Overview of Neurocutaneous Disorders

Welcome back to Dirty Medicine. In this video, we're going to be tackling the much maligned topic of neurocutaneous disorders. On this slide, you'll see the five diseases that we're going to be talking about in this video. Those diseases include Sturge-Weber syndrome, tuberous sclerosis, von Hippel-Lindau disease, and both neurofibromatosis type 1 and type 2. Now I've gotten a lot of requests for this topic. It seems to be one of those topics that confuses medical students and rightfully so. If you've ever studied these diseases you're very familiar with the fact that they all have different tumors that go along with them and very similar dermatologic manifestations. So the reason that these are so high yield is because the test writers love to ask you questions about diseases that have overlapping or similar features. And because many of these diseases share all different types of unique tumors and skin findings, it's a really excellent way for them to ask you a question. On one hand, they could ask you about pathophysiology. On the other, they could show you simply a picture of a tumor or a skin finding and ask you to pick the mechanism of how that disease takes place. So the pathophysiology, maybe they'll ask you the genetic defect or the chromosome. Maybe they'll ask you for the name of the picture that they're showing you because all of the tumors are unique. As you can see, this is a very complex topic that can quickly spiral out of control if you don't know what you're doing, which is where dirty medicine comes in. In this video, we'll talk about all of the high-yield findings and sort of give you a minimalist approach. And what I mean by that is that at the end of this video, if you know everything that I put in these slides, you'll have the minimum working knowledge to tackle these questions. And you'll probably get about 90%. of the first level fodder that they throw at you on USMLE and COMLEX. So let's start with a brief overview of the neurocutaneous disorders. So these are genetic diseases that predominantly affect the central nervous system. So that is the brain and the spinal cord, the skin and the bones. And if you think about this, all of the symptoms that you need to know for each of these diseases is really a sequelae of the pathophysiology affecting these regions. Now, by and large, the inheritance pattern for most of these diseases is going to be autosomal dominant. And I say most because there is an exception to that. And we'll point it out when we get there. The other risk factor is that all of these diseases lead to cancer or neoplasm. So because you have oftentimes in these diseases, as we'll get into, problems with tumor suppressor genes, you really have the growth of abnormal cells. And that is something that you need to know. And for each of these diseases, you have to know the specific neoplasm that you can expect to see. So here's our list once again. We're going to go through these one at a time. We'll start with the pathophysiology and the inheritance pattern. Then we'll talk about the high-yield symptoms. And each of these diseases will get wrapped up with a beautifully packaged mnemonic, which will help you get all of the high-yield findings on test day. So let's start with Sturge-Weber syndrome. Now, In case you don't see the name Sturge-Weber syndrome, you may see it written in some textbooks as encephalo-trigeminal angiomatosis. But by and large, you'll see this written and mentioned in questions as Sturge-Weber syndrome. Now, Sturge-Weber syndrome is inherited in a sporadic fashion. So this is non-inherited. It's sporadic. And this is the exception to the rule that I mentioned that most of these are autosomal dominance. So Sturge-Weber is sporadic. The pathophysiology here is that you have a somatic mutation of the GNAQ gene. So I'm going to call that GNAC as we talk about it. And what GNAC does is it stabilizes capillary webs. So what you see here is a capillary network with the GNAC protein coded by the GNAC gene, which stabilizes the capillary web. So the problem is that if you have a somatic or sporadic mutation, because this is sporadic and non-inherited, If you have a somatic mutation of the GNAC gene, then what happens is you knock out the product of that gene and therefore capillaries cannot be stabilized. So if capillaries cannot be stabilized, then all of the symptoms that you see are the result of crappy capillaries. So let's look at those symptoms now. So on the surface of the face, you're going to get a port wine stain. Again, the capillaries in the skin aren't working. In the brain... the capillaries aren't working. So you get what's known as a leptomeningeal angioma. And on the scleral part of the eye, you get an episcleral hemangioma. Okay, so again, capillaries on the eyeball don't work. capillaries on the face don't work. capillaries on the leptomeninges inside of the brain don't work. So in all of these cases, the capillaries don't work. They're not stable, so they rupture, and you get problems with the capillary web's integrity. So these are the high-yield symptoms. Now, think about this. What are going to be the actual clinical manifestations of these symptoms? Well, I'm going to just replace two of the names of these findings with their symptoms. So in the case of the leptomeningeal angioma, because that's in the brain and there's a little bit of blood leaking into the brain, you get seizures and intellectual disability. And in the eyeball, instead of the episcleral hemangioma, I'm going to replace that with early glaucoma. Because when you have a problem with the vasculature or the capillary web on the scleral portion of the eye, then intraocular pressure