Vitamin D efficacy in type 1 and type 2 diabetes.

It is well known that vitamin D has a profound effect on calcium and bone metabolism, but its influence on other organs (extraskeletal effect) has been proposed. Consistently, vitamin D deficiency is associated with an increased incidence of various diseases, including type 1 and type 2 diabetes, as reported by many observational studies. However, there has been no consensus on whether vitamin D deficiency is a causative factor in the incidence of diabetes mellitus. There have been no randomized controlled trials (RCTs) aimed at preventing the onset of type 1 diabetes with vitamin D intake. In addition, the results of RCTs evaluating the preventive effect of vitamin D supplementation on type 2 diabetes development have been inconsistent. The recent observational studies, randomized controlled trials, and meta-analyses are confirming that vitamin D or active vitamin D administration is effective in preventing the incident of type 1 and type 2 diabetes.

Vitamin D and Risk for Type 2 Diabetes in People With Prediabetes : A Systematic Review and Meta-analysis of Individual Participant Data From 3 Randomized Clinical Trials.

BACKGROUND: The role of vitamin D in people who are at risk for type 2 diabetes remains unclear. PURPOSE: To evaluate whether administration of vitamin D decreases risk for diabetes among people with prediabetes. DATA SOURCES: PubMed, Embase, and ClinicalTrials.gov from database inception through 9 December 2022. STUDY SELECTION: Eligible trials that were specifically designed and conducted to test the effects of oral vitamin D versus placebo on new-onset diabetes in adults with prediabetes. DATA EXTRACTION: The primary outcome was time to event for new-onset diabetes. Secondary outcomes were regression to normal glucose regulation and adverse events. Prespecified analyses (both unadjusted and adjusted for key baseline variables) were conducted according to the intention-to-treat principle. DATA SYNTHESIS: Three randomized trials were included, which tested cholecalciferol, 20 000 IU (500 mcg) weekly; cholecalciferol, 4000 IU (100 mcg) daily; or eldecalcitol, 0.75 mcg daily, versus matching placebos. Trials were at low risk of bias. Vitamin D reduced risk for diabetes by 15% (hazard ratio, 0.85 [95% CI, 0.75 to 0.96]) in adjusted analyses, with a 3-year absolute risk reduction of 3.3% (CI, 0.6% to 6.0%). The effect of vitamin D did not differ in prespecified subgroups. Among participants assigned to the vitamin D group who maintained an intratrial mean serum 25-hydroxyvitamin D level of at least 125 nmol/L (≥50 ng/mL) compared with 50 to 74 nmol/L (20 to 29 ng/mL) during follow-up, cholecalciferol reduced risk for diabetes by 76% (hazard ratio, 0.24 [CI, 0.16 to 0.36]), with a 3-year absolute risk reduction of 18.1% (CI, 11.7% to 24.6%). Vitamin D increased the likelihood of regression to normal glucose regulation by 30% (rate ratio, 1.30 [CI, 1.16 to 1.46]). There was no evidence of difference in the rate ratios for adverse events (kidney stones: 1.17 [CI, 0.69 to 1.99]; hypercalcemia: 2.34 [CI, 0.83 to 6.66]; hypercalciuria: 1.65 [CI, 0.83 to 3.28]; death: 0.85 [CI, 0.31 to 2.36]). LIMITATIONS: Studies of people with prediabetes do not apply to the general population. Trials may not have been powered for safety outcomes. CONCLUSION: In adults with prediabetes, vitamin D was effective in decreasing risk for diabetes. PRIMARY FUNDING SOURCE: None. (PROSPERO: CRD42020163522).

Atorvastatin, etidronate, or both in patients at high risk for atherosclerotic aortic plaques: a randomized, controlled trial.

