This is Chapter One in the series about what the Primary Care Provider (PCP), rather than the specialist, needs to know about their XLH patients. To avoid repetition and keep the chapters from becoming unwieldy in length, I’ve posted the footnotes separately here.
For the pediatric PCP
The diagnosis and genetics of chronic hypophosphatemia are fairly complicated, best left to a pediatric endocrinologist, but once the diagnosis has been made, a Primary Care Provider (PCP) still needs to be aware of how the conclusion was reached, in case it was done without the proper evidence.
Family history isn’t enough: Family history plus clinical signs, simple lab tests and an understanding of the transmission pattern can usually generate a preliminary diagnosis. Note, however, that up to thirty percent of XLH patients do not, in fact, inherit the condition, but are the result of a spontaneous mutation. FN2, 3. Another complication arises from the fact that most x-linked conditions are recessive, but XLH is a dominant condition FN4, and even genetic counselors can get this wrong by not checking their assumptions.
According to the National Cancer Institute, FN8, the child of a mother with an x-linked dominant condition has a 50% chance of inheriting the condition, while the odds of inheritance from an affected father depend on the child’s gender—all of his daughters will inherit the condition, while none of his sons will inherit.
The genetics of the ultra-rare autosomal hypophosphatemias are simpler, in that they follow the more typical transmission patterns—if it’s a recessive variant, both parents need to have the variant to pass it on, and it will not depend on the gender of the parent or the child; if it’s dominant, then there’s a fifty percent chance of transmission, regardless of the gender of the parent or child.
Initial testing: X-rays can reveal rickets (a key symptom in pediatric XLH), but not the cause of the soft bones. There are several blood/urine tests performed by specialists in the course of diagnosis, but the most typical, basic scenario is a combination of elevated FGF23, low phosphorus and normal calcium. FN6. Three caveats: 1) FGF23 levels in infants can vary significantly depending on methodology and age range, so careful attention to method/age are necessary FN3; 2) phosphorus testing in the first three months of infancy is unreliable due to normal phosphorus fluctuations, and not all laboratories even have a “normal” value for infants under twelve months FN10, 11; and 3) pediatric normal levels for phosphorus are significantly higher than adult values, so it’s important to confirm the lab used the correct age-specific normals. FN 10, 11.
Counterintuitive aspects of XLH that make the preliminary diagnosis look wrong when it’s actually correct:
1) Some XLH patients will have phosphorus levels reach the normal range, albeit the lower end, even in the absence of treatment (based on patient reporting, no footnote currently available)
2) FGF23 levels may be normal (rather than high) FN6 table 2
3) Vitamin D levels may be normal (rather than low) FN6 table 2
4) The known but unexplained variability in patients’ extent and severity of symptoms, FN1, 2, means that even patients within a single family line, with the exact same PHEX mutation, can have a different combination of symptoms and different severities. FN1
Genetic testing after preliminary diagnosis. Experts recommend genetic testing to confirm diagnosis. FN5, 6. There are three basic types of chronic hypophosphatemia patients, two of which are caused by a genetic variant (XLH and autosomal hypophosphatemia), and one by a tumor (Tumor-Induced Osteomalacia [TIO]). Note that state-of-the-art treatment with burosumab is only FDA-approved for XLH and TIO, not the autosomal hypophosphatemias, and insurance won’t pay without a genetic test.
I have been unable to find a database of genetic variants for the autosomal hypophosphatemias, but there is one for the over 800 variants known to cause XLH. FN2, FN9. To date, there is no evidence of any significant correlation between specific variants that cause XLH and the extent/severity of the patient’s symptoms. [There are journal articles that say this, but I wasn’t able to find them in time for this posting.]
For the adult PCP
The issues of diagnosis are ideally, but not always, long resolved before a patient becomes an adult. In a recent survey of adult patients, fourteen percent had not been diagnosed until adulthood FN2, so it’s important for an adult PCP to understand the basics of diagnosis, as laid out above, in case the patient was undiagnosed or misdiagnosed. Also, if the patient isn’t already on state-of-the-art treatment (burosumab), the PCP will be asked for confirmation of the diagnosis by way of genetic testing, so it will be important to have that report on file.
For most adults, however, the two main issues related to diagnosis are: 1) confirming that the diagnosis is correct (XLH versus an autosomal genetic cause), since treatment (or access to treatment) varies among the various genetic subcategories; and 2) family planning that addresses the inheritability of the condition, the transmission pattern, and the extreme variability in symptoms/severity even within a single family line (i.e., even if the parent’s symptoms are limited and mild, there’s no guarantee the child’s symptoms will be the same).
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Please note that the author is a well-read patient, not a doctor, and is not offering medical or legal advice.
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