Hypercalcemia, Hypercalciuria, and Elevated Calcitriol Concentrations with Autosomal Dominant Transmission Due to CYP24A1 Mutations: Effects of Ketoconazole Therapy
Hypercalcemia, Hypercalciuria, and Elevated Calcitriol Concentrations with Autosomal Dominant Transmission Due to CYP24A1 Mutations: Effects of Ketoconazole Therapy
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DOI：
10.1210/jc.2011-1935
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发表时间：
2012-03-01
影响因子：
5.8
通讯作者：
Kumar, Rajiv
中科院分区：
文献类型：
--
作者：
Tebben, Peter J.;Milliner, Dawn S.;Kumar, Rajiv
背景资料：CYP24A1基因编码1，25-二羟维生素D-24-羟化酶细胞色素P450，Cyp24A1，预计突变可导致1，25-二羟维生素D浓度升高、高钙血症、高钙尿症、肾结石和骨病。与CYP24A1基因突变相关的高钙血症的治疗尚未被描述。方法：在一个44岁的高加索男性特征为间歇性高钙血症，高钙尿症，血清1，25-二羟维生素D升高，检测不到血清24，25-二羟维生素D，代谢活跃的肾结石，腰椎骨密度降低综合征的遗传基础进行了检查。对该家系三代7名成员进行了CYP24A1基因测序和生化遗传分析。由于高钙血症，高钙尿症，代谢活跃的肾结石，患者与细胞色素3A抑制剂，酮康唑，200毫克口服每8小时，2 months.Results：CYP24A1基因的序列显示两个典型的剪接突变的先证者。对家族成员的分析表明，一个表型与一个或两个突变相关，提示常染色体显性遗传，部分遗传该性状。酮康唑治疗后，先前升高的尿钙在统计学上显著降低至正常范围。先前升高的血清1，25-二羟维生素D和钙浓度降低，先前降低的PTH浓度增加到正常范围，但差异无统计学意义。在以间歇性高钙血症、高钙尿症、1，25-二羟维生素D升高、24，25-二羟维生素D浓度检测不到、CYP 24 A1基因剪接点突变为特征的综合征中，以及该性状的常染色体显性遗传，用酮康唑治疗可有效降低尿钙。（临床内分泌代谢杂志97：E423-E427，2012）
Background: Mutations of the CYP24A1 gene, which encodes the 1,25-dihydroxyvitamin D-24-hydroxylase cytochrome P450, Cyp24A1, are predicted to result in elevated 1,25-dihydroxyvitamin D concentrations, hypercalcemia, hypercalciuria, nephrolithiasis, and bone disease. Treatment of hypercalcemia associated with CYP24A1 gene mutations has not been described.Methods: The genetic basis of a syndrome in a 44-yr-old Caucasian male characterized by intermittent hypercalcemia, hypercalciuria, elevated serum 1,25-dihydroxyvitamin D, undetectable serum 24,25-dihydroxyvitamin D, metabolically active nephrolithiasis, and reduced bone mineral density of the lumbar spine was examined. Sequencing of the CYP24A1 gene and biochemical and genetic analysis of seven family members in three generations was carried out. Because of hypercalcemia, hypercalciuria, and metabolically active nephrolithiasis, the patient was treated with a cytochrome 3A inhibitor, ketoconazole, 200 mg orally every 8 h, for 2 months.Results: The sequence of the CYP24A1 gene showed two canonical splice junction mutations in the proband. Analysis of family members showed a phenotype associated one or both mutations, suggesting autosomal dominant transmission with partial penetrance of the trait. After therapy with ketoconazole, statistically significant reductions in previously elevated urinary calcium into the normal range were noted. Previously elevated serum 1,25-dihydroxyvitamin D and calcium concentrations decreased, and previously decreased PTH concentrations increased into the normal range, but the differences were not statistically significant.Conclusions: In a syndrome characterized by intermittent hypercalcemia, hypercalciuria, elevated 1,25-dihydroxyvitamin D, undetectable 24,25-dihydroxyvitamin D concentrations, splice junction mutations of the CYP24A1 gene, and autosomal dominant transmission of the trait, treatment with ketoconazole is useful in reducing urinary calcium. (J Clin Endocrinol Metab 97: E423-E427, 2012)