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Objective: To determine whether fibroblast growth factor 23 (FGF23) concentrations are altered in women with ovarian cancers in which FGF physiology is known to be abnormal.Patients and Methods: Between May 2002 and September 2003 at the Mayo Clinic in Rochester, Minn, plasma or serum FGF23 concentrations were measured in 39 healthy women and in 14 with benign ovarian tumors, 14 with early-stage ovarian cancer, and 13 with advanced-stage ovarian cancer. Immunohistochemistry using anti-human FGF23 antibodies was performed on tissue from benign masses and advanced-stage tumors.Results: Serum or plasma FGF23 concentrations were significantly higher in women with advanced-stage ovarian cancer compared with concentrations in women with early-stage ovarian cancer or benign disease or in healthy women. A significant positive correlation was seen between serum iFGF23 and cFGF23 concentrations and stage of disease. Serum iFGF23 and cFGF23 concentrations were positively correlated with serum phosphorus among women with ovarian cancer. No patients with elevated iFGF23 or cFGF23 concentrations had hypophosphatemia. Immunohistochemistry detected FGF23 tissue staining in malignant ovarian cancer cells.Conclusion: Serum or plasma FGF23 concentrations are elevated in patients with advanced-stage epithellal ovarian cancer without reductions in serum phosphate concentrations. The presence of elevated FGF23 concentrations in patients with an ovarian mass should suggest advanced-stage disease. [ABSTRACT FROM AUTHOR]

Objective: To determine whether fibroblast growth factor 23 (FGF23) contributes to the hypophosphatemia of primary hyperparathyroldism.Patients and Methods: Thirteen adult patients with primary hyperparathyroidism had serum collected before and after parathyroidectomy for analysis of inorganic phosphorus, calcium, 1alpha,25-dihydroxyvitamin D (1alpha,25[OH]2D), parathyroid hormone (PTH), FGF23, creatinine, and bone-specific alkaline phosphatase (BSAP). Patients were recruited between July 24, 2003, and February 11, 2004.Results: Before surgery, patients had elevated serum calcium and PTH concentrations. Serum phosphorus concentrations were in the low-normal range. The FGF23 concentrations were not elevated in patients with primary hyperparathyroidism compared with healthy controls. Within 24 hours of surgery, serum calcium, PTH, 1alpha,25(OH)2D, and BSAP concentrations were lower (P < .002 for all) and phosphorus concentrations were higher (P = .003) than in the preoperative state. The FGF23 concentrations were similar 1 day and 6 weeks after surgery. The FGF23 concentrations did not correlate with serum phosphorus, calcium, PTH, 1alpha,25(OH)2D, creatinine, or BSAP concentrations in the preoperative or postoperative state.Conclusion: Parathyroid hormone is the major regulator of serum phosphorus concentrations in patients with primary hyperparathyroidism. Fibroblast growth factor 23 does not appear to play a role in phosphorus homeostasis in patients with surgically treated primary hyperparathyroidism. [ABSTRACT FROM AUTHOR]

Background: Protein-truncating germline pathogenic variants in the N- and C-terminal exons (2, 9, and 10) of the MEN1 gene may be associated with aggressive pancreatic neuroendocrine tumors. However, the impact of these variants on parathyroid disease is poorly understood. We sought to investigate the effects of genotype and surgical approach on clinical phenotype and postoperative outcomes in patients with multiple endocrine neoplasia type 1 (MEN1)-related primary hyperparathyroidism., Methods: We identified patients with MEN1 evaluated at our institution from 1985 to 2020 and stratified them by genotype, (truncating variants in exons 2, 9, or 10, or other variants), and index surgical approach, (less-than-subtotal parathyroidectomy [

Background: In the United States, rare disease (RD) is defined as a condition that affects fewer than 200,000 individuals. Collectively, RD affects an estimated 30 million Americans. A significant portion of RD has an underlying genetic cause; however, this may go undiagnosed. To better serve these patients, the Mayo Clinic Program for Rare and Undiagnosed Diseases (PRaUD) was created under the auspices of the Center for Individualized Medicine (CIM) aiming to integrate genomics into subspecialty practice including targeted genetic testing, research, and education., Methods: Patients were identified by subspecialty healthcare providers from 11 clinical divisions/departments. Targeted multi-gene panels or custom exome/genome-based panels were utilized. To support the goals of PRaUD, a new clinical service model, the Genetic Testing and Counseling (GTAC) unit, was established to improve access and increase efficiency for genetic test facilitation. The GTAC unit includes genetic counselors, genetic counseling assistants, genetic nurses, and a medical geneticist. Patients receive abbreviated point-of-care genetic counseling and testing through a partnership with subspecialty providers., Results: Implementation of PRaUD began in 2018 and GTAC unit launched in 2020 to support program expansion. Currently, 29 RD clinical indications are included in 11 specialty divisions/departments with over 142 referring providers. To date, 1152 patients have been evaluated with an overall solved or likely solved rate of 17.5% and as high as 66.7% depending on the phenotype. Noteworthy, 42.7% of the solved or likely solved patients underwent changes in medical management and outcome based on genetic test results., Conclusion: Implementation of PRaUD and GTAC have enabled subspecialty practices advance expertise in RD where genetic counselors have not historically been embedded in practice. Democratizing access to genetic testing and counseling can broaden the reach of patients with RD and increase the diagnostic yield of such indications leading to better medical management as well as expanding research opportunities., (© 2023. The Author(s).)

Background: Primary Hyperparathyroidism (PHPT) is rare in pediatric patients. Data regarding surgical outcomes are scarce., Methods: Single-center retrospective review (1994-2020) of patients ≤21 years undergoing surgery for PHPT., Results: 66 patients were identified (61% female, 17 ± 3 years). 71% of patients were symptomatic at diagnosis. 32% of patients had known familial syndromes, most commonly MEN-1. 23% of patients without a known mutation had genetic testing, 22% positive. 56% of the total and 19% of the familial cohort underwent focused exploration. Single gland disease was found in 19% of familial vs 85% of sporadic cases, p < 0.00001. Persistence was 9%, all in the sporadic group, p = 0.11. Recurrence was 15%: 38% in the familial vs 2% in the sporadic groups, p=0.0004. Time to recurrence was 59 months (Q1-38, Q3-95), familial 61 vs 124 months sporadic, p=0.001., Conclusion: Pediatric PHPT is frequently sporadic, although 5% of apparent sporadic cases are secondary to syndromes. Familial cases have higher rates of recurrence, requiring closer follow-up., Competing Interests: Declaration of competing interest Authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Phosphate plays a critical and diverse role in human physiology. In addition to its importance in skeletal mineralization, it is essential for energy homeostasis, enzyme function, and cell membrane integrity. These diverse functions of phosphate provide an explanation for the range of symptoms and clinical manifestations observed in patients with both acute and chronic causes of hypophosphatemia. Normal phosphate homeostasis involves several major systems, including the gastrointestinal tract, bones, and kidneys. Phosphate balance is maintained directly and indirectly by 1α,25-dihydroxyvitamin D 3 , parathyroid hormone, and the osteocyte-derived phosphatonin fibroblast growth factor 23. This review discusses normal phosphate homeostasis, the clinical manifestations and causes of hypophosphatemia, and an approach to establish a diagnosis and appropriate management., (Copyright © 2022 AACE. Published by Elsevier Inc. All rights reserved.)