will build up over time and prematurely, and you'll get early glaucoma. So that's Sturge-Weber syndrome. Once again, it's because of the GNAQ or GNAC gene having a somatic mutation. And because that gene's product is responsible for stabilizing the capillary web that you see here, you get problems with capillaries and they manifest as these clinical findings. Now for Sturge-Weber syndrome, the way that I want you to remember this is that Sturge-Weber makes me think of Sturge-Weber, like a spider web. And a spider web looks awfully similar to a capillary web, wouldn't you say? So in this case, you can remember that Sturge Weber affects the capillary webs. And which capillary webs? The ones in the face, causing the port wine stain. The ones in the leptomeninges, causing the angioma in the brain. And the one in the scleral portion of the eye, causing your scleral angioma. So these are the capillary webs affected in Sturge Weber syndrome. And again, the spider web looks like the capillary web. And when we tie that all together, it's pretty easy to remember our symptoms, which are all sequelae, clinically, of problems with capillaries. So that's the first disease. You guys already know 20% of all this BS that you need to memorize for USMLE and COMLEX. Now let's transition into tuberous sclerosis. So tuberous sclerosis is inherited in an autosomal dominant fashion. The pathophysiology here actually comes from two gene mutations. The first one is TSC1 on chromosome 9, and the second one is TSC2 on chromosome 16. Now, these genes are pretty easy to memorize because tuberous begins with a T, and sclerosis begins with SC, and conveniently the gene is named TSC, so tuberous sclerosis. So TSC for tuberous, the T from tuberous, and the S and the C from sclerosis, and then of course there's number one and number two. So we've got the TSC1 and the TSC2 gene on chromosomes 9 and 16, respectively. So these genes are actually tumor suppressor genes, and they each code for a protein. The TSC1 gene on chromosome 9 codes for hamartin, and the TSC2 gene on chromosome 16 codes for tuberin. In both cases here, if you knock out a tumor suppressor gene, then the protein that that gene would normally form... will be dysfunctional. And when they're dysfunctional or out of control growth of certain proteins, you get neoplasms. So because the TSC1 and TSC2 genes are knocked out, then you have dysregulation of protein production and Hamilton protein and tuberin protein is not going to be at normal levels in the body. And this will cause the growth of various tumors and symptoms that you find clinically in tuberous sclerosis. So those symptoms that you need to memorize are shown. on the next two slides. The big one is the ash leaf spot shown in the top left of this slide. So the ash leaf spot is this area of pigmented change usually found on the skin of the back. You also get cardiac rhabdomyoma shown there at the top right. You get renal angiomyolipoma shown there in the bottom left. And what's known as a chagrin patch, which is usually on the dorsolumbar area. It's sort of like a raised patch that can be slightly erythematous. So if you see any of these four findings, they're pointing you in the direction of tuberous sclerosis. The other two findings that are less known but definitely do show up on exams are the ungual fibromas, which are these little growths on the fingernails right around the nail bed, and what's known as adenoma sebaceum. Adenoma sebaceum oftentimes will show up on exams, and what the examiner is trying to do is trick you into picking some type of pathophysiology or answer related to acne. Because... After all, the adenoma sebaceum that you see in this picture does look a lot like acne, but these are actually fibromas. And it's very important to understand that these are not just your typical acne. These are actually sequelae of tuberous sclerosis. So tuberous sclerosis has a lot... of findings as you see on these two slides. And that makes it really challenging to memorize. So I've got a really cool mnemonic for you to use that's quite simple. So when you think about tuberous sclerosis, you should remember that this is the only neurocutaneous disorder that has cardiac rhabdomyoma and renal angiomyolipoma. And what you may notice is that this disease, tuberous sclerosis, has the only tumors with myo in the name. So the rhabdomyoma and the renal angiomyolipoma. Now, myo means muscle. That's what that prefix means. And what you should think about is what is an instrument that you need to have a lot of muscle to be able to hold? And the answer is the tuba. And this makes sense because tuba reminds me of tuberous sclerosis. So how do we tie this together and use this mnemonic on test day? If you're sitting there and they tell you that there's a rhabdomyoma or an angiomyolipoma, You're recognizing that in the name of the tumor is myo, and you're saying myo means muscle. What takes a lot of muscle to hold a tuba? What's tuba? Tuberous sclerosis. Okay, so that's how you think about it and use the mnemonic. It's pretty easy. And the reason that this is so useful is because no other disease in these neurocutaneous disorders has a tumor with myo in the name. So if you think myo, think muscle. Muscle, think tuba. Tuba, think tuberous sclerosis. Easy, done. You guys know 40%. of all the stuff that you need to know for the neurocutaneous disorders. Let's talk next about von Hippel-Lindau disease. Von Hippel-Lindau disease is inherited in an autosomal dominant fashion. So like I said at the beginning, most of these are autosomal dominant. So, you know, on test day, if you have to guess, guess autosomal dominant. The pathophysiology here is that you get a deletion of the VHL gene