Speaker 3: germ cells, and that each one was probably responsible for
Speaker 3: some traits. But the metabolic theory of sex, where sex
Speaker 3: was more pliable and could be changed after fertilization, that's
Speaker 3: still predominated McClung himself didn't really pursue the idea any further,
Speaker 3: but other researchers certainly did. Two in particular, would be
Speaker 3: instrumental in demonstrating that these accessory chromosomes played a role
Speaker 3: in sex determination. And it seems like it's only recently,
Speaker 3: really that one has gotten the credit she deserves. The
Speaker 3: same year that McClung published his hypothesis nineteen oh two,
Speaker 3: Nettie M. Stevens, who was at Brinmar College, and Edmund
Speaker 3: Wilson at Columbia University both began examining this accessory X chromosome,
Speaker 3: mostly using insects. I feel like insects were always being used.
Speaker 3: They're fascinating. There's just such variation.
Speaker 4: Yeah, they're so easy to raise.
Speaker 3: Histories of the X chromosome or sex determination by chromosomes
Speaker 3: often credit Wilson or even Thomas Hunt Morgan, who was
Speaker 3: also at Brynmar with Stevens, with making the connection between
Speaker 3: X and sex, while Nettie Stevens is included often as
Speaker 3: a footnote or maybe worse, as just providing supporting evidence
Speaker 3: of Wilson's claims. But closer examination of the timeline of
Speaker 3: events shows that Stevens should not only be recognized for
Speaker 3: being the first to demonstrate chromosomal sex determination, but also
Speaker 3: for her many other important contributions to the field of genetics,
Speaker 3: such as, I don't know, discovering the Y chromosome kind
Speaker 3: of a big deal, kind of a big deal. I
Speaker 3: think Nettie Stephens' story is fascinating, and so I just
Speaker 3: want to talk a bit about it before getting back
Speaker 3: to this history of discovery.
Speaker 4: I love it, can't wait.
Speaker 3: Nettie Stevens was born in Vermont in eighteen sixty one
Speaker 3: and went to school to become a teacher, which is
Speaker 3: what she did for a number of years. Somewhere along
Speaker 3: the way, though, she became fascinated with biology, and so
Speaker 3: she saved up money from her teaching jobs to go
Speaker 3: to Stanford University.
Speaker 5: Wow.
Speaker 3: She was thirty five when she enrolled and thirty eight
Speaker 3: when she graduated with her bachelor's I love her already,
Speaker 3: I know, I mean, I'm thirty five. The thought of
Speaker 3: going back to school, it's it's difficult, Like it's really
Speaker 3: hard to get that motivation and that.
Speaker 5: Yeah, so it's amazing.
Speaker 4: I imagine in the eighteen hundreds it would not have
Speaker 4: been easy either.
Speaker 3: No, exactly, that's what is so it's unbelievable. The next
Speaker 3: year she got her Masters, also at Stanford, and then
Speaker 3: went on to Brynmar for her PhD, which she got
Speaker 3: at the age of forty one. Wow, it is so inspirational.
Speaker 3: So it was yeah, like nineteen oh two when that happened.
Speaker 4: Wow.
Speaker 3: At Brynmar, first as a PhD student, during which she
Speaker 3: published nine papers, by the way, and then as a
Speaker 3: research Stephens became fascinated by the fields of embryology, genetics,
Speaker 3: and cytology. Her postdoctoral fellowship allowed her to pursue independent
Speaker 3: research at Brynmar while not having to teach, and it
Speaker 3: was during that fellowship that she did the bulk of
Speaker 3: her groundbreaking work on sex chromosomes. Okay, let me read
Speaker 3: to you part of the concluding paragraph of her nineteen
Speaker 3: oh five paper where she presented her findings about the
Speaker 3: common meal worm and sex determination by chromosomes.
Speaker 5: Quote.
