WEBVTT - Ep 106 Turner Syndrome: Let's talk about X 0:00:02.360 --> 0:00:06.640 So I don't really remember being diagnosed, because that happened 0:00:06.640 --> 0:00:09.440 the day that I was born. The story goes that 0:00:09.680 --> 0:00:12.639 my parents got told by the doctor that they'd seen 0:00:13.520 --> 0:00:17.759 swollen right's foot on their new baby, and they wanted 0:00:17.760 --> 0:00:21.840 to check that out. So it's basically always been something 0:00:21.880 --> 0:00:25.319 that I knew was a part of my life, that 0:00:25.360 --> 0:00:28.800 I understood was part of who I was. It didn't 0:00:28.920 --> 0:00:33.680 really register that not everybody spent that much time sitting 0:00:33.680 --> 0:00:37.279 in hospital waiting rooms for being weigh and measured. It 0:00:37.320 --> 0:00:41.159 didn't really mean very much to me other than just 0:00:41.920 --> 0:00:43.920 that was what life was like. Of course, you go 0:00:44.000 --> 0:00:47.839 in and you get checked out for various things. As 0:00:47.880 --> 0:00:50.239 I got a bit bigger, I understood that it was 0:00:50.320 --> 0:00:55.520 genetic and I kind of understood what that meant, but 0:00:55.680 --> 0:00:59.720 explaining that to other people was the bigger problem. I 0:00:59.880 --> 0:01:02.000 was wanted to try and explain it to other kids, 0:01:02.160 --> 0:01:04.640 but they, for some reason just didn't have as much 0:01:04.680 --> 0:01:08.759 interest in what, you know, a gene was as I did, 0:01:09.280 --> 0:01:12.319 And that became clear as I got older that that 0:01:12.400 --> 0:01:15.280 was a bit weird. I missed quite a lot of 0:01:15.360 --> 0:01:19.479 school comparatively. In retrospect, I'm pretty sure it was very 0:01:19.480 --> 0:01:22.080 annoying for my family to have to schedule around on 0:01:22.880 --> 0:01:27.440 various medical appointments, but again it was just something that happened. 0:01:27.680 --> 0:01:29.760 Of course, you have you go in and get your 0:01:29.760 --> 0:01:33.679 bloods taken, you go and get scanned for various things. 0:01:34.319 --> 0:01:37.880 That was just the thing that always happened. But it 0:01:38.000 --> 0:01:40.920 was sometimes hard not to be a little bit self conscious. 0:01:41.920 --> 0:01:46.119 I have one thought that's fairly swollen, and I felt 0:01:46.200 --> 0:01:50.040 quite aware of that and self conscious of that, but 0:01:50.160 --> 0:01:53.080 other people sometimes didn't even really notice, to be honest, 0:01:53.080 --> 0:01:54.840 and I sort of figured that out as I went along, 0:01:55.680 --> 0:01:58.560 Like my elbows don't go straight, they go off at 0:01:58.560 --> 0:02:02.800 an angle. And knows that at all unless I deliberately 0:02:02.800 --> 0:02:07.200 point it out to them. So what scans were there exactly? 0:02:07.280 --> 0:02:07.760 I think it was. 0:02:07.840 --> 0:02:10.320 It was mostly heart and kidneys, those are the big ones, 0:02:10.919 --> 0:02:14.160 and lots of hearing tests. My hearing is a bit dodgy. 0:02:14.919 --> 0:02:18.680 But the biggest thing was always about my growth pattern. 0:02:19.000 --> 0:02:21.760 Every time I went in as a child, I would 0:02:21.840 --> 0:02:25.680 get put next to measuring tape on the wall and 0:02:26.080 --> 0:02:27.760 the doctor will sort of try and pull my head 0:02:27.840 --> 0:02:29.440 up a little bit to try and get a little 0:02:29.440 --> 0:02:31.359 bit of extra height on me, and we'll make sure 0:02:31.400 --> 0:02:34.320 that I was standing up straight, to the point where 0:02:34.360 --> 0:02:36.320 I occasionally had to yell that my feet were coming 0:02:36.320 --> 0:02:39.000 off the floor. It was. It was. Actually one of 0:02:39.040 --> 0:02:42.280 the stranger things was that I would get my growth 0:02:42.360 --> 0:02:45.240 chart and I could see that on the Turner Syndrome 0:02:45.280 --> 0:02:48.440 growth chart, I was right at the top. I'm absolutely 0:02:48.480 --> 0:02:51.960 top one percent, a giant among turn of people. But 0:02:52.040 --> 0:02:55.280 then they'd do the same plot on a regular people graph, 0:02:55.639 --> 0:02:59.320 and suddenly I'm right down the bottom. I understood from 0:02:59.360 --> 0:03:03.200 that very that my comparisons of looking around the Turner 0:03:03.240 --> 0:03:08.120 Syndrome clinic waiting room, where I'm very tall and almost 0:03:08.120 --> 0:03:12.560 everybody is shorter than me, was very strange. Part of 0:03:12.560 --> 0:03:14.960 the reason for that is that as a child, I 0:03:15.000 --> 0:03:17.720 had growth hormone injections, so those are ones that you 0:03:17.880 --> 0:03:20.640 do every day. I think that started when I was 0:03:20.639 --> 0:03:25.520 about eight or nine, when I first started becoming notably 0:03:25.560 --> 0:03:29.600 smaller than my compatriots in my class at school. Initially, 0:03:29.639 --> 0:03:32.440 my dad tried to do them for me while I 0:03:32.480 --> 0:03:36.200 was asleep, but apparently that didn't work very well, and 0:03:36.240 --> 0:03:38.920 I was a complete brat about it. They have a 0:03:38.920 --> 0:03:41.720 lot of special kit that they use to try and 0:03:41.760 --> 0:03:44.960 make it more comfortable for children, especially people who aren't 0:03:45.240 --> 0:03:48.520 very keen on needles, which I wann't at that age. 0:03:49.080 --> 0:03:52.360 So there's like strange injector pends, and one I had 0:03:52.440 --> 0:03:55.680 was almost like a gun. It was on a spring 0:03:55.840 --> 0:03:58.320 and it made a huge noise whenever I pressed it, 0:03:58.800 --> 0:04:01.360 so that actually freaked me out more than just doing 0:04:01.360 --> 0:04:04.680 it myself. So I eventually, after a lot of annoying this, 0:04:05.520 --> 0:04:08.200 I ended up doing my own injections, which was a 0:04:08.280 --> 0:04:12.000 sort of single injection every day, and that was actually fine. 0:04:12.120 --> 0:04:14.640 I don't really mind that so much in the end. 0:04:14.680 --> 0:04:18.159 It was more the logistics of it that were really irritating. 0:04:18.600 --> 0:04:20.880 So if ever you went away, then you had to 0:04:20.920 --> 0:04:23.200 take all your medication with you in a cooler bag 0:04:23.240 --> 0:04:25.800 and then putting it in the fridge. There was always 0:04:26.080 --> 0:04:28.080 a lot of staring when I had to go and 0:04:28.080 --> 0:04:30.560 put medication in the fridge. If I went on school 0:04:30.600 --> 0:04:34.200 trips as a child, I remember going on one where 0:04:34.240 --> 0:04:37.080 we was I think we're in the lake district somewhere, 0:04:37.680 --> 0:04:40.440 and me having to do my injection at the end 0:04:40.480 --> 0:04:42.960 of the day. Some of the kids were like staring 0:04:43.000 --> 0:04:44.560 around the door as I was trying to do it. 0:04:44.720 --> 0:04:48.120 That was not great. When I got a bit older, 0:04:48.720 --> 0:04:52.600 the doctors started becoming very concerned about giving me what 0:04:52.640 --> 0:04:56.320 they called the normal experience of puberty, so they put 0:04:56.320 --> 0:05:01.560 me on HRT homeown Replacement therapy, a kind which includes 0:05:01.560 --> 0:05:03.839 giving you periods, which I could really have done without. 0:05:03.880 --> 0:05:07.640 Nobody needs that. But it was always, in retrospect quite 0:05:07.640 --> 0:05:10.520 strange that nobody ever talked about that as an identity 0:05:10.600 --> 0:05:13.840 issue or even referred to it as an intersex condition. 0:05:13.920 --> 0:05:17.279 I actually figured that out as an adult. Nobody said 0:05:17.279 --> 0:05:21.000 those words. It was quite strange in respect, especially because 0:05:21.040 --> 0:05:24.839 they were always very clear that I wouldn't have my 0:05:24.880 --> 0:05:28.440 own children, that that just simply wasn't a physical possibility 0:05:28.480 --> 0:05:32.120 for me. And you would have thought that there would 0:05:32.160 --> 0:05:34.599 be a little bit more about that, but apparently not. 0:05:35.640 --> 0:05:38.320 Then again, I guess it affects so many different potential 0:05:38.360 --> 0:05:42.239 things that it's quite difficult to explain that to children, 0:05:42.480 --> 0:05:45.800 and I do now as an adult, really appreciate that. 0:05:46.480 --> 0:05:49.320 So now my adult life is kind of well, how 0:05:49.360 --> 0:05:52.720 many other things can it affect? Is this another thing 0:05:52.720 --> 0:05:54.240 that I need to worry about, or do I need 0:05:54.279 --> 0:05:55.960 to get check that checked out, or do I need 0:05:56.000 --> 0:06:00.679 to consider this other thing? So currently I get scans 0:06:00.680 --> 0:06:04.159 of my heart and my kidneys regularly, but also bone 0:06:04.200 --> 0:06:09.240 scans because along with the lack of natural estrogen is 0:06:09.279 --> 0:06:11.960 problems with your bone density. And due to some of 0:06:11.960 --> 0:06:15.080 the medical issues, I had to stop the HRT. I 0:06:15.160 --> 0:06:17.240 just recently had a bit of a concern that my 0:06:17.320 --> 0:06:20.520 parathyroid land wasn't working right, although apparently it's actually fine 0:06:20.560 --> 0:06:23.440 because I didn't know what a paradyeroid gland was until then. 0:06:24.279 --> 0:06:26.400 And the other biggest things at the moment, I guess 0:06:26.440 --> 0:06:29.480 are getting shoes that fit one foot. An ankle is 0:06:29.560 --> 0:06:32.240 notably bigger than the other, so that's a bit of 0:06:32.240 --> 0:06:34.960 a pain, though I'm very lucky and I can usually 0:06:35.000 --> 0:06:38.960 just about manage a pair that are officially the same size. 0:06:39.240 --> 0:06:41.400 But I do have to wear a support of stocking, 0:06:41.400 --> 0:06:44.960 which is sort of a pressure sock, and that is 0:06:44.960 --> 0:06:48.120 a pain, especially when it's really hot, because if I 0:06:48.160 --> 0:06:51.760 don't do that, then my ankle starts to swallow and 0:06:51.760 --> 0:06:54.040 my foot saws up and it also sort of aches, 0:06:55.120 --> 0:06:59.520 so I do wear my sock. I guess I'm almost 0:06:59.520 --> 0:07:01.479 certainly going to need a hearing aid at some point 0:07:01.560 --> 0:07:05.040 or another. If you go around a Turner syndrome convention 0:07:05.240 --> 0:07:07.599 or a Turner syndrome clinic waiting room, you will see 0:07:07.640 --> 0:07:10.480 lots of people with hearing aids, and I've sort of, 0:07:10.800 --> 0:07:16.080 I guess accepted that. I guess that's most of my story. 0:07:17.440 --> 0:07:20.320 It's a strange one to think that that your life 0:07:20.360 --> 0:07:23.000 is a story, because it really is absolutely everything to 0:07:23.080 --> 0:07:24.960 do with with who I am and how I live. 0:07:26.120 --> 0:07:28.000 I don't I don't know what it would be like 0:07:28.080 --> 0:07:31.960 to not have that, and trying to explain that is 0:07:32.000 --> 0:07:32.720 a bit strange. 0:07:32.880 --> 0:07:35.000 But I hope that was helpful. There you go. That's 0:07:35.040 --> 0:08:22.560 the end of my story. 0:08:23.320 --> 0:08:26.360 Thank you so so much, Katie for taking the time 0:08:26.360 --> 0:08:29.040 to chat and for sharing your story with us and 0:08:29.080 --> 0:08:30.280 with everyone. 0:08:30.520 --> 0:08:32.400 Yeah, thank you, we really appreciate it. 0:08:33.520 --> 0:08:35.880 Hi. I'm Aaron Welsh. 0:08:35.280 --> 0:08:37.240 And I'm Aaron Almond Updyke. 0:08:37.200 --> 0:08:39.439 And this is this podcast will Kill You. 0:08:39.760 --> 0:08:42.120 And today we're talking about Turner syndrome. 0:08:42.640 --> 0:08:43.040 We are. 0:08:44.040 --> 0:08:47.600 I believe that this is it's not our first genetic 0:08:47.640 --> 0:08:51.920 foray no, but I think it is of this season, 0:08:52.600 --> 0:08:56.800 and it's definitely our first chromosomal one. 0:08:57.200 --> 0:08:59.080 Oh yeah, that's a good point. We've only done like 0:08:59.360 --> 0:09:03.599 single gene I think, so, I think, right, I don't know, 0:09:05.160 --> 0:09:06.920 it's almost like we should keep a list or something. 0:09:07.040 --> 0:09:11.840 Eric, Oh, yeah, this is going to be a very 0:09:11.880 --> 0:09:15.400 interesting one. I don't know really anything at all about 0:09:15.400 --> 0:09:17.160 the biology, and so I can't wait to ask you 0:09:17.200 --> 0:09:19.000 a thousand genetics questions. 0:09:19.040 --> 0:09:21.280 Oh gosh, I can't wait to be like, I don't 0:09:21.280 --> 0:09:27.520 know the answer, but I'll try, so maybe before we 0:09:27.600 --> 0:09:30.240 do that. I think it's quarantin any time. 0:09:30.960 --> 0:09:34.120 I think it is. What are we drinking this week? 0:09:34.240 --> 0:09:39.520 We're drinking nothing but Nettie? And I love that. I 0:09:39.520 --> 0:09:41.480 don't actually know what that means yet, because I know 0:09:41.679 --> 0:09:44.280 it's about a researcher, but I haven't gotten to hear 0:09:44.320 --> 0:09:45.000 about her yet. 0:09:45.520 --> 0:09:48.280 Well you will definitely get to hear about her. We 0:09:48.520 --> 0:09:53.960 named our drink after Nettie Stevens, who was not as 0:09:54.000 --> 0:09:58.720 involved in Turner syndrome research, but was involved in uncovering 0:09:58.720 --> 0:09:59.360 what the X and. 0:09:59.440 --> 0:10:03.400 Y chrome is zomes do. And also she just. 0:10:03.880 --> 0:10:06.880 Like her story is so interesting and so inspirational, and 0:10:06.920 --> 0:10:09.760 so we just kind of wanted to pay tribute to Netti. 0:10:10.600 --> 0:10:12.080 And what is in nothing but Netti? 0:10:12.640 --> 0:10:19.599 In nothing but Netti is gin basil, some lemon, and cucumber. 0:10:19.679 --> 0:10:24.600 It's like very refreshing and delicious I love it. 0:10:24.480 --> 0:10:27.960 It sounds phenomen We'll post the full recipe for nothing 0:10:28.000 --> 0:10:30.959 but Netti, as well as our non alcoholic Plussy Burta 0:10:31.040 --> 0:10:33.280 on our website, This Podcast will Kill You dot Com 0:10:33.320 --> 0:10:35.240 and all of our social media channels. 0:10:35.720 --> 0:10:36.800 We sure will. 0:10:37.400 --> 0:10:40.280 On our website you can find a whole lot of stuff. 0:10:40.480 --> 0:10:43.800 We're not going to go through everything again. But I 0:10:43.920 --> 0:10:47.800 also just want to say real quick, because we've not 0:10:47.960 --> 0:10:52.680 been mentioning it that we are always happy to receive firsthand. 