Albinism

"Hello, welcome to Eyes for Ears, through Orthomology OCAPs and Borderview podcast, for your host Ben Young." "And Andrew Powell, just a reminder that these episodes are meant for medical education only, not for diagnosing anything on anyone's eyes." "Each week we take a high-yield topic and talk about the why in the how." "What do we talk about this week, Andrew?" "Today, it's albinism relating to eyes, at least, both ocular, ocular-only, and ocular cootatius." "Yeah, you know, it's really relevant. It's not common, by any means. You know, it's very possible, I think, to go through, like, your whole residency training without having seen a patient with frank albinism, but we need to know about it, that it can affect the eyes in a lot of different ways, which we'll review. But first, let's talk about the terminology, so that it's, because I think you can get confusing between the different types of albinism. There's two broad classes of it, Andrew, can you tell us a little bit about what those are? "Yeah, it's really just, is this skin involved, or is it not? So one category is those where skin is involved, ocular-cutaneous albinism, which affects your eyes, your hair, and your skin, or the other category is ocular-albinism without the cutaneous part in their name, and that supposedly just affects only eyes." Yeah, is there a pathologic difference between them, or is it like a penetrance thing? Yeah, to be honest, I'm not sure how much you need to know this, but it does show up in the path book, the, at the histopathological level. The one with skin involvement, ocular-cutaneous, has reduced melanin in each melanism, whereas the one that only affects eyes, oA, ocular-albinism, just has fewer melanosomes. So ocA has reduced melanin in each melanism, whereas oA just has fewer melanosomes. Yeah, the interesting difference, and you know, just pure ocular-albinism is rare, but that's, like, it's possible to have someone who doesn't have skin involvement, but have ocular-albinism is what's important, and they can have a lot of the findings that we'll go into now, that affect the eyes. Let's start with the iris. Let's kind of sort of go front-to-back for this. Yeah, what color are a patient with albinism's eyes? Usually lighter than they would have been. Yeah, exactly. I have a, have I done my bit about eye color on the podcast yet? I've got, like, a two-minute bit. I'm a bit worried, but I don't know. I don't know. Okay, if you've heard this bit before, skip ahead, like, you know, a minute and 45 seconds. Okay. Like, here's my explanation of eye color in general, like, how it, because, you know, there's only kind of one toggle. This is, like, not specific to the albinism, but to, like, everything. You know, it's, like, one toggle, right, for eye color, and that's amount of melanin essentially within the iris, but then you have this whole spectrum, like, green, blue, brown, hazel, like, all these different colors. So how does that happen with, like, one toggle going through all these different colors? Well, remember the iris anatomy. There's a stroma, and then there's an epithelium, and, and basically, all patients have pigment in their epithelium, but then in their stroma, it's where the amount of melanin can vary, that changes eye color. So you have a lot of melanin, and then it'll look like brown or really dark brown, eye black, you know, et cetera, or if there's a little bit, you know, it'll have the kind of a lighter melanin color, so it'd be, like, light brown, et cetera. But then as you reduce it more and more, if you, let's pretend you have no pigment in your iris stroma, then you will have blue eyes, and why is, why do your eyes look blue? It's the same reason the sky is blue sort of, it's scattering of light. So the sky is blue, because there's something called rally scattering, and eyes can look blue because there's something called tindle scattering, which is just, it's just about, like, the size of particles that are scattering light, like, I don't think it's in BCC, we don't worry too much about, like, the difference between those two, but it's basically light will scatter, and then the shortwave length blue will kind of come back out after that scattering, and the eyes will look blue. And that's how you get green eyes as well, is there's just enough less pigment that you'll have kind of a light brown effect, like, or, like, a light orange yellow kind of effect with the blue, and combine they look green. So that's how you get from blue to green to, like, you know, like, hazel or, like, light brown to dark brown, and, you know, all with just one kind of dial turning, how much melanin in there is in this drama. And then the one exception is albinism, and I lied in the beginning, I