on chromosome 3. So VHL, like some of the other examples that we'll see today, is a tumor suppressor gene. And normally what this gene does is it ubiquinates using factor 1A, a complex known as VCB-COL2. Now, for the purposes of USMLE and complex, you absolutely do not need to know the name of that complex. I'm just putting it here for completeness sake. But you should know that it ubiquinates using factor 1A. Now, when that happens, when you ubiquinate something, you turn it off. And normally that complex is responsible for protein degradation. So if you're turning off something. that normally breaks down proteins, then proteins will grow out of control and cause cancer. Makes sense. So basically we're deleting a tumor suppressor gene and then things will go awry. So what are the symptoms that we can expect to see in von Hippel-Lindau disease as a result of this deletion? The two big ones are that you'll get bilateral renal cell carcinoma, also known as RCCs, and you get pheochromocytoma. So that's the most common adrenal tumor. So these two are really, really high yield, but the other ones that you should know are that you'll get hemangioblastomas and angiomas. So you're probably wondering, how am I going to remember all this? Well, instead of von hippo lindau, I want you to think von hippo lindau. And conveniently, there's this picture of a hippo playing a harp, and that's why our mnemonic is going to be harp, the hippo playing the harp. H for hemangioma, A for angioblastoma, R for renal cell carcinoma, and... of note they are bilateral, and P for pheochromocytoma. So von Hippo Lindell, remember the hippopotamus playing the harp? Harp is our mnemonic, H-A-R-P, hemangioma, angioblastoma, bilateral renal cell carcinomas, and pheochromocytoma. So if I can just pause for a second, we've done 60% or three of five of the neurocutaneous disorders. And the way that you remember this so far is that Sturge Weber, the web... messes with the capillary webs. So all of your symptoms are because of problems with capillaries. Tuberous sclerosis should make you think of the tuba, which is the large instrument that you need to have a lot of muscle to lift. Myo means muscle. So any tumor with myo in the name is going to be causing tuberous sclerosis. And then remember von Hippo, Lindau disease playing the harp, the hippo playing the harp, harp, H-A-R-P. And specifically the high yield ones in that to know are the pheos chromocytoma, which is your P in harp. and the R in HARP, which is your bilateral renal cell carcinomas. So I'm just kind of pointing out the really high yield findings, but definitely know all of the associations that I've mentioned. Next, let's talk about neurofibromatosis type 1. Neurofibromatosis type 1, or NF1, is an autosomal dominantly inherited disease. And the pathophysiology here is that the NF1 gene is altered on chromosome 17. Now, how easy is that? It's an NF1 gene. NF for neurofibromatosis, 1 for neurofibromatosis type 1. So neurofibromatosis type 1 is a problem with the NF1 gene. And the NF1 gene normally codes for a tumor suppressor protein known as neurofibromin. And typically, neurofibromin works through the RAS system, and specifically, it inhibits the RAS system. The problem is that when you knock out NF1 and therefore cannot use your tumor suppressor protein and cannot inhibit the RAS cascade, you get the growth of tumors, you get the clinical sequelae that you need to memorize for neurofibromatosis type 1. So those high-yield symptoms are cafe au lait spots shown here in the top left of the slide. Multiple cutaneous neurofibromas shown all over the skin, usually on the trunk, abdomen, the back, that area. Optic gliomas shown in the bottom left of this slide. And what's known as Lisch nodules, which you might see written out as Lisch nodules, but they also might describe it. So you may see it written as pigmented iris hematomas. So all of these symptoms are really, really high yield. And the reason that they're so high yield is for Lisch nodules, they could just show you a picture of an eyeball and you would have to differentiate this. against something like a Kaiser Fleischer ring. So anytime people see bronze things around the eye, they freak out because they don't know if it's a Kaiser Fleischer ring or a Lisch nodule. So I do recommend you take some time getting to know and recognize these pictures. The optic glioma is really high yield because they could show you the CAT scan as I'm doing on this slide, point to it and be like, you know, what's the disease or what's the pathophys or what other symptoms might you expect to find. Cutaneous neurofibromas do tend to be a little bit unique. So if you see a lot of that growth, think of NF1. and the cafe au lait spot is really important to differentiate against the ash leaf spot, which we've seen earlier in this video. So again, spending some time with these pictures is really important. The other findings of neurofibromatosis type 1, which tend to be lower yield, but I'll list them here for completeness sake, are axillary hyperpigmentation, theochromocytoma. So not only can you see that in von Hippel-Lindau disease, but you do see it here in NF1. Scoliosis, Wilms tumor. and bony involvement. So know these associated findings, but if you only have limited brain space and you're cramming this in before your test day, just know the four that you see here. So how do you remember this? Well, as far as remembering the chromosome, there are 17 letters in neurofibromatosis and it occurs due to the problem on chromosome 17. So that's beautiful. The other thing that I think about is somebody going to a coffee shop and they're going to order cafe au lait and they say, I'll have the number one, please. Let's