and it turned out to be issues with her thyroid. She had to be on medication pretty much forever to resolve the problem.

But if the Mayo Clinic can't find it I imagine it might be something more complicated and difficult to find.

I will be reading through replies and probably summarize thoughts to her including yours. Much appreciated.

She had to go in regularly for blood work even when her metabolism wasn't going haywire, so they could adjust the medication to the required dose.

She had the occasional "thyroid storm" which is when she'd spike a fever. Other symptoms were raging heartbeat and extreme agitation, so if your friend experiences symptoms like that I'd definitely have her get her thyroid levels checked.

I personally have a thyroid issue was over active years ago I decided to radiate (kill) it. I remember my endocrinologist telling me that the thyroid regulates every chemical in our body.

disease.

Is your sister hyper or hypo thyroid
I hope she is t suffering horribly

And can they not regulate with medication?

She does have some other mild symptoms
dry skin, thinning hair. No real mental issues.

She was in a car accident at age 16 & had a significant head injury. Following the accident, she had her thyroid “manipulated back into place”.

Before the accident she was 5’4” tall and weighed 110#. Three weeks after the accident she had ballooned up to ~ 140# (not fluid). So, I imagine her thyroid was damaged & out of whack in some way.

My mother took her down to a facility in Virginia Beach where she stayed for several months to rehab.
When she came home and walked through the front door, I remember being so happy to see her back to her old self. Her weight was back down too.

I wouldn't second guess the Mayo Clinic, but perhaps it is something related to the nervous system?

Regulation of body temperature by the nervous system

is better or worse at any time/season of the year? Also does he notice any seasonal stuffiness? Is he allergic to anything or has he ever been tested? Does he have any nail fungus? What occupations has he had? Did he work on farms? How is his sleep?

The reason I ask this is that some things can have strange origins. For many years I would get "dry" stuffy feeling in my head and my temp would go up and down but all doctors just passed it off as "sinuses". Finally one day I was at a clinic for some routine thing and I mentioned it when they casually asked me how I was feeling. When I said fine except for the dry stuffiness I always had they said that their Ear, Nose and Throat guy was in that day and I could see him. He took my history and said "Haven't any of these other guys run the scope on you?" Of course they hadn't. He ran the scope and was astonished at the sight of a very entrenched fungal, Candida, infection. He showed me the screen and asked me again how many years this had gone on. I told him it was well over 20 years. He was flabbergasted at the lack of care I'd been given.

So a strong prescription of pills taken daily cleared it up and my temperature problems went away. The point here being it doesn't matter if it is Mayo or who if they give up on looking to help you or to find the cause you are still stuck with the problem.
After about 6 days of taking the pills I was bent over picking something up and I felt this huge release inside my head and before I could stand straight a huge glob came pouring out of me that would be about cup or so in volume. I was kind of freaked and it was just a nasty grayish blob. But instantly I felt air going through my nose and into my lungs effortlessly. It was such a wonderful feeling. Over the years as I got worse and worse I simply "adapted" and so never noticed that I was putting more and more effort into breathing. I used to go through the dry stuffy thing every spring and fall with the changes in light and moisture.

I would recommend he keeps trying and a visit or two to a couple of different alternative medicine/Asian doctors might yield some help even if they don't find the cause.