BACKGROUND: Statins are not effective in reducing atherosclerotic plaques of the abdominal aorta, and accumulating evidence suggests that bisphosphonates have the potential to induce the regression of atherosclerotic plaques of the abdominal aorta. METHODS AND RESULTS: A prospective, randomized, open-label, blinded-end-point trial involving 108 participants with hypercholesterolemia was conducted. Participants received 20 mg atorvastatin daily, 400 mg etidronate daily, or both drugs daily. The primary end point was the percent change in maximal vessel wall thickness of atherosclerotic plaques in the thoracic and abdominal aortas as measured by magnetic resonance imaging after 12 months of treatment. In both the combination therapy and atorvastatin groups, maximal vessel wall thickness of the thoracic aorta was reduced by 13.8% (95% confidence interval, -16.4 to -11.3) and 12.3% (95% confidence interval, -14.9 to -9.7), respectively. These reduction rates were comparable between groups (P=0.61). Meanwhile, in the etidronate group, maximal vessel wall thickness of the thoracic aorta remained unchanged (2.2%; 95% confidence interval, -0.3 to 4.8). Conversely, maximal vessel wall thickness of the abdominal aorta was reduced more effectively in the combination therapy group (-11.4%) than in the atorvastatin group (-0.9%; P<0.001) and the etidronate group (5.5%; P=0.006). CONCLUSIONS: Atorvastatin plus etidronate combination therapy for 12 months significantly reduced both thoracic and abdominal aortic plaques, whereas atorvastatin monotherapy reduced only thoracic aortic plaques and etidronate monotherapy reduced only abdominal aortic plaques. The effectiveness of combination therapy in reducing atherosclerotic plaques in the abdominal aorta was significantly greater than for both atorvastatin and etidronate monotherapy. CLINICAL TRIAL REGISTRATION: URL: http://www.umin.ac.jp/ctr/. Unique identifier: UMIN 000002635.

Active vitamin D treatment in the prevention of sarcopenia in adults with prediabetes (DPVD ancillary study): a randomised controlled trial.

BACKGROUND: Observational studies show inverse associations between serum 25-hydroxyvitamin D concentrations and sarcopenia incidence; however, it remains unclear whether treatment with vitamin D prevents its development. We aimed to assess whether treatment with active vitamin D (eldecalcitol [0·75 µg per day]) can reduce the development of sarcopenia among adults with prediabetes. METHODS: This randomised, double-blind, placebo-controlled, multicenter trial as an ancillary study was conducted at 32 clinics and hospital sites in Japan. Participants were assigned (1:1) by using a central randomisation method in which a randomisation list was made for each hospital separately using a stratified permuted block procedure. The primary endpoint was sarcopenia incidence during 3 years in the intention-to-treat population defined as weak handgrip strength (<28 kg for men and <18 kg for women) and low appendicular skeletal muscle index (<7·0 kg/m2 for men and <5·7 kg/m2 for women in bioelectrical impedance analysis). Although the usual criterion of hypercalcaemia was 10·4 mg/dL (2·6 mmol/L) or higher, hypercalcaemia that was enough to discontinue the study was defined as 11·0 mg/dL or higher. This study is registered with the UMIN clinical trials registry, UMIN000005394. FINDINGS: A total of 1094 participants (548 in the eldecalcitol group and 546 in the placebo group; 44·2% [484 of 1094] women; mean age 60·8 [SD 9·2] years) were followed up for a median of 2·9 (IQR 2·8-3·0) years. Eldecalcitol treatment as compared with placebo showed statistically significant preventive effect on sarcopenia incidence (25 [4·6%] of 548 participants in the eldecalcitol group and 48 [8·8%] of 546 participants in the placebo group; hazard ratio 0·51; 95% CI 0·31 to 0·83; p=0·0065). The incidence of adverse events did not differ between the two groups. INTERPRETATION: We found that treatment with eldecalcitol has the potential to prevent the onset of sarcopenia among people with prediabetes via increasing skeletal muscle volume and strength, which might lead to a substantial risk reduction of falls. FUNDING: Kitakyushu Medical Association. TRANSLATION: For the Japanese translation of the abstract see Supplementary Materials section.

Usefulness of the SPACE pulse sequence at 1.5T MR cholangiography: comparison of image quality and image acquisition time with conventional 3D-TSE sequence.