0:10:52.760 --> 0:10:56.240 So if you are interested in sharing one of your 0:10:56.280 --> 0:10:58.959 stories on the podcast, please reach out to us, preferably 0:10:59.040 --> 0:11:03.280 either through the content on our website or by emailing 0:11:03.360 --> 0:11:06.040 us directly at this Podcast will Kill You at gmail 0:11:06.080 --> 0:11:06.679 dot com. 0:11:07.840 --> 0:11:11.240 Well, Aaron, should we get started on the biology of 0:11:11.320 --> 0:11:12.200 Turner syndrome. 0:11:12.600 --> 0:11:32.319 Let's do it right after this break. 0:11:39.760 --> 0:11:43.480 So, Turner syndrome, like we said at the top, this 0:11:43.720 --> 0:11:49.080 is a genetic condition, and in this case, Turner syndrome 0:11:49.160 --> 0:11:53.559 is a condition that results from the partial or complete 0:11:53.760 --> 0:11:58.800 loss of one X chromosome. So before I get into 0:11:58.840 --> 0:12:01.600 any of what that means, I want to first set 0:12:01.679 --> 0:12:05.679 up some definitions of things that listeners probably are familiar with, 0:12:05.840 --> 0:12:08.760 at least from our high school biology classes, but that 0:12:08.840 --> 0:12:11.760 might have been a long time, so we'll go over it, 0:12:11.800 --> 0:12:16.120 shall we h. So our X chromosome is one of 0:12:16.160 --> 0:12:19.960 our sex chromosomes. So what on earth is a sex chromosome? 0:12:21.280 --> 0:12:27.240 We'll start there. Essentially, our chromosomes, chromosomes in general, our 0:12:27.400 --> 0:12:31.240 conglomerations of our DNA and the proteins that our DNA 0:12:31.280 --> 0:12:36.080 wraps itself around humans us we have a total of 0:12:36.160 --> 0:12:39.920 forty six chromosomes, and each of these are present in pairs, 0:12:40.200 --> 0:12:44.160 so we have twenty three pairs of chromosomes. Twenty two 0:12:44.200 --> 0:12:47.640 of these pairs are what are called autosomes, and one 0:12:47.760 --> 0:12:51.920 pair is our sex chromosomes. We get one of each 0:12:52.040 --> 0:12:55.720 of these pairs from our parents, one full set of 0:12:55.760 --> 0:12:59.640 twenty two plus one sex chromosome from the egg, and 0:12:59.720 --> 0:13:02.920 one full set of twenty two plus one sex chromosome 0:13:03.080 --> 0:13:07.439 from a sperm. Those come together and toda, a zygote 0:13:07.480 --> 0:13:12.160 is formed. We can look at chromosomes in humans by 0:13:12.200 --> 0:13:14.640 looking at what's called a karyotype, and this is a 0:13:14.679 --> 0:13:18.240 way of taking DNA from our cells and literally like 0:13:18.400 --> 0:13:20.920 laying it out so that you can see them. It's 0:13:21.120 --> 0:13:24.120 very cool. If you haven't seen images since high school 0:13:24.160 --> 0:13:27.440 bio will post them or you can google it also. 0:13:29.480 --> 0:13:33.920 And sex chromosomes in humans are our X and Y chromosome. 0:13:34.679 --> 0:13:38.520 They are called sex chromosomes because they, in large part 0:13:38.640 --> 0:13:43.880 are responsible for the initiation of sex determination. What that 0:13:44.040 --> 0:13:47.960 means is that our X and Y chromosomes are those 0:13:48.040 --> 0:13:52.079 that contain genes that result in the formation of our 0:13:52.160 --> 0:13:57.680 gonads and other reproductive structures. Sex determination is then furthered 0:13:57.679 --> 0:14:00.920 along during development by the production of sex steroids like 0:14:01.080 --> 0:14:05.480 estrogen and testosterone, which often come from our go ads, 0:14:06.080 --> 0:14:11.120 and then the development of secondary sexual characteristics. So in humans, 0:14:11.160 --> 0:14:12.480 you can kind of think of it as like a 0:14:12.520 --> 0:14:16.800 three step process of sex determination, and sex chromosomes are 0:14:17.400 --> 0:14:22.200 integral to that first step of the process, and because 0:14:22.240 --> 0:14:25.120 they are then resulting in the formation of these goads 0:14:25.400 --> 0:14:29.120 which produce sex steroids, they affect later stages as well. 0:14:29.600 --> 0:14:33.240 Cool mm hm. And everyone probably learned in high school 0:14:33.240 --> 0:14:36.760 biology that when it comes to sex chromosomes, X y 0:14:37.080 --> 0:14:41.680 equals male and xx equals female, and that might have 0:14:41.800 --> 0:14:45.320 been the last of what we all learned about sex chromosomes. 0:14:46.200 --> 0:14:48.560 So today we get to start the process in all 0:14:48.600 --> 0:14:52.280 of our brains of flipping that script because as we'll 0:14:52.280 --> 0:14:55.040 talk a lot about, It's not that simple. 0:14:55.480 --> 0:14:56.520 It's not that simple. 0:14:56.760 --> 0:14:58.120 It never is on this podcast. 0:14:58.280 --> 0:14:59.080 It really is not. 0:15:00.880 --> 0:15:04.560 So what is Turner syndrome? Then? Turner syndrome is what 0:15:04.600 --> 0:15:08.120 happens when an individual ends up with either an entirely 0:15:08.680 --> 0:15:13.080 or a partially missing X chromosome. And it turns out 0:15:13.080 --> 0:15:15.080 that when it's just a part of that X chromosome, 0:15:15.160 --> 0:15:17.960 it's often the tip of the short arm of the 0:15:18.160 --> 0:15:20.920 X chromosome, which, as I'll talk about later, is where 0:15:20.960 --> 0:15:23.520 many of the very important genes happen to sit. 0:15:24.080 --> 0:15:27.000 That's very interesting. Okay, I have a question already. 0:15:27.120 --> 0:15:28.680 Okay, shoot, give it to time. 0:15:29.560 --> 0:15:32.280 When it's completely missing, does there tend to be a 0:15:32.360 --> 0:15:36.240 pattern in whether it's missing from the sperm X or 0:15:36.320 --> 0:15:37.560 from the egg X? 0:15:37.840 --> 0:15:40.280 Great question. I think from what I read, it's more 0:15:40.320 --> 0:15:43.720 common that it's from the sperm X. So more commonly 0:15:43.760 --> 0:15:47.600 what you see is that the X chromosome that is 0:15:47.760 --> 0:15:52.560 present is from maternal DNA. So interesting. Yeah, and I 0:15:52.600 --> 0:15:54.640 don't think that we have a great idea as to 0:15:54.720 --> 0:15:56.720 why that is, at least not from what I read. 0:15:57.280 --> 0:15:57.680 Okay. 0:15:58.600 --> 0:16:02.360 And what's interesting too is that this can happen both 0:16:02.520 --> 0:16:05.440 part of the X chromosome and an entire X chromosome 0:16:05.520 --> 0:16:09.840 being kind of left behind during the process of miosis, 0:16:09.960 --> 0:16:15.400 which is formation of gamates, eggs, and sperm, or it 0:16:15.520 --> 0:16:20.440 can happen during mitosis. And what's very interesting is that 0:16:20.480 --> 0:16:24.360 Turner syndrome can also happen due to something called mosaicism, 0:16:24.960 --> 0:16:29.440 and this is when a fetus that becomes a human 0:16:30.560 --> 0:16:34.480 has multiple cell lines in their body. And this happens 0:16:34.520 --> 0:16:39.920 when during very early cell division in like a forming zygote, 0:16:40.480 --> 0:16:44.800 there is abnormal mitosis that results to some cells having 0:16:44.920 --> 0:16:48.320 say only one X chromosome, and some cells having two 0:16:48.440 --> 0:16:49.200 X chromosomes. 0:16:49.720 --> 0:16:54.840 And so if you looked at the caryotype of this person, 0:16:55.200 --> 0:16:58.680 some cells would have two x's and some cells would 0:16:58.720 --> 0:17:01.120 have XO or like just one X. 0:17:01.200 --> 0:17:01.720 Yeah yeah. 0:17:01.920 --> 0:17:03.960 So the way that they tend to write these when 0:17:04.040 --> 0:17:07.119 you are writing out the result of a caryotype is 0:17:07.200 --> 0:17:12.080 someone with complete monosomey of the X chromosome with Turner 0:17:12.119 --> 0:17:16.760 syndrome would have the caryotype forty five comma X or 0:17:16.800 --> 0:17:20.639 forty five comma XO. It's sometimes written someone who was 0:17:20.680 --> 0:17:25.000 a mosaic could have the caryotype forty five X. In 0:17:25.040 --> 0:17:29.679 some of their cells and forty six xx or forty 0:17:29.720 --> 0:17:36.360 six x Y in other cells. Okay, so already how interesting. 0:17:37.320 --> 0:17:42.720 Yeah, And so Turner syndrome is not just one X. 0:17:43.040 --> 0:17:46.800 It's not just the mosaicism of two x's and some 0:17:46.960 --> 0:17:50.800 cells one x and other cells. It's also x y 0:17:51.440 --> 0:17:53.719 in some cells and X in others. 0:17:54.160 --> 0:17:59.520 Yes, it absolutely can be interesting. Yes, And I'll get 0:17:59.520 --> 0:18:02.320 into a little bit more too about the intricacies that 0:18:02.400 --> 0:18:05.919 might arise when somebody might have that carriotype of forty 0:18:05.960 --> 0:18:09.159 five X and forty six x Y, because, as it 0:18:09.160 --> 0:18:11.719 turns out, it results in some different organ structure that 0:18:11.760 --> 0:18:14.360 can have different effects down the line. Ooh, we'll get there. 0:18:14.520 --> 0:18:16.920 Whoa okay, okay, Yeah, And. 0:18:16.960 --> 0:18:20.040 Those are not the only caryotypes that can exist. This again, 0:18:20.119 --> 0:18:23.240 can be just from a partially missing or a structurally 0:18:23.359 --> 0:18:26.760 abnormal X chromosome. So you could have someone that is 0:18:27.000 --> 0:18:30.879 forty six xx but missing part of that X chromosome. 0:18:31.520 --> 0:18:34.919 So really the crucial thing is that that part of 0:18:34.960 --> 0:18:36.399 the X chromosome is gone. 0:18:36.680 --> 0:18:41.520 Yep. Okay, So there's a lot of possibilities there. Now, 0:18:41.600 --> 0:18:45.840 before we dive too deep into what this looks like 0:18:46.040 --> 0:18:49.080 or what this results in, I also want to make 0:18:49.119 --> 0:18:52.520 a quick disclaimer, especially for anyone who's going to go 0:18:52.600 --> 0:18:55.840 back and read some of the literature of Turner syndrome, 0:18:56.440 --> 0:18:58.680 and that is that in a lot of the literature, 0:18:58.800 --> 0:19:03.000 Turner syndrome is carearacterized as a condition of women and girls, 0:19:03.840 --> 0:19:08.960 and this characterization isn't entirely accurate, largely because gender is 0:19:09.040 --> 0:19:12.440 a social construct and it's not the same thing as sex, 0:19:13.119 --> 0:19:16.919 which tends to be a biological characterization that is in 0:19:17.080 --> 0:19:20.600 large part, as I said, driven by genetics and particular 0:19:21.040 --> 0:19:25.879 sex chromosomes. So the characterization of Turner syndrome as a 0:19:25.920 --> 0:19:29.679 condition of women and girls isn't accurate. On top of that, 0:19:30.200 --> 0:19:33.120 I think that what conditions like Turner syndrome show us 0:19:33.480 --> 0:19:36.960 is that even this idea of sex as a binary 0:19:37.080 --> 0:19:41.600 of male and female isn't entirely accurate either. Our genetics 0:19:41.600 --> 0:19:43.639 are not nearly as black and white as what we 0:19:43.720 --> 0:19:46.720 learned in high school, and so some of the papers 0:19:46.720 --> 0:19:50.159 that I read referred to Turner syndrome rather as a 0:19:50.200 --> 0:19:55.560 condition that affects phenotypic females, that is, individuals who have, 0:19:55.880 --> 0:20:00.600 especially at birth, a phenotype, a set of observable, often 0:20:00.680 --> 0:20:07.000 physical characteristics that make them be labeled as female. So 0:20:07.920 --> 0:20:11.160 just sort of throwing all that out there. Yeah, So 0:20:11.240 --> 0:20:18.080 what does Turner syndrome look like or result in? Unsurprisingly, 0:20:18.440 --> 0:20:22.359 given the variety of genotypes and caryotypes that I just discussed, 0:20:22.560 --> 0:20:26.040 there is a large amount of variation in what the 0:20:26.119 --> 0:20:30.080 phenotype can actually be. And what that means is that 0:20:30.119 --> 0:20:32.840 there's also a lot of variation in what the downstream 0:20:32.920 --> 0:20:36.480 effects or potential medical conditions that might come along with 0:20:36.560 --> 0:20:40.080 Turner syndrome are. And when you read back through a 0:20:40.080 --> 0:20:42.560 lot of the literature, especially as we get into what 0:20:42.680 --> 0:20:46.080 the epidemiology of Turner syndrome really is, there's also an 0:20:46.080 --> 0:20:49.320 important distinction to be made between people who might have 0:20:49.480 --> 0:20:54.560 a particular carriotype, so a particular set of chromosomes, and 0:20:54.760 --> 0:20:59.119 whether people have any observable characteristics that are associated with 0:20:59.200 --> 0:21:03.119 Turner syndrome. So, in more modern definitions, you have to 0:21:03.240 --> 0:21:07.280 have both the caryotype where you are missing part or 0:21:07.359 --> 0:21:10.160 all of an X chromosome in at least some proportion 0:21:10.240 --> 0:21:13.800 of your cells, as well as a couple in particular 0:21:14.320 --> 0:21:18.720 of characteristics that go along with Turner syndrome to actually 0:21:18.760 --> 0:21:20.680 meet the definition of Turner syndrome. 0:21:21.320 --> 0:21:27.080 Okay, so the number of individuals that might be missing 0:21:27.320 --> 0:21:31.560 that portion of the X could be higher than the 0:21:31.680 --> 0:21:39.600 number of individuals that are diagnosed with Turner syndrome. Absolutely, yes, Okay, 0:21:39.640 --> 0:21:41.280 do we know what that difference is. 0:21:41.480 --> 0:21:43.520 It's a great question. I'll talk more about it in 0:21:43.520 --> 0:21:47.280 the current event section. The short answer is like, not really. 0:21:47.359 --> 0:21:48.920 No, Yeah, okay, that makes sense. 