This, right here, is what you concentrate on.
Think of it in terms of "ages."
Forgotten Realms is just PoL land with different names. An age of darkness, lots of loss, things are just rolling downhill.
Eberron is between WWI and WWII. Two fisted pulp action, political intrigue - an age of chance.
Dark Sun is an age of ruin. Everything is terrible, you're on
Deathplanet, what few civilizations remain are ruled by tyrannical despots.
So what would Mystara concentrate on? Being an age of
discovery. I admittingly know little about Mystara as a setting, but concentrating on swashbuckling, expanding civilization, a very 1600's-1700's feel could help set it apart. Instead of the points of light idea of 4e geography, change the idea of geography to that of an empty map. A previous age ended long ago, and civilization has
finished picking itself up off the ground. It's not a world of darkness with points of light, it's a vast and sprawling "Unknown territories" that's just begging to be found, explored, and perhaps even looted. It's time to go into the unknown and uncharted lands. Heroic campaign, you belong to a country, perhaps a quazi-legal guild of adventurers. Paragon campaign, you've obtained your own land, building your own colony, gaining independence. And then epic campaign would be all about the Immortals and, well,
becoming one.
Would this scare away previous Mystara fans? Hell, I dunno. I made up half of that. Would it give the setting something that stands out? I think so. I am admittingly, to some degree, just utilizing my own homebrew setting for ideas here