Just had it happen to me that, after a recent upgrade, ZBrush 4R4 completely wiped each and every one of my user preferences including a custom UI and every setting in the “Preferences” menu.
After exiting out of PaintStop, ZBrush ran into some kind of error and then crashed straight to the desktop. On the next start, everything was back to factory defaults 
Good thing there’s such a thing as backups 
BTW, this happened with a pre-update2 4R4.