0:21:49.320 --> 0:21:51.840 Yeah, but we'll get there. But first let's talk about 0:21:51.880 --> 0:21:55.840 what are those characteristics to add to this carriotype to 0:21:55.920 --> 0:22:00.880 then result in this diagnosis of Turner syndrome. The two 0:22:01.359 --> 0:22:07.880 main things that we see are short stature and gonadal insufficiency, 0:22:08.280 --> 0:22:12.240 So that means generally what's called primary amenorehea, so not 0:22:12.320 --> 0:22:16.600 ever starting mensis or sometimes initiation of mensis that then 0:22:16.840 --> 0:22:20.360 over a couple of years stops and results in what's 0:22:20.400 --> 0:22:23.879 called secondary amenarea, so no longer having periods after just 0:22:23.920 --> 0:22:27.560 a couple of years. There are a lot of other 0:22:27.720 --> 0:22:31.760 things that can go along with this, like congenital heart 0:22:31.840 --> 0:22:37.960 defects and other heart conditions, kidney abnormalities, and a whole 0:22:38.000 --> 0:22:40.600 bunch of other things. And instead of just listing what 0:22:40.680 --> 0:22:43.840 they all are, what I want to do is kind 0:22:43.880 --> 0:22:48.160 of focus on those two in particular, most common characteristics, 0:22:48.200 --> 0:22:52.800 the short stature and the gonatal insufficiency. What we know 0:22:53.119 --> 0:22:57.359 about why we see those characteristics, like as it relates 0:22:57.440 --> 0:23:01.280 to this missing X chromosome, and then in that process 0:23:01.440 --> 0:23:04.760 we'll see what a lot of these other characteristic findings 0:23:04.880 --> 0:23:09.919 might be. Does that sound good? Yeah? Okay, spoiler, We 0:23:10.080 --> 0:23:13.040 don't have all the answers to this, like by a 0:23:13.040 --> 0:23:17.080 long shot, but the overall basis for a lot of 0:23:17.119 --> 0:23:20.359 the phenotypic characteristics as well as some of the medical 0:23:20.359 --> 0:23:23.719 conditions that can arise with Turner syndrome is something called 0:23:24.119 --> 0:23:28.760 Haplow insufficiency. What a great word. It basically just means 0:23:28.840 --> 0:23:34.639 there's not enough gene product being produced to preserve normal function. Okay, 0:23:34.800 --> 0:23:37.120 So we talked in some of our other genetics episodes 0:23:37.160 --> 0:23:40.639 like cystic fibrosis and sickle celenemia about this idea of 0:23:40.800 --> 0:23:44.560 recessive genetic disorders, like you need two copies of an 0:23:44.560 --> 0:23:48.840 abnormal gene to actually have the disease, because one copy 0:23:48.880 --> 0:23:52.119 that's normal gives you enough of whatever it is to 0:23:52.280 --> 0:23:55.639 like not have disease. So this is like it's like 0:23:55.680 --> 0:24:01.200 that same idea, except kind of different because it's chromosome and. 0:24:01.119 --> 0:24:03.119 It's like the same thing but kind of different. 0:24:03.440 --> 0:24:06.040 You know, I feel like it's a decent enough analogy. 0:24:06.480 --> 0:24:10.560 No it is, I'm with you, I get, but it's 0:24:10.600 --> 0:24:12.960 I guess it's that it's dominant, Like you really do 0:24:13.080 --> 0:24:16.840 need two copies of some of these genes to not 0:24:17.040 --> 0:24:21.560 have problems arise. Yeah, So here's where it gets even 0:24:21.560 --> 0:24:24.840 more interesting. Because you're dealing with sex chromosomes. In people 0:24:24.840 --> 0:24:29.199 who are forty six XX. They obviously have two X chromosomes, 0:24:29.240 --> 0:24:32.000 which is twice as many as somebody who is forty 0:24:32.040 --> 0:24:35.320 six X Y would have. And as it turns out, 0:24:35.359 --> 0:24:38.720 the X chromosome is a gene rich chromosome that has 0:24:38.800 --> 0:24:42.440 over a thousand genes on it, while the Y chromosome 0:24:42.560 --> 0:24:46.639 has less than two hundred. So what happens in the 0:24:46.680 --> 0:24:50.640 bodies of people who are forty six XX to prevent 0:24:50.960 --> 0:24:55.439 over expression too much of these one thousand genes is 0:24:55.440 --> 0:24:59.359 that one of the xes is actually inactivated. It's turned 0:24:59.359 --> 0:25:03.119 off in body cells, in the somatic cells, but not 0:25:03.440 --> 0:25:06.920 the gonadal cells in the ovaries. Of people who have 0:25:07.040 --> 0:25:10.640 two copies of this X chromosome. This is a process 0:25:10.680 --> 0:25:17.560 that's called silencing or X inactivation. But fifteen to twenty 0:25:17.560 --> 0:25:20.920 five percent of these one thousand genes are not in 0:25:20.960 --> 0:25:25.119 fact silenced, right, And these genes are called escape genes 0:25:25.160 --> 0:25:29.359 because they escape in activation or silencing. And these are 0:25:29.400 --> 0:25:32.720 the genes that we need and want to have two 0:25:32.760 --> 0:25:35.800 copies of in order to have enough gene product for 0:25:35.920 --> 0:25:40.119 normal function, in order to not have that HAPLO insufficiency. 0:25:41.359 --> 0:25:44.280 And do you know where else many of these genes 0:25:44.320 --> 0:25:45.480 are located. 0:25:45.760 --> 0:25:48.440 On the why I'm assuming all the WA chromosome. 0:25:49.280 --> 0:25:50.600 Isn't that so interesting? 0:25:51.000 --> 0:25:52.760 It is? This is really interesting. 0:25:53.119 --> 0:25:57.040 So, even though we don't necessarily know everything there is 0:25:57.080 --> 0:26:01.000 to know about the specific mech chganisms of some of 0:26:01.040 --> 0:26:04.360 what we see in Turner syndrome, in general, it's these 0:26:04.400 --> 0:26:08.240 specific genes, many of which are located on the tip 0:26:08.280 --> 0:26:11.480 of the short arm of the X chromosome, that part 0:26:11.560 --> 0:26:15.320 that's often missing in people with Turner syndrome. It's these 0:26:15.480 --> 0:26:19.119 escape genes that likely lead to many of the characteristics 0:26:19.200 --> 0:26:22.040 or conditions that we can see arise in Turner syndrome. 0:26:22.760 --> 0:26:26.280 That's fascinating. Okay, so what are these genes? 0:26:26.400 --> 0:26:29.919 Great questions? So glad you asked, Yeah, So, out of 0:26:29.960 --> 0:26:35.119 all those genes, we actually have one that we know 0:26:35.359 --> 0:26:38.800 for sure that we have good evidence of the kind 0:26:38.800 --> 0:26:42.720 of exact effect that we see due to haplo insufficiency. 0:26:43.560 --> 0:26:49.399 That gene is called SHOCKS SHO X, and this is 0:26:49.440 --> 0:26:53.480 a gene that is normally not inactivated on the X chromosome. 0:26:53.680 --> 0:26:56.840 It is present on both X and Y chromosomes, and 0:26:56.880 --> 0:27:01.480 it stands for short stature homeobox containing gene on the 0:27:01.720 --> 0:27:08.080 X chromosome shocks SHOCKS. So this particular gene SHOCKS is 0:27:08.119 --> 0:27:11.720 in a family of genes called homabox genes, which are 0:27:12.040 --> 0:27:14.800 really important genes, like a whole suite of them that 0:27:15.200 --> 0:27:21.680 regulate really key developmental processes during embryo genesis, during the 0:27:21.720 --> 0:27:25.639 process of the formation of an eventual human and in 0:27:25.680 --> 0:27:30.159 the case of Shocks, this gene is expressed during embryonic 0:27:30.200 --> 0:27:34.199 development in very specific tissues, including on the first and 0:27:34.280 --> 0:27:38.399 second pharyngeal arches. Who cares what that is, but what 0:27:38.600 --> 0:27:43.240 those structures develop into in the fetus are the maxilla, 0:27:43.280 --> 0:27:45.520 which is the top part of your jaw, and the 0:27:45.560 --> 0:27:48.360 mandible which is the bottom part of your jaw, as 0:27:48.400 --> 0:27:51.639 well as parts of your inner and outer and middle ear. 0:27:52.480 --> 0:27:55.240 It also is involved in muscles that are involved in 0:27:55.320 --> 0:27:59.080 chewing and hearing. This gene is involved in your soft 0:27:59.200 --> 0:28:04.040 palate and a whole host of other skeletal areas in 0:28:04.080 --> 0:28:06.840 the legs, in the hands. So this is a big 0:28:06.880 --> 0:28:12.400 deal gene and decreased expression of this one gene out 0:28:12.440 --> 0:28:16.120 of hundreds that are likely involved in particular, is the 0:28:16.160 --> 0:28:20.600 most strongly and convincingly correlated with some of the characteristics 0:28:20.600 --> 0:28:24.440 that are often seen in Turner syndrome. So we can 0:28:24.440 --> 0:28:27.760 talk about what some of those are. Yeah, they are 0:28:27.800 --> 0:28:31.280 things like developmental changes to the inner, middle, or outer 0:28:31.400 --> 0:28:34.679 ears that can lead to things like having ears that 0:28:34.720 --> 0:28:38.400 are low set, so lower on the cranium than is typical, 0:28:39.960 --> 0:28:43.200 which can lead to things like chronic ear infections, especially 0:28:43.200 --> 0:28:50.400 in childhood. Very commonly, either that process or other variability 0:28:50.440 --> 0:28:53.200 in the structure of the ear leads to some degree 0:28:53.240 --> 0:28:56.320 of hearing loss in people with Turner syndrome, which can 0:28:56.360 --> 0:28:58.960 manifest in a lot of different ways. It's usually not 0:28:59.200 --> 0:29:05.080 completeess but varying degrees of different forms of hearing loss. Interestingly, 0:29:07.000 --> 0:29:12.520 we also sometimes see things like scoliosis as well as osteoporosis, 0:29:12.600 --> 0:29:16.200 though that one is multifactorial, and that's because of some 0:29:16.240 --> 0:29:19.600 of the effects of shocks on the development of the skeleton, 0:29:20.240 --> 0:29:23.960 as well as other variations in the growth of the feet, 0:29:24.160 --> 0:29:27.360 or the ankles or the hands, many of which can 0:29:27.360 --> 0:29:28.560 be seen in Turner syndrome. 0:29:29.640 --> 0:29:32.520 It's so much, I know. 0:29:35.240 --> 0:29:38.600 There is also something that can be seen quite commonly 0:29:38.800 --> 0:29:43.840 in developing fetuses that have Turner syndrome on ultrasound that's 0:29:43.840 --> 0:29:48.440 called acystic hygroma. This is a collection of lymphatic fluid 0:29:48.520 --> 0:29:50.440 that often forms on the back of the neck and 0:29:50.480 --> 0:29:54.880 forms into this cyst. This process is likely due not 0:29:54.960 --> 0:29:58.040 only to shocks, but to potentially multiple genes that are 0:29:58.080 --> 0:30:02.520 related to lymphatic drainage. But in many cases, this cyst 0:30:02.680 --> 0:30:06.240 that's seen during fetal development resolves and can leave behind 0:30:06.400 --> 0:30:08.360 a more web shaped neck. 0:30:09.000 --> 0:30:10.320 Okay, so that's. 0:30:10.120 --> 0:30:13.720 A feature that's associated with Turner syndrome. It can also 0:30:13.880 --> 0:30:19.000 lead to a small mandible, so a slightly underdeveloped lower jaw, 0:30:19.720 --> 0:30:21.840 or a narrow palette on the roof of the mouth, 0:30:21.880 --> 0:30:24.720 which can sometimes lead to dental problems later in life. 0:30:26.440 --> 0:30:29.840 But probably the biggest and one of the singular defining 0:30:30.000 --> 0:30:34.840 features of Turner syndrome that has been very strongly shown 0:30:34.840 --> 0:30:38.520 to be associated with insufficiency of this gene in particular 0:30:38.800 --> 0:30:43.120 is the short stature that we often see in general. 0:30:43.200 --> 0:30:46.320 People with Turner syndrome reach average adult heights that are 0:30:46.360 --> 0:30:50.480 about twenty centimeters shorter than average when compared I should 0:30:50.520 --> 0:30:53.400 say to people who are forty six x x of 0:30:53.480 --> 0:30:58.280 their same ethnicity or race. Okay, And while there is 0:30:58.360 --> 0:31:02.280 obviously a very huge range of like full adult height, 0:31:03.120 --> 0:31:08.160 individuals with Turner syndrome often also show decreased growth trajectories 0:31:08.320 --> 0:31:11.840 both during fetal development as well as early childhood, so 0:31:11.880 --> 0:31:13.920 they can kind of fall off what we call their 0:31:14.040 --> 0:31:19.880 growth curves. But height, of course, is something that is multifactorial. 0:31:19.920 --> 0:31:23.840 It's not determined by this one specific gene. So the 0:31:24.040 --> 0:31:29.120 other reason that people with Turner syndrome often don't attain 0:31:29.680 --> 0:31:33.640 as great of a height as would be predicted, like 0:31:33.800 --> 0:31:38.080 especially by their parental heights, is because of a lack 0:31:38.160 --> 0:31:41.640 of a pubertal growth spurt. Why do we see the 0:31:41.720 --> 0:31:44.400 lack of a pubertal growth spurt. Well, that's because of 0:31:44.440 --> 0:31:47.720 the effects of Turner syndrome on gonadal function. So let's 0:31:47.720 --> 0:31:48.600 get into that, shall we. 0:31:49.040 --> 0:31:50.560 Yeah, I'm excited about this. 0:31:50.560 --> 0:31:55.520 Me too. I love talking about gonads. So in the ovaries, 0:31:56.240 --> 0:32:00.720 X chromosomes are not turned off entirely. It's only in 0:32:00.800 --> 0:32:04.440 our somatic cells. It's not just certain genes in the ovaries. 0:32:04.720 --> 0:32:07.800 It's the entirety of the X chromosome. Both of them 0:32:07.840 --> 0:32:11.600 are supposed to remain active. So if someone has part 0:32:11.880 --> 0:32:15.040 or all of their X chromosome missing, even if it's 0:32:15.240 --> 0:32:18.160 only in the gonads, such as, for example, in the 0:32:18.200 --> 0:32:21.800 case of a mosaicism, then there's going to be haplo 0:32:21.880 --> 0:32:25.480 insufficiency of genes involved in the function of the ovaries. 0:32:26.200 --> 0:32:29.920 We don't know in particular necessarily which genes these are, 0:32:30.160 --> 0:32:34.040 because could be any of them. But what this leads 0:32:34.120 --> 0:32:37.600 to is the loss of oocytes or eggs in the 0:32:37.640 --> 0:32:40.440 ovaries at a much more rapid pace than is typical, 0:32:41.400 --> 0:32:45.720 and this in turn leads to changes in hormone secretions, 0:32:45.800 --> 0:32:49.400 specifically our sex steroids, because our ovaries are what is 0:32:49.480 --> 0:32:53.080 secreting those hormones that then talk to our brain, which 0:32:53.120 --> 0:32:56.480 secretes more hormones to talk to various parts of our 0:32:56.520 --> 0:33:02.120 body to grow, especially during puberty, and also to do 0:33:02.200 --> 0:33:07.640 things like grow breasts, grow adult hair patterns, armpits, genitals, 0:33:07.680 --> 0:33:12.440 et cetera, and eventually begin ovulation and then menstruation. In 0:33:12.480 --> 0:33:16.760 the case of ovaries, so we first of all don't 0:33:16.800 --> 0:33:21.560 see this pubertal growth spurt, and most often we also 0:33:21.720 --> 0:33:24.600 don't see menarc or the beginning of menstruation. 0:33:25.320 --> 0:33:30.040 Okay, so what about people who have a Y chromosome? 