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Pediatric Clinics of North America Feb 2019Fanconi syndrome, also known as the DeToni, Debré, Fanconi syndrome is a global dysfunction of the proximal tubule characterized by glucosuria, phosphaturia,... (Review)
Review
Fanconi syndrome, also known as the DeToni, Debré, Fanconi syndrome is a global dysfunction of the proximal tubule characterized by glucosuria, phosphaturia, generalized aminoaciduria, and type II renal tubular acidosis. Often there is hypokalemia, sodium wasting, and dehydration. In children, it typically is caused by inborn errors of metabolism, principally cystinosis. In adults, it is mainly caused by medications, exogenous toxins, and heavy metals. Treatment consists of treating the underlying cause and replacing the lost electrolytes and volume.
Topics: Child; Diagnosis, Differential; Fanconi Syndrome; Humans
PubMed: 30454741
DOI: 10.1016/j.pcl.2018.09.002 -
Pediatric Nephrology (Berlin, Germany) Oct 2022Here, we discuss the management of different forms of rickets, including new therapeutic approaches based on recent guidelines. Management includes close monitoring of...
Here, we discuss the management of different forms of rickets, including new therapeutic approaches based on recent guidelines. Management includes close monitoring of growth, the degree of leg bowing, bone pain, serum phosphate, calcium, alkaline phosphatase as a surrogate marker of osteoblast activity and thus degree of rickets, parathyroid hormone, 25-hydroxyvitamin D, and calciuria. An adequate calcium intake and normal 25-hydroxyvitamin D levels should be assured in all patients. Children with calcipenic rickets require the supplementation or pharmacological treatment with native or active vitamin D depending on the underlying pathophysiology. Treatment of phosphopenic rickets depends on the underlying pathophysiology. Fibroblast-growth factor 23 (FGF23)-associated hypophosphatemic rickets was historically treated with frequent doses of oral phosphate salts in combination with active vitamin D, whereas tumor-induced osteomalacia (TIO) should primarily undergo tumor resection, if possible. Burosumab, a fully humanized FGF23-antibody, was recently approved for treatment of X-linked hypophosphatemia (XLH) and TIO and shown to be superior for treatment of XLH compared to conventional treatment. Forms of hypophosphatemic rickets independent of FGF23 due to genetic defects of renal tubular phosphate reabsorption are treated with oral phosphate only, since they are associated with excessive 1,25-dihydroxyvitamin D production. Finally, forms of hypophosphatemic rickets caused by Fanconi syndrome, such as nephropathic cystinosis and Dent disease require disease-specific treatment in addition to phosphate supplements and active vitamin D. Adjustment of medication should be done with consideration of treatment-associated side effects, including diarrhea, gastrointestinal discomfort, hypercalciuria, secondary hyperparathyroidism, and development of nephrocalcinosis or nephrolithiasis.
Topics: Calcium; Child; Familial Hypophosphatemic Rickets; Fanconi Syndrome; Fibroblast Growth Factors; Humans; Osteomalacia; Paraneoplastic Syndromes; Phosphates; Rickets; Rickets, Hypophosphatemic; Vitamin D
PubMed: 35352187
DOI: 10.1007/s00467-022-05505-5 -
BMJ Quality & Safety Jan 2024Diagnostic errors cause substantial preventable harms worldwide, but rigorous estimates for total burden are lacking. We previously estimated diagnostic error and...
BACKGROUND
Diagnostic errors cause substantial preventable harms worldwide, but rigorous estimates for total burden are lacking. We previously estimated diagnostic error and serious harm rates for key dangerous diseases in major disease categories and validated plausible ranges using clinical experts.
OBJECTIVE
We sought to estimate the annual US burden of serious misdiagnosis-related harms (permanent morbidity, mortality) by combining prior results with rigorous estimates of disease incidence.
METHODS
Cross-sectional analysis of US-based nationally representative observational data. We estimated annual incident vascular events and infections from 21.5 million (M) sampled US hospital discharges (2012-2014). Annual new cancers were taken from US-based registries (2014). Years were selected for coding consistency with prior literature. Disease-specific incidences for 15 major vascular events, infections and cancers ('Big Three' categories) were multiplied by literature-based rates to derive diagnostic errors and serious harms. We calculated uncertainty estimates using Monte Carlo simulations. Validity checks included sensitivity analyses and comparison with prior published estimates.