PURPOSE: To prospectively evaluate the image quality and image acquisition time at 3D magnetic resonance cholangiopancreatography (MRCP) using sampling perfection with application optimized contrasts (SPACE) and conventional turbo-spin-echo (TSE) sequences. MATERIALS AND METHODS: We acquired navigator-triggered SPACE and conventional 3D-TSE MRCP images using the same parameters where possible for 30 patients and compared the image acquisition time, contrast, and contrast-to-noise ratio (CNR) of the common bile duct (CBD). Two radiologists performed qualitative analyses using a 4-point scale. RESULTS: Image acquisition time was 31% shorter with the SPACE than the conventional TSE sequence (248.9 ± 73.0 sec vs. 360.5 ± 99.9 sec, P < 0.01). The contrast and CNR was significantly higher with the SPACE technique than conventional TSE (39.4 ± 14.7 vs. 33.5 ± 14.2, P < 0.01 and 18.6 ± 7.8 vs. 15.5 ± 9.3, P = 0.03). All visual scores were higher for the SPACE than the conventional TSE sequence; there was a significant difference in motion artifacts and the depiction of the CBD and the left hepatic and main pancreatic duct (P < 0.05). CONCLUSION: On the 1.5T MR scanner, 3D-MRCP with the SPACE sequence significantly improved the contrast and CNR of CBD. In addition, it yielded images of better quality at 30% shorter acquisition time than constant refocusing pulse flip angle TSE.

Total colectomy for poorly controlled hypokalaemia due to Gitelman syndrome.

Gitelman syndrome (GS) is an autosomal recessive tubulopathy caused by dysfunction of the thiazide-sensitive sodium-chloride cotransporter, which leads to hypokalaemia, metabolic alkalosis, hypomagnesaemia and hypocalciuria. Patients with GS show varied clinical features due to hypokalaemia: tetany, muscle weakness, periodical paralysis and constipation, which is one of the most frequent ones. This paper presents the case of a woman in her 40s referred to our endocrinology department for severe hypokalaemia. After biochemical and genetic analyses, a diagnosis of GS was established. Concurrently, the patient suffered from refractory constipation due to hypokalaemia and underwent a total colectomy with ileorectal anastomosis, which cured both disorders without any medication for 3 years.

Effectiveness of Double-J Metallic Mesh Ureteral Stents for Malignant Ureteral Obstruction: A Retrospective Study.

BACKGROUND/AIM: Malignant ureteral obstruction is associated with high rates of failure with traditional ureteral stents. Double-J metallic mesh ureteral stent is one of the latest options for treating malignant ureteral obstruction. However, data regarding the efficacy of using this stent in this context are limited. Thus, we retrospectively investigated the efficacy of this stent. PATIENTS AND METHODS: We retrospectively analyzed the records of all patients who required double-J metallic mesh ureteral stent placement for malignant ureteral obstruction at Ishikawa Prefectural Central Hospital (Kanazawa, Japan) between October 2018 and April 2022. Primary stent patency was defined as complete or partial resolution of hydronephrosis as shown by imaging studies or successful removal of a preexisting nephrostomy tube. Stent failure was defined as unplanned stent exchange or nephrostomy tube placement for signs or symptoms of recurrent ureteral obstruction. A competing risk model was used to estimate the cumulative incidence of stent failure. RESULTS: Double-J metallic mesh ureteral stents were placed in 63 ureters of 44 patients (13 males, 31 females). The median age of patients was 67 years (range=37-92 years). There was no grade 3 or higher complications. The overall primary patency rate was 95% (60 ureters). Stent failure occurred in seven patients (11%) during follow-up. The cumulative incidence of stent failure at 12 months after placement was 17.3%. CONCLUSION: Double-J metallic mesh ureteral stent is a safe, simple, and promising treatment option for malignant ureteral obstruction.

Frequency of Adrenal Insufficiency in Patients With Hypoglycemia in an Emergency Department: A Cross-sectional Study.

Context: In most patients presenting with hypoglycemia in emergency departments, the etiology of hypoglycemia is identified. However, it cannot be determined in approximately 10% of cases. Objective: We aimed to identify the causes of unknown hypoglycemia, especially adrenal insufficiency. Methods: In this cross-sectional study, we evaluated the etiology of hypoglycemia among patients in our emergency department with hypoglycemia (plasma glucose level < 70 mg/dL (3.9 mmol/L)] between April 1, 2016 and March 31, 2021 using a rapid adrenocorticotropic hormone (ACTH) test. Results: There were 528 cases with hypoglycemia included [52.1% male; median age 62 years (range 19-92)]. The majority [389 (73.7%)] of patients were using antidiabetes drugs. Additionally, 33 (6.3%) consumed alcohol; 17 (3.2%) had malnutrition; 13 (2.5%), liver dysfunction; 12 (2.3%), severe infectious disease; 11 (2.1%), malignancy; 9 (1.7%), heart failure; 4 (0.8%), insulin autoimmune syndrome; 3 (0.6%), insulinoma; 2 (0.4%) were using hypoglycemia-relevant drugs; and 1 (0.2%) suffered from non-islet cell tumor. Rapid ACTH tests revealed adrenal insufficiency in 32 (6.1%). In those patients, serum sodium levels were lower (132 vs 139 mEq/L, P < 0.01), eosinophil counts were higher (14 vs 8%, P < 0.01), and systolic blood pressure was lower (120 vs 128 mmHg, P < 0.05) at baseline than in patients with the other etiologies. Conclusion: The frequency of adrenal insufficiency as a cause of hypoglycemia was much higher than what we anticipated. When protracted hypoglycemia of unknown etiology is recognized, we recommend that the patient is checked for adrenal function using a rapid ACTH test.

