Hypercalcemia, Hypercalciuria, and Elevated Calcitriol Concentrations with Autosomal Dominant Transmission Due to<i>CYP24A1</i>Mutations: Effects of Ketoconazole Therapy

Tebben, Peter J.; Milliner, Dawn S.; Horst, Ronald L.; Harris, Peter C.; Singh, Ravinder J.; Wu, Yanhong; Foreman, John W.; Chelminski, Paul R.; Kumar, Rajiv

doi:10.1210/jc.2011-1935

Cited by 172 publications

(122 citation statements)

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“…In summary, our results show that increased 25(OH)D/24,25(OH) 2 D supports the diagnosis of reduced CYP24A1 activity in patients with mutations of the CYP24A1 gene (12,13 ). 25(OH)D/24,25(OH) 2 D Ն99 in a patient with hypercalcemia of unknown etiology warrants genetic confirmation.…”

Section: Participants and Samplessupporting

confidence: 62%

“…Depending on calcium and phosphorus demands, D (10, 11 ). Inactivating mutations of CYP24A1 (cytochrome P450, family 24, subfamily A, polypeptide 1) cause hypercalcemia, hypercalciuria, and increased 1,25(OH) 2 D concentrations (12)(13)(14)(15)(16)(17)(18)(19)(20). In studies describing LC-MS/MS assays for 24,25(OH) 2 D quantification, the relationship between 25(OH)D and 24,25(OH) 2 D has been used as a nutritional marker for assessment of optimum vitamin D supplementation (21 ).…”

Section: Hydroxyvitamin D [25(oh)d]mentioning

confidence: 99%

“…25(OH)D/24,25(OH) 2 D Ն99 in a patient with hypercalcemia of unknown etiology warrants genetic confirmation. Since the description of patients with CYP24A1 mutations independently by 2 groups (12,13 ), the availability of LC-MS/MS assays for 24,25(OH) 2 D quantification has enabled diagnosis of more cases. The increase in the number of reported cases in the last few years (14,16,19 ) suggests that CYP24A1-associated hypercalcemia is more prevalent than originally thought.…”

Section: Participants and Samplesmentioning

confidence: 99%

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LC-MS/MS for Identifying Patients with CYP24A1 Mutations

2016

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Section: Participants and Samplessupporting

confidence: 62%

Section: Hydroxyvitamin D [25(oh)d]mentioning

confidence: 99%

Section: Participants and Samplesmentioning

confidence: 99%

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LC-MS/MS for Identifying Patients with CYP24A1 Mutations

2016

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“…Recent studies have identified mutations in CYP24A1 to be a novel cause of hypercalcaemia 13,20,21 . Currently, more than 10 loss-of-function mutations in CYP24A1 have been described with this phenotype, supported by evidence of in vitro and in vivo loss of enzyme function.…”

Section: Discussionmentioning

confidence: 99%

“…Several findings suggest that they could. First, the pedigree described by Tebben et al 21 includes an adult (detailed above) with active renal stone disease, who was asymptomatic throughout childhood. Second, in response to the initial report describing CYP24A1 mutations in idiopathic infantile hypercalcaemia 13 , Streeten et al describe an adult patient with hypercalcaemia, nephrolithiasis and bone disease who was found to have a homozygous mutation in CYP24A1.…”

Section: Discussionmentioning

confidence: 99%

Searching for CYP24A1 mutations in cohorts of patients with calcium nephrolithiasis

Sayers¹,

Hynes²,

Rice³

et al. 2013

OA Nephrology

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IntroductionThe genetics underlying the idiopathic hypercalciuria leading to calciumcontaining renal stones remains elusive. The discovery of rare monogenic tubulopathies, often leading to hypercalciuria, has increased our understanding of tubular physiology and patho-physiology. However, insights into idiopathic calcium stone formation have not been gained from these disorders. The aim of this study is to examine CYP24A1 mutations in cohorts of patients with calcium nephrolithiasis. Materials and MethodsWe examined two cohorts of stoneforming patients for mutations in CYP24A1, which encodes the vitamin D24-hydroxylase enzyme. The first cohort had a biochemical phenotype of suppressed parathyroid hormone and high normal serum calcium, whilst the second cohort had a hypercalciuria phenotype. We did not identify bi-allelic sequence variants in CYP24A1 in our cohorts. ResultsIn cohort 1, we identified 9 known sequence variants. In cohort 2 we identified 7 known sequence variants. Conclusion CYP24A1 mutations remain a rare cause of calcium nephrolithiasis and hypercalciuria.