0:33:30.160 --> 0:33:34.040 How does this picture differ or how is it the same? 0:33:34.560 --> 0:33:38.520 Great great question. So it can get fairly complicated because 0:33:38.560 --> 0:33:42.520 there's a lot of potential ways that that caryotype can 0:33:43.120 --> 0:33:46.760 present where people might have part or all of a 0:33:46.880 --> 0:33:51.080 Y chromosome. But what can often happen, especially if someone 0:33:51.320 --> 0:33:54.720 is a mosaic that is, say forty five x in 0:33:54.800 --> 0:33:57.280 some of their cells and forty six x Y in 0:33:57.400 --> 0:34:03.200 other cells, often will not form true ovaries, but will 0:34:03.280 --> 0:34:07.520 rather form testes that then remain in the abdominal cavity 0:34:07.960 --> 0:34:10.800 rather than ending up in a scrotum because there generally 0:34:10.840 --> 0:34:14.160 is no scrotum, there is phenotypically female genitals. 0:34:14.560 --> 0:34:15.880 Okay, gotcha. 0:34:16.600 --> 0:34:18.719 And one of the big risk factors with this in 0:34:18.760 --> 0:34:22.520 particular is that when testicles remain in the abdomen, they're 0:34:22.520 --> 0:34:26.560 at higher risk of developing into certain types of gonadal cancers. 0:34:26.840 --> 0:34:27.600 Why is that? 0:34:28.480 --> 0:34:31.560 I think it in part has to do with temperature differences, 0:34:31.600 --> 0:34:36.520 but I'll be honest, I don't fully know. It's very interesting, Okay, yeah, 0:34:36.560 --> 0:34:39.719 And that's true across the board. If testies are retained 0:34:39.719 --> 0:34:43.480 in the abdomen, it's not specific to Turner syndrome. Okay, yeah, 0:34:43.520 --> 0:34:47.520 all right, But in all of these cases when it 0:34:47.600 --> 0:34:51.520 comes to gonadal insufficiency, whether we're talking about ovaries that 0:34:51.560 --> 0:34:55.560 are not fully developed, or we're talking about testes that 0:34:55.680 --> 0:35:01.200 might be retained or some combination thereof, because that's also possible. 0:35:02.000 --> 0:35:05.759 One big potential consequence of this is infertility, and so 0:35:05.920 --> 0:35:09.640 then the need for assisted reproductive technologies. If somebody decides 0:35:09.680 --> 0:35:11.560 that they want to try and get pregnant later on, 0:35:12.160 --> 0:35:16.239 what would that consist of, usually IVF and possibly with 0:35:16.400 --> 0:35:20.719 donor oocytes. It all just depends on what an individual's 0:35:20.719 --> 0:35:25.600 phenotype is and how much ovarian reserve they have, if any. Okay, gotchyah, 0:35:26.600 --> 0:35:29.399 And I do want to emphasize that this is a 0:35:29.840 --> 0:35:34.279 condition that has a very wide spectrum of phenotype. So 0:35:34.360 --> 0:35:38.480 some people about a third of people with Turner syndrome 0:35:38.719 --> 0:35:44.319 do initiate menstruation spontaneously, but the majority of them do 0:35:44.520 --> 0:35:48.800 then enter this secondary amnareea at a much more rapid 0:35:48.880 --> 0:35:51.040 rate than is typical for menopause. 0:35:51.880 --> 0:35:56.560 Okay, I have a question about the proportions of different 0:35:56.640 --> 0:36:01.200 carrier types, So like, in terms of Turner syndrome and 0:36:01.239 --> 0:36:04.880 people with Turner syndrome, what proportion of them are forty 0:36:04.880 --> 0:36:08.719 five X, what proportion of them are you know, have 0:36:08.840 --> 0:36:11.799 some misaicism, What proportions of them have a Y chromosome? 0:36:12.040 --> 0:36:13.160 What does that breakdown look like? 0:36:13.480 --> 0:36:16.520 Love that you asked. In general, most papers that I 0:36:16.560 --> 0:36:19.799 read estimate forty five to fifty percent of people with 0:36:19.840 --> 0:36:23.960 Turner syndrome are forty five X. That's their carriotype. About 0:36:24.000 --> 0:36:27.800 twenty to thirty percent of people have some kind of mosaicism, 0:36:28.040 --> 0:36:31.239 be that forty five X with forty six xx or 0:36:32.120 --> 0:36:35.799 xx y, forty seven xx y or et cetera, et cetera. 0:36:35.880 --> 0:36:38.760 There's a lot of possibility there, and then the rest 0:36:39.000 --> 0:36:42.279 have some other type of structural abnormality of one of 0:36:42.280 --> 0:36:48.720 those X chromosomes. Okay, so huge variation. Yeah, but wait, Aaron, 0:36:49.160 --> 0:36:56.560 there's more. Now, another very medically important condition that can 0:36:56.600 --> 0:37:00.279 arise as a result of Turner syndrome. And I'll just 0:37:00.400 --> 0:37:05.520 treface saying we do not understand the exact gene underpinnings. 0:37:05.560 --> 0:37:11.399 Here are a variety of congenital heart defects, and this 0:37:11.520 --> 0:37:14.480 can really range. One of the most common is what's 0:37:14.520 --> 0:37:17.800 called a bicuspid aortic valve. This is the valve between 0:37:17.840 --> 0:37:21.520 your left ventricle and your aorta, and like all of 0:37:21.560 --> 0:37:23.920 your valves in your heart are pretty important, but this 0:37:24.040 --> 0:37:30.000 one's like very important and it typically has three leaflets, 0:37:30.719 --> 0:37:34.040 but in a bicuspid valve there's only two. That means 0:37:34.040 --> 0:37:36.440 that these two leaflets are under a lot more stress, 0:37:36.640 --> 0:37:39.759 and that can lead to stiffness of these valves and 0:37:39.800 --> 0:37:42.360 then eventually insufficiency of this valve. 0:37:42.600 --> 0:37:43.000 Okay. 0:37:43.800 --> 0:37:48.640 Another condition that's even a little scarier is aortic root dilation, 0:37:48.800 --> 0:37:51.800 which means the root the first part of the aorta 0:37:51.840 --> 0:37:54.400 as it comes off of the heart. And as a 0:37:54.440 --> 0:37:58.000 reminder for all listeners, your aorta is what carries your 0:37:58.040 --> 0:38:02.640 blood to literally all the rest of your body. When 0:38:02.680 --> 0:38:07.839 this gets enlarged, and this enlargement makes it weaker, and 0:38:07.960 --> 0:38:10.760 this can then put you at risk for not only 0:38:10.840 --> 0:38:14.600 that aortic insufficiency where not enough blood is making it 0:38:14.640 --> 0:38:17.719 into your aorda to give blood to your body, but 0:38:17.800 --> 0:38:20.719 it also can put you at risk for aortic dissection, 0:38:21.160 --> 0:38:24.360 which is where the wall of the aorta comes apart, 0:38:24.400 --> 0:38:25.720 and that can be life threatening. 0:38:25.960 --> 0:38:26.920 Yeah. 0:38:27.200 --> 0:38:30.239 Turner syndrome can also be associated with other abnormalities like 0:38:30.360 --> 0:38:33.520 coorctation of the aorda, which is where later on in 0:38:33.560 --> 0:38:36.279 the course, the aorta kind of pinches in like gets 0:38:36.320 --> 0:38:40.080 more narrow, which can lead to increased pressure in some 0:38:40.239 --> 0:38:43.000 spots and decreased pressure in others. So you're not getting 0:38:43.360 --> 0:38:47.280 adequate blood flow to all of the body. And honestly, 0:38:47.320 --> 0:38:50.400 there's a lot of other potential congenital heart defects that 0:38:50.480 --> 0:38:53.960 can result as well. There's a few candidate genes that 0:38:54.040 --> 0:38:57.160 might be involved, and one paper that I read, which 0:38:57.280 --> 0:39:00.319 of course I will link to, really suggested that it's 0:39:00.560 --> 0:39:04.759 likely a two step process where there's likely genes that 0:39:04.800 --> 0:39:08.960 are involved, but then particular alleles that put you at 0:39:09.080 --> 0:39:13.120 higher risk for having these heart abnormalities. Like not just yeah, 0:39:13.200 --> 0:39:16.640 so it's not just a Haflo insufficiency issue, but yes, 0:39:16.760 --> 0:39:20.640 there's a lot of possibilities in terms of what the 0:39:21.160 --> 0:39:23.279 anomalies that we see in the heart can be, and 0:39:23.320 --> 0:39:26.320 so we don't have exact answers as to the cause. 0:39:27.160 --> 0:39:29.880 And that is true when it comes to a number 0:39:29.920 --> 0:39:33.759 of other phenotypic characteristics or medical conditions that can be 0:39:33.840 --> 0:39:37.640 seen in people with Turner syndrome. I can go through 0:39:37.719 --> 0:39:40.120 what some of them are, but we really don't have 0:39:40.200 --> 0:39:42.440 as clear of an idea when it comes to these 0:39:43.160 --> 0:39:48.040 less common conditions or characteristics, like what the genes are 0:39:48.080 --> 0:39:53.040 that are involved, or largely what kind of complex gene 0:39:53.040 --> 0:39:56.399 and hormonal interactions might lead to some of these. 0:39:56.840 --> 0:40:01.360 It's so incredibly complicated, it's it really really boggles the mind. 0:40:01.680 --> 0:40:04.880 So we can see things like kidney abnormalities, and just 0:40:05.000 --> 0:40:08.520 like with heart anomalies, can general heart anomalies, these can 0:40:08.600 --> 0:40:12.120 really range in terms of what kinds of structural kidney 0:40:12.200 --> 0:40:15.960 changes that we can see. People with Turner syndrome often 0:40:16.040 --> 0:40:19.279 also tend to be at higher risk for autoimmune conditions, 0:40:19.520 --> 0:40:24.240 especially thyroid disease, but also inflammatory bowel disease and others. 0:40:25.480 --> 0:40:28.640 They tend to be at higher risk for hypertension, and 0:40:28.719 --> 0:40:32.040 there's some questions arising as to whether they are also 0:40:32.120 --> 0:40:36.080 at higher risk for diabetes. Seems clear that they are 0:40:36.080 --> 0:40:41.000 at higher risk for osteoporosis, which is largely hormonally as 0:40:41.080 --> 0:40:44.920 well as gene regulated. Because estrogen is really important in 0:40:45.040 --> 0:40:50.160 healthy bone growth. Yeah, and in some cases, individuals with 0:40:50.239 --> 0:40:54.719 Turner syndrome can have difficulties in visual and spatial processing 0:40:55.200 --> 0:40:59.200 or visual motor tasks that can make some aspects of 0:40:59.280 --> 0:41:03.839 academics harder in some cases. But in general, there's very 0:41:03.960 --> 0:41:08.600 rarely any kind of global developmental delay or global learning 0:41:08.600 --> 0:41:13.000 disabilities or anything like that, which is very interesting, especially 0:41:13.120 --> 0:41:16.480 when it compares to many of the other annuploides or 0:41:16.560 --> 0:41:22.160 chromosomal genetic syndromes that we see. And I would say 0:41:22.200 --> 0:41:25.560 as well, there's a paucity of data on the potential 0:41:25.560 --> 0:41:28.680 psychosocial effects of living with Turner syndrome. 0:41:28.840 --> 0:41:31.280 I'm sure the research has really only just begun. 0:41:31.480 --> 0:41:33.359 It barely exists. 0:41:37.880 --> 0:41:43.560 Okay, So I have a couple questions about treatment number one, 0:41:43.800 --> 0:41:44.600 gene therapy. 0:41:46.120 --> 0:41:46.840 Does it exist? 0:41:47.120 --> 0:41:50.560 Great question? I saw nothing in my research about gene therapy. 0:41:51.640 --> 0:41:56.160 My guess is that it's largely because the shocks gene 0:41:56.200 --> 0:41:59.400 is the only one that we have like pretty decent 0:41:59.440 --> 0:42:04.319 evidence of its effect, whereas all of the rest of them, 0:42:04.440 --> 0:42:07.520 we're like, yes, we know that these like escape genes 0:42:07.560 --> 0:42:10.000 are potential targets, but we don't even know what they 0:42:10.040 --> 0:42:11.799 do yet, right, Yeah, we. 0:42:11.760 --> 0:42:13.480 Don't want to just like throw a bunch in there 0:42:13.480 --> 0:42:15.600 and be like, eh, then maybe this is okay, right 0:42:15.760 --> 0:42:17.360 exactly Okay. 0:42:17.480 --> 0:42:22.040 So then my other question is treatment in terms of timing. 0:42:22.600 --> 0:42:26.360 So a lot of the things you described happen during 0:42:26.600 --> 0:42:29.560 development while you're a fetus, while you're an embryo, while 0:42:29.600 --> 0:42:34.200 you're a fetus, Yeah, but not everything, and so how 0:42:34.239 --> 0:42:36.319 does treatment play into that? 0:42:37.120 --> 0:42:39.920 Such a great question. So when it comes to the 0:42:39.960 --> 0:42:43.960 things that might happen during development, like say cardiac anomalies, 0:42:44.040 --> 0:42:48.480 can genital heart anomalies. As of now, in general, we 0:42:48.480 --> 0:42:50.879 don't have much in the way of treatments. There may 0:42:50.920 --> 0:42:54.799 be some very rare times where people get heart surgeries 0:42:54.880 --> 0:42:58.160 in utero, but that's like very very rare, right. So 0:42:58.280 --> 0:43:01.160 in general, the way that Turns syndrome is dealt with 0:43:01.160 --> 0:43:04.719 in terms of treatment is twofold. There's two aspects of 0:43:04.719 --> 0:43:08.880 it that are often addressed during development if Turner syndrome 0:43:08.920 --> 0:43:13.080 is diagnosed early enough, and that is the growth insufficiency 0:43:13.239 --> 0:43:17.600 so short stature as well as the gonadal insufficiency, and 0:43:17.680 --> 0:43:22.040 those are treated with initiation of growth hormone and then 0:43:22.120 --> 0:43:27.560 eventually addition of estrogen therapy. Now, the timing of those 0:43:28.520 --> 0:43:33.560 very controversial. There are some societies that have like guidelines, 0:43:33.600 --> 0:43:36.080 but from what I read, we just don't have a 0:43:36.160 --> 0:43:38.799 ton of evidence as to like, win really is the 0:43:38.840 --> 0:43:43.040 best time to initiate growth hormone and then add in estrogen, 0:43:43.160 --> 0:43:47.160 et cetera. Yeah, yeah, so, but those are the two 0:43:47.239 --> 0:43:50.960 things that growth hormone has been shown to increase final 0:43:51.000 --> 0:43:54.920 adult height substantially, and the addition of estrogen reduces the 0:43:55.000 --> 0:44:00.680 risk of osteoporosis and can facilitate the growth of secondary 0:44:00.680 --> 0:44:05.719 sexual characteristics, and importantly does not seem to increase the 0:44:05.800 --> 0:44:08.000 risk of any cancers, which is always something we think 0:44:08.000 --> 0:44:10.799 about when it comes to estrogen. Right. Yeah, Now, the 0:44:10.880 --> 0:44:13.759 other thing that then we have to consider is the 0:44:13.920 --> 0:44:16.160 treatment of all of the other things that might go 0:44:16.280 --> 0:44:19.840 along with Turner syndrome, And for those, it generally just 0:44:19.880 --> 0:44:23.440 comes down to whatever typical medical management of those would be. 0:44:23.680 --> 0:44:26.319 So if you have high blood pressure, you treat it 0:44:26.320 --> 0:44:31.719 like high blood pressure. But yeah, that's pretty much I think, 0:44:31.800 --> 0:44:33.880 hopefully the biology of Turner syndrome. 