just pretend for a second that number one is, you know, Café au lait, which of course means coffee with hot milk. And that reminds you that in this one, you have the Café au lait spot. So I, again, just to repeat myself to really hammer this home, I think about NF1 and I think about somebody going, I'll have a number one, please. And that reminds me of NF1, not NF2, because Café au lait spots are only in NF1. And I think of that because if they're at a coffee shop ordering the number one, the number one corresponds to the Café au lait. which is coffee with hot milk. And the symptom in NF1, the high yield one is the cafe au lait spot. So that's all the high yield stuff for neurofibromatosis type one. Let's wrap up by differentiating that from neurofibromatosis type two. So like NF1, NF2 is also autosomal dominant. And also like NF1, NF2 is because of the NF2 gene. So it's named for the disease, really easy to recognize and memorize. So the neurofibromatosis 2 gene is a tumor suppressor gene, and that one is on chromosome 22. In this case, you've got a tumor suppressor gene that normally codes for a protein called merlin, and sometimes you might see merlin written as schwannomen. Now this is a tumor suppressor protein, which typically exerts its effect on various pathways in cell signaling. So when you knock out NF2 and therefore don't have a tumor suppressor protein, you get the growth of tumors that should not be there. The highest yield is the bilateral acoustic schwannoma. So if they show you a CAT scan like this and they point to something that's bilateral and it looks like a tumor, chances are they're telling you that it's neurofibromatosis type 2 because they're alluding to a bilateral acoustic schwannoma. Now, these arise from the nerves that come from cranial nerve 8, and that's why they're named acoustic schwannomas. The symptoms here, are going to depend on the cranial nerves that are involved. And typically, these tumors tend to occur at the cerebellopontine angle, and that's anatomically high yield because at that angle, you have cranial nerve 5, 7, and 8 running very close to the angle. So these tumors can compress cranial nerve 5, cranial nerve 7, and cranial nerve 8. So if you're wondering what are the symptoms of a bilateral acoustic schwannoma, they're typically related anatomically to the cranial nerve that gets compressed. So because we're compressing the trigeminal nerve, you get facial paresthesia. Because we're compressing the facial nerve, you get facial paresthesia. And because we're compressing the vestibulocochlear nerve, we're getting tinnitus and sensory neural hearing loss. So put all those symptoms into one package and you really can easily digest this information and understand what a bilateral acoustic schwannoma does. Now, what's really important to know, in addition to the three cranial nerves that are typically compressed and involved, is that, again, this occurs at the cerebellopontine angle. And that's easy to remember because NF2... is at the cerebellopontine angle. So the 2 looks like the 2Ls in cerebellopontine. So easy to remember. The other findings in neurofibromatosis type 2, in addition to the bilateral schwannoma, is ependymomas, meningiomas, and juvenile cataracts. So this tends to be things in the brain and things just below the brain in the case of the cataracts. But if you're looking for a mnemonic here, NF2 occurs on chromosome 22, and it affects things... like the twos, which is to say that it affects things that are bilateral. So again, remember that it causes tinnitus and sensory neural hearing loss, and we have two ears. You have an ear on each side. It causes facial pariasis, and we have cheeks on both sides. And it causes facial paresthesias, and we have cheeks on both sides. It also can cause, as you see here, juvenile cataracts, and we have eyes on both sides. And it causes ependymomas, meningiomas, and bilateral schwannomas. So this occurs in twos, things that are bilateral. 2s, chromosome 22, NF2. This is all of the 2s. And then again, remember that NF2 occurs at the cerebellopontine angle because the 2 in NF2 looks like the 2Ls in cerebellopontine. So that's it, guys. Those are the neurocutaneous disorders. And for your studying pleasure, I've created this summarized chart. Again, remember Sturge-Weber syndrome is the GNAC gene causing the port wine stain, leptomeningeal angioma, episcleral hemangioma. Tuberous sclerosis is your TSC1 and 2 gene causing ash leaf spots. All of the tumors with myo in it because myo means muscle. What does it take to, you need a lot of muscle to lift the tuba and tuba sounds like tuberous sclerosis. The von Hippolindau is the VHL gene causing hemangioma, angioblastoma, renal cell carcinoma, and pheochromocytoma or HARP. Remember the von Hippo, the hippopotamus playing the harp. NF1 is the NF1 gene. NF2 is the NF2 gene. In NF1, you have the cafe au lait spots, the cutaneous neurofibromas, the lish nodules, the optic glioma. Remember that you'll have the number one, please, when you're at the coffee shop, which reminds you of cafe au lait. And for NF2, it affects all of the twos or things that are bilateral. So the bilateral acoustic schwannomas, which will affect cranial nerves 5, 7, and 8, juvenile cataracts, ependymomas, and meningiomas. So I went through that really, really quickly at the end, but that's just your summary slide. Feel free to rewind the video and pause here if you just want a nice, beautiful summary. I hope this video was helpful to you. These diseases suck to memorize, but I do believe that if you watch this video, know the findings, know the pathophysiology, you'll be able to tackle most, if not all, of your USMLE and COMLEX questions.