RESULTS
Annual US incidence was 6.0 M vascular events, 6.2 M infections and 1.5 M cancers. Per 'Big Three' dangerous disease case, weighted mean error and serious harm rates were 11.1% and 4.4%, respectively. Extrapolating to all diseases (including non-'Big Three' dangerous disease categories), we estimated total serious harms annually in the USA to be 795 000 (plausible range 598 000-1 023 000). Sensitivity analyses using more conservative assumptions estimated 549 000 serious harms. Results were compatible with setting-specific serious harm estimates from inpatient, emergency department and ambulatory care. The 15 dangerous diseases accounted for 50.7% of total serious harms and the top 5 (stroke, sepsis, pneumonia, venous thromboembolism and lung cancer) accounted for 38.7%.
CONCLUSION
An estimated 795 000 Americans become permanently disabled or die annually across care settings because dangerous diseases are misdiagnosed. Just 15 diseases account for about half of all serious harms, so the problem may be more tractable than previously imagined.
Topics: Humans; United States; Cross-Sectional Studies; Stroke; Morbidity; Lung Neoplasms; Diagnostic Errors
PubMed: 37460118
DOI: 10.1136/bmjqs-2021-014130 -
World Journal of Pediatrics : WJP Feb 2021Dent disease is a rare tubulopathy characterized by manifestations of proximal tubular dysfunction, which occurs almost exclusively in males. It mainly presents symptoms... (Review)
Review
BACKGROUND
Dent disease is a rare tubulopathy characterized by manifestations of proximal tubular dysfunction, which occurs almost exclusively in males. It mainly presents symptoms in early childhood and may progress to end-stage renal failure between the 3rd and 5th decades of human life. According to its various genetic basis and to clinical signs and symptoms, researchers define two forms of Dent disease (Dent diseases 1 and 2) and suggest that these forms are produced by mutations in the CLCN5 and OCRL genes, respectively. Dent diseases 1 and 2 account for 60% and 15% of all Dent disease cases, and their genetic cause is generally understood. However, the genetic cause of the remaining 25% of Dent disease cases remains unidentified.
DATA SOURCES
All relevant peer-reviewed original articles published thus far have been screened out from PubMed and have been referenced.
RESULTS
Genetic testing has been used greatly to identify mutation types of CLCN5 and OCRL gene, and next-generation sequencing also has been used to identify an increasing number of unknown genotypes. Gene therapy may bring new hope to the treatment of Dent disease. The abuse of hormones and immunosuppressive agents for the treatment of Dent disease should be avoided to prevent unnecessary harm to children.
CONCLUSIONS
The current research progress in classification, genetic heterogeneity, diagnosis, and treatment of Dent disease reviewed in this paper enables doctors and researchers to better understand Dent disease and provides a basis for improved prevention and treatment.
Topics: Dent Disease; Humans; Mutation
PubMed: 32248351
DOI: 10.1007/s12519-020-00357-1 -
European Journal of Medical Genetics Aug 2022Nutritional vitamin D deficiency is the most frequent cause of rickets followed by genetic causes, that include entities like classic hypophosphatemic rickets (FGF23...
Nutritional vitamin D deficiency is the most frequent cause of rickets followed by genetic causes, that include entities like classic hypophosphatemic rickets (FGF23 related), Dent disease, Fanconi syndrome, renal tubular acidosis, and vitamin D dependent rickets. Hypophosphatemia is a feature in all these forms. The diagnosis relies on a combination of clinical, biochemical and radiological features, but genetic testing is required to confirm the diagnosis. We screened 66 patients with hypophosphatemic rickets referred to this center between May 2015 and July 2019 using whole exome sequencing (WES) in addition to the measurement of their intact serum fibroblast growth factor 23 (FGF23) levels. WES revealed 36 pathogenic and 28 likely pathogenic variants in 16 different genes (PHEX, FGF23, DMP1, ENPP1, CLCN5, CTNS, SLC2A2, GATM, SLC34A1, EHHADH, SLC4A1, ATP6V1B1, ATP6V0A4, CYP27B1, VDR and FGFR1) in 63 patients which helped differentiate between the various forms of hypophosphatemic rickets. Intact serum FGF23 levels were significantly higher in patients with variations in PHEX, FGF23, DMP1 or ENPP1 genes. The major genetic causes of rickets were classic hypophosphatemic rickets with elevated FGF23 levels, distal renal tubular acidosis, and vitamin D dependent rickets. Based on the present results, we propose a customized gene panel for targeted exome sequencing, which will be useful for confirming the diagnosis in most patients with hypophosphatemic rickets.