Effect of active vitamin D treatment on development of type 2 diabetes: DPVD randomised controlled trial in Japanese population.

OBJECTIVE: To assess whether eldecalcitol, an active vitamin D analogue2, can reduce the development of type 2 diabetes among adults with impaired glucose tolerance. DESIGN: Double blinded, multicentre, randomised, placebo controlled trial. SETTING: Three hospitals in Japan, between June 2013 and August 2019. PARTICIPANTS: People aged 30 years and older who had impaired glucose tolerance defined by using a 75 g oral glucose tolerance test and glycated haemoglobin level. INTERVENTIONS: Participants were randomised to receive active vitamin D (eldecalcitol 0.75 µg per day; n=630) or matching placebo (n=626) for three years. MAIN OUTCOMES: The primary endpoint was incidence of diabetes. Prespecified secondary endpoints were regression to normoglycaemia and incidence of type 2 diabetes after adjustment for confounding factors at baseline. In addition, bone densities and bone and glucose metabolism markers were assessed. RESULTS: Of the 1256 participants, 571 (45.5%) were women and 742 (59.1%) had a family history of type 2 diabetes. The mean age of participants was 61.3 years. The mean serum 25-hydroxyvitamin D concentration at baseline was 20.9 ng/mL (52.2 nmol/L); 548 (43.6%) participants had concentrations below 20 ng/mL (50 nmol/L). During a median follow-up of 2.9 years, 79 (12.5%) of 630 participants in the eldecalcitol group and 89 (14.2%) of 626 in the placebo group developed type 2 diabetes (hazard ratio 0.87, 95% confidence interval 0.67 to 1.17; P=0.39). Regression to normoglycaemia was achieved in 145 (23.0%) of 630 participants in the eldecalcitol group and 126 (20.1%) of 626 in the placebo group (hazard ratio 1.15, 0.93 to 1.41; P=0.21). After adjustment for confounding factors by multivariable fractional polynomial Cox regression analysis, eldecalcitol significantly lowered the development of diabetes (hazard ratio 0.69, 0.51 to 0.95; P=0.020). In addition, eldecalcitol showed its beneficial effect among the participants with the lower level of basal insulin secretion (hazard ratio 0.41, 0.23 to 0.71; P=0.001). During follow-up, bone mineral densities of the lumbar spine and femoral neck and serum osteocalcin concentrations significantly increased with eldecalcitol compared with placebo (all P<0.001). No significant difference in serious adverse events was observed. CONCLUSIONS: Although treatment with eldecalcitol did not significantly reduce the incidence of diabetes among people with pre-diabetes, the results suggested the potential for a beneficial effect of eldecalcitol on people with insufficient insulin secretion. TRIAL REGISTRATION: UMIN Clinical Trials Registry UMIN000010758.

Poor Prognosis With Intravesical Bacillus Calmette-Guérin History After Photodynamic Diagnosis-assisted Transurethral Resection Using 5-Aminolevulinic Acid.