0:44:34.719 --> 0:44:37.000 There's a lot there there, really really is. 0:44:37.040 --> 0:44:42.799 Aaron, So, I gotta know, how did we find out 0:44:42.840 --> 0:44:45.359 about this, Like, how did we figure out that this 0:44:45.840 --> 0:44:48.880 was a condition when it can have such varied appearance, 0:44:49.000 --> 0:44:51.759 and then how did we figure out like what we 0:44:51.840 --> 0:44:52.480 know about it? 0:44:53.640 --> 0:44:57.279 Good questions, Good questions. I will do my best right 0:44:57.360 --> 0:45:37.760 after this break. At its core, the history of Turner 0:45:37.880 --> 0:45:43.080 syndrome is a story of chromosomes, specifically the X chromosome. 0:45:43.760 --> 0:45:45.719 I mean, of course, there's more to it than that. 0:45:45.880 --> 0:45:49.400 There is doctor Henry Turner, the Oklahoma physician that in 0:45:49.480 --> 0:45:53.600 nineteen thirty eight first described some characteristics that were associated 0:45:53.600 --> 0:45:57.440 with the condition. There's the improvements in our understanding of 0:45:57.520 --> 0:46:01.440 genetics that allowed researchers to pinpoint the chromosomal cause in 0:46:01.520 --> 0:46:04.840 nineteen fifty nine. And there's the founding and growth of 0:46:04.960 --> 0:46:08.400 many Turner Syndrome organizations over the past fifty or so 0:46:08.560 --> 0:46:12.280 years that have done so very much in terms of education, 0:46:12.960 --> 0:46:17.200 access to treatment, and connecting affected individuals and families all 0:46:17.239 --> 0:46:20.399 over the world. But what I really want to dive 0:46:20.440 --> 0:46:24.960 into today is what came before all that, the story 0:46:25.040 --> 0:46:28.400 of this chromosome at the heart of Turner syndrome. Yeah, 0:46:28.920 --> 0:46:31.880 the X chromosome, like you said, Aaron is one half 0:46:31.920 --> 0:46:35.000 of the pair of chromosomes, the other being why that 0:46:35.040 --> 0:46:38.719 we usually referred to as the sex chromosomes because they're 0:46:38.760 --> 0:46:41.560 involved in the process that ultimately leads to the formation 0:46:41.760 --> 0:46:45.880 of sexual organs and other sexual characteristics. They're not the 0:46:45.920 --> 0:46:49.600 only things involved, of course, nor is sex determination the 0:46:49.640 --> 0:46:53.279 only thing they do as we know. So how did 0:46:53.320 --> 0:46:56.719 we come to call these two chromosomes sex chromosomes? 0:46:57.440 --> 0:46:58.000 I don't know. 0:46:58.200 --> 0:47:01.960 How did the growing field of medics uncover their functions, 0:47:02.480 --> 0:47:06.600 and how has our understanding of sex chromosomes changed since then? 0:47:07.760 --> 0:47:10.520 I want to dive into these questions about the history 0:47:10.520 --> 0:47:13.400 of sex chromosomes, and then I'll talk a bit about 0:47:13.400 --> 0:47:18.759 how Turner syndrome was first discovered. People have always been 0:47:19.480 --> 0:47:23.080 obsessed with explaining why some people are born with testes 0:47:23.160 --> 0:47:25.880 and others are born with ovaries, and all of the 0:47:25.960 --> 0:47:29.719 variation in between. And in the century leading up to 0:47:29.760 --> 0:47:33.520 the discovery of the X and Y chromosome, things like heat, 0:47:33.719 --> 0:47:36.160 the position of the fetus in the womb, and the 0:47:36.200 --> 0:47:39.680 types of food you ate were all contenders for what 0:47:39.760 --> 0:47:42.920 sex the infant would have, what venotypic sex the infant 0:47:42.920 --> 0:47:47.319 would have. There are countless other beliefs or explanations that 0:47:47.440 --> 0:47:50.719 emerged over the thousands of years since humans first thought 0:47:50.760 --> 0:47:54.719 to wonder about anatomical differences, and the vast majority of 0:47:54.760 --> 0:47:58.880 these explanations tended to suggest that it was kind of 0:47:58.920 --> 0:48:03.680 these more externsnal factors after conception that made all the difference. 0:48:04.040 --> 0:48:08.920 Sex was pliable, it could be influenced by things after conception, 0:48:10.360 --> 0:48:12.920 but humans only began to get a peak at the 0:48:13.040 --> 0:48:17.040 complex internal processes that go into determining what we call 0:48:17.160 --> 0:48:21.360 biological sex at the end of the nineteenth century beginning 0:48:21.400 --> 0:48:24.440 of the twentieth when the X and Y chromosomes were 0:48:24.480 --> 0:48:27.839 first discovered, and even then it would take a bit 0:48:27.880 --> 0:48:32.359 of time before this explanation of chromosomal sex determination. 0:48:32.120 --> 0:48:33.239 Was widely accepted. 0:48:34.200 --> 0:48:36.640 This was the end of the Victorian era, which was 0:48:36.680 --> 0:48:41.080 a period marked by strict gender roles both privately and publicly, 0:48:41.800 --> 0:48:44.760 and so it may be kind of surprising to learn 0:48:44.840 --> 0:48:49.279 that during that same time, scientists studying sex saw it 0:48:49.400 --> 0:48:54.680 as a spectrum, as extremely complicated and not necessarily a 0:48:54.760 --> 0:48:59.680 discrete binary trait, and this view is reflected in how 0:48:59.719 --> 0:49:03.840 these researchers thought sex was determined, which was, like I said, 0:49:03.960 --> 0:49:08.200 largely through these sort of external factors affecting the embryo 0:49:08.320 --> 0:49:12.719 or fetus, rather than something that was determined at fertilization, 0:49:13.920 --> 0:49:16.920 for instance, did the egg come from the. 0:49:17.000 --> 0:49:18.440 Left or the right ovary? 0:49:19.120 --> 0:49:22.160 How old was each parent, what time of day did 0:49:22.160 --> 0:49:24.520 fertilization happen, and what was the temperature? 0:49:24.680 --> 0:49:26.640 What did you eat like? All of these. 0:49:26.480 --> 0:49:31.640 Things and the research that many early embryologists and physiologists 0:49:31.640 --> 0:49:34.640 were doing at the end of the nineteenth century supported 0:49:34.640 --> 0:49:38.319 this notion that sex was highly flexible. Sex ratios of 0:49:38.400 --> 0:49:43.239 certain insects varied under certain environmental conditions, and studies of 0:49:43.280 --> 0:49:46.719 sex hormones in birds and rodents showed that sex or 0:49:46.760 --> 0:49:51.120 sex characteristics could be modified after fertilization occurred. 0:49:51.400 --> 0:49:56.879 I love talking about sex in other animals. I know. 0:49:57.120 --> 0:49:59.680 I think that we need to devote an episode to 0:49:59.760 --> 0:50:00.560 that somehow. 0:50:00.680 --> 0:50:02.240 Oh, it would be so fun. 0:50:02.440 --> 0:50:03.520 It would be so fun. 0:50:05.680 --> 0:50:09.120 And this idea that sex was a plastic, changeable trait 0:50:09.440 --> 0:50:13.200 influenced by both the internal and external environments led to 0:50:13.400 --> 0:50:17.400 the quote metabolic theory of sex put forth by Patrick 0:50:17.440 --> 0:50:20.560 Getty's and J. Arthur Thompson in their eighteen eighty nine. 0:50:20.440 --> 0:50:22.000 Book The Evolution of Sex. 0:50:22.880 --> 0:50:26.320 Essentially, the idea was that females of a species should 0:50:26.320 --> 0:50:29.520 have a higher metabolic rate due to the increased demands 0:50:29.560 --> 0:50:33.040 of producing large game meats eggs, while males of a 0:50:33.080 --> 0:50:37.280 species would have lower metabolic demands because they're gametes, sperm 0:50:37.440 --> 0:50:41.479 weren't as energetically costly to produce, and this fed into 0:50:41.480 --> 0:50:44.520 the concept that during times of scarcity, more males would 0:50:44.520 --> 0:50:47.520 be produced, while during times of plenty more females would 0:50:47.560 --> 0:50:52.120 be And that actually is, at least in part, what 0:50:52.320 --> 0:50:56.360 seems to happen in some species, I think insect species, 0:50:57.960 --> 0:51:01.600 not what happens in humans necessarily, as far as as 0:51:01.680 --> 0:51:03.640 far as I think we have learned at this point 0:51:03.960 --> 0:51:07.480 in twenty twenty two, but the metabolic theory of sex 0:51:07.560 --> 0:51:11.040 predominated for a few decades from around when it was 0:51:11.080 --> 0:51:15.000 introduced in eighteen eighty nine or so until the nineteen twenties. 0:51:15.960 --> 0:51:18.920 What ended up dethroning it chromosomes. 0:51:19.360 --> 0:51:23.520 Ooh, Before we get into the how and why of 0:51:23.600 --> 0:51:27.520 when chromosomes were recognized to be major players in sex determination, 0:51:28.200 --> 0:51:30.880 let's take a step back to get some broader context 0:51:31.040 --> 0:51:33.640 in what was going on in the world of genetics 0:51:33.760 --> 0:51:37.279 or evolutionary biology at this time. And this is fun 0:51:37.320 --> 0:51:39.279 because I don't think like I've done a whole lot 0:51:39.320 --> 0:51:43.840 of context setting for like germ theory and antibiotics and 0:51:43.840 --> 0:51:46.319 all the infectious disease stuff we cover that, I don't 0:51:46.360 --> 0:51:50.720 think I've really done it as much for like evolution. 0:51:50.560 --> 0:51:51.160 I don't think so. 0:51:51.640 --> 0:51:56.280 Yeah. Okay, Well, if it's a repeat, apologies and hope, 0:51:57.200 --> 0:51:57.880 hope it's okay. 0:51:57.960 --> 0:51:59.920 If it's a repeat, we don't remember, so like no 0:52:00.120 --> 0:52:00.959 one else does either. 0:52:01.320 --> 0:52:01.560 Yeah. 0:52:01.640 --> 0:52:07.480 Yeah, So, as we know, the nineteenth century was a 0:52:07.520 --> 0:52:11.600 tremendous time of change and progress in really all fields 0:52:11.600 --> 0:52:15.520 of science. We've talked on this podcast in depth about 0:52:15.680 --> 0:52:20.360 things like physics, about things like the revolution that was 0:52:20.440 --> 0:52:25.560 germ theory. Microscopes and medical measuring devices were changing the 0:52:25.560 --> 0:52:29.280 way that we saw both health and disease. And natural 0:52:29.400 --> 0:52:33.560 historians were traveling all over the world and returning home 0:52:33.719 --> 0:52:37.359 to fill the halls and basements of museums and their 0:52:37.360 --> 0:52:42.360 own private collections with specimens from every continent. One of 0:52:42.400 --> 0:52:46.120 these natural historians, by the name of Charles Darwin, came 0:52:46.200 --> 0:52:49.120 back with more than just an outrageous number of plants 0:52:49.120 --> 0:52:53.720 and animals. He also brought back with him an idea 0:52:53.800 --> 0:52:57.080 that would change the way we looked not just at ourselves, 0:52:57.440 --> 0:53:00.920 but at all life on Earth. His idea, which took 0:53:01.000 --> 0:53:03.279 him a few years to write up and publish was 0:53:03.320 --> 0:53:07.640 the theory of evolution by natural selection. The individuals of 0:53:07.640 --> 0:53:10.359 a species that are more fit for their environment are 0:53:10.400 --> 0:53:13.879 more likely to survive and reproduce, and their offspring will 0:53:13.880 --> 0:53:17.719 inherit those traits that made their parents more fit. In 0:53:17.760 --> 0:53:21.880 this way, species change over time in relation to their environment, 0:53:22.160 --> 0:53:25.840 all components of it. As you probably already know, this 0:53:25.920 --> 0:53:28.200 idea met with a lot of resistance when it was 0:53:28.239 --> 0:53:32.760 first introduced, with critics calling it sacrilegious or just bad science. 0:53:33.360 --> 0:53:36.560 But over the next few decades, research uncovered more and 0:53:36.680 --> 0:53:40.680 more evidence in support of Darwin's idea, and many scientists 0:53:40.840 --> 0:53:44.680 turned towards working out the details of how evolution actually 0:53:44.760 --> 0:53:48.600 happened rather than trying to disprove it. And one of 0:53:48.600 --> 0:53:51.800 the key questions that remained about the process of evolution 0:53:52.239 --> 0:53:55.800 was how the information got passed from parent to offspring, 0:53:56.600 --> 0:53:59.440 what was the information actually made of and where was 0:53:59.480 --> 0:54:05.320 it located. Fortunately, microscope technology could step up to provide 0:54:05.320 --> 0:54:06.440 some tentative answers. 0:54:06.880 --> 0:54:07.560 I love this. 0:54:07.760 --> 0:54:13.320 I just like the intersection that the Yeah, the combining 0:54:13.360 --> 0:54:18.239 of these different fields. So while Darwin was looking across 0:54:18.400 --> 0:54:25.080 eons of change, other researchers were a bit more microscopically focused. Literally, 0:54:26.080 --> 0:54:29.719 around the same time that Darwin was writing and rewriting, 0:54:29.840 --> 0:54:33.719 and editing and stressing out about On the Origin of Species, 0:54:34.040 --> 0:54:37.960 which was published in eighteen fifty nine, another biological theory 0:54:38.000 --> 0:54:41.799 was gaining traction, the cell theory, which basically stated that 0:54:41.840 --> 0:54:45.760 the basis of all life is cells. All living things 0:54:45.800 --> 0:54:49.279 are composed of cells. Cells are the basic units of 0:54:49.320 --> 0:54:53.200 all living tissue, and all cells come from pre existing cells. 0:54:54.440 --> 0:54:57.879 Of course, people had observed cells and use that name 0:54:58.120 --> 0:55:02.440 since around sixteen sixty five, when Robert Hook first used 0:55:02.440 --> 0:55:05.319 that word to describe the little boxes he saw in 0:55:05.360 --> 0:55:09.080 a piece of magnified cork, since they reminded him of 0:55:09.120 --> 0:55:11.880 the rooms that monks stayed in called cellula. 0:55:12.400 --> 0:55:14.560 Oh my goodness. 