Congenital nephrotic syndrome (CNS) is a complex condition that requires multidisciplinary care. Hyperlipidemia is a characteristic feature with elevation of serum cholesterol and triglycerides. Little evidence is available to guide treatment of dyslipidemia in infants with CNS. We describe successful treatment of severe hypertriglyceridemia through dietary changes in a boy with CNS. A 9-day-old boy presented to the emergency department with lower extremity edema caused by deep venous thrombosis. Laboratory evaluation identified hypoalbuminemia, nephrotic-range proteinuria, and a pathogenic variant of the NPHS1 gene. The initial triglyceride concentration of 369 mg/dl increased to 3096 mg/dl by 5 weeks of age, when his diet consisted of breast milk. Refrigerated breast milk was skimmed by removing the top layer after allowing it to separate for 24 h. This process was repeated prior to use. Skimmed breast milk was supplemented with medium-chain triglyceride oil and an infant protein powder. After 2 days, the triglyceride concentration declined to 481 mg/dl and, by day 10, to 148 mg/dl. When breast milk supply decreased, a 1:1 ratio of skimmed maternal breast milk to an elemental, very low-fat formula was utilized. The triglyceride concentration remained below 400 mg/dl for the first year of life, except when skimmed breast milk was not available during hospitalization. Severe hypertriglyceridemia caused by CNS can present in the neonatal period and be difficult to manage. In our patient, skimmed maternal breast milk was successful in reducing the triglyceride concentration and should be considered a therapeutic option for children with hyperlipidemia caused by CNS., (© 2021 American Society for Parenteral and Enteral Nutrition.)

Rationale & Objective: Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare monogenic disorder caused by SLC34A3 pathogenic variants. HHRH is characterized by kidney phosphate wasting, hypophosphatemia, hypercalciuria, an elevated 1,25-dihydroxyvitamin D level, nephrocalcinosis, and urinary stone disease. Previously, we reported a 100% prevalence of kidney cysts in the related CYP24A1 deficiency. Thus, in the current study, we characterized cysts' presence in HHRH, another monogenic cause of hypercalciuria, nephrocalcinosis, and urinary stone disease., Study Design: Case series., Setting & Participants: Medical records from the Mayo Clinic and the Rare Kidney Stone Consortium monogenic stone disease database were queried for patients with a genetically confirmed HHRH diagnosis. The number, sizes, and locations of kidney cysts in each patient were recorded., Results: Twelve patients with SLC34A3 pathogenic variants were identified (7 monoallelic, 5 biallelic). Of these, 5 (42%) were males, and the median (Q1, Q3) ages were 16 years (13, 35 years) at clinical presentation and 42 years (20, 57 years) at genetic confirmation. Kidney cysts were present in 9 of 12 (75%) patients, and the median (Q1, Q3) age at first cyst detection was 41 years (13, 50 years). The median number of cysts per patient was 2.0 (0.5, 3.5). Fifty percent of adult patients had a cyst number that exceeded the 97.5th percentile of an age- and sex-matched control population. All children had at least 2 or more total cysts. None had a family history of cystic kidney disease., Limitations: Retrospective study, possible selection bias, single-center experience., Conclusions: A strong association between HHRH and kidney cysts was observed. Similarities in the biochemical profiles of HHRH and CYP24A1 deficiency suggest elevated active vitamin D and hypercalciuria may be potential cystogenic factors. Further studies are needed to understand how genetic changes in SLC34A3 favor cyst formation., (© 2022 The Authors.)

Context: CYP24A1 encodes 24-hydroxylase, which converts 25(OH)D3 and 1,25(OH) 2 D 3 to inactive metabolites. Loss-of-function variants in CYP24A1 are associated with 24-hydroxylase deficiency (24HD), characterized by hypercalcemia, nephrolithiasis, and nephrocalcinosis. We retrospectively reviewed laboratory, imaging, and clinical characteristics of patients with suspected or confirmed 24HD and patients with other vitamin D-mediated hypercalcemia disorders: sarcoidosis, lymphoma, and exogenous vitamin D toxicity (EVT)., Objective: To identify features that differentiate 24HD from other vitamin D-mediated hypercalcemia disorders., Methods: Patients seen at the Mayo Clinic (Rochester, MN) from January 1, 2008, to 31 December, 2016, with the following criteria were retrospectively identified: serum calcium ≥9.6 mg/dL, parathyroid hormone <30 pg/mL, and 1,25(OH) 2 D 3 >40 pg/mL. Patients were considered to have 24HD if they had (1) confirmed CYP24A1 gene variant or (2) 25(OH)D 3 :24,25(OH) 2 D ratio ≥50. Patients with sarcoidosis, lymphoma, and EVT were also identified. Groups were compared using the Fisher exact test (categorical variables) or the Wilcoxon rank sum test (continuous variables)., Results: We identified 9 patients with 24HD and 28 with other vitamin D-mediated disorders. Patients with 24HD were younger at symptom onset (median 14 vs 63 years; P = .001) and had positive family history (88.9% vs 20.8%; P < .001), nephrocalcinosis (88.9% vs 6.3%; P < .001), lower lumbar spine Z-scores (median -0.50 vs 1.20; P = .01), higher peak serum phosphorus (% of peak reference range, median 107 vs 84; P = .01), and higher urinary calcium:creatinine ratios (median 0.24 vs 0.17; P = .047)., Conclusion: Patients with 24HD had clinical and laboratory findings that differed from other vitamin D-mediated hypercalcemia disorders. 24HD should be suspected in patients with hypercalcemia who present at younger age, have positive family history, and have nephrocalcinosis., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Context: Hypoparathyroidism is characterized by low serum calcium, increased serum phosphorus, and inappropriately low or decreased serum parathyroid hormone, which may be associated with soft tissue calcification in the basal ganglia of the brain., Objective: To assess the prevalence and factors involved in the pathophysiology of basal ganglia calcification (BGC) in the brain in chronic hypoparathyroidism and to evaluate proposed pathophysiologic mechanisms., Design: Case-control study with retrospective review of medical records over 20 years., Setting: Single academic medical center., Patients: 142 patients with chronic hypoparathyroidism and computed tomography (CT) head scans followed between January 1, 2000 and July 9, 2020, and 426 age- and sex-matched controls with CT head scans over the same interval., Interventions: None., Main Outcome Measures: Demographic, biochemical, and CT head imaging findings, with semiquantitative assessment of volumetric BGC., Results: The study found that 25.4% of 142 patients followed for a median of 17 years after diagnosis of chronic hypoparathyroidism had BGC, which developed at a younger age than in controls. BGC was 5.1-fold more common in nonsurgical patients and less common in postsurgical patients. Low serum calcium and low calcium/phosphate ratio correlated with BGC. Neither serum phosphorus nor calcium × phosphate product predicted BGC. Lower serum calcium was associated with greater volume of BGC. The extent of BGC varied widely, with nonsurgical patients generally having a greater volume and distribution of calcification., Conclusions: BGC is associated with low serum calcium and low serum calcium/phosphate ratio, which may be related to severity of the disease, its etiology, or duration of treatment., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Osteogenesis imperfecta (OI) is characterized by fractures and progressive bone deformities. Fracture rates peak during the toddler and adolescent years and decline during adulthood but do not stop entirely. We describe a kindred, the affected members of which were the mother and two sons, who presented with an apparently unique phenotype of OI. Our patients demonstrated a pattern of prenatal bone deformities followed by multiple, nontraumatic long bone fractures within the first two years of life and then an absence of nontraumatic fractures thereafter. No extra-skeletal manifestations have been noted to date. The mother did not receive bisphosphonate therapy but had no nontraumatic fractures after the age of five months. Intravenous bisphosphonate therapy was started for both sons within two months of birth, with the most recent infusions at age 18 months and 28 months in Patients 2 and 3, respectively. Two patients harbored a variant of uncertain significance in the COL1A1 gene. This heterozygous variant, c.3548C>T; p.(Pro1183Leu), is listed in the OI Variant Database as affecting only one other individual with osteopenia. We describe three family members with a unique presenting phenotype of OI, characterized by cessation of nontraumatic fractures after the first two years of life.