Those diseases include Sturge-Weber syndrome, tuberous sclerosis, von Hippel-Lindau disease, and both neurofibromatosis type 1 and type 2. Now I've gotten a lot of requests for this topic. It seems to be one of those topics that confuses medical students and rightfully so. If you've ever studied these diseases you're very familiar with the fact that they all have different tumors that go along with them and very similar dermatologic manifestations.

So the reason that these are so high yield is because the test writers love to ask you questions about diseases that have overlapping or similar features. And because many of these diseases share all different types of unique tumors and skin findings, it's a really excellent way for them to ask you a question. On one hand, they could ask you about pathophysiology.

On the other, they could show you simply a picture of a tumor or a skin finding and ask you to pick the mechanism of how that disease takes place. So the pathophysiology, maybe they'll ask you the genetic defect or the chromosome. Maybe they'll ask you for the name of the picture that they're showing you because all of the tumors are unique.

As you can see, this is a very complex topic that can quickly spiral out of control if you don't know what you're doing, which is where dirty medicine comes in. In this video, we'll talk about all of the high-yield findings and sort of give you a minimalist approach. And what I mean by that is that at the end of this video, if you know everything that I put in these slides, you'll have the minimum working knowledge to tackle these questions.

And you'll probably get about 90%. of the first level fodder that they throw at you on USMLE and COMLEX. So let's start with a brief overview of the neurocutaneous disorders.

So these are genetic diseases that predominantly affect the central nervous system. So that is the brain and the spinal cord, the skin and the bones. And if you think about this, all of the symptoms that you need to know for each of these diseases is really a sequelae of the pathophysiology affecting these regions. Now, by and large, the inheritance pattern for most of these diseases is going to be autosomal dominant. And I say most because there is an exception to that.

And we'll point it out when we get there. The other risk factor is that all of these diseases lead to cancer or neoplasm. So because you have oftentimes in these diseases, as we'll get into, problems with tumor suppressor genes, you really have the growth of abnormal cells. And that is something that you need to know. And for each of these diseases, you have to know the specific neoplasm that you can expect to see.

So here's our list once again. We're going to go through these one at a time. We'll start with the pathophysiology and the inheritance pattern.

Then we'll talk about the high-yield symptoms. And each of these diseases will get wrapped up with a beautifully packaged mnemonic, which will help you get all of the high-yield findings on test day. So let's start with Sturge-Weber syndrome.

Now, In case you don't see the name Sturge-Weber syndrome, you may see it written in some textbooks as encephalo-trigeminal angiomatosis. But by and large, you'll see this written and mentioned in questions as Sturge-Weber syndrome. Now, Sturge-Weber syndrome is inherited in a sporadic fashion.

So this is non-inherited. It's sporadic. And this is the exception to the rule that I mentioned that most of these are autosomal dominance.

So Sturge-Weber is sporadic. The pathophysiology here is that you have a somatic mutation of the GNAQ gene. So I'm going to call that GNAC as we talk about it.

And what GNAC does is it stabilizes capillary webs. So what you see here is a capillary network with the GNAC protein coded by the GNAC gene, which stabilizes the capillary web. So the problem is that if you have a somatic or sporadic mutation, because this is sporadic and non-inherited, If you have a somatic mutation of the GNAC gene, then what happens is you knock out the product of that gene and therefore capillaries cannot be stabilized.

So if capillaries cannot be stabilized, then all of the symptoms that you see are the result of crappy capillaries. So let's look at those symptoms now. So on the surface of the face, you're going to get a port wine stain. Again, the capillaries in the skin aren't working.

In the brain... the capillaries aren't working. So you get what's known as a leptomeningeal angioma.

And on the scleral part of the eye, you get an episcleral hemangioma. Okay, so again, capillaries on the eyeball don't work. capillaries on the face don't work. capillaries on the leptomeninges inside of the brain don't work. So in all of these cases, the capillaries don't work.

They're not stable, so they rupture, and you get problems with the capillary web's integrity. So these are the high-yield symptoms. Now, think about this. What are going to be the actual clinical manifestations of these symptoms?

Well, I'm going to just replace two of the names of these findings with their symptoms. So in the case of the leptomeningeal angioma, because that's in the brain and there's a little bit of blood leaking into the brain, you get seizures and intellectual disability. And in the eyeball, instead of the episcleral hemangioma, I'm going to replace that with early glaucoma.

Because when you have a problem with the vasculature or the capillary web on the scleral portion of the eye, then intraocular pressure will build up over time and prematurely, and you'll get early glaucoma. So that's Sturge-Weber syndrome. Once again, it's because of the GNAQ or GNAC gene having a somatic mutation. And because that gene's product is responsible for stabilizing the capillary web that you see here, you get problems with capillaries and they manifest as these clinical findings. Now for Sturge-Weber syndrome, the way that I want you to remember this is that Sturge-Weber makes me think of Sturge-Weber, like a spider web.

