"What is his problem?"
Translation:Quel est son problème ?
It's a common idiom. Litteraly "what's happening to him". I'd say it's the most natural way to translate this English sentence.
In real-life French (because I guess Duo rather teaches textbooks' French) "Quel est son problème ?" can sound a bit patronizing, like you're implying the person has a problem because he/she is stupid (I wonder if it's not the same thing in English though).
Hope it helps