Introduction: Loss-of-function variants in the CYP24A1 gene cause a rare hereditary disease characterized by reduced 24-hydroxylase enzyme activity, increased serum 1,25-dihydroxycholecalciferol levels, hypercalcemia, hypercalciuria, and nephrocalcinosis and/or nephrolithiasis. Kidney cysts in patients with CYP24A1 deficiency were first reported in a single case study from our center. However, a possible association between CYP24A1 deficiency and kidney cysts has not been described., Methods: Retrospective analysis of patients with confirmed or suspected CYP24A1 deficiency and available kidney imaging., Results: Among 16 patients with confirmed pathogenic variants, 38% were male and 31% were children, the median age at genetic confirmation was 38 years (range 1-66), and none had a family history of cystic kidney disease. Medullary and/or corticomedullary junction cysts were present in all cases. The median age at first detected cyst was 37 years (range 3-60). The mean and median number of cysts per patient were 5.3 and 2.5 (range 1-37), respectively. Four of 5 further patients with suspected but unconfirmed pathogenic variants had cysts. The number of cysts ≥5 mm in size was above the 97.5th percentile of an age- and sex-matched control population in 55% and 67% of patients with confirmed and suspected pathogenic variants, respectively. At least 1 cyst (≥5 mm in size) was found in 80% of children with confirmed CYP24A1 deficiency., Conclusions: These observations strongly suggest an association between CYP24A1 deficiency and kidney cysts. Further studies are needed to evaluate the role of CYP24A1, vitamin D metabolism, and/or hypercalciuria in cyst formation, and whether cysts exacerbate chronic kidney disease or modify nephrocalcinosis and stone risk., (© 2021 International Society of Nephrology. Published by Elsevier Inc.)

Background: (+)-Epicatechin (EPI) induces mitochondrial biogenesis and antioxidant metabolism in muscle fibers and neurons. We aimed to evaluate safety and efficacy of (+)-EPI in pediatric subjects with Friedreich's ataxia (FRDA)., Methods: This was a phase II, open-label, baseline-controlled single-center trial including 10 participants ages 10 to 22 with confirmed FA diagnosis. (+)-EPI was administered orally at 75 mg/d for 24 weeks, with escalation to 150 mg/d at 12 weeks for subjects not showing improvement of neuromuscular, neurological or cardiac endpoints. Neurological endpoints were change from baseline in Friedreich's Ataxia Rating Scale (FARS) and 8-m timed walk. Cardiac endpoints were changes from baseline in left ventricular (LV) structure and function by cardiac magnetic resonance imaging (MRI) and echocardiogram, changes in cardiac electrophysiology, and changes in biomarkers for heart failure and hypertrophy., Results: Mean FARS/modified (m)FARS scores showed nonstatistically significant improvement by both group and individual analysis. FARS/mFARS scores improved in 5/9 subjects (56%), 8-m walk in 3/9 (33%), 9-peg hole test in 6/10 (60%). LV mass index by cardiac MRI was significantly reduced at 12 weeks (P = .045), and was improved in 7/10 (70%) subjects at 24 weeks. Mean LV ejection fraction was increased at 24 weeks (P = .008) compared to baseline. Mean maximal septal thickness by echocardiography was increased at 24 weeks (P = .031). There were no serious adverse events., Conclusion: (+)-EPI was well tolerated over 24 weeks at up to 150 mg/d. Improvement was observed in cardiac structure and function in subset of subjects with FRDA without statistically significant improvement in primary neurological outcomes., Synopsis: A (+)-epicatechin showed improvement of cardiac function, nonsignificant reduction of FARS/mFARS scores, and sustained significant upregulation of muscle-regeneration biomarker follistatin., (© 2020 SSIEM.)

