Genotype and Phenotype Analysis in X-Linked Hypophosphatemia.

Peong Gang Park,Hee Gyung Kang,Yo Han Ahn,Seon Hee Lim,Hyunkyung Lee,Hae Il Cheong

doi:10.3389/fped.2021.699767

Abstract

Background: X-linked hypophosphatemia (XLH) is the most frequent form of hypophosphatemic rickets and is caused by mutations in the PHEX gene. We analyzed genotype-phenotype correlations in XLH patients with proven PHEX mutations.Methods:PHEX mutations were detected in 55 out of 81 patients who clinically presented with hypophosphatemic rickets. The patients were grouped into nontruncating (n = 9) and truncating (n = 46) mutation groups; their initial presentation as well as long-term clinical findings were evaluated according to these groups.Results: Initial findings, including presenting symptoms, onset age, height standard deviation scores (SDS), and laboratory tests, including serum phosphate level and tubular resorption of phosphate, were not significantly different between the two groups (onset age: nontruncating mutation group, 2.0 years, truncating mutation group, 2.2 years; height SDS: nontruncating mutation group, −1.9, truncating mutation group, −1.7; serum phosphate: nontruncating mutation group, 2.5 mg/dL, truncating mutation group, 2.6 mg/dL). However, at their last follow-up, the serum phosphate level was significantly lower in patients with truncating mutations (nontruncating mutation group: 3.2 mg/dl, truncating mutation group: 2.3 mg/dl; P = 0.006). Additionally, 62.5% of patients with truncating mutations developed nephrocalcinosis at their last follow-up, while none of the patients with nontruncating mutations developed nephrocalcinosis (P = 0.015). Orthopedic surgery due to bony deformations was performed significantly more often in patients with truncating mutations (52.3 vs. 10.0%, P = 0.019).Conclusion: Although considerable inconsistency exists regarding the correlation of truncating mutations and their disease phenotype in several other studies, we cautiously suggest that there would be genotype-phenotype correlation in some aspects of disease manifestation after long-term follow-up. This information can be used when consulting patients with confirmed XLH regarding their disease prognosis.

Highlights

X-linked hypophosphatemia (XLH, Online Mendelian Inheritance in Man # 307800) is the most frequent form of hypophosphatemic rickets, with an estimated prevalence of one in 20,000 individuals in the general population [1]
We found that patients with truncating mutations had significantly lower serum Pi and a high proportion of nephrocalcinosis during their long-term follow-up period, clinical manifestations were not significantly different at their initial presentation
Out of three previously reported genotype-phenotype studies, none of them reported significant differences in initial clinical characteristics between types of mutations, one study reported that patients with truncating mutations had lower tubular reabsorption of phosphate (TRPi) than patients without truncating mutations [9]

Summary

Introduction

X-linked hypophosphatemia (XLH, Online Mendelian Inheritance in Man # 307800) is the most frequent form of hypophosphatemic rickets, with an estimated prevalence of one in 20,000 individuals in the general population [1]. XLH is caused by pathologic loss-of-function mutations in the PHEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome) gene, located on Xp22.1, which causes an elevation of circulating levels of fibroblast growth factor 23 (FGF23), which regulates renal phosphate reabsorption and the production of calcitriol [4]. More than 400 types of PHEX variants have been annotated in the Human Gene Mutation Database (HGMD; http://www.hgmd.cf.ac.uk). These mutations, including frameshift mutations, missense mutations, intronic splice-site mutations, nonsense mutations, and deletions, are spread throughout the gene, with no identified specific hot spot. X-linked hypophosphatemia (XLH) is the most frequent form of hypophosphatemic rickets and is caused by mutations in the PHEX gene. We analyzed genotype-phenotype correlations in XLH patients with proven PHEX mutations

Results

Discussion

Conclusion