Department of Musculoskeletal Biology, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK.
Department of Clinical Biochemistry and Metabolic Medicine, Royal Liverpool University Hospital, Liverpool, UK.
Bone. 2018 Jan;106:30-34. doi: 10.1016/j.bone.2017.10.002. Epub 2017 Oct 3.
Adults presenting with sporadic hypophosphatemia and elevations in circulating fibroblast growth factor-23 (FGF23) concentrations are usually investigated for an acquired disorder of FGF23 excess such as tumor induced osteomalacia (TIO). However, in some cases the underlying tumor is not detected, and such patients may harbor other causes of FGF23 excess. Indeed, coding-region and 3'UTR mutations of phosphate-regulating neutral endopeptidase (PHEX), which encodes a cell-surface protein that regulates circulating FGF23 concentrations, can lead to alterations in phosphate homeostasis, which are not detected until adulthood. Here, we report an adult female who presented with hypophosphatemic osteomalacia and raised serum FGF23 concentrations. The patient and her parents, who were her only first-degree relatives, had no history of rickets. The patient was thus suspected of having TIO. However, no tumor had been identified following extensive localization studies. Mutational analysis of the PHEX coding-region and 3'UTR was undertaken, and this revealed the patient to be heterozygous for a novel germline PHEX mutation (c.2158G>T; p.Ala720Ser). In vitro studies involving the expression of WT and mutant PHEX proteins in HEK293 cells demonstrated the Ala720Ser mutation to impair trafficking of PHEX, with ~20% of the mutant protein being expressed at the cell surface, compared to ~80% cell surface expression for WT PHEX (p<0.05). Thus, our studies have identified a pathogenic PHEX mutation in a sporadic case of adult-onset hypophosphatemic osteomalacia, and these findings highlight a role for PHEX gene analysis in some cases of suspected TIO, particularly when no tumor has been identified.
成人出现散发性低磷血症和循环成纤维细胞生长因子 23（FGF23）浓度升高，通常会检查是否存在成纤维细胞生长因子 23 过量的获得性疾病，如肿瘤诱导性骨软化症（TIO）。然而，在某些情况下，并未检测到潜在肿瘤，并且此类患者可能存在其他原因导致的成纤维细胞生长因子 23 过量。事实上，磷酸调节中性内肽酶（PHEX）的编码区和 3'UTR 突变，该基因编码一种调节循环 FGF23 浓度的细胞表面蛋白，可导致磷酸盐稳态发生改变，直到成年后才会被发现。在此，我们报告了一位成年女性，她表现为低磷性骨软化症和血清 FGF23 浓度升高。患者及其父母（她唯一的一级亲属）没有佝偻病病史。因此，怀疑该患者患有 TIO。然而，经过广泛的定位研究，尚未发现肿瘤。对 PHEX 编码区和 3'UTR 进行了突变分析，结果发现该患者为 PHEX 基因杂合突变（c.2158G>T；p.Ala720Ser）。体外研究涉及在 HEK293 细胞中表达 WT 和突变 PHEX 蛋白，结果表明 Ala720Ser 突变会损害 PHEX 的运输，与 WT PHEX 相比，约 20%的突变蛋白在细胞表面表达，而 WT PHEX 的细胞表面表达率约为 80%（p<0.05）。因此，我们的研究在一例散发性成年低磷血症性骨软化症病例中鉴定出致病性 PHEX 突变，这些发现强调了 PHEX 基因分析在某些疑似 TIO 病例中的作用，特别是在未发现肿瘤时。
