I haven't put a TON of mileage on it yet, but the Otterbox Defender Pro was a lot nicer than I expected it to be as far as tolerable feel and size, definitely has solid protection. Dust cover over the USB port is nicely done, wireless charging works if you use that.
The 21U is ip68 dust and water protected, so as long as you hit it with some compressed air every now and then you shouldn't get terribly clogged ports and at least the internals are protected.
As far as screen protection I just use a standalone tempered glass one, I tried the Amfilm ones and the install just wouldn't work out to my satisfaction as far as being centered and the glue absolutely refused to spread to the bottom left corner, so I I some Whitestone film protectors, every single one from the 3 pack peeled off with the final step in one spot or another, and then I got the Whitestone tempered glass and it installed nearly flawlessly the first time, only a hairs width off center with the selfie-cam, fingerprint works, feels great, looks sleek, no issues with my PHNX MNML or the Otterbox.