Speaker 3: Since the somatic cells of the female contain twenty large chromosomes,
Speaker 3: while those of the male contain nineteen large ones and
Speaker 3: one small one, this seems to be a clear case
Speaker 3: of sex determination not by an accessory chromosome, but by
Speaker 3: a definite difference in the character of the elements of
Speaker 3: one pair of chromosomes of the spermatocytes of the first
Speaker 3: order the spermatozoa, which contained the small chromosome determining the
Speaker 3: male sex, while those that contain ten chromames of equal
Speaker 3: size determined the female sex.
Speaker 4: Rite out.
Speaker 3: Just boom done, yep. So that was very strong supporting evidence.
Speaker 3: And around the same time Wilson Edmund Wilson also published
Speaker 3: results that mirrored the findings of Stevens, but his conclusions
Speaker 3: about sex determination by chromosomes were undoubtedly influenced by her work.
Speaker 3: So one paper I went through, like traced the footnotes
Speaker 3: and like the revision process of the paper and how
Speaker 3: like the things that he changed after her paper came out.
Speaker 5: It's just like all this stuff and.
Speaker 4: So how interesting it's really.
Speaker 5: That this paper was great.
Speaker 3: Yeah, And also his study system was one in which
Speaker 3: the male of the species has one fewer chromosome than
Speaker 3: the female, and so initially he was thinking it was
Speaker 3: more about dose rather than dominant recessive characteristics. Interesting, yeah,
Speaker 3: and not to mention that even in that paper he said, yeah,
Speaker 3: chromosome probably play a role in sex, but it's more about.
Speaker 5: Metabolism find out.
Speaker 3: I mean, ultimately, the question of who gets priority for
Speaker 3: a certain discovery is always a bit of a sticky one,
Speaker 3: and maybe it's more important not to say this person
Speaker 3: is first, no, this person is first, but to take
Speaker 3: a closer look at why there's discrepancy or why one
Speaker 3: person is given credit over the other. And I think
Speaker 3: it's safe to say that in Nettie Stevens's case, her
Speaker 3: gender played a role. Despite her incredible accomplishments, she was
Speaker 3: never given a faculty position, and while her colleagues recognized
Speaker 3: her brilliance. Quote, of the graduate students that I have
Speaker 3: had during the last twelve years, I have had no
Speaker 3: one that was as capable and independent and research work
Speaker 3: as miss Stevens. I was in one letter of recommendation,
Speaker 3: I think from Thomas Hunt Morgan.
Speaker 4: You mean doctor Stevens.
Speaker 5: Doctor Stevens.
Speaker 3: Yeah, she's I'm pretty sure a doctor at that point.
Speaker 3: But a lot of these accolades, a lot of these
Speaker 3: this praise was almost always qualified by for a woman. Quote,
Speaker 3: I consider her not only the best of the women investigators,
Speaker 3: but one whose work will hold its own with that
Speaker 3: of any of the men of the same degree of advancement.
Speaker 4: Oh yeah, yeah, yeah, yeah, I.
Speaker 3: Mean yeah, it's that's I mean, it's like that sucks,
Speaker 3: but that's the way it was.
Speaker 5: And so but I think it is.
Speaker 3: Really important to acknowledge that. Yeah, yeah, but I don't know. Also,
Speaker 3: in one paper I read about Nettie Stevens, the author
Speaker 3: pointed out that it was probably for the best that
Speaker 3: Thomas Hunt Morgan, who was also at BRNMAR and like
Speaker 3: huge name in genetics, was initially so resistant to Stevens's
Speaker 3: ideas about the role of chromosomes and sex determination, because
Speaker 3: if he had been more on board, his name would
Speaker 3: have been on all her page and he probably would
Speaker 3: have gotten all the credit, and her name would have
Speaker 3: been forgotten entirely.
Speaker 1: Wow.
Speaker 5: Interesting to think about.
Speaker 4: Yeah.
