I've thought about altitude sickness, but the times it would come up are generally the worst possible time to have it. Plus it doesn't actually have the potential to create an interesting story the same way hypothermia does so goes largely in the negative pile unless you are a hardcoe realist.
Altitude sickness is a good idea I think, but we don't have the athletics skill or endurance attribute any more. If we still had those(and we could add them in for a mod like this), I would set it up like so:
Track the PC's elevation for a while, then use the average to set an "acclimation" range, where your stamina level is set to normal. If you go down to sea level, you will get an endurance/athletics bonus, if you go to the highest elevations, you will suffer penalties. Just like real life. If the PC moves to spend all of his time at lower elevations for a while, his "acclimation zone" would move down, and the PC would then suffer worse penalties at high elevations, etc. Basically simulating the real life effect, scaled down to video game time/elevation.
I think it would be a cool idea, for a more dynamic game experience. The highest peaks would be more dangerous and foreboding, knowing the added challenge of high altitude atmosphere.
I've experienced this in real life, having lived in a house at 9000 feet in the Colorado rocky mountains for a year. I did a lot of hiking during my time there, and experienced a lot of elevation change, between climbing the "fourteeners" (Mountains that are 14,000ft tall or higher) in Colorado and sometimes visiting other parts of the US near sea level. Being acclimated to higher altitude does make a huge difference in cardiovascular endurance and stamina, I can vouch for that.
PS: This would be moving a bit more off topic, but with hardcoe hydration/food mods, taking elevation into account would be huge. The rate at which you dehydrate is much faster at high elevations.