Collins Lucy, Boehm Emma, Luxford Catherine, Clifton-Bligh Roderick, Grill Vivian
Department of Endocrinology and Diabetes Western Health Melbourne Victoria Australia.
University of Melbourne Melbourne Victoria Australia.
JBMR Plus. 2023 Aug 8;7(9):e10788. doi: 10.1002/jbm4.10788. eCollection 2023 Sep.
Hypervitaminosis D as a cause of hypercalcemia may be due to vitamin D intoxication, granulomatous diseases, or abnormalities of vitamin D metabolism. The 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 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 loss-of-function mutation. Case 1 presented initially with PTH-dependent hypercalcemia, with localization of a left upper parathyroid adenoma on parathyroid technetium sestamibi (Tc-MIBI) uptake study. Despite parathyroidectomy (180 mg adenoma), hypercalcemia, hypercalciuria, and low normal PTH levels persisted. A repeat parathyroid Tc-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 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 (NM_000782.5). In clinical practice 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 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. published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
维生素D过多症作为高钙血症的一个病因，可能是由于维生素D中毒、肉芽肿性疾病或维生素D代谢异常所致。该基因编码24-羟化酶，该酶负责25-羟维生素D（25(OH)D）和1,25-二羟维生素D（1,25(OH)2D）的分解代谢。该基因的突变可导致1,25(OH)2D升高，引起甲状旁腺激素（PTH）非依赖性高钙血症、高钙尿症、肾结石和肾钙质沉着症。我们报告了两例因该基因功能丧失突变继发高钙血症的兄弟姐妹的病例。病例1最初表现为PTH依赖性高钙血症，甲状旁腺锝- sestamibi（Tc-MIBI）摄取研究显示左上甲状旁腺腺瘤定位。尽管进行了甲状旁腺切除术（180mg腺瘤），高钙血症、高钙尿症和PTH水平略低于正常仍持续存在。重复的甲状旁腺Tc-MIBI摄取研究定位了第二个腺瘤，并进行了右下甲状旁腺切除术（170mg腺瘤）。随后PTH检测不到，但高钙血症和高钙尿症仍持续存在。病例2其兄弟姐妹中发现的PTH非依赖性高钙血症的新表现提示了潜在病因。级联检测证实两兄弟姐妹均为该基因（NM_000782.5）致病变体c.1186C>T，p.Arg396Trp（R396W）的纯合子。在临床实践中，对于出现PTH非依赖性高钙血症、高钙尿症且1,25(OH)2D水平处于正常上限或升高范围的患者，应考虑该基因功能丧失突变。尽管在我们的病例中无法进行24,25(OH)2D检测，但计算25(OH)D:24,25(OH)2D比值有助于诊断过程。对于有该基因功能丧失突变的患者，管理高钙血症风险的可能治疗方法包括避免维生素D过度补充和过度日晒。补液和双膦酸盐治疗对控制高钙血症可能有用。尽管我们的病例中未使用，但酮康唑、氟康唑和利福平治疗已被描述为潜在的治疗选择。©2023作者。由Wiley Periodicals LLC代表美国骨与矿物质研究学会出版。
