Game of Thrones: greyscale, diagnosed and explained

One of the most mysterious puzzles on Game of Thrones is greyscale, a strange disease that causes human skin to become stone-like. What on earth could actually cause it? We asked a dermatologist.

The signs are unmistakable: Hardened gray skin makes those who suffer unrecognizable to friends and family. They become extremely contagious and must be quarantined.

And yet how much do we really know about greyscale, the plague that citizens of Westeros fear but do not yet understand? Game of Thrones has only revealed a few afflicted patients onscreen, but this handful of cases provides an opportunity to investigate what causes the mysterious illness.

The facts we know to be true

We must rely only on what we've seen onscreen (or read in the books that Game of Thrones is based on) to attempt a diagnosis. Unfortunately, facts on the ground are few.

Here's what we know:

• Greyscale is contagious by physical contact and can be transmitted between people with only a moment’s touch skin to skin.
• Greyscale starts with skin changes that begin where the patient was touched (the inoculation site).
• Greyscale may also have been transmitted by a child’s doll, as seen in the case of Shireen Baratheon.
• As far as we know, these are the only ways greyscale can be transmitted. It does not appear to be spread by respiratory droplets (coughing/sneezing) or sex (though, presumably, having sex with someone with greyscale would involve physical touch).
• One patient, Jorah Mormont, has been kept at the Citadel without transmitting the disease to others, seemingly corroborating an assumption that it is not transmitted through the air; if that were the case, many people at the Citadel would be in danger of contracting it.

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• A quarantine of cases in Valyria has mostly stopped the transmission of greyscale.
• Greyscale causes the skin to become very thick and scaly (or hyperkeratotic), with rashes that spread over time and may eventually cover the entire body. As we have seen with Jorah, as the disease progresses, the thick scale can also become scabbed, with pus underneath.
• With time, patients with advanced greyscale develop aggressive, even psychotic behavior. Although not verified, the Archmaester at the Citadel told Jorah that he could live 10 or 20 years with the disease but would likely lose his mind in six months, if not sooner.
• At least one patient’s greyscale rash — Shireen Baratheon’s — remained limited to one side of her face, and did not progress. According to the Archmaester at the Citadel, the key to stopping the disease from spreading is immediate treatment. “You should have cut off your arm the moment that you were touched,” the Archmaester said to Jorah. In Shireen's case, she was infected as an infant and treated from the moment her greyscale was discovered, though the precise details of her treatment are unknown.

It remains unclear if any treatments for greyscale are effective, aside from some wizardry. However, as we saw in season seven’s “Stormborn,” Samwell uncovered two case reports (in The Study of Rare Diseases by Archmaester Pylos) in which excision of affected tissues was curative, although Pylos likely acquired greyscale during the procedure, causing it to be forbidden.

If an infection was limited to certain tissues, excision (or debridement — the removal of infected, damaged, or dead tissue) could be an effective strategy, assuming infection has not spread to other tissues. Given the high skin contact contagiousness for greyscale, surgeons would be prudent to wear full protective gear including a full facial mask while performing this procedure (safety first, Samwell).

Let's make a diagnosis

To make a diagnosis, let’s consider five separate questions.

1) Is greyscale infectious?

Greyscale must be infectious. Cases were transmitted person to person, and the disease was controlled when affected patients were isolated via quarantine. However, it is difficult to prove the type of infection, though we know transmission is by skin-to-skin contact.

For instance, despite close proximity to those affected by greyscale — known to many on Game of Thrones as Stonemen — Tyrion was untouched and unaffected, but Jorah developed a lesion within a day of skin-to-skin contact with a Stoneman (as seen in season five’s “Kill the Boy”). Shireen, who never had contact with affected patients, owned a doll that possibly carried the infection.

Greyscale, thus, is extremely contagious, far more so than Ebola (which is spread through bodily fluids, usually blood), making greyscale more like anthrax or smallpox. For comparison, anthrax is not spread person to person but instead by contact with the skin or through inhalation. Smallpox is spread by respiratory transmission and via fomites (clothes/linens/items that may carry an infection), in addition to being spread by person-to-person contact.

Despite its high contagiousness and fast appearance after contact, as far as we can tell, greyscale progresses slowly. Anthrax and smallpox can kill someone in days, but greyscale is insidious, getting worse over a long period of time, though it may never kill the infected person.

One final word of warning: If isolated, the infectious agent in greyscale would be a bioterrorism risk.

2) What kind of infectious agent might cause greyscale?