BACKGROUND/AIM: Diagnostic efficacy and treatment outcome of orally administered 5 aminolevulinic acid (ALA) assessment for photodynamic diagnosis (PDD) in transurethral resection for non-muscle-invasive bladder cancer (NMIBC) in clinical practice. PATIENTS AND METHODS: A retrospective analysis was performed of 105 patients who underwent PDD transurethral resection using orally administered ALA and were pathologically diagnosed with Ta, T1, or Tis at the Ishikawa Prefectural Central Hospital from December 2018 to May 2022. RESULTS: Fluorescent light had a significantly higher sensitivity but a lower specificity in detecting carcinoma compared to white light (91.7% vs. 77.1%; p<0.05 and 43.0% vs. 85.2%; p<0.05, respectively), as well as in detecting carcinoma in situ lesions (80.4% vs. 28.6%; p<0.05 and 23.3% vs. 84.5%; p<0.05, respectively). The cumulative frequency of recurrence and progression 1 year after treatment were 26.3% and 12.3%, respectively. Multivariate analyses indicated that a Bacillus Calmette-Guérin (BCG) history instillation was an independent predictive factor for intravesical recurrence (hazard ratio=4.439; p=0.002) and disease progression (hazard ratio=8.534; p=0.005). The 1-year cumulative recurrence rates were 66.2% and 16.5%, respectively (p<0.001), and progression rates for patients with and without prior BCG intravesical instillation were 50.4% and 3.5%, respectively (p<0.001). CONCLUSION: Sufficient diagnostic accuracy and relatively good treatment outcome was shown in PDD-transurethral resection using ALA. However, prior BCG intravesical instillation for NMIBC patients was a poor prognostic factor of cancer recurrence and progression, and may be useful for clinicians in their postoperative follow-up.

E3710, a new proton pump inhibitor, with a long-lasting inhibitory effect on gastric acid secretion.

We have investigated the pharmacology of sodium (R)-2-[4-(2,2-dimethyl-1,3-dioxan-5-yl) methoxy-3,5-dimethylpyridin-2-yl]methylsulfinyl-1H-benzimidazol (E3710), a new proton pump inhibitor (PPI), and its effect on gastric acid secretion. E3710 irreversibly inhibited H(+),K(+)-ATPase activity in pig gastric vesicles with an acidic internal environment with an IC(50) of 0.28 microM. Administration of E3710 (0.1, 0.2, 0.4, and 0.8 mg/kg; n = 6) intraduodenally in a gastric fistula model in dogs inhibited histamine-stimulated gastric acid secretion at 0 to 2 and 24 to 26 h after administration with ED(50) values of 0.18 and 0.22 mg/kg, respectively. The inhibition by E3710 was 2.3 times more potent than that of another representative PPI, esomeprazole (0.2, 0.4, 0.8, and 1.6 mg/kg; n = 6) at 0 to 2 h after administration (ED(50) = 0.40 mg/kg) and 2.8 times more potent at 24 to 26 h (ED(50) = 0.71 mg/kg). In the gastric fistula dogs, the intragastric pH was >or=4 for 17% (n = 27) of a 24-h period with vehicle alone, but when E3710 was administered, at 0.2 (n = 4), 0.4 (n = 8), and 0.8 mg/kg (n = 5), the pH was >or=4 for 40, 79, and 88% of a day, respectively. The corresponding values for esomeprazole at 0.8 (n = 4) and 1.6 mg/kg (n = 8) were 55 and 59%, respectively. In a crossover study with vehicle, E3710 at 0.4 mg/kg and esomeprazole at 1.6 mg/kg (n = 6), E3710 increased the intragastric pH to >4 for 82% of a day compared with 61% of a day with esomeprazole. These results show that E3710 is a long-acting inhibitor of gastric acid secretion and a promising novel therapy for acid-related diseases, such as gastroesophageal reflux disease.

Vitamin D Supplementation for Prevention of Type 2 Diabetes Mellitus: To D or Not to D?

CONTEXT: Over the last decade, vitamin D has emerged as a risk determinant for type 2 diabetes and vitamin D supplementation has been hypothesized as a potential intervention to lower diabetes risk. Recently, several trials have reported on the effect of vitamin D supplementation on diabetes prevention in people with prediabetes. EVIDENCE ACQUISITION: A comprehensive literature review was performed using PubMed, Embase, and ClinicalTrials.gov to identify: (1) recent meta-analyses of longitudinal observational studies that report on the association between blood 25-hydroxyvitamin D (25[OH]D) level and incident diabetes, and (2) clinical trials of adults with prediabetes that have reported on the effect of vitamin D supplementation on incident diabetes. EVIDENCE SYNTHESIS: Longitudinal observational studies report highly consistent associations between higher blood 25(OH)D levels and a lower risk of incident diabetes in diverse populations, including populations with prediabetes. Trials in persons with prediabetes show risk reduction in incident diabetes with vitamin D supplementation. In the 3 large trials that were specifically designed and conducted for the prevention of diabetes, vitamin D supplementation, when compared with placebo, reduced the risk of developing diabetes by 10% to 13% in persons with prediabetes not selected for vitamin D deficiency. CONCLUSIONS: Results from recent trials are congruent with a large body of evidence from observational studies indicating that vitamin D has a role in modulating diabetes risk. Participant-level meta-analysis of the 3 largest trials should provide a more refined estimate of risk reduction and identify patient populations that are likely to benefit the most from vitamin D supplementation.

