Even decades after graduating from the last of many schools, I still feel like September is a time of fresh starts and new learning. Which is just what we need in the chronic hypophosphatemia world. I often talk about some major XLH-related misconceptions (i.e., it’s purely pediatric, purely bone-related), but there are a number of other assumptions, some of which I make myself, that really need to be re-examined.
I’ve been thinking about it for two reasons. First, I was chatting with a patient about hearing loss, and I’ve always assumed it had to do with mineralization issues in the earbones. And I think that’s the general consensus. BUT, the (well-informed) patient had a different theory, that it was nerve-based. The problem is that there’s no solid evidence either way! There are a couple of research papers suggesting that ear bones could be involved, but they’re extremely limited, in that one studied MICE (with hypophosphatemia), and the other wasn’t specific to hypophosphatemia. Nowhere near conclusive proof, one way or another. And, the thing is, the answer to whether it’s bone-based or nerve-based maybe be “neither.”
Second, and this really got my attention, is that we’ve always assumed that the bowing in hypophosphatemia patients is due to weight-bearing, and that statement is widely accepted and seldom questioned. It just makes sense, after all, given the timing of when the bowing is noticed, right around the time when kids start to walk. But it doesn’t account for why some kids have extreme bowing, and other kids have extremely mild bowing when they’re both essentially the same weight. I first became aware of the issue a few years ago when an expert in a continuing medical education webinar mentioned that he’d seen torsion (twisting) in XLH kids’ leg bones BEFORE they began walking. And there’s a newly published article, “Lower limb maltorsion … in children and adolescents with XLH” that notes the same thing. Their conclusion: “The occurrence of severe femoral retrotorsion in a 2-year-old child prior to ambulation raises questions regarding the biomechanical impact of gait on the development of torsional deformities in XLH.” (Retrotorsion, and its opposite, antetorsion, is new terminology for me, but they’re basically just a variation on “torsion” or twisting, indicating the direction of the twist, sort of like genu varus and genu valgum both refer to bending of the bone, but one refers to bow-legs and the other refers to knock-knees.)
In both examples, we’ve long assumed one set of facts (our hearing loss is bone-based, and our bowing is due to weight-bearing), even though, from a scientific point of view, we just don’t know. Sure, both theories (because they are just hypotheses, not facts) make sense, but that doesn’t make them true. Remember, in the 1905s, everyone took as fact that XLH was a disorder of vitamin D blood levels, and the doctors would likely have laughed at you if you suggested it was a problem with phosphate blood levels. Researchers had to ignore the accepted wisdom in order to approach the disorder with an open mind, and when they did, they found out that XLH has (almost) nothing to do with vitamin D, and everything to do with phosphate-wasting.
Science is based on researchers asking a lot of “What if…” questions, and then designing a project that might answer that question. But those questions are, in turn, based on what the researcher thinks they already know about the condition. They’re not coming to a topic (or medical condition) completely fresh, unbound by what is already “known” about it, and we don’t really want them to be completely ignorant about a condition, wasting time on issues that are already well-documented. Imagine how different the understanding of XLH might be if we could erase the past research (just for a few minutes), and start from scratch, but with the tools (DNA testing, organic chemistry) we have now. What would scientists of today do if the genetic variant for XLH didn’t exist until some random event triggered it, and all of a sudden, kids started showing up in doctors’ offices with unexplained bowing. They might well start (as clinicians did historically) with the hypothesis that it’s a form of rickets that doesn’t respond to vitamin D treatment, but it wouldn’t take long (months, rather than decades) with the tools available today for them to figure out that that’s not the real problem, and we’d never have to endure the Vitamin-D-resistant labeling that’s so harmful to getting correct treatment! But beyond that, they might well pick up on the non-bone/teeth symptoms faster, because they’re not starting out with decades of misinformation that it’s purely a bone/teeth disorder.
The thing that might well make the biggest difference between the current state of XLH science and my imagined scenario is that scientists starting fresh might well not make distinctions between x-linked versions and the autosomal hypophosphatemias that are FGF23-based, or even between XLH and TIO. Instead, they’d start with what we have in common: phosphate-wasting due to excessive FGF23. “XLH” would be part of a larger group, jointly referred to as “FGF23-mediated hypophosphatemia,” and would be a subcategory, along with TIO and the relevant autosomals.
The reason I think this would be such a great reset of the mindset is that studying the subgroups together (and then looking for similarities and differences among them) might well provide some insights into a number of issues that have stumped researchers. Like why patients with the same genetic variation (family members) can have such different symptom severity, and why, as I wrote about recently, it appears that something about XLH offers some protection against developing Type 2 diabetes. There’s similar data about how we seem to be somewhat resistant to the ways that FGF23 excesses affect the heart in the non-XLH population.
We can’t actually go back to a time when absolutely nothing was known about XLH (nor would we want to!), but it’s a useful exercise for researchers to undertake, pretending that they know absolutely nothing about the condition and questioning everything. The researchers in Vienna who published the article questioning whether XLH bowing is due to weight-bearing, also recently published an article about Osteogenesis Imperfecta’s upper-limb issues, again looking at something that’s often overlooked about that rare bone disorder. Like with XLH, everyone assumes that most of the symptoms and disabling effects of OI are from lower-limb symptoms, but this research (“Clinical, Radiographic, and Biomechanical Evaluation of the Upper Extremity in Patients with Osteogenesis Imperfecta”) revealed significant challenges due to upper-limb symptoms of OI. I’d love to see similar research into the upper extremities of XLHers. It’s generally assumed that our upper limbs are unaffected, but we know that’s not true. Most clinicians are unaware that many of us are unable to straighten our arms fully. Phlebotomists are always asking me to straighten my arm more, and I have to explain that the only way for me to do that involves breaking bones. I didn’t realize that was an XLH thing until about ten years ago, when I was talking to an expert XLH clinician, and he mentioned that it’s common among XLH adults. I immediately assumed that the bones had been affected when my arms were weight-bearing, while I was in the crawling stage, before learning to walk. But perhaps there’s something else going on, if our legs are bowing before we’re weight-bearing.
We all make assumptions, but the trick is to be aware of them. I’m going to be talking more about XLH (and rare bone disorders generally) research in the next few weeks, and I hope to remember to question the assumptions that existing research is based on, as well as my own assumptions. I hope you will too, and you’ll let me know if you see me treating something as fact without having any actual data.
***
Please note that the author is a well-read patient, not a doctor, and is not offering medical or legal advice.
If you’d prefer to read this blog as a newsletter, sent straight to your inbox, please sign up here.