Novel PHEX Mutation Associated with Hypophosphatemic Rickets

Roetzer, Katharina; Varga, Franz; Zwettler, Elisabeth; Nawrot-Wawrzyniak, Kamilla; Haller, Joerg; Förster, E; Klaushofer, Klaus

doi:10.1159/000101487

Cited by 13 publications

(9 citation statements)

References 58 publications

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“…Despite the treatment, normal phosphate serum levels were not achieved, nor was osteomalacia prevented. Subsequently, the patient developed reactive hyperparathyroidism with gland hyperplasia, a feared complication of the treatment [33][34][35][36], shortly before the responsible tumor could be localized and removed. After surgery serum markers normalized and remained stable, and in particular, FGF23 values were found to be much lower also 5 years postsurgery.…”

Section: Histomorphometric Analyses Of Bone Biopsy Revealed Osteomalamentioning

confidence: 99%

Effects of Tumor-Induced Osteomalacia on the Bone Mineralization Process

et al. 2009

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Fibroblast growth factor 23 (FGF23) overexpression has been identified as a causative factor for tumor-induced osteomalacia (TIO) characterized by hypophosphatemia due to increased renal phosphate wasting, low 1,25(OH)(2)D(3) serum levels, and low bone density. The effects of long-lasting disturbed phosphate homeostasis on bone mineralization are still not well understood. We report on a patient with a 12-year history of TIO, treated with 1,25(OH)(2)D(3) and phosphate, who finally developed hyperparathyroidism with gland hyperplasia before the tumor could be localized in the scapula and removed. During surgery a transiliac bone biopsy was obtained. FGF23 expression in the tumor cells was confirmed by in situ hybridization. Serum FGF23 levels as measured by ELISA were found to be extremely elevated before and decreased after removal of the tumor. Bone histology/histomorphometry and measurement of bone mineralization density distribution using quantitative backscattered electron imaging were performed on the bone biopsy. The data showed important surface osteoidosis and a slightly increased osteoblast but markedly decreased osteoclast number. The mineralized bone volume (-11%) and mineralized trabecular thickness (-18%) were low. The mean degree of mineralization of the bone matrix (-7%), the most frequent calcium concentration (-4.1%), and the amounts of fully mineralized bone (-40.3%) were distinctly decreased, while the heterogeneity of mineralization (+44.5%) and the areas of primary mineralization (+131.6%) were dramatically increased. We suggest that the elevated levels of FGF23 and/or low phosphate concentrations disturb the mineralization kinetics in vivo without affecting matrix mineralization of pre-existing bone packets.

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Section: Histomorphometric Analyses Of Bone Biopsy Revealed Osteomalamentioning

confidence: 99%

Effects of Tumor-Induced Osteomalacia on the Bone Mineralization Process

et al. 2009

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“…Hypophosphatemic rickets is most commonly caused by mutations in the phosphate-regulating endopeptidase gene (PHEX), transmitted as an X-linked trait (X-linked hypophosphatemic rickets, XLH) (1,3,4).…”