And a spider web looks awfully similar to a capillary web, wouldn't you say? So in this case, you can remember that Sturge Weber affects the capillary webs. And which capillary webs?

The ones in the face, causing the port wine stain. The ones in the leptomeninges, causing the angioma in the brain. And the one in the scleral portion of the eye, causing your scleral angioma.

So these are the capillary webs affected in Sturge Weber syndrome. And again, the spider web looks like the capillary web. And when we tie that all together, it's pretty easy to remember our symptoms, which are all sequelae, clinically, of problems with capillaries. So that's the first disease. You guys already know 20% of all this BS that you need to memorize for USMLE and COMLEX.

Now let's transition into tuberous sclerosis. So tuberous sclerosis is inherited in an autosomal dominant fashion. The pathophysiology here actually comes from two gene mutations. The first one is TSC1 on chromosome 9, and the second one is TSC2 on chromosome 16. Now, these genes are pretty easy to memorize because tuberous begins with a T, and sclerosis begins with SC, and conveniently the gene is named TSC, so tuberous sclerosis.

So TSC for tuberous, the T from tuberous, and the S and the C from sclerosis, and then of course there's number one and number two. So we've got the TSC1 and the TSC2 gene on chromosomes 9 and 16, respectively. So these genes are actually tumor suppressor genes, and they each code for a protein. The TSC1 gene on chromosome 9 codes for hamartin, and the TSC2 gene on chromosome 16 codes for tuberin. In both cases here, if you knock out a tumor suppressor gene, then the protein that that gene would normally form...

will be dysfunctional. And when they're dysfunctional or out of control growth of certain proteins, you get neoplasms. So because the TSC1 and TSC2 genes are knocked out, then you have dysregulation of protein production and Hamilton protein and tuberin protein is not going to be at normal levels in the body. And this will cause the growth of various tumors and symptoms that you find clinically in tuberous sclerosis.

So those symptoms that you need to memorize are shown. on the next two slides. The big one is the ash leaf spot shown in the top left of this slide. So the ash leaf spot is this area of pigmented change usually found on the skin of the back.

You also get cardiac rhabdomyoma shown there at the top right. You get renal angiomyolipoma shown there in the bottom left. And what's known as a chagrin patch, which is usually on the dorsolumbar area. It's sort of like a raised patch that can be slightly erythematous.

So if you see any of these four findings, they're pointing you in the direction of tuberous sclerosis. The other two findings that are less known but definitely do show up on exams are the ungual fibromas, which are these little growths on the fingernails right around the nail bed, and what's known as adenoma sebaceum. Adenoma sebaceum oftentimes will show up on exams, and what the examiner is trying to do is trick you into picking some type of pathophysiology or answer related to acne. Because...

After all, the adenoma sebaceum that you see in this picture does look a lot like acne, but these are actually fibromas. And it's very important to understand that these are not just your typical acne. These are actually sequelae of tuberous sclerosis. So tuberous sclerosis has a lot... of findings as you see on these two slides.

And that makes it really challenging to memorize. So I've got a really cool mnemonic for you to use that's quite simple. So when you think about tuberous sclerosis, you should remember that this is the only neurocutaneous disorder that has cardiac rhabdomyoma and renal angiomyolipoma.

And what you may notice is that this disease, tuberous sclerosis, has the only tumors with myo in the name. So the rhabdomyoma and the renal angiomyolipoma. Now, myo means muscle. That's what that prefix means. And what you should think about is what is an instrument that you need to have a lot of muscle to be able to hold?

And the answer is the tuba. And this makes sense because tuba reminds me of tuberous sclerosis. So how do we tie this together and use this mnemonic on test day?

If you're sitting there and they tell you that there's a rhabdomyoma or an angiomyolipoma, You're recognizing that in the name of the tumor is myo, and you're saying myo means muscle. What takes a lot of muscle to hold a tuba? What's tuba? Tuberous sclerosis.

Okay, so that's how you think about it and use the mnemonic. It's pretty easy. And the reason that this is so useful is because no other disease in these neurocutaneous disorders has a tumor with myo in the name. So if you think myo, think muscle.

Muscle, think tuba. Tuba, think tuberous sclerosis. Easy, done.

You guys know 40%. of all the stuff that you need to know for the neurocutaneous disorders. Let's talk next about von Hippel-Lindau disease. Von Hippel-Lindau disease is inherited in an autosomal dominant fashion. So like I said at the beginning, most of these are autosomal dominant.

So, you know, on test day, if you have to guess, guess autosomal dominant. The pathophysiology here is that you get a deletion of the VHL gene on chromosome 3. So VHL, like some of the other examples that we'll see today, is a tumor suppressor gene. And normally what this gene does is it ubiquinates using factor 1A, a complex known as VCB-COL2. Now, for the purposes of USMLE and complex, you absolutely do not need to know the name of that complex. I'm just putting it here for completeness sake.

