TY - JOUR
T1 - Differential diagnosis of vitamin D–related hypercalcemia using serum vitamin D metabolite profiling
AU - Kaufmann, Martin
AU - Schlingmann, Karl Peter
AU - Berezin, Linor
AU - Molin, Arnaud
AU - Sheftel, Jesse
AU - Vig, Melanie
AU - Gallagher, John C.
AU - Nagata, Akiko
AU - Masoud, Shadi Sedghi
AU - Sakamoto, Ryota
AU - Nagasawa, Kazuo
AU - Uesugi, Motonari
AU - Kottler, Marie Laure
AU - Konrad, Martin
AU - Jones, Glenville
N1 - Funding Information:
This work was supported by the European Rare Diseases Consortium (E‐Rare‐2)/Canadian Institutes of Health Research (grant No. ERA‐132931 to Glenville Jones). Through a Queen's University–Waters Corporation research agreement, Waters generously provided the LC‐MS/MS instrument used in this study. This work was also supported by the National Institutes of Health (grant No. NIA AG28168 to John C. Gallagher) and AMED‐CREST, Japan Agency for Medical Research (to Motonari Uesugi). We thank Miguel Maestro, University A Coruna, and Antonio Mournio, University of Santiago de Compostela for providing d‐24,25‐(OH)D. We thank Joy Wu, Stanford University, and Joel Finkelstein, Endocrine Unit, Massachusetts General Hospital, for providing serum samples from patients with hypervitaminosis D. 6 2 3
Publisher Copyright:
© 2021 American Society for Bone and Mineral Research (ASBMR).
PY - 2021
Y1 - 2021
N2 - 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)2D 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-D3:24,25-(OH)2D3 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)3D3 and 25-OH-D3-26,23-lactone than normals, as well as very low serum 1,25-(OH)2D3 (2–5 pg/ml) and elevated 1,24,25-(OH)3D3, 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-D3 and 24,25-(OH)2D3 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.
AB - 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)2D 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-D3:24,25-(OH)2D3 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)3D3 and 25-OH-D3-26,23-lactone than normals, as well as very low serum 1,25-(OH)2D3 (2–5 pg/ml) and elevated 1,24,25-(OH)3D3, 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-D3 and 24,25-(OH)2D3 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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U2 - 10.1002/jbmr.4306
DO - 10.1002/jbmr.4306
M3 - Article
C2 - 33856702
AN - SCOPUS:85105465080
JO - Journal of Bone and Mineral Research
JF - Journal of Bone and Mineral Research
SN - 0884-0431
ER -