Hypervitaminosis D Secondary to a CYP24A1 Loss‐of‐Function Mutation: An Unusual Cause of Hypercalcemia in Two Siblings
ABSTRACT Hypervitaminosis D as a cause of hypercalcemia may be due to vitamin D intoxication, granulomatous diseases, or abnormalities of vitamin D metabolism. The CYP24A1 gene encodes for the 24‐hydroxylase enzyme, which is responsible for the catabolism of 25‐hydroxyvitamin D (25(OH)D) and 1,25‐di...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-09-01
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| Series: | JBMR Plus |
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| Online Access: | https://doi.org/10.1002/jbm4.10788 |
| _version_ | 1797688603750432768 |
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| author | Lucy Collins Emma Boehm Catherine Luxford Roderick Clifton‐Bligh Vivian Grill |
| author_facet | Lucy Collins Emma Boehm Catherine Luxford Roderick Clifton‐Bligh Vivian Grill |
| author_sort | Lucy Collins |
| collection | DOAJ |
| description | ABSTRACT Hypervitaminosis D as a cause of hypercalcemia may be due to vitamin D intoxication, granulomatous diseases, or abnormalities of vitamin D metabolism. The CYP24A1 gene encodes for the 24‐hydroxylase enzyme, which is responsible for the catabolism of 25‐hydroxyvitamin D (25(OH)D) and 1,25‐dihydroxyvitamin D (1,25(OH)2D). Mutations in CYP24A1 can result in elevated 1,25(OH)2D causing parathyroid hormone (PTH)‐independent hypercalcemia, hypercalciuria, nephrolithiasis, and nephrocalcinosis. We present the cases of two siblings exhibiting hypercalcemia secondary to a CYP24A1 loss‐of‐function mutation. Case 1 presented initially with PTH‐dependent hypercalcemia, with localization of a left upper parathyroid adenoma on parathyroid technetium sestamibi (99mTc‐MIBI) uptake study. Despite parathyroidectomy (180 mg adenoma), hypercalcemia, hypercalciuria, and low normal PTH levels persisted. A repeat parathyroid 99mTc‐MIBI uptake study localized a second adenoma and a right inferior parathyroidectomy was performed (170 mg adenoma). PTH subsequently became undetectable, however hypercalcemia and hypercalciuria persisted. A new presentation of PTH‐independent hypercalcemia found to be secondary to a CYP24A1 loss‐of‐function mutation in his sibling, Case 2, signaled the underlying cause. Cascade testing confirmed both siblings were homozygous for the pathogenic variant c.1186C>T, p.Arg396Trp (R396W) of CYP24A1 (NM_000782.5). In clinical practice CYP24A1 loss‐of‐function mutations should be considered in patients presenting with PTH‐independent hypercalcemia, hypercalciuria, and 1,25(OH)2D levels in the upper normal or elevated range. Although in our case assays of 24,25(OH)2D were not available, calculation of the 25(OH)D:24,25(OH)2D ratio can assist in the diagnostic process. Possible treatments to manage the risk of hypercalcemia in patients with a CYP24A1 loss‐of‐function mutation include avoidance of vitamin D oversupplementation and excessive sun exposure. Hydration and bisphosphonate therapy can be useful in managing the hypercalcemia. Although not utilized in our cases, treatment with ketoconazole, fluconazole, and rifampicin have been described as potential therapeutic options. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. |
| first_indexed | 2024-03-12T01:34:13Z |
| format | Article |
| id | doaj.art-6b379878253e48f9ac3247f97783ebba |
| institution | Directory Open Access Journal |
| issn | 2473-4039 |
| language | English |
| last_indexed | 2024-03-12T01:34:13Z |
| publishDate | 2023-09-01 |
| publisher | Wiley |
| record_format | Article |
| series | JBMR Plus |