Calreticulin and integrin alpha dissociation induces anti-inflammatory programming in animal models of inflammatory bowel disease.

Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, is a chronic intestinal inflammatory condition initiated by integrins-mediated leukocyte adhesion to the activated colonic microvascular endothelium. Calreticulin (CRT), a calcium-binding chaperone, is known as a partner in the activation of integrin α subunits (ITGAs). The relationship between their interaction and the pathogenesis of IBD is largely unknown. Here we show that a small molecule, orally active ER-464195-01, inhibits the CRT binding to ITGAs, which suppresses the adhesiveness of both T cells and neutrophils. Transcriptome analysis on colon samples from dextran sodium sulfate-induced colitis mice reveals that the increased expression of pro-inflammatory genes is downregulated by ER-464195-01. Its prophylactic and therapeutic administration to IBD mouse models ameliorates the severity of their diseases. We propose that leukocytes infiltration via the binding of CRT to ITGAs is necessary for the onset and development of the colitis and the inhibition of this interaction may be a novel therapeutic strategy for the treatment of IBD.

Rapid detection of R90H mutations in the human urate transporter 1 gene.

BACKGROUND: Hypouricaemia is a relatively common disorder in the general population. Since the discovery of the human urate transporter 1 (hURAT1) gene, the number of patients diagnosed with renal hypouricaemia caused by hURAT1 gene mutation(s) has increased. A rapid method for detecting such a mutation(s) for diagnostic aid is described herein. METHODS: A rapid method for detecting G269A (R90H) mutations by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was developed. RESULTS: The patient had compound heterozygous mutations in the hURAT1 gene (R90H and W258X), but showed no clinical manifestations such as urolithiasis or exercise-induced acute renal failure. The G269A (R90H) mutation was detected by PCR-RFLP using the Notl restriction enzyme. CONCLUSIONS: PCR-RFLP is useful for detecting G269A (R90H) mutations in the hURAT1 gene.

Rationale and design of Diabetes Prevention with active Vitamin D (DPVD): a randomised, double-blind, placebo-controlled study.

INTRODUCTION: Recent research suggests that vitamin D deficiency may cause both bone diseases and a range of non-skeletal diseases. However, most of these data come from observational studies, and clinical trial data on the effects of vitamin D supplementation on individuals with pre-diabetes are scarce and inconsistent. The aim of the Diabetes Prevention with active Vitamin D (DPVD) study is to assess the effect of eldecalcitol, active vitamin D analogue, on the incidence of type 2 diabetes among individuals with pre-diabetes. METHODS AND ANALYSIS: DPVD is an ongoing, prospective, multicentre, randomised, double-blind and placebo-controlled outcome study in individuals with impaired glucose tolerance. Participants, men and women aged ≥30 years, will be randomised to receive eldecalcitol or placebo. They will also be given a brief (5-10 min long) talk about appropriate calorie intake from diet and exercise at each 12-week visit. The primary end point is the cumulative incidence of type 2 diabetes. Secondary endpoint is the number of participants who achieve normoglycaemia at 48, 96 and 144 weeks. Follow-up is estimated to span 144 weeks. ETHICS AND DISSEMINATION: All protocols and an informed consent form comply with the Ethics Guideline for Clinical Research (Japan Ministry of Health, Labour and Welfare). The study protocol has been approved by the Institutional Review Board at Kokura Medical Association and University of Occupational and Environmental Health. The study will be implemented in line with the CONSORT statement. TRIAL REGISTRATION NUMBER: UMIN000010758; Pre-results.

A Novel PHEX Mutation in Japanese Patients with X-Linked Hypophosphatemic Rickets.

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.