Many different kinds of infectious agents cause skin diseases, but in the case of greyscale, only a few types are likely to be the cause. Here are the three most likely to cause problems:

• Bacteria, such as staph and strep. These cause the majority of skin infections, including impetigo, furuncles (boils), and cellulitis, but all of these conditions look very different from greyscale. Anthrax, another gram-positive bacteria like staph and strep, is easily transmitted and can spread from contact with the skin (and through inhalation or through the gastrointestinal tract), but not skin to skin.
• Viruses such as herpes viruses, human papillomaviruses (HPVs), and poxviruses (including molluscum contagiosum, orf, and smallpox) can all be transmitted via skin-to-skin contact.
• Mycobacterial infections, such as tuberculosis and leprosy, which are typically spread by respiratory transmission, although skin transmission is possible. For instance, in previously exposed patients, at the site of injury, tuberculosis can cause a wart-like reaction.

In Jorah's case, greyscale appeared at the inoculation site within a day, suggesting rapid transmission without penetrating injury. Over time, the infection has continued to spread to adjacent skin and has developed pus under the scales. Pus (the viscous yellow-white fluid composed of white blood cells, tissue debris, and infection) can be caused by any of these types of infectious agents, though it is most common with bacterial infections and some viral infections (herpes viruses).

We can't surmise everything from that, but we can make a good guess. Given that the infectious agent must be transmissible skin to skin, develop quickly, and survive on fabric, the most likely candidate would be a virus.

3) Is greyscale like leprosy?

Not really. Leprosy (or Hansen's disease) is caused by mycobacteria, but it isn't very contagious and isn't transmitted by skin-to-skin contact. Like greyscale patients, patients with leprosy may become obviously deformed with time, and isolation limits transmission, but the parallels between the two conditions end there.

Leprosy patients undergo completely different skin changes. Unlike the scaly thick rashes all over the body seen in greyscale patients, leprosy patients display thickened areas without scaling (e.g., thickening of the skin on the face), as well as changes from the neuropathy they develop (e.g., shortening of digits). Leprosy is thought to be transmitted only by respiratory droplets, yet most contacts will not develop the disease — indeed, there may be a genetic predisposition.

Interestingly, in recent years in the United States, cases of leprosy in Florida, Texas, and Louisiana have been reported in patients that had one thing in common: contact with armadillos. The mycobacteria responsible for leprosy has been detected in armadillos.

4) Does greyscale only affect humans?

Thus far, it seems that greyscale is limited to humans. It remains to be seen if armadillos, dragons, or White Walkers would be vulnerable.

5) Why is there an odd skin pattern in patient Shireen?

Perhaps the pattern on Shireen Baratheon’s face occurred because of the acuity of her treatment, which occurred immediately upon discovery of her condition and seemingly halted the infection from progressing. Still, Shireen’s skin changes as a result of her greyscale — limited to one side of her face — are actually more suggestive of an inherited skin condition with a mosaic pattern, perhaps with delayed onset.

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Mosaicism occurs when certain cells in the body have different genetic expression, thus giving a mosaic of expression. This is the same explanation for what occurs in calico cats, who express different genes in different parts of their skin, causing patches of hair with different colors.

In Shireen, given her mosaic pattern, the differential diagnosis would include rare mosaic skin diseases, such as epidermal nevus syndromes and inherited ichthyoses. (An ichthyosis is a skin disease that causes dry and scaly "fish-like" rashes.)

It is possible that greyscale could be both infectious and related to an inherited disease. In the HPV-caused disease epidermodysplasia verruciformis, for instance, only certain people carry mutations that allow them to be infected.

Perhaps only certain cells in Shireen’s skin were susceptible to infection, and maybe that is why progression of her disease was halted, rather than by the magic of her father's wizards, who are generally given credit for her condition's control.

Conclusion and official diagnosis

From the available evidence, greyscale would seem an insidious infection that is most likely caused by a smallpox or HPV-like virus. Such a virus could be easily transmitted skin to skin.

Once the infectious agent is isolated, work can begin immediately on a greyscale vaccine — or, more likely, a series of spells meant to halt its process.

Jules Lipoff, MD, is an assistant professor of clinical dermatology at the University of Pennsylvania. His research interests include telemedicine and global health, and he serves as a volunteer telemedicine consultant for Doctors Without Borders. His writing has appeared in the New York Times, McSweeney's, and the Village Voice, in addition to numerous academic journals. He is the author of the only report of greyscale in the medical literature.

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