| spelling | doaj.art-6b379878253e48f9ac3247f97783ebba2023-09-11T11:34:52ZengWileyJBMR Plus2473-40392023-09-0179n/an/a10.1002/jbm4.10788Hypervitaminosis D Secondary to a CYP24A1 Loss‐of‐Function Mutation: An Unusual Cause of Hypercalcemia in Two SiblingsLucy Collins0Emma Boehm1Catherine Luxford2Roderick Clifton‐Bligh3Vivian Grill4Department of Endocrinology and Diabetes Western Health Melbourne Victoria AustraliaDepartment of Endocrinology and Diabetes Western Health Melbourne Victoria AustraliaRoyal North Shore Hospital Kolling Institute St Leonards New South Wales AustraliaRoyal North Shore Hospital Kolling Institute St Leonards New South Wales AustraliaDepartment of Endocrinology and Diabetes Western Health Melbourne Victoria AustraliaABSTRACT Hypervitaminosis D as a cause of hypercalcemia may be due to vitamin D intoxication, granulomatous diseases, or abnormalities of vitamin D metabolism. The CYP24A1 gene encodes for the 24‐hydroxylase enzyme, which is responsible for the catabolism of 25‐hydroxyvitamin D (25(OH)D) and 1,25‐dihydroxyvitamin D (1,25(OH)2D). Mutations in CYP24A1 can result in elevated 1,25(OH)2D causing parathyroid hormone (PTH)‐independent hypercalcemia, hypercalciuria, nephrolithiasis, and nephrocalcinosis. We present the cases of two siblings exhibiting hypercalcemia secondary to a CYP24A1 loss‐of‐function mutation. Case 1 presented initially with PTH‐dependent hypercalcemia, with localization of a left upper parathyroid adenoma on parathyroid technetium sestamibi (99mTc‐MIBI) uptake study. Despite parathyroidectomy (180 mg adenoma), hypercalcemia, hypercalciuria, and low normal PTH levels persisted. A repeat parathyroid 99mTc‐MIBI uptake study localized a second adenoma and a right inferior parathyroidectomy was performed (170 mg adenoma). PTH subsequently became undetectable, however hypercalcemia and hypercalciuria persisted. A new presentation of PTH‐independent hypercalcemia found to be secondary to a CYP24A1 loss‐of‐function mutation in his sibling, Case 2, signaled the underlying cause. Cascade testing confirmed both siblings were homozygous for the pathogenic variant c.1186C>T, p.Arg396Trp (R396W) of CYP24A1 (NM_000782.5). In clinical practice CYP24A1 loss‐of‐function mutations should be considered in patients presenting with PTH‐independent hypercalcemia, hypercalciuria, and 1,25(OH)2D levels in the upper normal or elevated range. Although in our case assays of 24,25(OH)2D were not available, calculation of the 25(OH)D:24,25(OH)2D ratio can assist in the diagnostic process. Possible treatments to manage the risk of hypercalcemia in patients with a CYP24A1 loss‐of‐function mutation include avoidance of vitamin D oversupplementation and excessive sun exposure. Hydration and bisphosphonate therapy can be useful in managing the hypercalcemia. Although not utilized in our cases, treatment with ketoconazole, fluconazole, and rifampicin have been described as potential therapeutic options. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.https://doi.org/10.1002/jbm4.10788CELL/TISSUE SIGNALING – ENDOCRINE PATHWAYSDISORDERS OF CALCIUM/PHOSPHATE METABOLISMOTHERPTH/VIT D/FGF23THERAPEUTICS |
| spellingShingle | Lucy Collins Emma Boehm Catherine Luxford Roderick Clifton‐Bligh Vivian Grill Hypervitaminosis D Secondary to a CYP24A1 Loss‐of‐Function Mutation: An Unusual Cause of Hypercalcemia in Two Siblings JBMR Plus CELL/TISSUE SIGNALING – ENDOCRINE PATHWAYS DISORDERS OF CALCIUM/PHOSPHATE METABOLISM OTHER PTH/VIT D/FGF23 THERAPEUTICS |
| title | Hypervitaminosis D Secondary to a CYP24A1 Loss‐of‐Function Mutation: An Unusual Cause of Hypercalcemia in Two Siblings |
| title_full | Hypervitaminosis D Secondary to a CYP24A1 Loss‐of‐Function Mutation: An Unusual Cause of Hypercalcemia in Two Siblings |
| title_fullStr | Hypervitaminosis D Secondary to a CYP24A1 Loss‐of‐Function Mutation: An Unusual Cause of Hypercalcemia in Two Siblings |
| title_full_unstemmed | Hypervitaminosis D Secondary to a CYP24A1 Loss‐of‐Function Mutation: An Unusual Cause of Hypercalcemia in Two Siblings |
| title_short | Hypervitaminosis D Secondary to a CYP24A1 Loss‐of‐Function Mutation: An Unusual Cause of Hypercalcemia in Two Siblings |
| title_sort | hypervitaminosis d secondary to a cyp24a1 loss of function mutation an unusual cause of hypercalcemia in two siblings |
| topic | CELL/TISSUE SIGNALING – ENDOCRINE PATHWAYS DISORDERS OF CALCIUM/PHOSPHATE METABOLISM OTHER PTH/VIT D/FGF23 THERAPEUTICS |
| url | https://doi.org/10.1002/jbm4.10788 |
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