0:55:14.560 --> 0:55:15.759 So that's where cell comes from. 0:55:16.080 --> 0:55:17.400 I don't think I ever knew that. 0:55:19.760 --> 0:55:22.640 But over the next two hundred years or so, microscope 0:55:22.640 --> 0:55:25.360 technology had advanced to the point where people could not 0:55:25.480 --> 0:55:29.520 only look at cells in a tremendous variety of organisms 0:55:29.560 --> 0:55:35.879 and tissues, but also within cells themselves, identifying different components, 0:55:36.000 --> 0:55:40.000 making inferences about their functions, and observing the variety of 0:55:40.080 --> 0:55:46.759 processes involved in day to day cellular activities processes including 0:55:46.880 --> 0:55:55.759 cellular division via mitosis or myosis. Researchers observed that the 0:55:55.880 --> 0:56:00.680 cells produced vamosis were germ cells. So these spur and eggs, 0:56:01.000 --> 0:56:04.160 and they were different from those produced during mitosis. And 0:56:04.239 --> 0:56:06.920 I'll get into that in a second. And in the 0:56:06.960 --> 0:56:12.000 eighteen nineties, German physiologist August Weismann integrated Darwin's theory of 0:56:12.040 --> 0:56:16.080 evolution with cell theory, proposing that the recombination of the 0:56:16.160 --> 0:56:20.040 germ cells was how information from each parent was passed 0:56:20.040 --> 0:56:24.880 down to their offspring, and that the recombination process introduced 0:56:24.920 --> 0:56:28.239 the variation that would allow for natural selection to act, 0:56:28.239 --> 0:56:31.239 because there has to be variation for natural selection act. 0:56:31.600 --> 0:56:34.880 Oh my goodness, it's beautiful, It's so beautiful. 0:56:35.880 --> 0:56:39.600 But still the question remained, where is that information stored? 0:56:40.600 --> 0:56:43.759 Experiments in the eighteen eighties demonstrated that it had to 0:56:43.800 --> 0:56:44.200 be in. 0:56:44.160 --> 0:56:46.600 The nucleus, but in what form? 0:56:46.920 --> 0:56:47.360 How is it? 0:56:47.400 --> 0:56:47.920 Packaged? 0:56:48.680 --> 0:56:54.200 Chromosomes seemed a likely contender. Okay, While early cell biologists 0:56:54.280 --> 0:56:57.719 were hunched over their microscopes watching these cells go through 0:56:57.719 --> 0:57:03.120 this beautiful dance of division. One in particular, German cytologist 0:57:03.239 --> 0:57:08.160 Walter Fleming noticed something happening in the nucleus. He wrote 0:57:08.200 --> 0:57:12.680 that he observed the separation and copying of quote threads 0:57:12.880 --> 0:57:17.400 in the nucleus during division. Ten years later, those threads 0:57:17.440 --> 0:57:22.200 would be designated chromosomes by Heinrich Waldyer because they stained 0:57:22.360 --> 0:57:25.360 so easily you could visualize them very well with staining. 0:57:26.280 --> 0:57:31.040 Wait, why does that mean chromosome? Chromo chromo? Yeah, wow, 0:57:31.080 --> 0:57:31.760 I never got that. 0:57:33.720 --> 0:57:34.800 I never thought about it. 0:57:34.880 --> 0:57:35.600 Yeah, me neither. 0:57:36.400 --> 0:57:40.320 Okay, So chromosomes got the name because they were so 0:57:40.440 --> 0:57:41.520 easily stained. 0:57:41.760 --> 0:57:42.280 I love it. 0:57:43.040 --> 0:57:47.280 And it turns out that mitosis and myosis acted differently 0:57:47.520 --> 0:57:48.600 on these chromosomes. 0:57:49.520 --> 0:57:50.760 So mitosis is. 0:57:50.680 --> 0:57:54.520 When a cell divides to produce two identical daughter cells, 0:57:54.880 --> 0:57:59.880 each containing two full sets of chromosomes, while myosis produces 0:58:00.160 --> 0:58:05.200 four granddaughter cells, each with only one set of chromosomes. 0:58:05.800 --> 0:58:09.280 And so it stood to reason that these chromosomes contained 0:58:09.360 --> 0:58:12.640 in the nucleus with only one set present in germ 0:58:12.680 --> 0:58:19.600 cells could contain that hereditary information, and crucially that information 0:58:20.000 --> 0:58:23.320 in the germ cells, those chromosomes would be passed down 0:58:23.320 --> 0:58:26.720 to offspring without the changes that would accumulate in the 0:58:26.760 --> 0:58:32.200 somatic cells during an individual's lifetime, basically making it actual 0:58:32.280 --> 0:58:36.240 evolution as we know it, rather than this Lamarchian passing 0:58:36.280 --> 0:58:42.280 down acquired traits during a lifetime type of thing. Yeah, okay, yeah, okay. 0:58:42.960 --> 0:58:45.680 So it took some time for the role of chromosomes 0:58:45.680 --> 0:58:48.600 in genetics to be fully embraced, but in the meantime, 0:58:48.880 --> 0:58:51.920 plenty of researchers had turned their efforts to learning more 0:58:52.000 --> 0:58:56.160 about these mysterious threads and the things they do, including 0:58:56.560 --> 0:59:01.560 possibly sex determination. I know we're finally here, we come 0:59:01.600 --> 0:59:05.440 full circle. I haven't even mentioned Turner syndrome in this yet, 0:59:05.440 --> 0:59:07.360 and it's still gonna be a while. But still it's 0:59:07.400 --> 0:59:13.080 still good though, Okay. In eighteen ninety one, a researcher 0:59:13.160 --> 0:59:18.840 named Hermann Henking observed a strange extra chromosome question mark 0:59:19.200 --> 0:59:22.400 in the sperm of the fire wasp. At least he 0:59:22.480 --> 0:59:25.080 thought it was a chromosome. He also thought it could 0:59:25.160 --> 0:59:30.240 be a quote peculiar chromatin element or the quote X element. 0:59:32.320 --> 0:59:36.400 People debated what this X element might do, but generally 0:59:36.440 --> 0:59:41.400 the consensus was dismissal. It was a degenerate was the 0:59:41.400 --> 0:59:44.720 word they used. Chromosome that was at the end of 0:59:44.720 --> 0:59:48.800 its evolutionary history and had little to no function, and 0:59:49.000 --> 0:59:51.040 for a few years. That was the end of it 0:59:51.760 --> 0:59:54.800 until around nineteen oh two, when a PhD student at 0:59:54.840 --> 0:59:59.440 the University of Kansas named Clarence McClung found a quote 0:59:59.480 --> 1:00:03.600 peculiar nuclear element that he ended up calling the accessory 1:00:03.680 --> 1:00:08.600 chromosome in the sperm of some locusts. He commented on 1:00:08.640 --> 1:00:11.560 the similarity between what he found and what Hanking had 1:00:11.600 --> 1:00:15.080 found and suggested that this was not some crumbling chromosome 1:00:15.160 --> 1:00:17.160 at the end of its life, but rather a fully 1:00:17.360 --> 1:00:21.680 functional chromosome that played a role in determining sex, since 1:00:21.720 --> 1:00:24.760 he observed its presence in some sperm but its absence 1:00:24.840 --> 1:00:30.320 in others. Quote, A careful consideration will suggest that nothing 1:00:30.360 --> 1:00:33.720 but sexual characters thus divide the members of a species 1:00:33.760 --> 1:00:37.080 into two well defined groups, and we are logically forced 1:00:37.120 --> 1:00:40.720 to the conclusion that the peculiar chromosome has some bearing 1:00:40.880 --> 1:00:41.840 upon this arrangement. 1:00:42.600 --> 1:00:42.920 Huh. 1:00:43.120 --> 1:00:43.680 Interesting. 1:00:44.040 --> 1:00:48.160 At the time, this was a very bold claim. Chromosomes 1:00:48.160 --> 1:00:50.680 were generally thought to be the heritable units in the 1:00:50.720 --> 1:00:54.360 germ cells, and that each one was probably responsible for 1:00:54.440 --> 1:00:58.600 some traits. But the metabolic theory of sex, where sex 1:00:58.680 --> 1:01:03.000 was more pliable and could be changed after fertilization, that's 1:01:03.000 --> 1:01:08.680 still predominated McClung himself didn't really pursue the idea any further, 1:01:09.040 --> 1:01:14.080 but other researchers certainly did. Two in particular, would be 1:01:14.240 --> 1:01:18.439 instrumental in demonstrating that these accessory chromosomes played a role 1:01:18.520 --> 1:01:22.480 in sex determination. And it seems like it's only recently, 1:01:22.800 --> 1:01:27.120 really that one has gotten the credit she deserves. The 1:01:27.160 --> 1:01:30.680 same year that McClung published his hypothesis nineteen oh two, 1:01:31.360 --> 1:01:35.000 Nettie M. Stevens, who was at Brinmar College, and Edmund 1:01:35.040 --> 1:01:40.760 Wilson at Columbia University both began examining this accessory X chromosome, 1:01:41.040 --> 1:01:45.440 mostly using insects. I feel like insects were always being used. 1:01:45.440 --> 1:01:47.760 They're fascinating. There's just such variation. 1:01:48.240 --> 1:01:50.200 Yeah, they're so easy to raise. 1:01:54.960 --> 1:01:58.600 Histories of the X chromosome or sex determination by chromosomes 1:01:58.680 --> 1:02:02.560 often credit Wilson or even Thomas Hunt Morgan, who was 1:02:02.600 --> 1:02:06.800 also at Brynmar with Stevens, with making the connection between 1:02:07.040 --> 1:02:11.000 X and sex, while Nettie Stevens is included often as 1:02:11.160 --> 1:02:15.480 a footnote or maybe worse, as just providing supporting evidence 1:02:15.560 --> 1:02:19.960 of Wilson's claims. But closer examination of the timeline of 1:02:20.000 --> 1:02:23.560 events shows that Stevens should not only be recognized for 1:02:23.680 --> 1:02:28.000 being the first to demonstrate chromosomal sex determination, but also 1:02:28.120 --> 1:02:31.680 for her many other important contributions to the field of genetics, 1:02:32.200 --> 1:02:36.640 such as, I don't know, discovering the Y chromosome kind 1:02:36.680 --> 1:02:39.880 of a big deal, kind of a big deal. I 1:02:39.880 --> 1:02:42.880 think Nettie Stephens' story is fascinating, and so I just 1:02:42.920 --> 1:02:45.200 want to talk a bit about it before getting back 1:02:45.240 --> 1:02:46.800 to this history of discovery. 1:02:47.000 --> 1:02:47.880 I love it, can't wait. 1:02:49.040 --> 1:02:52.840 Nettie Stevens was born in Vermont in eighteen sixty one 1:02:53.480 --> 1:02:56.040 and went to school to become a teacher, which is 1:02:56.040 --> 1:02:59.040 what she did for a number of years. Somewhere along 1:02:59.120 --> 1:03:03.080 the way, though, she became fascinated with biology, and so 1:03:03.120 --> 1:03:05.640 she saved up money from her teaching jobs to go 1:03:05.680 --> 1:03:06.960 to Stanford University. 1:03:07.280 --> 1:03:07.680 Wow. 1:03:08.080 --> 1:03:11.600 She was thirty five when she enrolled and thirty eight 1:03:11.680 --> 1:03:14.600 when she graduated with her bachelor's I love her already, 1:03:14.920 --> 1:03:18.720 I know, I mean, I'm thirty five. The thought of 1:03:18.760 --> 1:03:23.360 going back to school, it's it's difficult, Like it's really 1:03:23.400 --> 1:03:25.960 hard to get that motivation and that. 1:03:26.280 --> 1:03:27.520 Yeah, so it's amazing. 1:03:27.720 --> 1:03:30.920 I imagine in the eighteen hundreds it would not have 1:03:30.920 --> 1:03:32.120 been easy either. 1:03:32.160 --> 1:03:36.400 No, exactly, that's what is so it's unbelievable. The next 1:03:36.480 --> 1:03:39.560 year she got her Masters, also at Stanford, and then 1:03:39.600 --> 1:03:42.600 went on to Brynmar for her PhD, which she got 1:03:42.680 --> 1:03:48.200 at the age of forty one. Wow, it is so inspirational. 1:03:48.880 --> 1:03:51.480 So it was yeah, like nineteen oh two when that happened. 1:03:51.640 --> 1:03:52.080 Wow. 1:03:52.560 --> 1:03:55.840 At Brynmar, first as a PhD student, during which she 1:03:55.920 --> 1:03:59.640 published nine papers, by the way, and then as a 1:03:59.680 --> 1:04:04.960 research Stephens became fascinated by the fields of embryology, genetics, 1:04:04.960 --> 1:04:10.000 and cytology. Her postdoctoral fellowship allowed her to pursue independent 1:04:10.080 --> 1:04:13.400 research at Brynmar while not having to teach, and it 1:04:13.480 --> 1:04:16.040 was during that fellowship that she did the bulk of 1:04:16.040 --> 1:04:20.320 her groundbreaking work on sex chromosomes. Okay, let me read 1:04:20.360 --> 1:04:23.160 to you part of the concluding paragraph of her nineteen 1:04:23.240 --> 1:04:26.040 oh five paper where she presented her findings about the 1:04:26.080 --> 1:04:29.040 common meal worm and sex determination by chromosomes. 1:04:29.440 --> 1:04:30.680 Quote. 1:04:30.920 --> 1:04:35.160 Since the somatic cells of the female contain twenty large chromosomes, 1:04:35.280 --> 1:04:38.360 while those of the male contain nineteen large ones and 1:04:38.400 --> 1:04:41.600 one small one, this seems to be a clear case 1:04:41.640 --> 1:04:45.800 of sex determination not by an accessory chromosome, but by 1:04:45.840 --> 1:04:49.040 a definite difference in the character of the elements of 1:04:49.160 --> 1:04:52.440 one pair of chromosomes of the spermatocytes of the first 1:04:52.560 --> 1:04:56.960 order the spermatozoa, which contained the small chromosome determining the 1:04:56.960 --> 1:05:01.000 male sex, while those that contain ten chromames of equal 1:05:01.040 --> 1:05:02.880 size determined the female sex. 1:05:04.480 --> 1:05:04.919 Rite out. 1:05:05.240 --> 1:05:10.720 Just boom done, yep. So that was very strong supporting evidence. 1:05:11.560 --> 1:05:15.880 And around the same time Wilson Edmund Wilson also published 1:05:15.920 --> 1:05:20.040 results that mirrored the findings of Stevens, but his conclusions 1:05:20.080 --> 1:05:24.480 about sex determination by chromosomes were undoubtedly influenced by her work. 1:05:24.880 --> 1:05:27.960 So one paper I went through, like traced the footnotes 1:05:28.000 --> 1:05:30.320 and like the revision process of the paper and how 1:05:30.360 --> 1:05:34.080 like the things that he changed after her paper came out. 1:05:34.080 --> 1:05:35.160 It's just like all this stuff and. 1:05:35.120 --> 1:05:37.560 So how interesting it's really. 1:05:37.320 --> 1:05:38.959 That this paper was great. 1:05:39.040 --> 1:05:43.280 Yeah, And also his study system was one in which 1:05:43.320 --> 1:05:46.360 the male of the species has one fewer chromosome than 1:05:46.400 --> 1:05:49.680 the female, and so initially he was thinking it was 1:05:49.720 --> 1:05:56.280 more about dose rather than dominant recessive characteristics. Interesting, yeah, 1:05:56.320 --> 1:05:59.520 and not to mention that even in that paper he said, yeah, 1:05:59.600 --> 1:06:02.760 chromosome probably play a role in sex, but it's more about. 1:06:02.640 --> 1:06:04.520 Metabolism find out. 1:06:05.480 --> 1:06:09.960 I mean, ultimately, the question of who gets priority for 1:06:10.080 --> 1:06:12.960 a certain discovery is always a bit of a sticky one, 1:06:13.520 --> 1:06:16.760 and maybe it's more important not to say this person 1:06:16.840 --> 1:06:19.800 is first, no, this person is first, but to take 1:06:19.840 --> 1:06:23.760 a closer look at why there's discrepancy or why one 1:06:23.840 --> 1:06:27.120 person is given credit over the other. And I think 1:06:27.160 --> 1:06:30.560 it's safe to say that in Nettie Stevens's case, her 1:06:30.640 --> 1:06:35.760 gender played a role. Despite her incredible accomplishments, she was 1:06:35.800 --> 1:06:39.800 never given a faculty position, and while her colleagues recognized 1:06:39.840 --> 1:06:43.520 her brilliance. Quote, of the graduate students that I have 1:06:43.640 --> 1:06:46.840 had during the last twelve years, I have had no 1:06:46.920 --> 1:06:50.040 one that was as capable and independent and research work 1:06:50.080 --> 1:06:52.840 as miss Stevens. I was in one letter of recommendation, 1:06:52.960 --> 1:06:54.800 I think from Thomas Hunt Morgan. 