We have characterised and analysed a range of health dimensions for adults with XLH, grouped the participants into two separate clusters, and found little change in outcomes over time. Many of the adults with XLH reported no or slight problems with mobility (EQ-5D-5L, 60.41%) and pain (EQ-5D-5L, 39.58%), normal levels of sleepiness (ESS, 91.30%), no neuropathic pain (painDETECT, 65.12%), and normal levels of anxiety (HADS, 63.41%) and depression (HADS, 85.37%). However, a distinct few reported having severe or unable difficulty with mobility (EQ-5D-5L, 22.92%) and pain (EQ-5D-5L, 22.92%), and low mean scores for fatigue (FACIT-F FS, 31.33) and functional well-being (FACIT-F FWB, 18.25). These results are supported by previous research which found that for adults with XLH, pain was the most prominent symptom which then additionally impacted physical functioning (43). Furthermore, a greater weighting of females in the RUDY study is representative of the demographic of the XLH population and supports previous findings (44, 45).
The correlation between mental health and fatigue was found to be the highest of all the PROMs. Except for females experiencing worse quality sleep than males, no other statistically significant difference was found between males and females. This result is supported by previous research, which also found no significant difference in the symptom severity between males and females (46).
Cluster analysis found that, even with a small sample of individuals with XLH, they could be divided into two distinct groups, where one group reported better quality of life, fatigue, sleep, pain, and depression than the other group. For those who report good outcomes it may be that they have learnt to live with and manage condition or have a good support system of care. Sensitivity analysis increasing the sample size by removing instruments with the lowest response rates at first submission also identified two clusters with very similar PROMs scores. Further analysis of these group differences could in the future enable learnings to be found from those who report good outcomes and a better streamline of care and resources to those who experience the worst symptoms. More research with a larger sample size is needed to confirm that these group differences persist.
Over a two-year period, we found evidence of stability across the health outcomes with signals of worsening anxiety and fatigue. If this deterioration were to continue beyond the two years, this could significantly impact the well-being of people with XLH suffering from these ailments. However, for all other health dimensions there was no evidence of change over the two years examined. We are not able to compare the FACIT-F fatigue subscale scores of our XLH sample against a UK-based general population study, but our findings report a much lower mean (31.33) than that of the German population obtained from a household survey via a nationwide random sampling (43.5) (47). Although differences may be explained by both differences in health between adults with XLH and the general population and differences in the UK and German populations, it is likely that the former dominates suggesting that on average people with XLH experience a greater level of fatigue than the general population.
Mean HRQL (SF-36-PCS and SF-36-MCS) of individuals with XLH (SF-36-PCS = 32.67 and SF-36-MCS = 48.38) is comparable to scores reported by people with musculoskeletal pain (SF-36-PCS = 32.93 and SF-36-MCS = 48.03) (48). However, our mean SF-36-PCS and SF-36-MCS results were lower (worse) than previous research of XLH populations has found (45). This difference may be due to the reported use of phosphate and/or vitamin D supplements reported by the latter research. In addition, part of the differences could be due to differences in study design; RUDY is an online study where participants can complete instruments in their own time, whereas the previous research was a hospital-based study, where applicants would complete instruments on paper as part of the hospital visit. Both XLH study populations reported a lower mean SF-36-PCS than mean SF-36-MCS suggesting that the physical impact of the condition may be greater than the mental impact. We found mean HRQL of adults with XLH (EQ-5D-5L = 0.651) to be higher than that of a Spanish study of adults with XLH (EQ-5D-5L = 0.562)(49). This difference may be due to limited generalisability between UK and Spanish populations or the latter study identifying their participants through specialized clinics which may infer a more severe case mix. Comparison of UK and Spanish EQ-5D population norms show that reported health-related quality of life in the UK is lower than in Spain (0.852 and 0.914, respectively)(50).
A comparison with previous research shows that adults with XLH participating in RUDY report less neuropathic pain on average than those diagnosed with musculoskeletal pain (mean = 9.28 vs. mean = 17.13) (48).We also found that, although the mean anxiety score of both male and female adults with XLH participating in RUDY (M = 5.78 and F = 6.28) were similar to UK population norms (M = 5.51 and F = 6.78), the percentage of those with moderate/severe anxiety was lower in RUDY (F:9.4% and M:22.2% compared to F:19.0% and M:12.5%) (51). This is consistent with previous studies reporting the resilience and acceptance of people living with some rare diseases(52, 53). Conversely, the proportion of participants with moderate/severe depression was slightly higher for the RUDY sample than the UK population comparator (F:9.4% and M:11.1% vs F:6.9% and M:6.9%) (51). However, it should be noted that the RUDY study covered a slightly wider age range than the comparator study (25–65 years old) and that, additionally, differences between people with XLH and the general population, as well as across countries, could stem from varying and relatively lower levels of deprivation experienced by people with XLH (3).
This analysis benefited from the richness of the data collected through the RUDY study, with questionnaires measuring a wide range of health dimensions. This enabled the health dimensions to be compared and investigated simultaneously developing the characterisation of the HRQL of people with XLH. Furthermore, RUDY participants who complete an instrument multiple times enable longitudinal analysis of how their PROMs change overtime. This gives further insight into how the condition develops and changes overtime and a better understanding of the experiences of individuals with a diagnosis of XLH.
Our study faced limitations. Due to the rarity of the disease, the sample size is small which in turn may limit the power of our results. A small sample size also brings doubt as to whether the sample is truly representative of the XLH population. Furthermore, as participants are free to complete any number of questionnaires for a given submission this means that some questionnaires results are missing for a given submission and consequently limited the comparability of the questionnaires. Finally, as RUDY is self-reported we were unable to validate the accuracy of clinical diagnosis but the diagnostic accuracy in other rare bone disorders is high (54, 55).