Speaker 3: Well, and then I think there's the trend that happens
Speaker 3: where if someone is very highly accomplished in a number
Speaker 3: of different fields, they tend to be given credit for things,
Speaker 3: even if they maybe didn't play the biggest role in it. So,
Speaker 3: in any case, I just wanted to spend a bit
Speaker 3: of time on this brilliant scientist who made so many
Speaker 3: incredible accomplishments in the field of genetics in such a
Speaker 3: short amount of time and during a time when so
Speaker 3: many things were working against her, and she probably would
Speaker 3: have made many more if her life was not cut
Speaker 3: short sadly by breast cancer. She died at the age
Speaker 3: of fifty, only nine years after finishing her PhD.
Speaker 4: Oh my goodness, I know, I know.
Speaker 3: But the work by Stevens and Wilson greatly advanced our
Speaker 3: understanding of how chromosomes are involved in sexy termination, but
Speaker 3: it would take a number of years before that idea
Speaker 3: was widely accepted, due in part to just how much
Speaker 3: variation there is across the animal kingdom. Geneticists looking for
Speaker 3: a universal answer as to what determined sex, such as
Speaker 3: XX produces females and xy produces males, were continually thwarted
Speaker 3: by exceptions to that narrow rule some bird, sea, urchin,
Speaker 3: and insects species where females were x y or ZW
Speaker 3: and males were xx or zz, or insect species where
Speaker 3: males were either xo or x y.
Speaker 2: I mean.
Speaker 3: The variation in these systems kept researchers from concluding definitively
Speaker 3: that these chromosomes were involved in sex determination, and this
Speaker 3: is reflected by it taking until the nineteen twenties for
Speaker 3: these chromosomes to be widely referred to as sex chromosomes.
Speaker 4: Interesting.
Speaker 5: Yeah.
Speaker 3: Up until then, they were known by a variety names,
Speaker 3: including heterochromosomes and accessory chromosomes idio chromosomes. Even when it
Speaker 3: became clear that sex determination was part of what these
Speaker 3: chromosomes did, some researchers rejected these labels, partly because they
Speaker 3: weren't quite convinced that that was how it worked, partly
Speaker 3: because they felt that too much was still unknown about
Speaker 3: other processes of sex determination and the function of these chromosomes,
Speaker 3: and partly because they felt that it was too simplistic
Speaker 3: and didn't capture the full spectrum of sex. It turned
Speaker 3: sex into a binary And I'm going to come back
Speaker 3: to this aspect of sex and sex chromosomes in a bit,
Speaker 3: but for now I want to turn briefly towards the
Speaker 3: actual topic of today's episode, Turner syndrome or should I
Speaker 3: say Ulric Turner syndrome. M Perhaps the first half of
Speaker 3: the twentieth century saw continued interest in sex chromosomes and
Speaker 3: genetics as well.
Speaker 4: Well.
Speaker 3: Is another rapidly growing field, that of endochronology. So around
Speaker 3: the same time that people were debating what to call
Speaker 3: the X and Y chromosomes. Other researchers were busy characterizing hormones,
Speaker 3: particularly the ones that seemed to play a role in
Speaker 3: the development of secondary sexual characters. For example, these hormones
Speaker 3: that you mentioned aaron, estrogen and testosterone right. Henry Turner,
Speaker 3: an Oklahoma physician, was one of these early endochronologists, and
Speaker 3: he would frequently be asked to consult on cases where
Speaker 3: people were suspected to have different hormone levels or a
Speaker 3: different hormone functionality. Throughout the nineteen thirties, he noticed in
Speaker 3: seven of his patients that were assigned female at birth
Speaker 3: what he thought might be a previously undescribed hormonal condition
Speaker 3: that led to a suite of physical characteristics, including short stature,
Speaker 3: cubitus valgus is like one thing that he pointed out,
Speaker 3: which is that extra angling of the forearm at the
Speaker 3: elbow and under development of sexual organs and secondary sexual characteristics.