1:06:54.840 --> 1:06:56.480 You mean doctor Stevens. 1:06:56.720 --> 1:06:57.640 Doctor Stevens. 1:06:57.720 --> 1:07:00.240 Yeah, she's I'm pretty sure a doctor at that point. 1:07:01.240 --> 1:07:03.880 But a lot of these accolades, a lot of these 1:07:03.960 --> 1:07:09.520 this praise was almost always qualified by for a woman. Quote, 1:07:10.360 --> 1:07:13.920 I consider her not only the best of the women investigators, 1:07:14.320 --> 1:07:16.840 but one whose work will hold its own with that 1:07:17.040 --> 1:07:20.160 of any of the men of the same degree of advancement. 1:07:20.520 --> 1:07:22.480 Oh yeah, yeah, yeah, yeah, I. 1:07:22.400 --> 1:07:28.520 Mean yeah, it's that's I mean, it's like that sucks, 1:07:28.520 --> 1:07:29.760 but that's the way it was. 1:07:30.080 --> 1:07:31.320 And so but I think it is. 1:07:31.320 --> 1:07:38.280 Really important to acknowledge that. Yeah, yeah, but I don't know. Also, 1:07:38.400 --> 1:07:41.320 in one paper I read about Nettie Stevens, the author 1:07:41.360 --> 1:07:43.800 pointed out that it was probably for the best that 1:07:43.920 --> 1:07:47.120 Thomas Hunt Morgan, who was also at BRNMAR and like 1:07:47.480 --> 1:07:52.160 huge name in genetics, was initially so resistant to Stevens's 1:07:52.200 --> 1:07:55.960 ideas about the role of chromosomes and sex determination, because 1:07:56.040 --> 1:07:58.760 if he had been more on board, his name would 1:07:58.800 --> 1:08:01.439 have been on all her page and he probably would 1:08:01.480 --> 1:08:03.160 have gotten all the credit, and her name would have 1:08:03.160 --> 1:08:04.520 been forgotten entirely. 1:08:04.920 --> 1:08:05.520 Wow. 1:08:06.440 --> 1:08:07.400 Interesting to think about. 1:08:07.640 --> 1:08:08.480 Yeah. 1:08:08.520 --> 1:08:11.400 Well, and then I think there's the trend that happens 1:08:11.440 --> 1:08:14.320 where if someone is very highly accomplished in a number 1:08:14.360 --> 1:08:17.759 of different fields, they tend to be given credit for things, 1:08:17.840 --> 1:08:20.840 even if they maybe didn't play the biggest role in it. So, 1:08:21.680 --> 1:08:23.960 in any case, I just wanted to spend a bit 1:08:24.000 --> 1:08:27.800 of time on this brilliant scientist who made so many 1:08:27.840 --> 1:08:31.240 incredible accomplishments in the field of genetics in such a 1:08:31.280 --> 1:08:34.800 short amount of time and during a time when so 1:08:34.960 --> 1:08:38.720 many things were working against her, and she probably would 1:08:38.760 --> 1:08:42.040 have made many more if her life was not cut 1:08:42.080 --> 1:08:45.720 short sadly by breast cancer. She died at the age 1:08:45.760 --> 1:08:48.759 of fifty, only nine years after finishing her PhD. 1:08:49.040 --> 1:08:51.479 Oh my goodness, I know, I know. 1:08:53.200 --> 1:08:56.559 But the work by Stevens and Wilson greatly advanced our 1:08:56.680 --> 1:09:01.200 understanding of how chromosomes are involved in sexy termination, but 1:09:01.240 --> 1:09:03.839 it would take a number of years before that idea 1:09:03.960 --> 1:09:07.200 was widely accepted, due in part to just how much 1:09:07.280 --> 1:09:11.559 variation there is across the animal kingdom. Geneticists looking for 1:09:11.600 --> 1:09:15.680 a universal answer as to what determined sex, such as 1:09:15.920 --> 1:09:21.080 XX produces females and xy produces males, were continually thwarted 1:09:21.200 --> 1:09:25.639 by exceptions to that narrow rule some bird, sea, urchin, 1:09:25.760 --> 1:09:30.200 and insects species where females were x y or ZW 1:09:30.280 --> 1:09:34.439 and males were xx or zz, or insect species where 1:09:34.479 --> 1:09:36.960 males were either xo or x y. 1:09:37.320 --> 1:09:37.559 I mean. 1:09:37.600 --> 1:09:42.120 The variation in these systems kept researchers from concluding definitively 1:09:42.320 --> 1:09:47.240 that these chromosomes were involved in sex determination, and this 1:09:47.439 --> 1:09:51.280 is reflected by it taking until the nineteen twenties for 1:09:51.439 --> 1:09:55.800 these chromosomes to be widely referred to as sex chromosomes. 1:09:55.840 --> 1:09:56.480 Interesting. 1:09:57.000 --> 1:09:57.360 Yeah. 1:09:57.760 --> 1:10:00.639 Up until then, they were known by a variety names, 1:10:00.680 --> 1:10:07.439 including heterochromosomes and accessory chromosomes idio chromosomes. Even when it 1:10:07.479 --> 1:10:10.439 became clear that sex determination was part of what these 1:10:10.520 --> 1:10:15.479 chromosomes did, some researchers rejected these labels, partly because they 1:10:15.520 --> 1:10:18.759 weren't quite convinced that that was how it worked, partly 1:10:18.800 --> 1:10:21.960 because they felt that too much was still unknown about 1:10:22.040 --> 1:10:26.040 other processes of sex determination and the function of these chromosomes, 1:10:26.720 --> 1:10:29.480 and partly because they felt that it was too simplistic 1:10:29.600 --> 1:10:33.719 and didn't capture the full spectrum of sex. It turned 1:10:33.920 --> 1:10:37.360 sex into a binary And I'm going to come back 1:10:37.400 --> 1:10:41.160 to this aspect of sex and sex chromosomes in a bit, 1:10:41.280 --> 1:10:43.880 but for now I want to turn briefly towards the 1:10:43.960 --> 1:10:50.400 actual topic of today's episode, Turner syndrome or should I 1:10:50.439 --> 1:10:54.720 say Ulric Turner syndrome. M Perhaps the first half of 1:10:54.760 --> 1:10:58.680 the twentieth century saw continued interest in sex chromosomes and 1:10:58.760 --> 1:10:59.960 genetics as well. 1:11:00.000 --> 1:11:00.120 Well. 1:11:00.200 --> 1:11:05.160 Is another rapidly growing field, that of endochronology. So around 1:11:05.200 --> 1:11:08.080 the same time that people were debating what to call 1:11:08.160 --> 1:11:12.880 the X and Y chromosomes. Other researchers were busy characterizing hormones, 1:11:13.240 --> 1:11:15.519 particularly the ones that seemed to play a role in 1:11:15.560 --> 1:11:20.280 the development of secondary sexual characters. For example, these hormones 1:11:20.280 --> 1:11:24.960 that you mentioned aaron, estrogen and testosterone right. Henry Turner, 1:11:25.240 --> 1:11:29.760 an Oklahoma physician, was one of these early endochronologists, and 1:11:29.800 --> 1:11:32.880 he would frequently be asked to consult on cases where 1:11:32.920 --> 1:11:36.439 people were suspected to have different hormone levels or a 1:11:36.439 --> 1:11:41.360 different hormone functionality. Throughout the nineteen thirties, he noticed in 1:11:41.479 --> 1:11:44.160 seven of his patients that were assigned female at birth 1:11:44.280 --> 1:11:48.559 what he thought might be a previously undescribed hormonal condition 1:11:49.080 --> 1:11:53.600 that led to a suite of physical characteristics, including short stature, 1:11:54.400 --> 1:11:58.040 cubitus valgus is like one thing that he pointed out, 1:11:58.080 --> 1:12:00.600 which is that extra angling of the forearm at the 1:12:00.600 --> 1:12:06.360 elbow and under development of sexual organs and secondary sexual characteristics. 1:12:07.160 --> 1:12:10.360 And in nineteen thirty eight he published case summaries of 1:12:10.400 --> 1:12:13.880 these seven individuals and suggested that this was a newly 1:12:13.960 --> 1:12:17.760 described condition that was likely caused by a hormonal imbalance. 1:12:18.600 --> 1:12:22.480 He tried pituitary growth hormones to no avail and anterior 1:12:22.560 --> 1:12:26.240 pituitary gnatotropic hormone to some avail. I don't know what 1:12:26.960 --> 1:12:30.759 that hormone actually was that was in the paper. 1:12:30.920 --> 1:12:31.160 Yeah. 1:12:31.640 --> 1:12:34.720 Yeah, he was right that it was a condition with 1:12:34.880 --> 1:12:38.519 one specific cause, which is what ultimately ended up making 1:12:38.600 --> 1:12:42.720 him the namesake of Turner syndrome, and that hormones were involved, 1:12:43.479 --> 1:12:47.320 But he was wrong about it never having been described before. 1:12:48.439 --> 1:12:50.799 Remember how I called it Ulric Turner syndrome. 1:12:50.880 --> 1:12:52.160 You might have seen that placens. 1:12:52.240 --> 1:12:52.920 Yeah, I sure did. 1:12:53.439 --> 1:12:57.439 Turns out a German pediatrician named Otto Ulrich had actually 1:12:57.439 --> 1:12:59.800 published a case study of an eight year old with 1:13:00.080 --> 1:13:03.880 the same suite of characteristics that Turner had described, but 1:13:04.080 --> 1:13:05.439 eight years before. 1:13:05.280 --> 1:13:06.519 Turner's paper came out. 1:13:06.760 --> 1:13:08.080 Ooh h. 1:13:08.880 --> 1:13:12.040 With Ulric and especially Turner's work, there was now a 1:13:12.080 --> 1:13:17.000 clinical description of this condition, but the ultimate cause remained 1:13:17.000 --> 1:13:19.800 a mystery for a couple of decades. Was it hormones? 1:13:19.960 --> 1:13:20.920 Was it something else? 1:13:21.040 --> 1:13:21.120 Like? 1:13:21.240 --> 1:13:23.439 Where where did this? How did this happen? 1:13:24.240 --> 1:13:27.839 And it was only in nineteen fifty nine that genetic 1:13:27.920 --> 1:13:32.000 technology and imaging had advanced to the point where researchers 1:13:32.320 --> 1:13:35.840 forward at all were able to link cases of Turner 1:13:35.920 --> 1:13:38.280 syndrome with the presence of only one X. 1:13:38.840 --> 1:13:40.719 Wow, that's a long time. 1:13:41.000 --> 1:13:42.000 It's a long time. 1:13:42.080 --> 1:13:43.880 I mean it makes sense, I guess in terms of 1:13:44.720 --> 1:13:49.679 technology and our understanding of chromosomes and how everything worked 1:13:49.680 --> 1:13:51.719 and being able to actually work with them. 1:13:51.880 --> 1:13:55.559 Right and like tereotype enough people or individuals and things 1:13:55.600 --> 1:13:55.960 like that. 1:13:56.360 --> 1:13:57.120 Yeah, exactly. 1:13:57.840 --> 1:14:00.640 Side note, Remember the person that Ulric scribes in his 1:14:00.760 --> 1:14:03.479 case report, the eight year old yea, So a couple 1:14:03.479 --> 1:14:07.840 of researchers followed up in the nineteen seventies and confirmed 1:14:08.360 --> 1:14:09.120 just one X. 1:14:09.560 --> 1:14:12.080 Wow, that's kind of cool, isn't that cool? 1:14:12.280 --> 1:14:15.960 Yeah. In the years since the nineteen fifty nine paper 1:14:16.120 --> 1:14:18.400 showing that a single X was at the root of 1:14:18.400 --> 1:14:22.720 Turner syndrome, we've learned so much more about it, including 1:14:22.720 --> 1:14:25.760 the fact that it isn't always a whole X missing. Right, 1:14:26.040 --> 1:14:30.120 you talked about erin which specific genes might be involved, 1:14:30.280 --> 1:14:33.479 and what types of treatment seemed to be helpful, and 1:14:33.600 --> 1:14:37.439 right alongside that, we've been expanding our view of sex overall. 1:14:38.200 --> 1:14:41.479 The X and Y for humans I think provides this 1:14:42.000 --> 1:14:47.439 enticingly simple binary picture of sex. XX means female, x 1:14:47.560 --> 1:14:50.200 Y means male. But obviously there's much more to it 1:14:50.240 --> 1:14:52.360 than that. And I think it's important to remember that 1:14:52.439 --> 1:14:55.559 there are so many different ways you can categorize sex, 1:14:56.120 --> 1:15:00.599 and some categories might be discreete. Others are continuous and 1:15:00.760 --> 1:15:06.200 none are binary. Yeah, chromosomal sex, gonadal sex, hormonal sex, 1:15:06.280 --> 1:15:10.400 genital sex, sexual identity, to name just a few. The 1:15:10.439 --> 1:15:15.000 diversity of sex in humans alone is amazing. And I 1:15:15.040 --> 1:15:20.120 didn't even talk about other animals. For instance, like I 1:15:20.200 --> 1:15:24.519 mentioned earlier, instead of the thisxxy system that we're familiar with, 1:15:24.920 --> 1:15:29.160 some birds and other organisms have a ZZZW system where 1:15:29.280 --> 1:15:33.439 zz develops as males zws female. There are also systems 1:15:33.439 --> 1:15:37.000 that don't just use this master switch on the distinct 1:15:37.080 --> 1:15:41.800 chromosome like the SRY on the Y chromosome to kick 1:15:41.800 --> 1:15:48.080 off the sex determination process, but also use genes on autosomes, 1:15:48.840 --> 1:15:52.799 the non sex chromosomes that are involved in this process. 1:15:53.000 --> 1:15:56.080 Well, and then there's so many animals too that can 1:15:56.200 --> 1:16:00.360 switch sex during their lifetime, like well after development like 1:16:00.400 --> 1:16:01.360 what what well? 1:16:01.680 --> 1:16:05.439 And for some like environmental factors play a huge role 1:16:05.520 --> 1:16:09.200 temperature stuff like that. It's like, it's not ridiculous, like 1:16:09.240 --> 1:16:12.080 the metabolg theory of sex works, It's just there is 1:16:12.080 --> 1:16:15.960 is there an overarching theory of sex and how sex 1:16:15.960 --> 1:16:20.599 determination works. I don't think there is, does there need 1:16:20.680 --> 1:16:22.440 to be? 1:16:22.600 --> 1:16:24.160 Isn't that sort of the beauty of it all? 1:16:24.360 --> 1:16:25.840 But it's fascinating. 1:16:26.439 --> 1:16:29.439 I mean there's there's Like I am going to link 1:16:29.479 --> 1:16:32.080 to some papers because don't you want to know more 1:16:32.200 --> 1:16:35.960 about species that have lost the Y chromosome entirely or 1:16:36.160 --> 1:16:39.680 those that have evolved to have another type of X. 1:16:40.520 --> 1:16:43.519 Read about the African pygmy mouse with the X y 1:16:43.640 --> 1:16:44.320 W system. 1:16:44.640 --> 1:16:45.599 What what? What? 1:16:46.000 --> 1:16:51.400 I know? The variety in this is, it's just it's beautiful. 1:16:51.520 --> 1:16:52.400 It's breathtaking. 