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Hypercalcemia

Walker

Shane

2022

JAMA

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ImportanceHypercalcemia affects approximately 1% of the worldwide population. Mild hypercalcemia, defined as total calcium of less than 12 mg/dL (&lt;3 mmol/L) or ionized calcium of 5.6 to 8.0 mg/dL (1.4-2 mmol/L), is usually asymptomatic but may be associated with constitutional symptoms such as fatigue and constipation in approximately 20% of people. Hypercalcemia that is severe, defined as total calcium of 14 mg/dL or greater (&gt;3.5 mmol/L) or ionized calcium of 10 mg/dL or greater (≥2.5 mmol/L) or that develops rapidly over days to weeks, can cause nausea, vomiting, dehydration, confusion, somnolence, and coma.ObservationsApproximately 90% of people with hypercalcemia have primary hyperparathyroidism (PHPT) or malignancy. Additional causes of hypercalcemia include granulomatous disease such as sarcoidosis, endocrinopathies such as thyroid disease, immobilization, genetic disorders, and medications such as thiazide diuretics and supplements such as calcium, vitamin D, or vitamin A. Hypercalcemia has been associated with sodium-glucose cotransporter 2 protein inhibitors, immune checkpoint inhibitors, denosumab discontinuation, SARS-CoV-2, ketogenic diets, and extreme exercise, but these account for less than 1% of causes. Serum intact parathyroid hormone (PTH), the most important initial test to evaluate hypercalcemia, distinguishes PTH-dependent from PTH-independent causes. In a patient with hypercalcemia, an elevated or normal PTH concentration is consistent with PHPT, while a suppressed PTH level (&lt;20 pg/mL depending on assay) indicates another cause. Mild hypercalcemia usually does not need acute intervention. If due to PHPT, parathyroidectomy may be considered depending on age, serum calcium level, and kidney or skeletal involvement. In patients older than 50 years with serum calcium levels less than 1 mg above the upper normal limit and no evidence of skeletal or kidney disease, observation may be appropriate. Initial therapy of symptomatic or severe hypercalcemia consists of hydration and intravenous bisphosphonates, such as zoledronic acid or pamidronate. In patients with kidney failure, denosumab and dialysis may be indicated. Glucocorticoids may be used as primary treatment when hypercalcemia is due to excessive intestinal calcium absorption (vitamin D intoxication, granulomatous disorders, some lymphomas). Treatment reduces serum calcium and improves symptoms, at least transiently. The underlying cause of hypercalcemia should be identified and treated. The prognosis for asymptomatic PHPT is excellent with either medical or surgical management. Hypercalcemia of malignancy is associated with poor survival.Conclusions and RelevanceMild hypercalcemia is typically asymptomatic, while severe hypercalcemia is associated with nausea, vomiting, dehydration, confusion, somnolence, and coma. Asymptomatic hypercalcemia due to primary hyperparathyroidism is managed with parathyroidectomy or observation with monitoring, while severe hypercalcemia is typically treated with hydration and intravenous bisphosphonates.

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Hypercalcemia, Hypercalciuria, and Elevated Calcitriol Concentrations with Autosomal Dominant Transmission Due toCYP24A1Mutations: Effects of Ketoconazole Therapy

Cited by 172 publications

References 18 publications

LC-MS/MS for Identifying Patients with CYP24A1 Mutations

LC-MS/MS for Identifying Patients with CYP24A1 Mutations

Searching for CYP24A1 mutations in cohorts of patients with calcium nephrolithiasis

Hypercalcemia

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