Speaker 3: And in nineteen thirty eight he published case summaries of
Speaker 3: these seven individuals and suggested that this was a newly
Speaker 3: described condition that was likely caused by a hormonal imbalance.
Speaker 3: He tried pituitary growth hormones to no avail and anterior
Speaker 3: pituitary gnatotropic hormone to some avail. I don't know what
Speaker 3: that hormone actually was that was in the paper.
Speaker 4: Yeah.
Speaker 3: Yeah, he was right that it was a condition with
Speaker 3: one specific cause, which is what ultimately ended up making
Speaker 3: him the namesake of Turner syndrome, and that hormones were involved,
Speaker 3: But he was wrong about it never having been described before.
Speaker 3: Remember how I called it Ulric Turner syndrome.
Speaker 5: You might have seen that placens.
Speaker 4: Yeah, I sure did.
Speaker 3: Turns out a German pediatrician named Otto Ulrich had actually
Speaker 3: published a case study of an eight year old with
Speaker 3: the same suite of characteristics that Turner had described, but
Speaker 3: eight years before.
Speaker 5: Turner's paper came out.
Speaker 4: Ooh h.
Speaker 3: With Ulric and especially Turner's work, there was now a
Speaker 3: clinical description of this condition, but the ultimate cause remained
Speaker 3: a mystery for a couple of decades. Was it hormones?
Speaker 3: Was it something else?
Speaker 2: Like?
Speaker 5: Where where did this? How did this happen?
Speaker 3: And it was only in nineteen fifty nine that genetic
Speaker 3: technology and imaging had advanced to the point where researchers
Speaker 3: forward at all were able to link cases of Turner
Speaker 3: syndrome with the presence of only one X.
Speaker 4: Wow, that's a long time.
Speaker 5: It's a long time.
Speaker 3: I mean it makes sense, I guess in terms of
Speaker 3: technology and our understanding of chromosomes and how everything worked
Speaker 3: and being able to actually work with them.
Speaker 4: Right and like tereotype enough people or individuals and things
Speaker 4: like that.
Speaker 5: Yeah, exactly.
Speaker 3: Side note, Remember the person that Ulric scribes in his
Speaker 3: case report, the eight year old yea, So a couple
Speaker 3: of researchers followed up in the nineteen seventies and confirmed
Speaker 3: just one X.
Speaker 4: Wow, that's kind of cool, isn't that cool?
Speaker 3: Yeah. In the years since the nineteen fifty nine paper
Speaker 3: showing that a single X was at the root of
Speaker 3: Turner syndrome, we've learned so much more about it, including
Speaker 3: the fact that it isn't always a whole X missing. Right,
Speaker 3: you talked about erin which specific genes might be involved,
Speaker 3: and what types of treatment seemed to be helpful, and
Speaker 3: right alongside that, we've been expanding our view of sex overall.
Speaker 3: The X and Y for humans I think provides this
Speaker 3: enticingly simple binary picture of sex. XX means female, x
Speaker 3: Y means male. But obviously there's much more to it
Speaker 3: than that. And I think it's important to remember that
Speaker 3: there are so many different ways you can categorize sex,
Speaker 3: and some categories might be discreete. Others are continuous and
Speaker 3: none are binary. Yeah, chromosomal sex, gonadal sex, hormonal sex,
Speaker 3: genital sex, sexual identity, to name just a few. The
Speaker 3: diversity of sex in humans alone is amazing. And I
Speaker 3: didn't even talk about other animals. For instance, like I
Speaker 3: mentioned earlier, instead of the thisxxy system that we're familiar with,
Speaker 3: some birds and other organisms have a ZZZW system where
Speaker 3: zz develops as males zws female. There are also systems
Speaker 3: that don't just use this master switch on the distinct
Speaker 3: chromosome like the SRY on the Y chromosome to kick
Speaker 3: off the sex determination process, but also use genes on autosomes,
Speaker 3: the non sex chromosomes that are involved in this process.
