Hajime Kato, Yasuki Ishihara, Yasuhisa Ohata, Koki Irie, So Watanabe, Soichiro Kimura, Yoshitomo Hoshino, Naoko Hidaka, Yuka Kinoshita, Yuki Taniguchi, Hiroshi Kobayashi, Demetrios T Braddock, Takuo Kubota, Keiichi Ozono, Masaomi Nangaku, Noriko Makita, Nobuaki Ito
{"title":"Effect of Mutation Type on Ectopic Ossification Among Adult Patients With X-Linked Hypophosphatemia.","authors":"Hajime Kato, Yasuki Ishihara, Yasuhisa Ohata, Koki Irie, So Watanabe, Soichiro Kimura, Yoshitomo Hoshino, Naoko Hidaka, Yuka Kinoshita, Yuki Taniguchi, Hiroshi Kobayashi, Demetrios T Braddock, Takuo Kubota, Keiichi Ozono, Masaomi Nangaku, Noriko Makita, Nobuaki Ito","doi":"10.1210/jendso/bvae184","DOIUrl":null,"url":null,"abstract":"<p><strong>Context: </strong>Causative factors for ectopic ossifications in X-linked hypophosphatemia (XLH) remain to be elucidated.</p><p><strong>Objective: </strong>This work aimed to investigate the genotype-phenotype correlations between the phosphate-regulating endopeptidase homologue, X-linked gene (<i>PHEX</i>) and ectopic ossifications in XLH.</p><p><strong>Methods: </strong>Biochemical data, spinal computed tomography scans, and x-rays of hip/knee joints were retrospectively reviewed. Genetic analysis and the measurement of plasma inorganic pyrophosphate (PP<sub>i</sub>)-a potent inhibitor of tissue calcification-were performed. The effect of <i>PHEX</i> mutations on protein function was predicted using nonsense-mediated decay (NMD) and 3-dimensional structure modeling. The index of ossification of the anterior/posterior longitudinal ligament and yellow ligament (OA/OP/OY index) and the sum of the OA/OP/OY index (OS index) were used to quantify the severity of spinal ligament ossification. The severity of the hip/knee osteoarthritis was evaluated by the Kellgren-Lawrence classification.</p><p><strong>Results: </strong>We examined 24 distinct pathogenic <i>PHEX</i> variants in 28 patients from a study population of 33 individuals in 27 unrelated, nonconsanguineous families. Among the 31 patients whose plasma samples were analyzed for PP<sub>i</sub>, 14 patients (45%) showed decreased plasma PP<sub>i</sub> concentrations; however, PP<sub>i</sub> concentrations did not correlate with mutation type or ectopic ossification. Fibroblast growth factor 23 levels in women with NMD-insensitive mutations trended lower than in men with NMD-sensitive mutations but failed to reach statistical significance. Both models revealed no correlations between <i>PHEX</i> pathogenic variant and ectopic ossification.</p><p><strong>Conclusion: </strong>Neither modeling found correlates between PHEX pathogenic variants and ectopic ossification. The effects of PP<sub>i</sub> on ectopic ossifications in adults with XLH revealed trends that should be investigated with a large sample size.</p>","PeriodicalId":17334,"journal":{"name":"Journal of the Endocrine Society","volume":null,"pages":null},"PeriodicalIF":3.0000,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11532897/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of the Endocrine Society","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1210/jendso/bvae184","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/10/29 0:00:00","PubModel":"eCollection","JCR":"Q2","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
引用次数: 0
Abstract
Context: Causative factors for ectopic ossifications in X-linked hypophosphatemia (XLH) remain to be elucidated.
Objective: This work aimed to investigate the genotype-phenotype correlations between the phosphate-regulating endopeptidase homologue, X-linked gene (PHEX) and ectopic ossifications in XLH.
Methods: Biochemical data, spinal computed tomography scans, and x-rays of hip/knee joints were retrospectively reviewed. Genetic analysis and the measurement of plasma inorganic pyrophosphate (PPi)-a potent inhibitor of tissue calcification-were performed. The effect of PHEX mutations on protein function was predicted using nonsense-mediated decay (NMD) and 3-dimensional structure modeling. The index of ossification of the anterior/posterior longitudinal ligament and yellow ligament (OA/OP/OY index) and the sum of the OA/OP/OY index (OS index) were used to quantify the severity of spinal ligament ossification. The severity of the hip/knee osteoarthritis was evaluated by the Kellgren-Lawrence classification.
Results: We examined 24 distinct pathogenic PHEX variants in 28 patients from a study population of 33 individuals in 27 unrelated, nonconsanguineous families. Among the 31 patients whose plasma samples were analyzed for PPi, 14 patients (45%) showed decreased plasma PPi concentrations; however, PPi concentrations did not correlate with mutation type or ectopic ossification. Fibroblast growth factor 23 levels in women with NMD-insensitive mutations trended lower than in men with NMD-sensitive mutations but failed to reach statistical significance. Both models revealed no correlations between PHEX pathogenic variant and ectopic ossification.
Conclusion: Neither modeling found correlates between PHEX pathogenic variants and ectopic ossification. The effects of PPi on ectopic ossifications in adults with XLH revealed trends that should be investigated with a large sample size.