said, all patients have pigment in their iris epithelium, not true, with albinism, you don't have, like, any pigment anywhere. So they don't have that pigment in their iris epithelium. So that means light will penetrate through and through, and then bounce back. And that's why patients with albinism look like they have, like, quote, violet eyes is because you're really seeing red reflects shine through, and it makes a little bit with that scattering effect in the stroma, a little bit of blue makes that kind of red reflects look violet. And that's basically all eye colors, I think. Thanks, Ben. That was super helpful. And it connected to pop culture. That's why, you know, if any Game of Thrones nerds out there, or remember, the valerians have, like, violet, like, blue eyes, they all have albinism. What do you know? Oh, I did not expect production values to go into ocular anatomy, okay? Yeah, there you go. Yeah, that's why, like, at least in the books, I don't know if in the show, I don't think they made, like, deniers have violet eyes, right? I think they're, like, blue in the show. I don't get dealt with that. I think you can count on biological accuracy to reduce and consistency through the seasons. Yeah, yeah. That's, it's probably the details probably dropped off, you know? Anyways, okay, that's eye color, sorry to take half the episode with that. Okay, is you, what else can we notice with the iris besides this whole color thing? That it just has a lot of transorbitmination defects as you'd expect. And that might even, like, you see the edge of the fake egg lens in much greater detail than you ever would have before on these folks. This isn't really exam finding, but as you can imagine, without all this, like, iris pigment to act as a barrier for sunlight to help the pinhole effect more or less, just too much light gets in the eye and they can be very photophobic. Yeah, very light-sensitive. And just to clarify, too, the transorbitmination defects don't have to be, like, complete and diffuse. You know, there's, like, variable presentations. They might have, like, speckled TIDs, if they have, like, some irisipithelial pigmentation. And, you know, that's the concept of TIDs in general, right, is loss of irisipithelial pigmentation. That's why surgically, you can get TIDs if, you know, that layer gets chafed-off during surgery or something. Okay. I think it's tough about the iris, right? Yeah. The iris will look striking, but something we don't have down is, like, even before use, if we're really going, like, front to back, the first thing you'll really notice is there abnormal eye movements, all those eye-stagmus movements, but we will get there in a bit. Yeah. And, like, I guess, kind of why they have abnormal eye movements, which is the phobia, which is really the big area where vision has problems and patients with albinism. Then, I guess, we'll just, why is that? Well, they have hypoplastic phobias, which, if you haven't seen it, means that the phobia doesn't have the normal, nice dip that it had the pitting that it normally has. It usually is kind of flat looking. Some people will term that phobia plana, because, like, a flat phobia, it's why they term it that way, and that just, tends to happen to patients with albinism. It's also not the only cause of phobia plana to be clear. You know, we were debating how much of the mechanism we should go into, who are prepping for this episode, but I think, hopefully, it's a little bit useful to have, at least, know the speculation, because, to be clear, with albinism, from our look at the literature up to, like, 2022, it's not definitive why albinic patients have phovial hypoplasia. But here's, like, a framework that, I think, makes sense, at least to me. The, you know, we all know the retinal vessels start development and grow through gestation. And as they grow, they are repelled by something near the phobia, which is why most adult phobias have a phobia, a vascular zone. There's something stopping the blood vessels from getting, you know, to the central phobia. The best candidate for that in the literature is something called pigment epithelial derived factor, PEDF, which is made by the retinal pigment epithelial in the RPE, and is basically like a natural antivagia effect that's produced mainly at the phobia. The hypothesis about why some patients have phobia, planar phobia, hypoplasia or not, is probably a mismatch between how much VEGF is produced when the retinal vessels are developing and how much PEDF, this anti-vascular growth factor is produced. And albinism, it's likely, not definitive, but likely that because of the issues of their pigment epithelium, because of their pigment issues, they make less PEDF, which means that the VEGF