Background The objective of this study was to evaluate the age at onset and frequency of individual pituitary hormone deficiencies (PHDs) in optic nerve hypoplasia (ONH). Methods We performed a retrospective chart review of patients ≤21 years of age evaluated between 1996 and 2014. Patients were included if they had: (1) ONH diagnosed by an ophthalmologist and/or magnetic resonance imaging (MRI), (2) documentation of pituitary hormone function on at least two separate occasions and (3) at least one PHD documented or a midline abnormality of the brain on MRI. Results Thirty-two patients (18 females, 14 males) were included (median age, 8 years [range, 1.1-21.0 years]). All patients had ONH (bilateral, n = 31; unilateral, n = 1) and at least one midline abnormality of the brain. At least one PHD was present in 75% of patients (n = 24). The remaining 25% of patients (n = 8) did not develop any PHD at least until the last follow-up (<2-8.6 years of follow-up), despite the presence of ONH and a midline abnormality of the brain. The median age (years) at diagnosis of antidiuretic hormone (ADH), thyroid-stimulating hormone (TSH), adrenocorticotropic hormone (ACTH) and growth hormone (GH) deficiencies was 0.5, 0.6, 0.7 and 1.6, respectively. Twenty-three percent of all PHDs were identified during the neonatal period, 56% by 12 months and 72% by 36 months of age. The latest age at diagnosis of GH, ACTH and TSH deficiencies was 9.6, 9.9 and 12.6 years, respectively. Conclusions The majority of the PHDs in ONH develop within the first 3 years of life. We propose evaluation for endocrinopathies at the time of diagnosis of ONH, with repeat assessment for new deficiencies every 3-4 months until age 3 years and at least semi-annually until growth and puberty are complete.

The Rickets Severity Score (RSS) was used to evaluate X-linked hypophosphatemic rickets (XLH), a genetic disorder mediated by increased circulating FGF23. The reliability of the RSS was assessed using data from a randomized, phase 2 clinical trial that evaluated the effects of burosumab, a fully human anti-FGF23 monoclonal antibody, in 52 children with XLH ages 5 to 12 years. Bilateral knee and wrist radiographs were obtained at baseline, week 40, and week 64. We evaluated the relationships of the RSS to the Radiographic Global Impression of Change (RGI-C), serum alkaline phosphatase (ALP), height Z-score, 6-minute walk test (6MWT) percent predicted, and the Pediatric Orthopedic Society of North America Pediatric Outcomes Data Collection Instrument (POSNA-PODCI). The RSS showed moderate-to-substantial inter-rater reliability (weighted kappa, 0.45-0.65; Pearson correlation coefficient (r), 0.83-0.89) and substantial intra-rater reliability (weighted Kappa, 0.66; r = 0.91). Baseline RSS correlated with serum ALP (r = 0.47). Baseline RSS identified two subgroups (higher [RSS ≥1.5] and lower RSS [RSS <1.5]) that discriminated between subjects with greater and lesser rachitic disease. Higher RSS was associated with more severe clinical features, including impaired growth (Z-score, -2.12 vs -1.44) and walking ability (6MWT percent predicted, 77% vs 86%), more severe self-reported pain (29.9 [more severe] vs 45.3 [less severe]) and less physical function (29.6 [more severe] vs 40.9 [less severe]). During burosumab treatment, greater reductions in RSS corresponded to higher RGI-C global scores (r = -0.65). Improvements in RSS correlated with decreased serum ALP (r = 0.47). These results show the reliability of the RSS in XLH, and demonstrate that higher RSS values are associated with greater biochemical, clinical, and functional impairments in children with XLH., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Rationale, Aims, and Objectives: Waist circumference (WC) and waist-to-height ratio (WHtR) are superior surrogate markers of central obesity than body mass index. However, WC is not measured routinely in paediatric clinics. The objective of this study was to implement measurement of WC during routine assessment of children in an ambulatory outpatient clinic setting and subsequent dissemination of cardiometabolic risk counselling in children with central obesity (defined as WHtR ≥0.5)., Method: Prospective cohort of patients aged 6 to 20 years. Study period was divided into three phases: baseline (3 months), process improvement (2 months), and implementation (6 months). Define-Measure-Analyse-Improve-Control (DMAIC) strategy was applied. Measurement of WC was implemented as a component of the physical examination in patients. Outcome measures were (1) improvement in frequency of WC measurement and (2) utilization of WHtR in cardiometabolic risk counselling., Results: Waist circumference was not measured in any patient during baseline phase (n = 551). During process improvement phase, of the total 347 patients, WC was measured in 35% vs target of 30%. In the implementation phase, WC was measured in 37% patients (365 out of 964). Of these 365 patients, 175 (48%) had elevated WHtR, and 73% of them (n = 128) were counselled about their increased cardiometabolic risk., Conclusions: Application of an evidence-based DMAIC protocol led to significant improvement in assessment for central obesity in an ambulatory clinic practice and appropriate counselling regarding cardiometabolic risk reduction in children and adolescents with central obesity over an 8-month period. Meticulous planning and execution, frequent reinforcement, and integrating feedback from the involved multi-disciplinary team were important factors in successful implementation of this quality improvement project., (© 2018 John Wiley & Sons, Ltd.)

Tumor-induced osteomalacia (TIO), also known as "oncogenic osteomalacia", is a rare cause of osteomalacia. TIO often has an insidious onset characterized clinically by progressive muscle weakness and bone pain with fractures. The hallmark biochemical finding is a persistent low serum phosphorus concentration due to renal phosphate wasting. The vast majority of cases of TIO result from production of the phosphaturic hormone fibroblast growth factor 23 (FGF23) by a histologically distinctive mesenchymal tumor, termed "phosphaturic mesenchymal tumor" (PMT). Circulating FGF23 induces internalization of renal sodium/phosphate co-transporters resulting in reduced proximal tubular phosphate reabsorption. FGF23 also inhibits production of 1α,25-dihydroxyvitamin D which is inappropriately low or normal in the context of hypophosphatemia. Diagnosis is often delayed owing to the rarity of the condition and an underappreciation for the role of phosphorus as a cause for the constellation of symptoms. Primary treatment for TIO is identification of the offending tumor and surgical removal. However, these tumors are notoriously difficult to find, precluding the opportunity for a curative surgery in many. In such cases, phosphate and calcitriol therapy is used to improve symptoms and heal the osteomalacia. Recently, molecular genetic studies have shown recurrent genetic events in PMT, including the novel fusions FN1-FGFR1 and less commonly FN1-FGF1. These fusion events are hypothesized to result in autocrine/paracrine signaling loops within the tumor, spurring tumorigenesis. This review will cover the clinical features, imaging characteristics, pathologic features, molecular genetic aspects, and therapy of PMT, with a brief discussion of other neoplasms that may cause TIO.