But you should know that it ubiquinates using factor 1A. Now, when that happens, when you ubiquinate something, you turn it off. And normally that complex is responsible for protein degradation.

So if you're turning off something. that normally breaks down proteins, then proteins will grow out of control and cause cancer. Makes sense. So basically we're deleting a tumor suppressor gene and then things will go awry. So what are the symptoms that we can expect to see in von Hippel-Lindau disease as a result of this deletion?

The two big ones are that you'll get bilateral renal cell carcinoma, also known as RCCs, and you get pheochromocytoma. So that's the most common adrenal tumor. So these two are really, really high yield, but the other ones that you should know are that you'll get hemangioblastomas and angiomas.

So you're probably wondering, how am I going to remember all this? Well, instead of von hippo lindau, I want you to think von hippo lindau. And conveniently, there's this picture of a hippo playing a harp, and that's why our mnemonic is going to be harp, the hippo playing the harp. H for hemangioma, A for angioblastoma, R for renal cell carcinoma, and... of note they are bilateral, and P for pheochromocytoma.

So von Hippo Lindell, remember the hippopotamus playing the harp? Harp is our mnemonic, H-A-R-P, hemangioma, angioblastoma, bilateral renal cell carcinomas, and pheochromocytoma. So if I can just pause for a second, we've done 60% or three of five of the neurocutaneous disorders. And the way that you remember this so far is that Sturge Weber, the web...

messes with the capillary webs. So all of your symptoms are because of problems with capillaries. Tuberous sclerosis should make you think of the tuba, which is the large instrument that you need to have a lot of muscle to lift. Myo means muscle. So any tumor with myo in the name is going to be causing tuberous sclerosis.

And then remember von Hippo, Lindau disease playing the harp, the hippo playing the harp, harp, H-A-R-P. And specifically the high yield ones in that to know are the pheos chromocytoma, which is your P in harp. and the R in HARP, which is your bilateral renal cell carcinomas.

So I'm just kind of pointing out the really high yield findings, but definitely know all of the associations that I've mentioned. Next, let's talk about neurofibromatosis type 1. Neurofibromatosis type 1, or NF1, is an autosomal dominantly inherited disease. And the pathophysiology here is that the NF1 gene is altered on chromosome 17. Now, how easy is that?

It's an NF1 gene. NF for neurofibromatosis, 1 for neurofibromatosis type 1. So neurofibromatosis type 1 is a problem with the NF1 gene. And the NF1 gene normally codes for a tumor suppressor protein known as neurofibromin.

And typically, neurofibromin works through the RAS system, and specifically, it inhibits the RAS system. The problem is that when you knock out NF1 and therefore cannot use your tumor suppressor protein and cannot inhibit the RAS cascade, you get the growth of tumors, you get the clinical sequelae that you need to memorize for neurofibromatosis type 1. So those high-yield symptoms are cafe au lait spots shown here in the top left of the slide. Multiple cutaneous neurofibromas shown all over the skin, usually on the trunk, abdomen, the back, that area. Optic gliomas shown in the bottom left of this slide. And what's known as Lisch nodules, which you might see written out as Lisch nodules, but they also might describe it.

So you may see it written as pigmented iris hematomas. So all of these symptoms are really, really high yield. And the reason that they're so high yield is for Lisch nodules, they could just show you a picture of an eyeball and you would have to differentiate this. against something like a Kaiser Fleischer ring. So anytime people see bronze things around the eye, they freak out because they don't know if it's a Kaiser Fleischer ring or a Lisch nodule.

So I do recommend you take some time getting to know and recognize these pictures. The optic glioma is really high yield because they could show you the CAT scan as I'm doing on this slide, point to it and be like, you know, what's the disease or what's the pathophys or what other symptoms might you expect to find. Cutaneous neurofibromas do tend to be a little bit unique.

So if you see a lot of that growth, think of NF1. and the cafe au lait spot is really important to differentiate against the ash leaf spot, which we've seen earlier in this video. So again, spending some time with these pictures is really important.

The other findings of neurofibromatosis type 1, which tend to be lower yield, but I'll list them here for completeness sake, are axillary hyperpigmentation, theochromocytoma. So not only can you see that in von Hippel-Lindau disease, but you do see it here in NF1. Scoliosis, Wilms tumor. and bony involvement.

So know these associated findings, but if you only have limited brain space and you're cramming this in before your test day, just know the four that you see here. So how do you remember this? Well, as far as remembering the chromosome, there are 17 letters in neurofibromatosis and it occurs due to the problem on chromosome 17. So that's beautiful.

The other thing that I think about is somebody going to a coffee shop and they're going to order cafe au lait and they say, I'll have the number one, please. Let's just pretend for a second that number one is, you know, Café au lait, which of course means coffee with hot milk. And that reminds you that in this one, you have the Café au lait spot.