is able to drive the vessels into the phobia more than they otherwise should. This is like a counter example. You can get the phobia, hypoplasia, and run up the imprimaturity as well. And that might be the other way around where they just have too much VEGF in RLP, which might help those phobia of vascular, let's start off the phobia of vessels penetrating the phobia of vascular zone two. Now, why does that have anything to do with having a flat phobia? The hypothesis is that the structure of the phobia may, or the structural rigidity of The retina may impart be to you. to the retinal vascular, so if you don't have vessels in an area like in the foveal vascular zone, as the eye develops and like your intracurricular pressure starts to develop, it'll indent that area because it's not as rigid as in the rest of the retina where it has blood vessels. But if you have blood vessels that invade your foveal vascular zone, then it'll become more rigid and it won't indent like it's supposed to as the eye develops. Just a bunch of theory, it may not help you remember any of this. You can also ignore all of that if it's not helpful to you. But to me, it kind of helps to remember like why do we see this and like why do we have to be worried? And the last caveat I'll make is patients can have like a flat fovea and have perfectly normal vision too. We see this on RLP and like there's patients who just for adiopathically have a normal fovea. Unfortunately, we tend to not see that in alpinism, you know, they tend to have quite poor vision with foveal hyponplasia. It's just the nuances of foveal hyponplasia, which probably could have been so nuttersound. I'll let you decide whether to keep that or not later. I'm keeping it. Sorry, listeners. I mean, in that case, I'll mention another weird possible cause of this while we're just talking about theory anyway. You don't have as much pigment in any of the retinal pigment epithelium and nobody really knows exactly how that is going to affect the retina above it, but that's another possible rabbit's hole to dive into. Yeah, migration and stuff, for sure. All that could maybe explain some of the refractive error that is often seen for alpinism, albinoid individuals, right? Yeah. Yeah, for sure. Without that drive of having normally developing central vision, you know, that, you know, I, I mean, the mechanisms between eye growth and myopia development and like hyperopiodevelopment and all that is very complicated and not completely sust out, but not having good central fixation probably affects it somehow. So that's, but, you know, to be clear out, patients with albinism can have any kind of refractive error, you know, they can be, you know, astigmatic, myopic hyperopathy. Well they tend to have some issue, they tend not to be ambitropic. The niestagmas that they end up developing since childhood really affects things too. You can imagine it just ends up sort of being like the retina never gets a clear image because it's always blurry, so, um, yep, sometimes stagmas just shows up whenever you have poor central fixation. Yeah. It tends to be pendular if you need to remember which kind of niestagmas, a pendular niestagmas. And I think the first time you see a patient with albinism, it's quite striking. It will be like easier to remember, you know, it's like very common in patients with albinism. And along with that is stribusmas. They tend to have stribusmas, you know, to go along with all these things too, but they don't have to. Okay. And then even further back, there's another odd thing that happens with their optic pathway. All the way back to the occipital lobe. Yeah. Yeah. Yeah. The chiasmal pathway with the decassation of nerve fibers leading to roughly 50/50, like, you know, once the temporal side of your field, those nerves go over those fibers decassate to the contralateral part of the brain when same with the nasal fibers, that's usually a 50/50 split. But in albinism, there's overdecassation where it could be, I think, less 50/50, much more asymmetric and through sort of written in a hand-wave-y way, everything we've read about it says this can contribute to lack of stereopsis, more stribusmas, and even maybe be related to some of the niestigma issues, hard to know what that's all about. I feel like I believe it, the most, that it contributes to stereopsis issues, like, suddenly, your brain is wired just unevenly for different parts of your visual field. But you can even see this, the BCSE text pains to point out, you can even see this on a visual evoked potential, where normally, you know, one light flash evinces sort of symmetric responses on both occipital lobe sides, left and right. But for an albinism patient, the EP would show it asymmetric response