X-Linked Hypophosphatemia: Uniquely Mild Disease Associated With PHEX 3′-UTR Mutation c.*231A>G (A Retrospective Case–Control Study)

Abstract

X-linked hypophosphatemia (XLH), the most prevalent heritable renal phosphate (Pi) wasting disorder, is caused by deactivating mutations of PHEX. Consequently, circulating phosphatonin FGF23 becomes elevated and hypophosphatemia in affected children leads to rickets with skeletal deformity and reduced linear growth while affected adults suffer from osteomalacia and forms of ectopic mineralization. In 2015, we reported uniquely mild XLH in six children and four of their mothers carrying the non-coding PHEX 3 0 -UTR mutation c.*231A>G. Herein, we characterize this mild XLH variant by comparing its features in 30 individuals to 30 age-and sexmatched patients with XLH but without the 3 0 -UTR mutation. The "UTR" and "XLH" groups, both comprising 17 children (2 to 17 years, 3 girls) and 13 adults (23 to 63 years, 10 women), had mean ages of 23 years. Only 43% of the UTR group versus 90% of the XLH group had received medical treatment for their disorder, including 0% versus 85% of the females, respectively (ps < .0001). The UTR group was taller: mean AE SD height Z-score (HZ) −1.0 AE 1.0 versus −2.0 AE 1.4 (p = .0034), with significantly greater height for females (−0.9 AE 0.7 versus −2.3 AE 1.4; p = .0050) but not males (−1.2 AE 1.1 versus −1.9 AE 1.5; p = .1541), respectively. Mean AE SD "arm span Z-score" (AZ) did not differ between the UTR −0.8 AE 1.3 versus XLH −1.3 AE 1.8 groups (p = .2269). Consequently, the UTR group was more proportionate with a mean ΔZ (AZ -HZ) of 0.1 AE 0.6 versus 0.7 AE 1.0 (p = .0158), respectively. Compared to the XLH group, the UTR group had significantly higher fasting serum Pi and renal tubular threshold maximum for phosphorus per glomerular filtration rate (TmP/GFR) (ps ≤ .0060), serum FGF23 concentrations within the reference range (p = .0068), and similar serum alkaline phosphatase levels (p = .6513). UTR lumbar spine bone mineral density Z-score was higher (p = .0343). Thus, the 3 0 -UTR variant of XLH is distinctly mild, especially in girls and women, posing challenges for its recognition and management.

Novel PHEX gene locus‐specific database: Comprehensive characterization of vast number of variants associated with X‐linked hypophosphatemia (XLH)

“…Earlier, small cohort studies identified c.*231A>G as a disease‐causing variant in multiple probands leading to XLH (Ichikawa et al, 2008 ; Smith et al, 2020 ), however, these studies did not detect CNV, so it is not known whether these patients also carried the Ex‐13–15 duplication. The recent readout from the hypophosphatemia genetic testing program found that all XLH patients who had the 3′‐UTR c.*231A>G variant also carried the Ex13–15 duplication, but one affected proband carried the duplication without the c.*231A>G variant, suggesting that the duplication can contribute to disease on its own (Rush et al, 2021 ).…”

Consensus Recommendations for the Diagnosis and Management of X-Linked Hypophosphatemia in Belgium

“…Genetic testing by Sanger sequencing or next-generation sequencing is readily available in several genetic centers in Belgium for PHEX as well as for other skeletal dysplasia genes using a whole-exome sequencing-based gene panel. Genetic testing also examines the 3' untranslated region in which mutations associated with milder XLH phenotypes have been reported (111)(112)(113). In general however, mutations can affect any exon, without a clear genotype-phenotype correlation (114).…”

Molecular Diagnoses of X-Linked and Other Genetic Hypophosphatemias: Results From a Sponsored Genetic Testing Program

“…Recently, the c.*231A>G variant was reported to be associated with mild disease severity in a small cohort. ( 88 ) However, within our cohort, a wide spectrum of clinical features was reported for patients with both the gain of exons 13–15 and the c.*231A>G variant. Supporting our result, another large family with these variants, tested through the program, was recently reported to have symptoms with a wide spectrum of severity, including hearing loss.…”