What are the differences between Rise of the Runelords and Skull and Shackles?
Skull and Shackles has two main changes from Rise of the Runelords.


The boat mechanic.  This mechanic is completely new to S&amp;S, but I don't think it adds to the game overall.  The rules for it are not intuitive.  Your party will have a boat in most adventures and have opportunity to fight other boats.
General iterative rules development.  Despite what I said about the boat, S&amp;S is a better game than RotR just due to them having another chance to write the rules and balance things.  Specific things I liked better


More skills are useful in challenges
Characters are better balanced
The rulebook is much better organized
As they went thru the RotR adventures they used certain templates on the cards. These are incorporated as basic rule terms in S&amp;S. These leads to more clarity.



Overall, unless the pirate theme doesn't appeal to you I'd recommend skipping Rise of the Runelords and starting right in Skull and Shackles.

You didn't ask, but this advice holds even if you consider the newer release Wrath of the Righteous.  WotR is much harder and has a few more moving parts than either of the other two sets.  It's a fine second game to get, but if it is your first purchase in the Adventure game line it could lead to disappointment.