What's (up) with (someone)?
Why is someone so upset or acting in such an unusual way? What's with Jeff? He just screamed at me and stormed out of the room. I wonder what's up with Sarah—she's been avoiding me for days now.
What's (up) with (something)?
1. What is the meaning or purpose of the something; why is something happening or the case? What's with these tiny portions? For how much the food costs, I was expecting to get a bit more on the plate. We've been waiting to hear what's up company's new expansion plan.
2. What is wrong with something? Hey, what's with your computer? The screen just keeps flashing when I turn it on.
What's with someone or something?
Why is someone or something in that condition?; What's going on with someone or something? Mary: What's with Tom? He looks depressed. Bill: He broke up with Sally. "What's with this stupid coffee maker? It won't get hot!" groused Alice.