Background: There is a lack of consensus on the cardiometabolic consequences of mild subclinical hypothyroidism (SCH) among children. The objective of the current study was to compare lipid profiles in children with mild SCH with those of euthyroid children., Study Design: Retrospective medical record review., Patients: Children (ages 2-18 years) who had undergone simultaneous measurement of TSH, free thyroxine (T4) and lipids. Lipids in children with mild SCH (TSH 5-<10 mIU/L and normal free T4, n = 228) were compared with those in euthyroid children (n = 1215)., Results: TSH level was positively associated with total cholesterol and nonhigh density lipoprotein (non-HDL) cholesterol [β 0.05(0.03-0.08), P < .0001 and β 0.05(0.03-0.08), P < .0001, respectively]. Total cholesterol was significantly higher in children and adolescents with mild SCH compared with euthyroid children (4.43 ± 1.14 mmol/L vs 4.2 ± 0.85 mmol/L, P = .0005). Similarly, non-HDL cholesterol level was also higher in children with mild SCH relative to euthyroid children (3.08 ± 1.14 mmol/L vs 2.91 ± 0.8 mmol/L, P = .001). The adjusted odds ratio of having elevated total cholesterol and elevated non-HDL cholesterol was greater in children with mild SCH compared with euthyroid children (OR 1.88, 95% CI; 1.28-2.73; P = .001 and 1.72, 95% CI 1.2-2.5; P = .003, respectively). The presence of thyroid autoimmunity was not associated with higher rates of dyslipidaemia., Conclusions: Mild SCH in children and adolescents was associated with higher rates of elevated total cholesterol and elevated non-HDL cholesterol. Randomized placebo controlled studies are warranted to determine if treatment of mild SCH in children leads to improvement in lipid profile., (© 2018 John Wiley & Sons Ltd.)

Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Previous studies suggest normal mineral status in children receiving elemental formula. However, a recent multicenter survey described 51 children who developed hypophosphatemia and bone disease while receiving elemental formula. Our aim is to determine the prevalence of metabolic bone disease in children receiving extensively hydrolyzed or amino acid-based formula., Methods: We established a retrospective cohort using an institutional database of tube-fed children. We defined a "confirmed case" as a child with biochemical and radiographic evidence of bone disease (rickets and/or low-trauma fractures). We defined a "suspected case" as a child who had biochemical evidence and/or radiographic evidence of bone disease but with incomplete data during the review period., Results: A total of 102 tube-fed children receiving elemental or semi-elemental formula were identified. The four elemental and semi-elemental formulas evaluated were Neocate®, EleCare®, Pregestimil®, and Alimentum®. Not all children had complete monitoring data performed during the review period. Of the children receiving Neocate who had monitoring data (46%), 23% developed hypophosphatemia and radiographic abnormalities (fractures or rickets), which resolved with phosphorus supplementation and/or change in the formula brand., Conclusions: We estimate that at least 11% and up to 23% of all tube-fed children receiving Neocate develop metabolic bone disease. Based upon the estimated prevalence, we recommend cautious use of this formula with monitoring for evolving bone disease in this population., (© 2018 S. Karger AG, Basel.)

Unlabelled: Mutations of the CYP24A1 gene can result in hypercalcemia, hyerpercalciuria, and nephrolithiasis, but disease severity is variable. Clinical and biochemical phenotypes were correlated with gene sequence information in a family with two CYP24A1 mutations. A gene dose effect was apparent with monoallelic mutations demonstrating milder disease manifestations than biallelic mutations., Introduction: The objective was to examine the spectrum of clinical and biochemical phenotypes in a family with monoallelic and biallelic mutations of CYP24A1 after identification of the proband with two mutations of the CYP24A1 gene: (A) p.R396W and (B) E143del-Het., Methods: Clinical and biochemical phenotypes were correlated with CYP24A1 sequence information in the proband and four siblings, a daughter, and two nieces of the proband. The subjects' medical histories were evaluated, and measurement of serum minerals, vitamin D metabolites, PTH, bone turnover markers, and urinary calcium and sequencing of the CYP24A1 gene were performed., Results: The proband had nephrolithiasis, osteopenia, hypercalcemia, hypercalciuria, elevated serum 1,25(OH)2D, undetectable 24,25(OH)2D, and inappropriately low PTH concentrations. Two subjects with biallelic (A/B) mutations had nephrolithiasis, marked hypercalciuria (583 ± 127 mg/24 h, mean ± SD), compared with five subjects with monoallelic mutations (A or B) with a urine calcium of 265 ± 85 mg/24 h. Two subjects with monoallelic mutations had nephrolithiasis and one had non-PTH dependent hypercalcemia. Five subjects had high 1,25(OH)2D measurements, including three with monoallelic mutations. The 25OHD/24,25(OH)2D ratio, in subjects with biallelic mutations was 291 versus 19.8 in the subjects with monoallelic mutations., Conclusions: In this family, adults with CYP24A1 mutations a gene dose effect is apparent: subjects with biallelic, compound heterozygous mutations (A/B) have a more severe clinical and biochemical phenotype, whereas, subjects with monoallelic mutations demonstrate milder disease manifestations which are not easily characterized through biochemical assessment.

Hypercalcemia occurs in up to 4% of the population in association with malignancy, primary hyperparathyroidism, ingestion of excessive calcium and/or vitamin D, ectopic production of 1,25-dihydroxyvitamin D [1,25(OH) 2 D], and impaired degradation of 1,25(OH) 2 D. The ingestion of excessive amounts of vitamin D 3 (or vitamin D 2 ) results in hypercalcemia and hypercalciuria due to the formation of supraphysiological amounts of 25-hydroxyvitamin D [25(OH)D] that bind to the vitamin D receptor, albeit with lower affinity than the active form of the vitamin, 1,25(OH) 2 D, and the formation of 5,6-trans 25(OH)D, which binds to the vitamin D receptor more tightly than 25(OH)D. In patients with granulomatous disease such as sarcoidosis or tuberculosis and tumors such as lymphomas, hypercalcemia occurs as a result of the activity of ectopic 25(OH)D-1-hydroxylase (CYP27B1) expressed in macrophages or tumor cells and the formation of excessive amounts of 1,25(OH) 2 D. Recent work has identified a novel cause of non-PTH-mediated hypercalcemia that occurs when the degradation of 1,25(OH) 2 D is impaired as a result of mutations of the 1,25(OH) 2 D-24-hydroxylase cytochrome P450 (CYP24A1). Patients with biallelic and, in some instances, monoallelic mutations of the CYP24A1 gene have elevated serum calcium concentrations associated with elevated serum 1,25(OH) 2 D, suppressed PTH concentrations, hypercalciuria, nephrocalcinosis, nephrolithiasis, and on occasion, reduced bone density. Of interest, first-time calcium renal stone formers have elevated 1,25(OH) 2 D and evidence of impaired 24-hydroxylase-mediated 1,25(OH) 2 D degradation. We will describe the biochemical processes associated with the synthesis and degradation of various vitamin D metabolites, the clinical features of the vitamin D-mediated hypercalcemia, their biochemical diagnosis, and treatment.