Speaker 4: Well, and then there's so many animals too that can
Speaker 4: switch sex during their lifetime, like well after development like
Speaker 4: what what well?
Speaker 3: And for some like environmental factors play a huge role
Speaker 3: temperature stuff like that. It's like, it's not ridiculous, like
Speaker 3: the metabolg theory of sex works, It's just there is
Speaker 3: is there an overarching theory of sex and how sex
Speaker 3: determination works. I don't think there is, does there need
Speaker 3: to be?
Speaker 5: Isn't that sort of the beauty of it all?
Speaker 4: But it's fascinating.
Speaker 3: I mean there's there's Like I am going to link
Speaker 3: to some papers because don't you want to know more
Speaker 3: about species that have lost the Y chromosome entirely or
Speaker 3: those that have evolved to have another type of X.
Speaker 3: Read about the African pygmy mouse with the X y
Speaker 3: W system.
Speaker 4: What what? What?
Speaker 3: I know? The variety in this is, it's just it's beautiful.
Speaker 5: It's breathtaking.
Speaker 3: And I'll link to a few papers on our website
Speaker 3: that go into these examples so you can read more
Speaker 3: and get hyped also about the diversity of sex. I
Speaker 3: especially recommend more and Roberts from twenty thirteen titled Polygenic
Speaker 3: Sex Determination. It's a really well written, accessible, fascinating paper.
Speaker 5: And there's so much more that we.
Speaker 3: Could talk about in terms of sex and sex chromosomes.
Speaker 3: But I have to stop somewhere because otherwise I will
Speaker 3: never stop ever.
Speaker 5: So what I want to.
Speaker 3: Do is I want to ask listeners to send in
Speaker 3: your favorite sex chromosome trivia and all the different animals
Speaker 3: and then hands it off to you Aerin. So tell
Speaker 3: me where do we stand with Turner syndrome today?
Speaker 4: Oh, I can't wait too, but also Aarin. That's how
Speaker 4: we make our whole episode about sex chromosomes, as we
Speaker 4: just share listener facts.
Speaker 3: I love it.
Speaker 5: I love actually, I love that a lot.
Speaker 4: But I'll get into the what we know about Turner
Speaker 4: syndrome today right after this break. Most of the papers
Speaker 4: that I read cited relatively similar statistics, which is interesting,
Speaker 4: especially in the context as we'll learn that we don't know.
Speaker 4: These are estimates.
Speaker 5: We never know, we never know.
Speaker 4: That's the theme of this section. But in general, the
Speaker 4: estimate is about one in two thousand phenotypically female live
Speaker 4: births result in Turner syndrome. Another way to enumerate that,
Speaker 4: although it's looking at the literature a little bit more problematic,
Speaker 4: is that about fifty to sixty of every one hundred
Speaker 4: thousand adult the literature says adult women have Turner syndrome. Okay, right,
Speaker 4: so rare, but not that rarely.
Speaker 3: It's like one of the most common, if not the
Speaker 3: most common, of sex chromosome anomalies.
Speaker 4: Right, absolutely, yes, Okay, Now we don't have information on
Speaker 4: what the variation is globally in different populations in different regions,
Speaker 4: largely because we just don't have data for most of
Speaker 4: the world to be able to say, like, these regions
Speaker 4: have higher or lower incidents of Turner syndrome. But what's
Speaker 4: interesting about Turner syndrome is looking at the timeframe of diagnoses.
Speaker 4: I think because there are three main peaks of when
Speaker 4: people are diagnosed. It can be diagnosed prenatally via genetic testing, amniocentesis,
Speaker 4: things like that, and so some percentage of people and
Speaker 4: I don't have an exact number on this, are diagnosed
Speaker 4: very early, like before births even potentially, and then there's
Speaker 4: usually a second peak of people being diagnosed not until
Speaker 4: young childhood when they fall off their growth curves. And
Speaker 4: then pediatricians are like, hmm, let me think, look at
Speaker 4: these other characteristics, perhaps we should get a karyotype, okay,
Speaker 4: and especially through adolescents when people perhaps have primary amenorrhea
Speaker 4: and present, you know, in teen years having no period
Speaker 4: and then get worked up. And then the last peak
Speaker 4: might not come until adulthood when someone might be diagnosed
Speaker 4: because they're struggling with infertility.