in the occipital response. Yeah, I don't know when you would do, like, you're not going to diagnose albinism with the VP, but I suppose, isn't born, if you're doing a VP for another reason, and you're like seeing this binding, it's good to know that's normal. And just a small clarification, it's not quite 50/50 splitting, it's like, you know, depending on which text you read, like, 47/53 splitting, which is why, like, optic tract lesions can give you, like, a slight, you know, it's like the explanation for why you can get, if you have an optic tract lesion, you can get an APD because there's like a slight difference between the, yeah, the people responses, anyway, very, it's a cold percentage point difference. And the different BCSE books disagree on how much the percentage point difference it is. Some of them say it's like 45 to 55, some say it's like 47 to 53, it's a very small difference. But in albinism, it's a much larger difference. That's why I said, sort of 50/50 at normal pace. Yeah, it's like, it's like, yeah, it's, it's basically 50/50, there's like a couple points different that note the BCSE can agree on what that is. But albinism is a very less symmetric. Yeah, yeah, yeah, yeah, for sure. So I better make, you know, if they had an optic tract lesion as well, I bet they would also have a much more prominent APD. But I don't know. I would say. Well, last albinism is up to 90% asymmetry. So that's a little bit. Holy smokes compared to 47/53. Yeah. It's a big difference. That's a big difference. And the last thing we didn't mention, this is just an exam finding is, you know, if they don't have RP pigmentation, then their retina is going to look way different. Like I encourage everyone to take, like, you know, look up a picture of like maybe like an obtose photo or something with an patient with albinism. It just looks completely different from a normal retina. Why? Because the RP doesn't have as much pigmentation. And normally that pigmentation filters out the coroid. But without the RP, you'll be able to see the coroid, like, you know, you know, in the full day, and you'll see like a ton more vessels. And I think it doesn't mean much in terms of diagnosis, but it does mean something in terms of helping you appreciate what the corid anatomy normally looks like when you can't see in most patients without imaging techniques, like ICG or something. And it's the only clinical reason this matters is it's don't ask people how I know, but it's really hard to get laser uptake in an albinatic retina if they have like holes or detachment or something, so, but that's why God created cryotherapy. Oh my God. Yeah, it's horrible, but cryotherapy is great in albinatic patients if they have a retinal detachment. Isn't that just because there's no pigment to soak up the thermal laser? Yeah. Yeah. It's really hard to get it to get laser uptake, so yeah, I recommend it. And the cryo works. Like it'll cause adhesion. Cryo's miserable. Yeah. Yeah. Yeah, but they're out. Usually the attached to like younger people you want to just KO. Cryo's half the reason I didn't go into retina, it's just like I don't want any business of that. Oh, it's so funny. The my fellows will tell you that like I'm addicted to cryo, cryo's so like any retina issue. We can probably just cryo that. It's okay. Don't think about too long. Oh my God. Yeah. Yeah. I love cryo, but yeah, it's got its issues for sure. And like, you know, I know the total sign up because of that pigment differentiation. If you have a patient who has a royal attachment, it's so hard to find the tears because you don't. Oh, gosh. So yeah, it's so I already feel like I'm a bit straws with it. Yeah, I don't. Anyways. Okay. That's all like not BCSC stuff. I just pick her. You know, maybe you're on call. You have this issue. Real world. Feel bad. Like if you're a resident, don't feel bad if you can't find the holes in a patient with albinism. They're like, you should be a little fun to detach. There is still one BCSC thing that's going to be super testable, which is the genetics of this stuff. Yeah. But I don't. I think Ben, you've simplified this mortgaged board of genetics, like types into basically two main categories. Thank goodness for you. Thanks. Yeah. There's like a bunch of different subtypes. I don't think they're really helpful for BCSC, for OCAPs of the board. Yeah, they're not going to make you go like OCA type seven versus one or something. Yeah. Yeah, but I think it's important to know that genetics of OCA, which again, it's the one effects eyes, hair and skin, and then OA, which just affects the eyes, octheralbinism. So OCA, which affects everything, tends to be autosomal recessive. And within that, I think there's two categories that are