Check out IVAN, Iter Vehemens Ad Necem, if you haven't yet. It has an interesting limb system where, if your wisdom is high enough, you can use scrolls of 'change material' to change your body parts to ridiculously strong materials. Similarly, losing limbs doesn't even effect the game too much. You can even get strong enough to use two-handed weapons in one hand. You'll eventually get a new limb or your limb back either through Gods or through some other mechanism. However, there is no advantage to having lost that limb (it may effect to-hit calculations, haven't looked into it). It's a game that does a lot of things very well though.
I put IVAN in the top 3, but I personally like a more permanent damage/curse/corruption/mutation system like the one you suggest and mentioned elsewhere in the thread.
A paradigm I've been looking at is one in which abilities and stats take the form of equip-able powers. To use the powers and to, more or less, level-up those powers, you have to enter into a contract with that power. The contract requires that you arbitrarily change the way you play the game to fulfill the contract. One contract may be to murder 7 young and innocent girls. Another may be to throw a rock into every stream of the land. It isn't quite the same as limb damage, but the obfuscation of fortunes and maladies, imo, is something to strive for in a general sense.
IVAN, for example, becomes more difficult the more powerful you are. If you find a lot of epic weapons or permanent invisibility, the game's reactive difficulty will send some impossible threats your way. If you happen to find the most powerful weapon in the first dungeon, it isn't wise to take the stairs down with it, as that will cause the next level to generate with that weapon's strength in mind. It's exploitable, but only to a point.