There’s been so much progress in understanding XLH in the last 25-ish years since the discovery of FGF23, but one area that’s been overlooked is the effect on XLHers of non-XLH conditions.
It’s tempting to think that since we have such a potentially devastating (in quality-of-life terms, rather than quantity of life) disorder, the universe wouldn’t be so cruel as to give us more common conditions as well. But that’s clearly not true. Cancer and heart disease and any number of other serious conditions can affect us.
It’s even possible that our XLH can increase our risks of the more common health conditions, but we don’t have the research to know if that’s true. While I frequently remind everyone that our kidneys are not defective simply because we have XLH, it’s also true that the old phosphorus/calcitriol treatment can cause kidney stones and, over the long term, kidney disease. The pain medications (especially NSAIDs) that we take can also lead to kidney disease. There has also long been suspicions that XLH makes us more susceptible to heart disease, given that there is a correlation between elevated FGF23 and an increased risk of heart disease in the general population. (Anecdotally, however, we don’t seem to fit that pattern, so perhaps there’s some kind of protective factor in our weird metabolism. Good news for us, but also if we understood that protective factor, it might be leveraged to help the general public.)
A comprehensive natural history study might contribute to better understanding of whether XLH patients are at the same, higher, or lower risk of various common conditions. When I was working on the BeyondXLH natural history study (no longer active), I pushed hard to include questions about general health issues for exactly this reason. I got some pushback from skeptics who didn’t think it would be useful to ask about non-bone/teeth/muscle conditions. They were thinking in terms of developing definitive answers, and it’s true that a natural history study, alone, wouldn’t be enough to establish causation between XLH and other conditions, or any other interaction possibilities. But what a natural history study COULD do is identify patterns that we might not be aware of, and then a more definitive and carefully planned research study could pursue the issue in more depth.
The problem with developing research projects in general is that the investigator doesn’t know what they don’t know. As a silly example, what if there’s a correlation between people with blue eyes and spontaneous cases of XLH? No one would think to look into that, because it’s not really something that seems logical. But if you collect enough random bits of information about the community’s biological traits, you can stumble across unexpected connections, and who knows, if we ask enough general questions, perhaps we’ll see a clue to why there are so many spontaneous mutations in the PHEX gene.
As patients with a rare condition, we seldom know more than a small number of other patients (often just family members with the exact same gene variant out of hundreds), so we generally don’t have any way of knowing whether a condition we have is more or less common in the XLH community as a whole. Consider hearing loss—we know now that there’s a higher risk of early-onset hearing loss in the XLH community than in the population at large, but we didn’t know that until patients began engaging with a larger community than their own family, and noticed how common early hearing-loss occurred.
I’ve been thinking about this problem (researchers don’t know what they don’t know) a lot lately, because I’m having a flare-up of my Dupuytren’s Disease (trigger finger), so of course I’m wondering about the incidence of Duputren’s in the XLH community. It’s not something I’ve ever heard another patient talk about, and I’m not sure how aware patients are of the condition. I have a relatively mild case, with no actual “trigger finger” happening, just the nodules in the palm that can lead to the finger bending permanently (as if pulling a trigger). In fact, originally, I thought those nodules were the typical XLH calcium deposits, so there may well be XLHers who have it, but attribute it to the wrong cause. (This is where even a comprehensive natural history study can still miss things, because even if you ask a general question, like “What other medical conditions have you been diagnosed with?” it won’t get you anything useful if the patient hasn’t been diagnosed, because they didn’t know to ask their doctor about the symptom, wrongly attributing it to the XLH and thinking nothing could be done about it.)
There is some good natural-history-of-XLH work happening in Europe and Asia, but since I don’t live there, I haven’t seen their questions and don’t know how comprehensive their surveys are. It may not be possible to be truly comprehensive, so we may need to do the work piecemeal, starting with a natural history study of the obvious/known correlations, and then adding more focused work on different body systems or different phases of life. The Osteogenesis Imperfecta community is doing this kind of focused work on issues that are peripheral to their bone metabolism issues. In particular, I really love this project, “Understanding Menopause and Women’s Health in Osteogenesis Imperfecta.” It’s both connected to bone metabolism (which changes during menopause), so you’d expect to see some patterns that could lead to in-depth research, and also somewhat attenuated from OI per se, so it’s possible there will be insights that weren’t anticipated when designing the survey.
I’d really love to see someone in the XLH-research community do something similar. The initial work of setting up a survey (the OI one is simple, using Survey Monkey, not some fancy software) and analyzing the responses would be relatively inexpensive, I think. This kind of really basic preliminary research would likely be enough to either reassure XLHers that menopause issues are essentially the same as the general population (still potentially traumatic, but at least “normal” in a setting where it feels like nothing else in our lives is normal!), or highlight areas where additional, more complicated and expensive research might be fruitful. Especially in a community where something like two-thirds of patients are female (and a hundred percent of those female patients will go through menopause if they live long enough), having some answers about menopause ought to be a priority for our community.
***
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.