Introduction: Zoledronic acid is an intravenous bisphosphonate used to increase bone mineral density and reduce the risk of fractures. Its safety profile compares well with pamidronate in pediatric patients. We describe an acute, severe, life-threatening, inflammatory reaction in a child., Methods: A 7-year-old boy with complex medical problems and chronic ventilator requirements was admitted to the pediatric intensive care unit (due to ventilator needs) for zoledronic acid infusion and subsequent monitoring. His history was significant for osteoporosis secondary to immobilization with multiple fractures since 2 years of age, hypoxic-ischemic encephalopathy, quadriplegic cerebral palsy, seizure disorder, ventilator dependence, and pulmonary hypertension. He had previously been treated with four cycles of pamidronate without adverse events. He received 0.013 mg/kg of zoledronic acid infused over 30 minutes. Beginning 3 hours after completion of the infusion, he developed progressive tachycardia, fever, hypotension requiring vasopressor infusion, and increasing oxygen requirements. Laboratory studies revealed leukopenia, thrombocytopenia, elevated C-reactive protein, abnormal coagulation profile, metabolic acidosis, and negative cultures. The following day, he developed moderate acute respiratory distress syndrome and pulmonary hemorrhage requiring higher ventilatory settings, and subsequently diarrhea and abdominal distension. Initial clinical resolution was noted from the third day onward, and he was discharged on the sixth day after zoledronate administration., Results: Our pediatric patient demonstrated an acute, severe, life-threatening reaction to zoledronic acid requiring intensive cardiorespiratory support without an underlying pre-existing inflammatory disorder., Conclusion: Our case highlights the importance of careful monitoring of children following zoledronic acid therapy. We recommend inpatient observation after an initial infusion of zoledronic acid in medically complex children. Children and their parents should be thoroughly counseled on the potential risks of bisphosphonate treatment, which can sometimes be severe and life threatening.

Context: Surgically managed endocrinopathies are rare in children. Most surgeons have limited experience in this field. Herein we report our operative experience with pediatric patients, performed over two decades by high-volume endocrine surgeons., Setting: The study was conducted at the Mayo Clinic (a tertiary referral center)., Patients: Patients were <19 years old and underwent an endocrine operation (1993-2012)., Main Outcome Measures: Demographics, surgical procedure, diagnoses, morbidity, and mortality were retrospectively reviewed., Results: A total of 241 primary cases included 177 thyroid procedures, 13 neck dissections, 24 parathyroidectomies, 14 adrenalectomies, 7 paragangliomas, and 6 pancreatic procedures. Average age of patients was 14.2 years. There were 133 total thyroidectomies and 40 hemithyroidectomies. Fifty-three cases underwent a central or lateral neck dissection. Six-month follow-up was available for 98 total thyroidectomy patients. There were four cases of permanent hypoparathyroidism (4%) and no permanent recurrent laryngeal nerve (RLN) paralyses. Sequelae of neck dissections included temporary RLN neurapraxia and Horner's syndrome. Parathyroidectomy was performed on 24 patients: 20 with primary hyperparathyroidism (HPT), three with tertiary HPT, and one with familial hypocalciuric hypocalcemia. Three patients (16%) had recurrent HPT, all with multiglandular disease. One patient had temporary RLN neurapraxia. We performed seven bilateral and seven unilateral adrenalectomies; eight were laparoscopic. Indications included pheochromocytoma, Cushing's syndrome, adrenocortical carcinoma, congenital adrenal hyperplasia, and ganglioneuroma. One death was due to adrenocortical carcinoma. Five paraganglioma patients had succinate dehydrogenase subunit B mutations, and one recurred. Six patients with insulinoma underwent enucleation (n = 5) or distal pancreatectomy (n = 1). A single postoperative abscess was managed nonoperatively., Conclusion: Pediatric endocrine procedures are uncommon but can be safely performed with complication rates comparable to those of the adult population. It is imperative that these operations be performed by high-volume surgeons.

As female athletic participation has increased, the positive effects of exercise on health have become evident. However, with this growth in sports activity, a set of health problems unique to the female athlete has emerged. The female athlete triad as first described in 1992 by the American College of Sports Medicine consisted of disordered eating, amenorrhea, and osteoporosis; the definition was updated in 2007 to include a spectrum of dysfunction related to energy availability, menstrual function, and bone mineral density. For this review, a comprehensive search of databases-MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, and Scopus, from earliest inclusive dates to January 2013-was conducted by an experienced librarian with input from the authors. Controlled vocabulary supplemented with keywords such as female athlete triad, amenorrhea, oligomenorrhea, fracture, osteopenia, osteoporosis, bone disease, anorexia, bulimia, disordered eating, low energy availability was used to search for articles on female athlete triad. Articles addressing the prevalence, screening, and management of the female athlete triad were selected for inclusion in the review. This article reviews the current definitions of the triad components, epidemiology, pathophysiology, and recommended screening and management guidelines. The lack of efficacy of current screening of athletes is highlighted. Low energy availablity, from either dietary restriction or increased expenditure, plays a pivotal role in development of the triad. Athletes involved in "lean sports" (those that emphasize weight categories or aesthetics, such as ballet, gymnastics, or endurance running) are at highest risk. Treatment is centered on restoring energy availability to reverse adverse changes in the metabolic milieu. Prevention and early recognition of triad disorders are crucial to ensure timely intervention. Caregivers and physicians of female athletes must remain vigilant in education, recognition, and treatment of athletes at risk., (Copyright © 2013 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

