Genetic causes of vitamin D-related hypercalcemia are known to involve mutation of 25-hydroxyvitamin D-24-hydroxylase CYP24A1 or the sodium phosphate co-transporter SLC34A1, which result in excessive 1,25-(OH) 2 D hormonal action. However, at least 20% of idiopathic hypercalcemia (IH) cases remain unresolved. In this case-control study, we used precision vitamin D metabolite profiling based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) of an expanded range of vitamin D metabolites to screen German and French cohorts of hypercalcemia patients, to identify patients with altered vitamin D metabolism where involvement of CYP24A1 or SLC34A1 mutation had been ruled out and who possessed normal 25-OH-D 3 :24,25-(OH) 2 D 3 ratios. Profiles were compared to those of hypercalcemia patients with hypervitaminosis D, Williams-Beuren syndrome (WBS), CYP24A1 mutation, and normal subjects with a range of 25-OH-D levels. We observed that certain IH and WBS patients exhibited a unique profile comprising eightfold to 10-fold higher serum 23,25,26-(OH) 3 D 3 and 25-OH-D 3 -26,23-lactone than normals, as well as very low serum 1,25-(OH) 2 D 3 (2-5 pg/ml) and elevated 1,24,25-(OH) 3 D 3 , which we interpret implies hypersensitive expression of vitamin D-dependent genes, including CYP24A1, as a general underlying mechanism of hypercalcemia in these patients. Because serum 25-OH-D 3 and 24,25-(OH) 2 D 3 remained normal, we excluded the possibility that the aberrant profile was caused by hypervitaminosis D, but instead points to an underlying genetic cause that parallels the effect of Williams syndrome transcription factor deficiency in WBS. Furthermore, we observed normalization of serum calcium and vitamin D metabolite profiles at follow-up of an IH patient where 25-OH-D was reduced to 9 ng/ml, suggesting that symptomatic IH may depend on vitamin D nutritional status. Other hypercalcemic patients with complex conditions exhibited distinct vitamin D metabolite profiles. Our work points to the importance of serum vitamin D metabolite profiling in the differential diagnosis of vitamin D-related hypercalcemia that can rationalize expensive genetic testing, and assist healthcare providers in selecting appropriate treatment.

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BACKGROUND: Sleep disorders affect up to 25% of the general population and are associated with increased risk of adverse perioperative events. The key sleep medicine topics that are most important for the practice of anesthesiology have not been well-defined. The objective of this study was to determine the high-priority sleep medicine topics that should be included in the education of anesthesia residents based on the insight of experts in the fields of anesthesia and sleep medicine. METHODS: We conducted a prospective cross-sectional survey of experts in the fields of sleep medicine and anesthesia based on the Delphi technique to establish consensus on the sleep medicine topics that should be incorporated into anesthesia residency curricula. Consensus for inclusion of a topic was defined as >80% of all experts selecting “agree” or “strongly agree” on a 5-point Likert scale. Responses to the survey questions were analyzed with descriptive statistical methods and presented as percentages or weighted mean values with standard deviations (SD) for Likert scale data. RESULTS: The topics that were found to have 100% agreement among experts were the influence of opioids and anesthetics on control of breathing and upper airway obstruction; potential interactions of wake-promoting/hypnotic medications with anesthetic agents; effects of sleep and anesthesia on upper airway patency; and anesthetic management of sleep apnea. Less than 80% agreement was found for topics on the anesthetic implications of other sleep disorders and future pathways in sleep medicine and anesthesia. CONCLUSIONS: We identify key topics of sleep medicine that can be included in the future design of anesthesia residency training curricula.