Topics: Acidosis, Renal Tubular; Familial Hypophosphatemic Rickets; Fibroblast Growth Factors; Humans; PHEX Phosphate Regulating Neutral Endopeptidase; Rickets, Hypophosphatemic; Vacuolar Proton-Translocating ATPases; Vitamin D
PubMed: 35738466
DOI: 10.1016/j.ejmg.2022.104540 -
Pediatric Clinics of North America Feb 2019Dent disease is an X-linked form of chronic kidney disease characterized by hypercalciuria, low molecular weight proteinuria, nephrocalcinosis, and proximal tubular... (Review)
Review
Dent disease is an X-linked form of chronic kidney disease characterized by hypercalciuria, low molecular weight proteinuria, nephrocalcinosis, and proximal tubular dysfunction. Clinical presentation is highly variable. Male patients may present with early-onset rickets, recurrent nephrolithiasis, or insidiously with asymptomatic proteinuria or chronic kidney disease. Mutations in both the CLCN5 and OCRL1 genes have been associated with the Dent phenotype and are now classified as Dent-1 and Dent-2, respectively. This article describes the clinical presentation, laboratory evaluation, genetics, pathophysiology, management, and future therapies of Dent disease.
Topics: Child; Dent Disease; Diagnosis, Differential; Disease Progression; Humans
PubMed: 30454742
DOI: 10.1016/j.pcl.2018.09.003 -
British Dental Journal Jun 2022
Topics: Disease Outbreaks; Humans; Mpox (monkeypox)
PubMed: 35689039
DOI: 10.1038/s41415-022-4358-8 -
Seminars in Nephrology Mar 2022A number of genes that cause inherited kidney disorders reside on the X chromosome. Given that males have only a single active X chromosome, these disorders clinically... (Review)
Review
A number of genes that cause inherited kidney disorders reside on the X chromosome. Given that males have only a single active X chromosome, these disorders clinically manifest primarily in men and boys. However, phenotypes in female carriers of X-linked kidney conditions are becoming more and more recognized. This article reviews the biology of X inactivation as well as the kidney phenotype in women and girls with a number of X-linked kidney disorders including Alport syndrome, Fabry disease, nephrogenic diabetes insipidus, X-linked hypophosphatemic rickets, Dent disease, and Lowe syndrome.
Topics: Diabetes Insipidus, Nephrogenic; Fabry Disease; Female; Humans; Kidney; Male; Mutation; Nephritis, Hereditary; Phenotype
PubMed: 35718359
DOI: 10.1016/j.semnephrol.2022.04.002 -
Journal of Lipid Research Feb 2019Phosphoinositides (PIs) play pivotal roles in the regulation of many biological processes. The quality and quantity of PIs is regulated in time and space by the activity... (Review)
Review
Phosphoinositides (PIs) play pivotal roles in the regulation of many biological processes. The quality and quantity of PIs is regulated in time and space by the activity of PI kinases and PI phosphatases. The number of PI-metabolizing enzymes exceeds the number of PIs with, in many cases, more than one enzyme controlling the same biochemical step. This would suggest that the PI system has an intrinsic ability to buffer and compensate for the absence of a specific enzymatic activity. However, there are several examples of severe inherited human diseases caused by mutations in one of the PI enzymes, although other enzymes with the same activity are fully functional. The kidney depends strictly on PIs for physiological processes, such as cell polarization, filtration, solute reabsorption, and signal transduction. Indeed, alteration of the PI system in the kidney very often results in pathological conditions, both inherited and acquired. Most of the knowledge of the roles that PIs play in the kidney comes from the study of KO animal models for genes encoding PI enzymes and from the study of human genetic diseases, such as Lowe syndrome/Dent disease 2 and Joubert syndrome, caused by mutations in the genes encoding the PI phosphatases, OCRL and INPP5E, respectively.
Topics: Animals; Humans; Kidney; Kidney Diseases; Molecular Targeted Therapy; Phosphatidylinositols
PubMed: 30314999
DOI: 10.1194/jlr.R089946