The presentation of hypophosphatasia (HPP) diagnosed in adults demonstrates a wide range of clinical manifestations, many of which are nonspecific. We sought to assess clinical characteristics of adult HPP by evaluation of Mayo Clinic Rochester adults diagnosed with HPP from 1976 through 2008. Subjects were identified by diagnostic code or medical records. Inclusion criteria were age ≥18 years at diagnosis; low serum alkaline phosphatase (AP) without bisphosphonate therapy; and one additional element: elevated pyridoxal 5'-phosphate (PLP) or urine phosphoethanolamine (PEA), evidence of osteomalacia, or family history. We were unable to distinguish manifesting carriers from silent unaffected carriers due to lack of a prospective standardized clinical evaluation and the absence of genetic testing. HPP was diagnosed in 22 unrelated adults (median age 49 years; 68% women). Most patients (68%) were symptomatic at presentation with features including musculoskeletal pain (41%) or incident fracture (18%). A history of fracture was present in 54%: hip/femoral neck (23%), feet (23%, all women), wrist (18%), and spine (9%, all men). Nine patients (36%) had multiple fractures while 4 (all women) had subtrochanteric femur fractures. Radiographic chondrocalcinosis (27%) and documented pyrophosphate arthropathy (14%) were only observed in women. Median minimum serum AP was 43% below the lower normal limit. Urine PEA was elevated in 15/16 patients (94%). PLP median was 68 μg/L (normal, 5-50 μg/L) and all (n=8) were above normal. Symptomatic subjects had more fractures and chondrocalcinosis, lower median minimum AP and PLP and higher median PEA levels. Clinical features more common in fracture patients included symptoms at presentation, history of childhood rickets, dental abnormalities, lower median minimum AP and PLP, and higher median urine PEA. Four subjects had iliac crest bone biopsies, with 2/4 specimens consistent with osteomalacia. These results suggest that adult HPP demonstrates a wide spectrum of clinical manifestations including musculoskeletal pain, fractures, chondrocalcinosis and dental anomalies with some overlap in laboratory characteristics in relationship to disease severity. In addition to genetic and environmental factors, gender may influence the clinical expression of HPP., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: To determine temporal trends in incidence and risk factors of nutritional rickets in a community-based population., Patients and Methods: Rochester Epidemiology Project data were used to identify all children (aged <18 years) residing in Olmsted County, Minnesota, between January 1, 1970, and December 31, 2009, with diagnostic codes corresponding to rickets, vitamin D deficiency, hypovitaminosis D, rachitis, osteomalacia, genu varum, genu valgum, craniotabes, hypocalcemia, hypocalcemic seizure, and tetany. Record abstraction was performed to select individuals with radiographic confirmation of rickets. Age- and sex-matched controls were identified for the evaluation of risk factors. The main outcome measure was radiographic evidence of rickets without identifiable inherited, genetic, or nonnutritional causes. Incidence rates were calculated using Rochester Epidemiology Project census data., Results: Of 768 children with eligible diagnostic codes, 23 had radiographic evidence of rickets; of these, 17 children had nutritional rickets. All 17 children were younger than 3 years, and 13 (76%) were of nonwhite race/ethnicity. Clinical presentation included poor growth (n=12), leg deformity (n=8), motor delay (n=5), leg pain (n=3), weakness (n=3), and hypocalcemia or tetany (n=2). The incidence of nutritional rickets in children younger than 3 years was 0, 2.2, 3.7, and 24.1 per 100,000 for the decades beginning in 1970, 1980, 1990, and 2000, respectively (P=.003 for incidence trend). Nutritional rickets was associated with black race, breast-feeding, low birth weight, and stunted growth (P<.05 for all). Four of 13 patients (31%) who underwent 25-hydroxyvitamin D testing had values less than 10 ng/mL., Conclusion: Nutritional rickets remains rare, but its incidence has dramatically increased since 2000. Not all cases of rickets can be attributed to vitamin D deficiency., (Copyright © 2013 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

The kidney is essential for the maintenance of normal calcium and phosphorus homeostasis. Calcium and inorganic phosphorus are filtered at the glomerulus, and are reabsorbed from tubular segments by transporters and channels which are regulated by 1α,25-dihydroxyvitamin (1α,25(OH)(2)D) and parathyroid hormone (PTH). The kidney is the major site of the synthesis of 1α,25(OH)(2)D under physiologic conditions, and is one of the sites of 24,25-dihydroxyvitamin D (24,25(OH)(2)D) synthesis. The activity of the 25(OH)D-1α-hydroxylase, the mixed function oxidase responsible for the synthesis of 1α,25(OH)(2)D, is regulated by PTH, 1α,25(OH)(2)D, fibroblast growth factor 23 (FGF23), inorganic phosphorus and other growth factors. Additionally, the vitamin D receptor which binds to, and mediates the activity of 1α,25(OH)(2)D, is widely distributed in the kidney. Thus, the kidney, by regulating multiple transport and synthetic processes is indispensible in the maintenance of mineral homeostasis in physiological states., (Published by Elsevier Inc.)

Background: Mutations of the CYP24A1 gene, which encodes the 1,25-dihydroxyvitamin D-24-hydroxylase cytochrome P450, Cyp24A1, are predicted to result in elevated 1,25-dihydroxyvitamin D concentrations, hypercalcemia, hypercalciuria, nephrolithiasis, and bone disease. Treatment of hypercalcemia associated with CYP24A1 gene mutations has not been described., Methods: The genetic basis of a syndrome in a 44-yr-old Caucasian male characterized by intermittent hypercalcemia, hypercalciuria, elevated serum 1,25-dihydroxyvitamin D, undetectable serum 24,25-dihydroxyvitamin D, metabolically active nephrolithiasis, and reduced bone mineral density of the lumbar spine was examined. Sequencing of the CYP24A1 gene and biochemical and genetic analysis of seven family members in three generations was carried out. Because of hypercalcemia, hypercalciuria, and metabolically active nephrolithiasis, the patient was treated with a cytochrome 3A inhibitor, ketoconazole, 200 mg orally every 8 h, for 2 months., Results: The sequence of the CYP24A1 gene showed two canonical splice junction mutations in the proband. Analysis of family members showed a phenotype associated one or both mutations, suggesting autosomal dominant transmission with partial penetrance of the trait. After therapy with ketoconazole, statistically significant reductions in previously elevated urinary calcium into the normal range were noted. Previously elevated serum 1,25-dihydroxyvitamin D and calcium concentrations decreased, and previously decreased PTH concentrations increased into the normal range, but the differences were not statistically significant., Conclusions: In a syndrome characterized by intermittent hypercalcemia, hypercalciuria, elevated 1,25-dihydroxyvitamin D, undetectable 24,25-dihydroxyvitamin D concentrations, splice junction mutations of the CYP24A1 gene, and autosomal dominant transmission of the trait, treatment with ketoconazole is useful in reducing urinary calcium.