Speaker 5: Interesting, okay, And.
Speaker 4: It's estimated that potentially up to twenty percent of people
Speaker 4: may never be diagnosed. And the reason that this is
Speaker 4: important is because it kind of gets back to like,
Speaker 4: what is the definition of Turner syndrome?
Speaker 5: Yeah?
Speaker 4: Right, if you are never diagnosed with Turner syndrome, do
Speaker 4: you have Turner syndrome and are just undiagnosed or do
Speaker 4: you not actually have any of these phenotypic characteristics of Turners? Therefore,
Speaker 4: you might have this carriotype but you don't actually have
Speaker 4: Turner syndrome. And that's kind of like a I don't know,
Speaker 4: a philosophical question.
Speaker 5: Or right, well, but I think it's also a clinical question.
Speaker 4: It is a clinical question definitely. Where we get this
Speaker 4: twenty percent number is from some studies that have been
Speaker 4: done in Great Britain and a few other countries that
Speaker 4: have looked at carriotypes of people across the board and
Speaker 4: found a much higher prevalence of Turner syndrome than would
Speaker 4: be expected m hm, so underdiagnosis essentially. Now, another thing
Speaker 4: that I think is important to note because it's really
Speaker 4: fascinating and gets to a lot of what you were
Speaker 4: talking about, Aaron on just how interesting sex chromosomes are,
Speaker 4: is that it's actually very rare to be born with
Speaker 4: Turner syndrome, especially with a forty five X caryotype. So
Speaker 4: those numbers that I just cited, one in twenty five
Speaker 4: hundred not that rare, and forty five to fifty percent
Speaker 4: of those people are forty five X. But it's estimated
Speaker 4: that up to ninety nine percent of fetuses with a
Speaker 4: kareotype of forty five X actually result in spontaneous abortion,
Speaker 4: i e. Miscarriage or early pregnancy loss.
Speaker 3: That's a very interesting because, yeah, you're right, it's not
Speaker 3: it's common, but also extremely rare.
Speaker 4: Right, And it's also important to note because fascinating that
Speaker 4: I am fairly positive that Turner syndrome, especially as forty
Speaker 4: five X is the only known survivable monosomy where you
Speaker 4: have a complete absence of one chromosome. The complete absence
Speaker 4: of any of the other sets of chromosomes results in
Speaker 4: a non viable fetus. Wow, there are partial monosomis like
Speaker 4: cretis shot. There's seventeen Q twelve microdeletions, there's other types
Speaker 4: of chromosomal anomalies, and of course there are various trisomes,
Speaker 4: a number of which are compatible with life. But forty
Speaker 4: five XO is the only one with an entirely missing
Speaker 4: chromosome that's compatible with life, which is pretty incredible. And
Speaker 4: there is actually some suggestion that perhaps those fetuses that
Speaker 4: do survive might have some degree of mosaicism that we're
Speaker 4: just not detecting, but so far there's not a lot
Speaker 4: of evidence to actually confirm that hypothesis, right, So suffice
Speaker 4: to say, there are a lot of areas that are
Speaker 4: ripe for research, so many there are a few really
Speaker 4: great papers that I will direct to that have a
Speaker 4: lot more detail on kind of what especially the medical
Speaker 4: community thinks are the greatest needs when it comes to
Speaker 4: research on Turner syndrome. But a lot of it is
Speaker 4: like we need to understand the true genetic mechanisms underpinning
Speaker 4: a lot of the conditions that we see. We don't
Speaker 4: have all that information. We need better evidence based guidelines
Speaker 4: for care, because like I said earlier, we have guidelines,
Speaker 4: but we need more evidence to support those, of course,
Speaker 4: and I think that we also need a much better
Speaker 4: understanding of how people living with Turner syndrome are doing psychosocially, emotionally, physically.