So I, again, just to repeat myself to really hammer this home, I think about NF1 and I think about somebody going, I'll have a number one, please. And that reminds me of NF1, not NF2, because Café au lait spots are only in NF1. And I think of that because if they're at a coffee shop ordering the number one, the number one corresponds to the Café au lait.

which is coffee with hot milk. And the symptom in NF1, the high yield one is the cafe au lait spot. So that's all the high yield stuff for neurofibromatosis type one. Let's wrap up by differentiating that from neurofibromatosis type two. So like NF1, NF2 is also autosomal dominant.

And also like NF1, NF2 is because of the NF2 gene. So it's named for the disease, really easy to recognize and memorize. So the neurofibromatosis 2 gene is a tumor suppressor gene, and that one is on chromosome 22. In this case, you've got a tumor suppressor gene that normally codes for a protein called merlin, and sometimes you might see merlin written as schwannomen. Now this is a tumor suppressor protein, which typically exerts its effect on various pathways in cell signaling. So when you knock out NF2 and therefore don't have a tumor suppressor protein, you get the growth of tumors that should not be there.

The highest yield is the bilateral acoustic schwannoma. So if they show you a CAT scan like this and they point to something that's bilateral and it looks like a tumor, chances are they're telling you that it's neurofibromatosis type 2 because they're alluding to a bilateral acoustic schwannoma. Now, these arise from the nerves that come from cranial nerve 8, and that's why they're named acoustic schwannomas. The symptoms here, are going to depend on the cranial nerves that are involved.

And typically, these tumors tend to occur at the cerebellopontine angle, and that's anatomically high yield because at that angle, you have cranial nerve 5, 7, and 8 running very close to the angle. So these tumors can compress cranial nerve 5, cranial nerve 7, and cranial nerve 8. So if you're wondering what are the symptoms of a bilateral acoustic schwannoma, they're typically related anatomically to the cranial nerve that gets compressed. So because we're compressing the trigeminal nerve, you get facial paresthesia.

Because we're compressing the facial nerve, you get facial paresthesia. And because we're compressing the vestibulocochlear nerve, we're getting tinnitus and sensory neural hearing loss. So put all those symptoms into one package and you really can easily digest this information and understand what a bilateral acoustic schwannoma does. Now, what's really important to know, in addition to the three cranial nerves that are typically compressed and involved, is that, again, this occurs at the cerebellopontine angle. And that's easy to remember because NF2...

is at the cerebellopontine angle. So the 2 looks like the 2Ls in cerebellopontine. So easy to remember.

The other findings in neurofibromatosis type 2, in addition to the bilateral schwannoma, is ependymomas, meningiomas, and juvenile cataracts. So this tends to be things in the brain and things just below the brain in the case of the cataracts. But if you're looking for a mnemonic here, NF2 occurs on chromosome 22, and it affects things... like the twos, which is to say that it affects things that are bilateral.

So again, remember that it causes tinnitus and sensory neural hearing loss, and we have two ears. You have an ear on each side. It causes facial pariasis, and we have cheeks on both sides. And it causes facial paresthesias, and we have cheeks on both sides. It also can cause, as you see here, juvenile cataracts, and we have eyes on both sides.

And it causes ependymomas, meningiomas, and bilateral schwannomas. So this occurs in twos, things that are bilateral. 2s, chromosome 22, NF2.

This is all of the 2s. And then again, remember that NF2 occurs at the cerebellopontine angle because the 2 in NF2 looks like the 2Ls in cerebellopontine. So that's it, guys.

Those are the neurocutaneous disorders. And for your studying pleasure, I've created this summarized chart. Again, remember Sturge-Weber syndrome is the GNAC gene causing the port wine stain, leptomeningeal angioma, episcleral hemangioma. Tuberous sclerosis is your TSC1 and 2 gene causing ash leaf spots. All of the tumors with myo in it because myo means muscle.

What does it take to, you need a lot of muscle to lift the tuba and tuba sounds like tuberous sclerosis. The von Hippolindau is the VHL gene causing hemangioma, angioblastoma, renal cell carcinoma, and pheochromocytoma or HARP. Remember the von Hippo, the hippopotamus playing the harp. NF1 is the NF1 gene. NF2 is the NF2 gene.

In NF1, you have the cafe au lait spots, the cutaneous neurofibromas, the lish nodules, the optic glioma. Remember that you'll have the number one, please, when you're at the coffee shop, which reminds you of cafe au lait. And for NF2, it affects all of the twos or things that are bilateral.

So the bilateral acoustic schwannomas, which will affect cranial nerves 5, 7, and 8, juvenile cataracts, ependymomas, and meningiomas. So I went through that really, really quickly at the end, but that's just your summary slide. Feel free to rewind the video and pause here if you just want a nice, beautiful summary. I hope this video was helpful to you.

These diseases suck to memorize, but I do believe that if you watch this video, know the findings, know the pathophysiology, you'll be able to tackle most, if not all, of your USMLE and COMLEX questions.

Transcript for:Overview of Neurocutaneous Disorders

Transcript for:
Overview of Neurocutaneous Disorders