worth knowing about because they are probably test questions that will come up regarding them. And they have to do with the protein terrocinase, which is important in the melanosome that are like melanoproduction pathway, which we're not going to go like into deep depth about. But it's either terrocinase positive, which means that they have, still have terrocinase, but it has difficulty penetrating into the melanosomes. So it's like a terrocinase that for one mechanism or another, isn't working well with this upstream redundancy from terrocinase. Or terrocinase negative, which they don't have, they just don't make it, or they don't make a functional copy, and those patients don't have much more severe ocA. So if you had to pick, you want, at least they still have terrocinase even doesn't work as well. Terrocinase positive, and terrocinase negative tends to be more severe. And there's different symptoms of age, but it's not worth going into. Yeah. And that's all again, all autosomal recessive. What about octheralbinism? is not autosomally recessive inherited, but it's instead ex-linked inherited, and I think I try to remember that based on ocular albinism seeming less severe of a condition because it's just your eyes, not your hair or your skin, and autosomal recessive conditions seem more severe in general to me. So that seems to fit with the autolocotaneous albinism, whereas the ex-linked, usually that's a little more mild of a genetic inheritance. It's more of a common one. You can imagine if this genetic hit is passed down a little more easily through ex-linked inheritance, that the problem itself should be less severe. Okay, the last thing we'll go into is that there are three syndromes that we should know about that also present with albinism that aren't in the categories that the genetics we just talked about. And you do want to give us the first one. Sure. So this one is called Hermansky-Pudlach syndrome. It is autosomal recessive, and mostly involves platelets, disorders of platelet function, but also has pigment problems, hence the albinism. There's also a lot of pulmonary issues, and I see this is how bends that things up for me. I was supposed to talk about the illiteration, platelets, pigment problems, pulmonary problems, and that really helps because most test questions about this are in the question stem, they'll mention that they're probably going to be Puerto Rican of Puerto Rican descent, though a caveat here may be also in Swiss people too. Ben? Yeah, it's really annoying. So when I was a resident, I only remember Puerto Rican, and then I was reading more about this as it was prepping for the episode. Apparently, it's barely prominent in Swiss populations too. It was darn Swiss, so it was missing up our-- It's a benign nomotics. Come on, ex. No, this is not benign nomotics. This is like, yeah, the four P's of Hermansky-Pudlach, I think, are-- I wish I could have claimed my invented. Yeah. Platelet's pigmentation, pulmonary issues, which is interstitial lung disease, if you have to know it, and then tends to be Puerto Ricans plus the darn Swiss. I guess that Swiss can be the asset at the end of four P's, you know? Okay. Yeah, yeah, yeah, yeah, I don't know. Okay, that's Hermansky-Pudlach. But that definitely could be like its own discreet question, so I would definitely try to commit that one to memory. Another one is Chidi-Kigashi disease, which can give you, like, classically, silvery hair, and, you know, albinos, oxiditis, like we talked about. And severe apologetic infections that tend to be lethal and can come with, because I think it's through these infections, neurologic problems, coagulation defects, mucosal defects, like, gingivitis, oral restorations, parodontal disease. Yeah, it's like, basically, they have a big problem with their neutrophils. That leads to, like, all these, you know, pyogenic infections. And then, for some reason, also, can lead to, like, albinosam type findings. The mechanism, I think we had to learn this for step one. The mechanism is abnormal protein-track trafficking, to dysfunctional fusion of vesicles and failure to transport the lysosomes, sorry, lysosomes to help, you know, destroy things within neutrophils and such. So Chidi-Kigashi, it's basically a ton of infections, and they can have albinosam too. So we meet in albinetic patients that's very young, and they're getting infections. They don't have a reason for it. Then maybe think about getting a workup for Chidi-Kigashi. I think it's a takeaway for that. Yeah, for the next and last one, we'll talk about I had to look up what pi-balled meant again, which is like the thing that sticks in your memory the most for this last one, which is Wardenberg syndrome, because this is the one that's