Loeys-Dietz syndrome (LDS, OMIM # 609192) caused by heterozygous mutations in TGFBR1 and TGFBR2 has recently been described as an important cause of familial aortic aneurysms. These patients have craniofacial and skeletal features that overlap with the Marfan syndrome (MFS), and more importantly, have significant vascular fragility as is seen in MFS and Ehlers-Danlos syndrome Type IV (EDS-IV). The skeletal phenotype with respect to low bone mineral density and skeletal fragility is not clear. We present two patients with LDS with significant skeletal fragility. The first is a 17-year-old male who had talipes equinovarus, diaphragmatic and inguinal and herniae, aortic root dilatation necessitating surgical repair, craniofacial and skeletal dysmorphism consistent with LDS, and a history of numerous fragility fractures leading to significant skeletal deformity. He was found to be heterozygous for a c.923T > C transition in exon 4 of TGFBR2. The second is a 26-year-old male with submucous cleft palate, talipes equinovarus, pectus excavatum requiring surgery, inguinal hernia, and aneurysms in the ascending aorta, abdominal aorta, carotid, subclavian, vertebral and brachial arteries requiring surgical repairs. He also had craniofacial and skeletal dysmorphism consistent with LDS, multiple fractures in childhood, low bone mineral density, and was found to be heterozygous for a c.1561 T > C transition in exon 7 of TGFBR2. These case studies highlight the importance of paying close attention to fractures and bone density in patients with LDS. Osteopenia or osteoporosis may become increasingly important issues as earlier detection and treatment of the vascular complications of LDS improves life expectancy in these patients., ((c) 2010 Wiley-Liss, Inc.)

Objective: To describe a case of granulomatous hypophysitis occurring after treatment with interferon alfa-2b and ribavirin for hepatitis C., Methods: Clinical, radiologic, laboratory, and pathologic assessments of a woman with granulomatous hypophysitis and interferon-induced thyroiditis are presented., Results: A 42-year-old woman with hepatitis C was treated with interferon alfa-2b and ribavirin for 5 months. She was referred after symptoms of thyrotoxicosis developed, in conjunction with laboratory and radiographic evidence of thyroiditis. During the initial evaluation, she was weak and hypotensive; biochemical evaluation showed undetectable plasma cortisol and corticotropin concentrations. Magnetic resonance imaging revealed diffuse enlargement of the pituitary gland, which encroached on but did not compress the optic chiasm. Treatment with supraphysiologic doses of prednisone resulted in clinical and radiographic improvement. Once physiologic doses of glucocorticoids were instituted, however, follow-up magnetic resonance imaging showed substantial progression of the diffuse pituitary enlargement and mild compression of the optic chiasm. Surgical debulking of the mass and histologic evaluation showed chronic, noncaseating granulomatous hypophysitis. An extensive evaluation for secondary causes of granulomatous inflammation of the pituitary revealed only an elevated angiotensin-converting enzyme level; no organisms were identified. After 2 courses of high-dose glucocorticoids, she had radiographic evidence of decreased size of the pituitary lesion but continued to have multiple anterior pituitary hormone deficiencies., Conclusion: Granulomatous hypophysitis and sarcoidosis of the pituitary are rare disorders. Hypophysitis should be considered in patients receiving interferon and ribavirin therapy who have symptoms consistent with pituitary dysfunction.

Objective: To highlight a strategy for potential detection of mesenchymal tumors in oncogenic malacia, as illustrated by 3 cases., Methods: Three case reports are presented in which successful localization of the offending neoplasm was accomplished by using whole-body Tc 99m sestamibi scanning. Alternative localization techniques are also reviewed., Results: Oncogenic osteomalacia occurs infrequently and is caused by neoplasms that secrete phosphatonins, substances that interfere with proximal tubular resorption of phosphorus and can result in phosphaturia, hypophosphatemia, reduced 1,25-dihydroxyvitamin D concentration, and osteomalacia. Removal of the underlying neoplasm results in complete resolution of all biochemical, pathologic, and physical manifestations of this disorder, as shown in our 3 patients. Because the neoplasms are small and can occur in any tissue compartment, they are difficult to localize, a feature that often results in therapeutic failure., Conclusion: We conclude that use of whole-body Tc 99m sestamibi scanning may be an appropriate and cost-effective initial strategy for the localization of peripheral phosphatonin-secreting tumors.

The phosphatonin, secreted frizzled-related protein-4 (sFRP-4), induces phosphaturia and inhibits 25-hydroxyvitamin D 1alpha-hydroxylase activity normally induced in response to hypophosphatemia. To determine the mechanism by which sFRP-4 alters renal phosphate (P(i)) transport, we examined the effect of sFRP-4 on renal brush border membrane (BBMV) Na(+)-dependent P(i) uptake, and the abundance and localization of the major Na(+)-P(i)-IIa co-transporter in proximal tubules and opossum kidney (OK) cells. Infusion of sFRP-4 increased renal fractional excretion of P(i) and decreased renal beta-catenin concentrations. The increase in renal P(i) excretion with sFRP-4 infusion was associated with a 21.9 +/- 3.4% decrease in BBMV Na(+)-dependent P(i) uptake (P < 0.001) compared with a 39.5 +/- 2.1% inhibition of Na(+)-dependent P(i) transport in renal BBMV induced by PTH (P < 0.001). sFRP-4 infusion was associated with a 30.7 +/- 4.8% decrease in Na(+)-P(i)-IIa co-transporter protein abundance (P < 0.01) assessed by immunoblotting methods compared to a 45.4 +/- 8.8% decrease induced by PTH (P < 0.001). In OK cells, sFRP-4 reduced surface expression of a heterologous Na(+)-P(i)-IIa co-transporter. We conclude that sFRP-4 increases renal P(i) excretion by reducing Na(+)-P(i)-IIa transporter abundance in the brush border of the proximal tubule through enhanced internalization of the protein.

Rationale and Objectives: The authors have addressed the ability of magnetic resonance (MR) imaging to resolve incremental thinning of articular cartilage by assessment of three-dimensional (3-D) and two-dimensional (2-D) representations., Methods: Using a porcine knee model, sequential cartilage shavings were characterized using a 3-D fat suppressed spoiled gradient-echo (SPGR) MR imaging protocol that provided good contrast between high-signal articular cartilage and lower signal surrounding tissues. Lesion dimensional measurements were made on both MR images and 3-D computerized reconstructions. Volumes of cartilage removed were approximately 0.06 mL., Results: Incremental articular cartilage thinning typically was apparent on 3-D reconstructed images. Three-dimensional articular cartilage reconstructions were effective in depicting location and orientation of shaved cartilage regions. Average percent error associated with length and with measurements based on 2-D MR images was approximately 19% for observer 1 and 33% for observer 2 when compared with direct measurements of the shaved cartilage. Average percent error of thickness measurements based on 2-D MR was approximately 21% for observer 1 and 37% for observer 2. Overall average errors associated with length, width, and thickness measurements were approximately 25%., Conclusions: Incremental thinning of articular cartilage can be tracked qualitatively and quantitatively using 3-D computerized reconstructions and 2-D MR images. Errors associated with the quantitative measurements can be attributed to limitations of measurement methods and intrinsic limitation of MR resolution.