1:16:53.000 --> 1:16:55.759 And I'll link to a few papers on our website 1:16:55.840 --> 1:16:58.040 that go into these examples so you can read more 1:16:58.120 --> 1:17:01.120 and get hyped also about the diversity of sex. I 1:17:01.240 --> 1:17:05.960 especially recommend more and Roberts from twenty thirteen titled Polygenic 1:17:06.000 --> 1:17:10.519 Sex Determination. It's a really well written, accessible, fascinating paper. 1:17:11.240 --> 1:17:12.400 And there's so much more that we. 1:17:12.400 --> 1:17:15.480 Could talk about in terms of sex and sex chromosomes. 1:17:15.960 --> 1:17:18.439 But I have to stop somewhere because otherwise I will 1:17:18.680 --> 1:17:19.920 never stop ever. 1:17:20.880 --> 1:17:22.439 So what I want to. 1:17:22.360 --> 1:17:24.360 Do is I want to ask listeners to send in 1:17:24.560 --> 1:17:28.600 your favorite sex chromosome trivia and all the different animals 1:17:29.160 --> 1:17:31.240 and then hands it off to you Aerin. So tell 1:17:31.280 --> 1:17:33.880 me where do we stand with Turner syndrome today? 1:17:34.000 --> 1:17:35.920 Oh, I can't wait too, but also Aarin. That's how 1:17:35.920 --> 1:17:39.479 we make our whole episode about sex chromosomes, as we 1:17:39.560 --> 1:17:41.280 just share listener facts. 1:17:41.320 --> 1:17:41.680 I love it. 1:17:41.680 --> 1:17:43.200 I love actually, I love that a lot. 1:17:45.040 --> 1:17:48.240 But I'll get into the what we know about Turner 1:17:48.320 --> 1:18:18.960 syndrome today right after this break. Most of the papers 1:18:19.000 --> 1:18:23.240 that I read cited relatively similar statistics, which is interesting, 1:18:23.320 --> 1:18:27.000 especially in the context as we'll learn that we don't know. 1:18:27.200 --> 1:18:28.400 These are estimates. 1:18:28.640 --> 1:18:30.400 We never know, we never know. 1:18:30.560 --> 1:18:34.040 That's the theme of this section. But in general, the 1:18:34.200 --> 1:18:39.719 estimate is about one in two thousand phenotypically female live 1:18:39.880 --> 1:18:45.040 births result in Turner syndrome. Another way to enumerate that, 1:18:45.160 --> 1:18:49.240 although it's looking at the literature a little bit more problematic, 1:18:49.880 --> 1:18:54.439 is that about fifty to sixty of every one hundred 1:18:54.520 --> 1:19:01.120 thousand adult the literature says adult women have Turner syndrome. Okay, right, 1:19:02.080 --> 1:19:05.640 so rare, but not that rarely. 1:19:05.720 --> 1:19:08.800 It's like one of the most common, if not the 1:19:08.840 --> 1:19:11.760 most common, of sex chromosome anomalies. 1:19:11.840 --> 1:19:17.880 Right, absolutely, yes, Okay, Now we don't have information on 1:19:17.960 --> 1:19:22.920 what the variation is globally in different populations in different regions, 1:19:23.000 --> 1:19:25.160 largely because we just don't have data for most of 1:19:25.200 --> 1:19:28.000 the world to be able to say, like, these regions 1:19:28.040 --> 1:19:32.880 have higher or lower incidents of Turner syndrome. But what's 1:19:32.960 --> 1:19:38.240 interesting about Turner syndrome is looking at the timeframe of diagnoses. 1:19:38.320 --> 1:19:41.880 I think because there are three main peaks of when 1:19:41.960 --> 1:19:48.240 people are diagnosed. It can be diagnosed prenatally via genetic testing, amniocentesis, 1:19:48.360 --> 1:19:51.920 things like that, and so some percentage of people and 1:19:51.960 --> 1:19:54.560 I don't have an exact number on this, are diagnosed 1:19:55.280 --> 1:19:59.519 very early, like before births even potentially, and then there's 1:19:59.600 --> 1:20:03.520 usually a second peak of people being diagnosed not until 1:20:03.880 --> 1:20:08.040 young childhood when they fall off their growth curves. And 1:20:08.080 --> 1:20:11.320 then pediatricians are like, hmm, let me think, look at 1:20:11.360 --> 1:20:14.879 these other characteristics, perhaps we should get a karyotype, okay, 1:20:15.240 --> 1:20:20.440 and especially through adolescents when people perhaps have primary amenorrhea 1:20:20.600 --> 1:20:24.759 and present, you know, in teen years having no period 1:20:25.040 --> 1:20:28.120 and then get worked up. And then the last peak 1:20:28.439 --> 1:20:32.120 might not come until adulthood when someone might be diagnosed 1:20:32.160 --> 1:20:33.840 because they're struggling with infertility. 1:20:34.280 --> 1:20:35.879 Interesting, okay, And. 1:20:35.880 --> 1:20:39.120 It's estimated that potentially up to twenty percent of people 1:20:39.479 --> 1:20:42.880 may never be diagnosed. And the reason that this is 1:20:42.920 --> 1:20:45.360 important is because it kind of gets back to like, 1:20:45.439 --> 1:20:48.200 what is the definition of Turner syndrome? 1:20:48.479 --> 1:20:48.839 Yeah? 1:20:49.000 --> 1:20:52.320 Right, if you are never diagnosed with Turner syndrome, do 1:20:52.400 --> 1:20:56.080 you have Turner syndrome and are just undiagnosed or do 1:20:56.120 --> 1:21:01.280 you not actually have any of these phenotypic characteristics of Turners? Therefore, 1:21:01.560 --> 1:21:04.880 you might have this carriotype but you don't actually have 1:21:04.960 --> 1:21:07.920 Turner syndrome. And that's kind of like a I don't know, 1:21:07.920 --> 1:21:09.280 a philosophical question. 1:21:09.600 --> 1:21:12.320 Or right, well, but I think it's also a clinical question. 1:21:12.479 --> 1:21:16.000 It is a clinical question definitely. Where we get this 1:21:16.080 --> 1:21:18.400 twenty percent number is from some studies that have been 1:21:18.400 --> 1:21:20.960 done in Great Britain and a few other countries that 1:21:21.000 --> 1:21:23.840 have looked at carriotypes of people across the board and 1:21:23.880 --> 1:21:26.760 found a much higher prevalence of Turner syndrome than would 1:21:26.760 --> 1:21:33.320 be expected m hm, so underdiagnosis essentially. Now, another thing 1:21:33.360 --> 1:21:35.880 that I think is important to note because it's really 1:21:35.920 --> 1:21:38.000 fascinating and gets to a lot of what you were 1:21:38.000 --> 1:21:42.040 talking about, Aaron on just how interesting sex chromosomes are, 1:21:43.280 --> 1:21:47.920 is that it's actually very rare to be born with 1:21:48.040 --> 1:21:52.960 Turner syndrome, especially with a forty five X caryotype. So 1:21:53.280 --> 1:21:55.639 those numbers that I just cited, one in twenty five 1:21:55.720 --> 1:22:00.240 hundred not that rare, and forty five to fifty percent 1:22:00.320 --> 1:22:04.760 of those people are forty five X. But it's estimated 1:22:05.000 --> 1:22:08.160 that up to ninety nine percent of fetuses with a 1:22:08.240 --> 1:22:12.400 kareotype of forty five X actually result in spontaneous abortion, 1:22:12.640 --> 1:22:15.080 i e. Miscarriage or early pregnancy loss. 1:22:15.960 --> 1:22:18.599 That's a very interesting because, yeah, you're right, it's not 1:22:18.920 --> 1:22:21.479 it's common, but also extremely rare. 1:22:21.720 --> 1:22:26.640 Right, And it's also important to note because fascinating that 1:22:26.920 --> 1:22:31.240 I am fairly positive that Turner syndrome, especially as forty 1:22:31.280 --> 1:22:35.559 five X is the only known survivable monosomy where you 1:22:35.720 --> 1:22:40.200 have a complete absence of one chromosome. The complete absence 1:22:40.240 --> 1:22:44.800 of any of the other sets of chromosomes results in 1:22:44.920 --> 1:22:49.920 a non viable fetus. Wow, there are partial monosomis like 1:22:50.000 --> 1:22:54.439 cretis shot. There's seventeen Q twelve microdeletions, there's other types 1:22:54.479 --> 1:22:58.560 of chromosomal anomalies, and of course there are various trisomes, 1:22:58.880 --> 1:23:02.920 a number of which are compatible with life. But forty 1:23:02.960 --> 1:23:07.360 five XO is the only one with an entirely missing 1:23:07.439 --> 1:23:11.280 chromosome that's compatible with life, which is pretty incredible. And 1:23:11.320 --> 1:23:15.360 there is actually some suggestion that perhaps those fetuses that 1:23:15.400 --> 1:23:19.559 do survive might have some degree of mosaicism that we're 1:23:19.600 --> 1:23:22.200 just not detecting, but so far there's not a lot 1:23:22.200 --> 1:23:28.480 of evidence to actually confirm that hypothesis, right, So suffice 1:23:28.479 --> 1:23:32.200 to say, there are a lot of areas that are 1:23:32.320 --> 1:23:37.519 ripe for research, so many there are a few really 1:23:37.520 --> 1:23:39.680 great papers that I will direct to that have a 1:23:39.720 --> 1:23:43.360 lot more detail on kind of what especially the medical 1:23:43.400 --> 1:23:46.320 community thinks are the greatest needs when it comes to 1:23:46.360 --> 1:23:49.360 research on Turner syndrome. But a lot of it is 1:23:49.760 --> 1:23:53.120 like we need to understand the true genetic mechanisms underpinning 1:23:53.200 --> 1:23:55.400 a lot of the conditions that we see. We don't 1:23:55.400 --> 1:23:59.360 have all that information. We need better evidence based guidelines 1:23:59.360 --> 1:24:03.160 for care, because like I said earlier, we have guidelines, 1:24:03.560 --> 1:24:06.599 but we need more evidence to support those, of course, 1:24:07.800 --> 1:24:12.040 and I think that we also need a much better 1:24:12.160 --> 1:24:19.160 understanding of how people living with Turner syndrome are doing psychosocially, emotionally, physically. 1:24:19.280 --> 1:24:21.320 Like there's a lot to be said, and we've talked 1:24:21.320 --> 1:24:25.000 about this in a lot of our genetics episodes about 1:24:25.040 --> 1:24:29.120 involving people living with these conditions in the research, not 1:24:29.320 --> 1:24:37.639 merely as subjects of research. So, yeah, that is Turner syndrome. 1:24:38.200 --> 1:24:38.880 There's a lot. 1:24:38.960 --> 1:24:40.760 I think I've already said this, but there's just so 1:24:40.880 --> 1:24:41.559 much there. 1:24:42.560 --> 1:24:45.439 It really does. One of the things that really excites 1:24:45.479 --> 1:24:49.680 me about this is just talking about the variety inherent 1:24:49.880 --> 1:24:54.200 in sex chromosomes and sex determination because it is so 1:24:54.760 --> 1:24:58.200 much more interesting than the black and white that we 1:24:58.360 --> 1:24:59.360 learned in. 1:24:59.280 --> 1:25:02.400 School, right, I mean the black and white we learned 1:25:02.439 --> 1:25:06.760 that way because it's it's convenient, right, It's not accurate, right, 1:25:06.880 --> 1:25:10.040 and you're missing out if that's what you're if that's 1:25:10.040 --> 1:25:14.200 how you're looking at sex. Is this irreversible, constant thing, 1:25:14.439 --> 1:25:17.320 Like there are so many different ways to define it. 1:25:17.320 --> 1:25:19.040 It's it's really cool. 1:25:19.200 --> 1:25:22.040 It's really cool, And yeah, I think it also makes 1:25:22.120 --> 1:25:24.679 us think that there is one thing that is normal 1:25:25.080 --> 1:25:27.920 and the rest of everything outside of that is abnormal, 1:25:28.240 --> 1:25:32.400 which isn't the case. There's a lot of variation in 1:25:32.520 --> 1:25:36.080 what can happen during the process of development, during the 1:25:36.120 --> 1:25:41.559 process of cell replication and division. Like, it's awesome, it 1:25:41.640 --> 1:25:47.040 is so so sources, sources so everyone can read some more. 1:25:47.400 --> 1:25:48.040 Let's do it. 1:25:49.080 --> 1:25:51.360 I have several I'm going to shout out a couple 1:25:51.400 --> 1:25:54.559 that I found super helpful. One is by Abbot at 1:25:54.560 --> 1:25:57.920 All from twenty seventeen about the history of sex chromism discovery. 1:25:58.600 --> 1:26:01.320 A paper by Brush. 1:26:01.160 --> 1:26:04.760 Nineteen seventy eight about that was the one about Nettie Stevens. 1:26:05.040 --> 1:26:06.000 It's a great paper. 1:26:06.520 --> 1:26:10.719 And then also I got some info from a book 1:26:10.760 --> 1:26:14.160 by Sarah Richardson called Sex Itself. And then finally I 1:26:14.200 --> 1:26:16.599 just want to shout out again that great paper by 1:26:16.640 --> 1:26:20.160 Moore and Roberts from twenty thirteen called Polygenic Sex Determination. 1:26:21.160 --> 1:26:23.439 I had a number of papers a couple of my 1:26:23.560 --> 1:26:27.560 favorites that are more recent. One was Turner Syndrome Mechanisms 1:26:27.560 --> 1:26:32.240 and Management from Nature Reviews Endercronology twenty nineteen, and another 1:26:32.479 --> 1:26:35.519 was the Changing Face of Turner Syndrome from Endocan Reviews 1:26:35.560 --> 1:26:38.360 twenty twenty two. Both of those have a lot on 1:26:38.439 --> 1:26:40.800 like where we stand with Turner syndrome, what we know, 1:26:40.880 --> 1:26:43.280 and what we need to know. But we'll post the 1:26:43.400 --> 1:26:46.600 list of all of our sources from this episode and 1:26:47.000 --> 1:26:49.719 every one of our episodes on our website. This podcast 1:26:49.720 --> 1:26:51.320 will kill you dot com go check it out. 1:26:53.439 --> 1:26:57.080 I want to give a special thank you to Emily Moore, 1:26:57.280 --> 1:27:01.400 who helped me talk through this part of my history 1:27:01.439 --> 1:27:02.280 for this episode. 1:27:03.080 --> 1:27:03.719 You're the best. 1:27:03.880 --> 1:27:06.920 Thank you, and thank you again to Katie, the provider 1:27:06.960 --> 1:27:10.200 of our first hand account. Thank you so much for 1:27:10.240 --> 1:27:12.280 sharing your story with us and all of our listeners. 1:27:13.080 --> 1:27:15.800 I mean, we can't thank you enough. Thank you to 1:27:15.880 --> 1:27:19.320 Bloodmobile for providing the music for this episode. 1:27:18.800 --> 1:27:20.160 And all of our episodes. 1:27:20.439 --> 1:27:23.840 Thank you as always to the Exactly Right Network, and. 1:27:23.960 --> 1:27:25.320 Thank you to you listeners. 1:27:25.880 --> 1:27:28.400 We hope that you liked this and that we did okay. 1:27:28.360 --> 1:27:32.040 Yeah, let us know when we or the other. Yeah, 1:27:32.080 --> 1:27:34.000 but I had a lot of fun I did too, 1:27:34.200 --> 1:27:36.880 and especial thank you to our patrons. Thank you so 1:27:37.080 --> 1:27:39.000 much for your support. It means the world to us. 1:27:39.320 --> 1:27:40.080 It really does. 1:27:41.000 --> 1:27:45.120 Okay, Well, until next time, wash your hands. 1:27:45.000 --> 1:28:01.880 You failthy animals. U