always referred to with the four-lock of hair, white four-lock of hair. I guess if you had a horse that was, like, I don't know, calico or whatever. A calico cat could be said to be colored in a pi-balled distribution, a pi-balled horse would just have patchy areas of different color on its coat. So a pi-balled hair for a patient is usually in Wardenberg syndrome. I'm going to manifest with just a tuft of hair. Boy, I just had to suppress like a super nerdy relusion to X-Men characters. Anyway. Don't suppress it. Don't suppress it. Don't suppress it. No. If it's not, not go at it. You can't do it. You don't even fill that with your magic. Listeners. So that's not the only thing. Oh, sorry, but go ahead. Yeah. No, no, no, yeah, what else is there? Besides, they have this interesting kind of hair or skin. Yeah, they're like, they have albino hair and just like one patch of hair for it. But of course, they can also have a heterochromia. This can affect their iris. And usually it is just so distinctly one iris is lighter colored than the other iris. Apparently, their nose also has a broad nasal root or something. And a fit of the merdef. Yeah. And they tend to, this is I think in the plastics textbook. I didn't include in our script. I think this is like the classics textbook that they have their inner can thigh are more widely displaced. So they can look like they have like a broad nose. But like their inner can thigh are more biased, you know, are are are further apart. My, but that's I like remember that was like a question on something. I don't think I could specify what, but like there was some question about that. So like Wardenberg. Wardenberg is spelled with two A's just, you know, V. A. Wardenberg. Wardenberg. Wardenberg. And I kind of remember that like can't I think I think about like the two A's like being pushed apart and like the eyes being kind of pushed apart. It's like a little mean, but that's that's higher. So like in my head, it's always W a dash A like Wardenberg syndrome. That probably helped literally no one else, but that's time. Wait, can't thigh has one I A in it, doesn't it? Yeah. Yeah. But then you have two can thigh because. Oh my gosh. Yeah. If you didn't know, okay, it's not a helpful thing. That's how I just like it stuck in my head that the two A's are getting pushed apart. So it's like the can't thigh are getting pushed apart. Wardenberg. Okay. That's all the speculation that we have about albinism and like the things I hope you highlighted that we need to know. Should we go do like a super quick run through sans speculation? Okay. Review. Sounds good. So yeah, can start with the terminology. There's two broad categories, ocular cutaneous albinism, which affects eyes hair and skin and is has melanin, but it's just reduced in each melanosome and is usually autosomal recessive inherited. And then there's ocular albinism, which affects eyes only has melanin, but just fewer melanosomes and is usually excellent in heredite. Their irises are usually very light or violet in color. They can have translimination defects and photophobia. They have a hypoplastic phobia, which can result in the stagmus, refractive error, and strabismus most likely. And they have this weird post chiasmol overdecacation of their optic nerve pathway. And the most obvious thing that you'll see right away, pendular, nice stagmus, likely related to that hypoplastic phobia also. The syndromes you need to remember that can pop up with albinism or hermansky putlock, which has issues of platelets, pigmentation, pulmonary issues, and are tends to be important regions for the Swiss. The other syndrome that's even more dangerous to life is Chediak Higashi, which has a problem with lysis, somal, storage, and trafficking, which leads to a lot of neutrophilic deficiencies and trouble fighting off infections. And an award in Berg syndrome causes patchy depigmentation so you can get like heterochromic irises. And a fifth of them tend to be deaf for some reason. Well, not for some reason. Pigmentation, RP, not RP. Melon pigmentation is important for middle ear function. Oh, yeah. Or it might be inner ear function. Is it middle or inner ear function? It's important for ear function. And I've tried to look into the explanation for that. And it's like very bad. Oh, worry about it, Ben. Darn it, ENTs. Don't worry about our eyes, don't worry about your ears. Don't worry about your ears. Don't worry about ears for eyes. Forget it. Yeah. Yeah. Your ears for eyes could start the road podcast. If you like this episode, a rating review on iTunes, or if you found it is extremely helpful. Oh, I forgot to mention that last time. But yes, thanks, everybody. And thanks for coming back along with us. All right, bye. Take care.