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Increased prevalence, reduced survival observed among adults with X-linked hypophosphatemia
Conservative estimates suggest that the prevalence of X-linked hypophosphatemia, or XLH, a rare form of rickets, has more than tripled in the past 25 years in the United Kingdom, with researchers noting a concerning reduction in survival among patients with the disease.
“Three previous studies of the prevalence of XLH in children have used a mixture of hospital surveys and registry data with conflicting prevalence rates, due in part to differences in criteria for case identification and validation,” Samuel Hawley, DPhil, an epidemiologist and statistician in the department of orthopedics, rheumatology and musculoskeletal sciences at the University of Oxford, United Kingdom, and colleagues wrote in the study background. “[Lack of] accurate data for adults is compounded by the lack of any standard management for adults with XLH in terms of monitoring laboratory values, skeletal status and other characteristics. Hence, it is possible that in the United Kingdom most adults are managed principally in the primary care setting. The National Health Service (NHS) health care system within the U.K. has near-universal coverage and a single reimbursement guideline and represents an opportune data resource to explore the prevalence of a rare disease such as XLH and its associated mortality rate.”
In a population-based cohort study, Hawley and colleagues analyzed potential XLH cases using a large primary care database in the U.K. from 1995 to 2016. XLH cases were matched by age, sex and practice with up to four controls. Researchers estimated trends in prevalence during the study period, stratified by age, and survival among cases compared with controls.
From 522 potential cases, 122 (23.4%) were scored as at least possible XLH, whereas 62 (11.9%) were classified as highly likely or likely cases.
In main analyses, prevalence increased from 3.1 per million in 1995-1999 (95% CI, 1.5-6.7) to 14 per million in 2012-2016 (95% CI, 10.8-18.1). Using the conservative definition of XLH, corresponding estimates were 3 per million in 1995-1999 (95% CI, 1.4-6.5) to 8.1 per million in 2012-2016 (95% CI, 5.8-11.4). During follow-up, nine (7.4%) possible cases and 14 (2.9%) controls died (median age, 64 vs. 73 years, respectively).
“We observed an unexpected reduction in survival among XLH cases relative to controls (with average age at death being approximately 8 years younger in cases relative to controls), which was evident when using either the more or less conservative case definition,” the researchers wrote.
Compared with controls, researchers found that mortality was increased among individuals with possible XLH (HR = 2.93; 95% CI, 1.24-6.91) and among those with likely or highly likely XLH (HR = 6.65; 95% CI, 1.44-30.72).
The researchers noted that the mechanism for the observed increase in mortality among adults with XLH is not known.
“It could be that the reduced survival is indirect, driven by an imbalance in comorbidities and other associated characteristics of XLH patients relative to controls,” the researchers wrote. “Furthermore, a difference in the management of comorbidities between cases and controls may also exist. A direct FGF23 pathway is also possible. It has previously been shown that neutralizing circulating FGF23 reverses several key biochemical and musculoskeletal features of XLH in both animals and humans, suggesting a key role of FGF23 in XLH.” – by Regina Schaffer
Disclosures: Kyowa Kirin International provided funding for this project. Hawley reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.