Spectrum of PHEX Mutations and FGF23 Profiles in a Taiwanese Cohort With X-Linked Hypophosphatemia Including 102 Patients

Abstract

Background/aim: X-linked hypophosphatemia (XLH), the most common form of hereditary rickets, results from loss-of-function mutations in the phosphate-regulating PHEX gene. Elevated fibroblast growth factor 23 (FGF23) contributes to hypophosphatemia in XLH. This study aimed to characterize PHEX variants and serum FGF23 profiles in Taiwanese patients with XLH.

Patients and methods: We retrospectively reviewed the records of 102 patients clinically suspected of having hypophosphatemic rickets from 2006 to 2022. Serum intact Fibroblast growth factor-23 (iFGF23) levels were measured on clinic visit days. PHEX mutations were identified using Sanger sequencing, and negative cases were analyzed using whole-exome sequencing.

Results: The majority (92.1%) of patients exhibited elevated FGF23 compared with normal individuals. Among 102 patients, 44 distinct PHEX mutations were identified. Several mutations recurred in multiple unrelated Taiwanese families. We discovered a high frequency of novel PHEX mutations and identified variants associated with extreme FGF23 elevation and tumorigenesis.

Conclusion: Our findings revealed the PHEX genotypic variants and FGF23 levels in Taiwanese patients with XLH. These results are crucial given the recent approval of burosumab, a monoclonal FGF23 antibody, for XLH therapy. This study provides key insights into the clinical management of XLH in Taiwan.

Keywords: X-linked hypophosphatemia; fibroblast growth factor 23; hypophosphatemic rickets; phosphate-regulating endopeptidase gene; tumor-induced osteomalacia.

Figure 1. Distribution of all PHEX mutations identified in this study. A total of 44 different PHEX mutations were detected in 102 patients. Yellow corresponds to silent mutations, green corresponds to missense mutations, red corresponds to nonsense mutations, blue corresponds to frameshift mutations, and purple corresponds to intron insertions.

Figure 2. Frequency of PHEX variants in Taiwan. A total of 74 PHEX mutations were detected in 102 patients, including 1 silence mutation (1.4%), 22 missense mutations (29.7%), 21 nonsense mutations (28.4%), 19 frameshift mutations (25.7%), 101 intron mutations (9 at splice-site included) (14.9%).

Figure 3. Distribution of PHEX mutations identified in different countries. Blue corresponds to mutations in Taiwanese patients, green corresponds to mutations in Korean patients, purple corresponds to mutations in Japanese patients, Yellow corresponds to mutations in both Taiwanese and Korean patients, Light blue corresponds to mutations in both Taiwanese and Japanese patients, and red corresponds to mutations in all three countries.

Figure 4. Comparing PHEX mutations in neighboring countries (Japan and Korea). Of all the mutations identified in our study and the references, 15 were unique to Japan, 35 were unique to Korea, 32 were unique to Taiwan, three were shared by Taiwan and Japan, four were shared by Taiwan and Korea, and five were shared by all three countries.