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confidence: 99%

Cortical and Trabecular Bone Density in X-Linked Hypophosphatemic Rickets

Cheung

Roschger

Klaushofer

et al. 2013

The Journal of Clinical Endocrinology &Amp; Metabolism

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Context: X-linked hypophosphatemic rickets is caused by mutations in PHEX. Even though the disease is characterized by disordered skeletal mineralization, detailed bone densitometric studies are lacking.Objective: The aim of the study was to assess volumetric bone mineral density (vBMD) in X-linked hypophosphatemic rickets using forearm peripheral quantitative computed tomography. Setting:The study was conducted in the metabolic bone clinic of a pediatric orthopedic hospital.Patients: Thirty-four patients (age, 6 to 60 years; 24 female) with PHEX mutations were studied, of whom 7 children (age, 6 to 11 years) were actively being treated with calcitriol and phosphate supplementation. Twenty-one patients (age, 16 to 40 years) had received the same therapy before but had discontinued the treatment; 6 patients (age, 12 to 60 years) had never received this treatment. Main Outcome Measures: Trabecular and cortical vBMD of the radius.Results: Trabecular vBMD was elevated (mean age-specific and sex-specific z-score: ϩ1.0) when all patients were analyzed together, due to very high results in currently treated patients (mean z-score: ϩ2.4) and slightly above-average mean values in the other patients. Cortical vBMD was low when the entire cohort was analyzed together (mean z-score: Ϫ3.3), but was higher in currently treated patients (mean z-score: Ϫ1.3) than in patients who had discontinued therapy (mean zscore: Ϫ3.8) or who had never been treated (mean z-score: Ϫ4.1). Conclusions:Patients with PHEX mutations have elevated trabecular vBMD at the distal radius while receiving calcitriol and phosphate supplementation, but low cortical vBMD at the radius diaphysis. Low cortical vBMD presumably reflects the underlying mineralization defect that is not entirely corrected by current treatment approaches. (J Clin Endocrinol Metab 98: E954 -E961, 2013) H ereditary hypophosphatemic rickets is characterized by hypophosphatemia due to renal phosphate wasting, resulting in leg deformities and short stature (1, 2). Hypophosphatemic rickets is most commonly caused by mutations in the phosphate-regulating endopeptidase gene (PHEX), transmitted as an X-linked trait (X-linked hypophosphatemic rickets, XLH) (1, 3, 4).The current treatment for XLH consists of oral phosphate supplementation and calcitriol and aims at maximizing growth and preventing bone deformities (1, 2). Because these main benefits are dependent on skeletal growth and the treatment schedule is quite burdensome, therapy is often discontinued once final height is achieved. Abbreviations: BMD, bone mineral density; LS-aBMD, lumbar spine areal bone mineral density; pQCT, peripheral quantitative computed tomography; vBMD, volumetric bone mineral density; XLH, X-linked hypophosphatemic rickets.

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“…Genomic DNA was obtained and extracted from whole blood samples using the blood and cell genomic DNA extraction kit (Qiagen, Venlo, Netherlands). PCR amplified all 22 exons and exon-intron boundaries of PHEX and also all exons and exon-intron boundaries of FGF23 , DMP1 , and ENPP1 to exclude ADHR, ARHR1, and ARHR2, respectively, using previously described primer pairs [ 1 , 11 , 14 , 15 ]. Additionally, for PHEX , we analyzed the approximately 2 kb promoter region upstream the start codon.…”

Section: Case Presentationmentioning

confidence: 99%

“…X-linked hypophosphatemic rickets (XLH; OMIM number 307800) is the most common genetic disorder of renal phosphate wasting, with an approximate prevalence of 1 in 20,000 [ 1 ]. The clinical features of this X-linked dominant disease include short stature, bone pain, enthesopathy, and lower extremity deformities from rickets and osteomalacia.…”

Section: Introductionmentioning

confidence: 99%

A NovelPHEXMutation in Japanese Patients with X-Linked Hypophosphatemic Rickets

Kawahara¹,

Watanabe

Omae

et al. 2015

Case Reports in Genetics

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X-linked hypophosphatemic rickets (XLH) is a dominant inherited disorder characterized by renal phosphate wasting, aberrant vitamin D metabolism, and abnormal bone mineralization. Inactivating mutations in the gene encoding phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) have been found to be associated with XLH. Here, we report a 16-year-old female patient affected by hypophosphatemic rickets. We evaluated her serum fibroblast growth factor 23 (FGF23) levels and conducted sequence analysis of the disease-associated genes of FGF23-related hypophosphatemic rickets: PHEX, FGF23, dentin matrix protein 1, and ectonucleotide pyrophosphatase/phosphodiesterase 1. She was diagnosed with XLH based on her clinical features and family history. Additionally, we observed elevated FGF23 levels and a novel PHEX exon 9 mutation (c.947G>T; p.Gly316Val) inherited from her father. Although bioinformatics showed that the mutation was neutral, Gly316 is perfectly conserved among humans, mice, and rats, and there were no mutations in other FGF23-related rickets genes, suggesting that in silico analysis is limited in determining mutation pathogenicity. In summary, we present a female patient and her father with XLH harboring a novel PHEX mutation that appears to be causative of disease. Measurement of FGF23 for hypophosphatemic patients is therefore useful for the diagnosis of FGF23-dependent hypophosphatemia.

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Novel PHEX Mutation Associated with Hypophosphatemic Rickets

Cited by 13 publications

References 58 publications

Effects of Tumor-Induced Osteomalacia on the Bone Mineralization Process

Effects of Tumor-Induced Osteomalacia on the Bone Mineralization Process

Cortical and Trabecular Bone Density in X-Linked Hypophosphatemic Rickets

A NovelPHEXMutation in Japanese Patients with X-Linked Hypophosphatemic Rickets

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