In children with X-linked hypophosphatemia, treatment with burosumab improved renal tubular phosphate reabsorption, serum phosphorus levels, linear growth, and physical function and reduced pain and the severity of rickets. (Funded by Ultragenyx Pharmaceutical and Kyowa Hakko Kirin; ClinicalTrials.gov number, NCT02163577 ; EudraCT number, 2014-000406-35 ).

We conclude that in healthy men, changes in dietary phosphorus within the physiological range of intakes regulate serum FGF-23 concentrations and suggest that dietary phosphorus regulation of 1,25(OH)(2)D production is mediated, at least in part, by changes in circulating FGF-23.

Background-X-linked hypophosphatemia in children is characterized by elevated serum FGF23, hypophosphatemia, rickets, lower extremity bowing, and growth impairment. We compared the efficacy and safety of continuing conventional therapy, consisting of oral phosphate and active vitamin D, versus switching to burosumab, a fully human monoclonal antibody against FGF23, in pediatric X-linked hypophosphatemia.Methods-In this randomised, active-controlled, open-label, phase 3 trial at 16 clinical sites, we enrolled children with X-linked hypophosphataemia aged 1-12 years. Key eligibility criteria were a total Thacher rickets severity score of at least 2•0, fasting serum phosphorus lower than 0•97 mmol/L (3•0 mg/dL), confirmed PHEX (phosphate-regulating endopeptidase homolog, X-linked) mutation or variant of unknown significance in the patient or a family member with appropriate Xlinked dominant inheritance, and receipt of conventional therapy for at least 6 consecutive months for children younger than 3 years or at least 12 consecutive months for children older than 3 years. Eligible patients were randomly assigned (1:1) to receive either subcutaneous burosumab starting at 0•8 mg/kg every 2 weeks (burosumab group) or conventional therapy prescribed by investigators (conventional therapy group). Both interventions lasted 64 weeks. The primary endpoint was change in rickets severity at week 40, assessed by the Radiographic Global Impression of Change global score. All patients who received at least one dose of treatment were included in the primary and safety analyses. The trial is registered with ClinicalTrials.gov, number NCT02915705.

SUMMARYThe syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a common cause of hyponatremia. We describe two infants whose clinical and laboratory evaluations were consistent with the presence of SIADH, yet who had undetectable arginine vasopressin (AVP) levels. We hypothesized that they had gain-of-function mutations in the V2 vasopressin receptor (V2R). DNA sequencing of each patient's V2R gene (AVPR2) identified missense mutations in both, with resultant changes in codon 137 from arginine to cysteine or leucine. These novel mutations cause constitutive activation of the receptor and are the likely cause of the patients' SIADH-like clinical picture, which we have termed "nephrogenic syndrome of inappropriate antidiuresis."Fluid homeostasis depends on proper water intake, governed by an intact thirst mechanism, and on urinary excretion of free water, mediated by appropriate secretion of arginine vasopressin (AVP) (also known as antidiuretic hormone). 1 AVP exerts its antidiuretic action by binding to the V2 vasopressin receptor (V2R), a G protein-coupled receptor, on the basolateral membrane of epithelial cells in the collecting duct of the kidney. Ligand binding activates the V2R, stimulating adenylate cyclase by means of G s proteins. The resulting increase in intracellular cyclic AMP (cAMP) promotes shuttling of intracellular vesicles containing the water channel aquaporin-2 to the apical membrane of the collecting-duct cells, thereby increasing water permeability and inducing antidiuresis.Clinical disorders of water balance are common, and alterations in many steps of this pathway have been described. 1 Urinary concentrating defects associated with diabetes insipidus may result from a deficiency of AVP or from nephrogenic causes, such as Xlinked, inactivating mutations in the V2R or autosomal recessive or autosomal dominant lesions in aquaporin-2. 2 Conversely, the syndrome of inappropriate antidiuretic hormone secretion (SIADH) manifests as an inability to excrete a free water load, with inappropriately concentrated urine and resultant hyponatremia, hypo-osmolality, and We describe two unrelated male infants whose clinical presentation was consistent with the presence of chronic SIADH but who had undetectable AVP levels. We postulated that novel activating mutations of the V2R might account for their unique presentation. Evaluation revealed novel activating mutations of the V2R leading to what we term "nephrogenic syndrome of inappropriate antidiuresis" (NSIAD). HHS Public Access CASE REPORTSPatient 1 presented at 3 months of age with irritability, and Patient 2 presented at 2.5 months of age with two generalized seizures. Both children had had unremarkable early neonatal courses. Both were exclusively bottle-fed formula (7 mmol of sodium per liter). Both infants had mild systolic hypertension with otherwise normal physical examinations. Initial laboratory evaluations demonstrated hyponatremia with normal serum levels of potassium and bicarbonate (Table 1). Both children had serum hypo-o...