Speaker 4: Like there's a lot to be said, and we've talked
Speaker 4: about this in a lot of our genetics episodes about
Speaker 4: involving people living with these conditions in the research, not
Speaker 4: merely as subjects of research. So, yeah, that is Turner syndrome.
Speaker 5: There's a lot.
Speaker 3: I think I've already said this, but there's just so
Speaker 3: much there.
Speaker 4: It really does. One of the things that really excites
Speaker 4: me about this is just talking about the variety inherent
Speaker 4: in sex chromosomes and sex determination because it is so
Speaker 4: much more interesting than the black and white that we
Speaker 4: learned in.
Speaker 3: School, right, I mean the black and white we learned
Speaker 3: that way because it's it's convenient, right, It's not accurate, right,
Speaker 3: and you're missing out if that's what you're if that's
Speaker 3: how you're looking at sex. Is this irreversible, constant thing,
Speaker 3: Like there are so many different ways to define it.
Speaker 5: It's it's really cool.
Speaker 4: It's really cool, And yeah, I think it also makes
Speaker 4: us think that there is one thing that is normal
Speaker 4: and the rest of everything outside of that is abnormal,
Speaker 4: which isn't the case. There's a lot of variation in
Speaker 4: what can happen during the process of development, during the
Speaker 4: process of cell replication and division. Like, it's awesome, it
Speaker 4: is so so sources, sources so everyone can read some more.
Speaker 5: Let's do it.
Speaker 3: I have several I'm going to shout out a couple
Speaker 3: that I found super helpful. One is by Abbot at
Speaker 3: All from twenty seventeen about the history of sex chromism discovery.
Speaker 5: A paper by Brush.
Speaker 3: Nineteen seventy eight about that was the one about Nettie Stevens.
Speaker 4: It's a great paper.
Speaker 3: And then also I got some info from a book
Speaker 3: by Sarah Richardson called Sex Itself. And then finally I
Speaker 3: just want to shout out again that great paper by
Speaker 3: Moore and Roberts from twenty thirteen called Polygenic Sex Determination.
Speaker 4: I had a number of papers a couple of my
Speaker 4: favorites that are more recent. One was Turner Syndrome Mechanisms
Speaker 4: and Management from Nature Reviews Endercronology twenty nineteen, and another
Speaker 4: was the Changing Face of Turner Syndrome from Endocan Reviews
Speaker 4: twenty twenty two. Both of those have a lot on
Speaker 4: like where we stand with Turner syndrome, what we know,
Speaker 4: and what we need to know. But we'll post the
Speaker 4: list of all of our sources from this episode and
Speaker 4: every one of our episodes on our website. This podcast
Speaker 4: will kill you dot com go check it out.
Speaker 3: I want to give a special thank you to Emily Moore,
Speaker 3: who helped me talk through this part of my history
Speaker 3: for this episode.
Speaker 5: You're the best.
Speaker 4: Thank you, and thank you again to Katie, the provider
Speaker 4: of our first hand account. Thank you so much for
Speaker 4: sharing your story with us and all of our listeners.
Speaker 3: I mean, we can't thank you enough. Thank you to
Speaker 3: Bloodmobile for providing the music for this episode.
Speaker 5: And all of our episodes.
Speaker 4: Thank you as always to the Exactly Right Network, and.
Speaker 5: Thank you to you listeners.
Speaker 3: We hope that you liked this and that we did okay.
Speaker 4: Yeah, let us know when we or the other. Yeah,
Speaker 4: but I had a lot of fun I did too,
Speaker 4: and especial thank you to our patrons. Thank you so
Speaker 4: much for your support. It means the world to us.
Speaker 5: It really does.
Speaker 3: Okay, Well, until next time, wash your hands.
Speaker 4: You failthy animals. U