This is a mechanism of disease map for Klinefelter syndrome. I'll be talking about the etiology, the pathophysiology, the manifestations, and then a quick note on the pharmacology, how to treat Klinefelter syndrome. As in all of these flowcharts, each of these boxes is color-coded according to these core concepts in the top right. And I'll be clearing each of these items and going through them one by one as I explain them. So let's get started. The core feature of Klinefelter syndrome is this presence of a bar body, this inactivated X chromosome. So real quick, if we do a karyotype on somebody with Klinefelter syndrome, we'll see 47XXY. You'll notice that a normal male has just XY, but in Klinefelter they have that additional X chromosome. In rare cases, you can get 48XXXY or even 48XXYY, but those are exceedingly rare for And it's usually 47 xxy. How does this happen? It's usually non-disjunction of the sex chromosomes during meiosis. Let me give you an example of this. Here's a picture of meiosis where the male's cells are coming from the blue and the female is coming from the pink. And you could see that in meiosis 2 of the female, there's non-disjunction. These two chromosomes are failing to separate. So this cell that I'm circling right now ends up with an extra chromosome that it then gives to the new embryo. And that new embryo has double X chromosomes with one small Y in blue there. So that's how you end up with XXY. Turns out that advanced maternal age causes this, among other chromosomal deficits, and that's the biggest risk factor for Klinefelter syndrome. Now there are many manifestations somewhat ranging throughout the body, but largely related to low androgens, low testosterone, and we'll go through how we end up there. So, the presence of this bar body, this extra X chromosome, leads to testicular dysgenesis, and that's going to cause some hormonal imbalances in your body, mainly high FSH and high LH. Let's see how we get there. Testicular dysgenesis, specifically, we have seminiferous tubule dysgenesis, which means that you'll have a loss of the Sertoli cells. You'll have low inhibin, which results in low FSH. So that explains the FSH. Now for the LH. Part of the testicular dysgenesis is also Leydig cell dysgenesis, which means that you won't be making testosterone, which breaks the feedback inhibition and ends up with high LH. When you have high FSH and high LH, you'll have increased conversion of testosterone to estrogen, and that kind of further exacerbates your low testosterone state. So not only are your LADIG cells not working and you're not producing enough testosterone, you're also increasing the conversion of testosterone to estrogen. The end result is many features of hypoandrogenism, and these are the main manifestations from a clinical perspective of Klinefelter syndrome. Patients will have a unicoid habitus. This results from delayed growth plate closure, which also is a result of low testosterone. And the patient will be tall, will have a slim stature, and have long extremities. The patient will have gynecomastia, or breast development in men. They'll have decreased facial and body hair. They can have testicular atrophy, decreased fertility, and decreased libido. Azospermia, which is a decreased or no sperm count in the ejaculate. They can have a micropenis. They don't always. It's normal to have a normal penis in Klinefelter syndrome. And they'll have osteoporosis in adulthood, also a result of the low testosterone. There are many other features from the neurocognitive perspective and psychiatry perspective. They'll have problems with executive functioning, memory, intelligence, and these tend to get worse with more X chromosomes. So the 48XXXY would be worse in terms of neurocognitive dysfunction than the 47XXY. Patients will also have language impairment and poor social skills. Other medical conditions include mitral valve prolapse, metabolic syndrome, and an increased risk of breast and testicular cancer. Now, how do you diagnose Klinefelter syndrome? A lot of the stuff we already talked about. You'll have these hormonal imbalances. You'll have all of these clinical symptoms. So you might be able to make it a clinical diagnosis in the beginning. You can confirm more hormonal imbalances. Patients will have a high aromatase and high estrogen if the conversion of testosterone to estrogen is increased. You'll of course do karyotyping to confirm. And if you want another confirmatory test, you can do histology. You can take a testicle biopsy. usually done post-puberty, and you'll see these exact changes in latex cells and seminiferous tubules. So you'll have fibrosis in the seminiferous tubules and latex cell hyperplasia. Lastly, a quick note on pharmacology. What can you do to treat this? You can exactly combat the hypoandrogenism symptoms by giving more androgens, by giving lifelong testosterone placement. So that should address some of the symptoms related to low testosterone. That's it for this flowchart of Klinefelter syndrome. I hope it was helpful. And thank you for listening.