Mercy Healthcare, Edmond, OK 73142, USA.
J Clin Endocrinol Metab. 2012 Mar;97(3):E423-7. doi: 10.1210/jc.2011-1935. Epub 2012 Feb 15.
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.
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.
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.
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.
CYP24A1 基因编码 1,25-二羟维生素 D-24-羟化酶细胞色素 P450，Cyp24A1，其突变预测会导致 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。尚未描述 CYP24A1 基因突变相关高钙血症的治疗方法。
研究了一名 44 岁白种男性间歇性高钙血症、高钙尿症、血清 1,25-二羟维生素 D 升高、血清 24,25-二羟维生素 D 不可检测、代谢活跃性肾结石和腰椎骨密度降低的综合征的遗传基础。对 CYP24A1 基因进行测序，并对三代 7 名家族成员进行生化和遗传分析。由于高钙血症、高钙尿症和代谢活跃性肾结石，患者接受细胞色素 3A 抑制剂酮康唑治疗，每天 2 次，每次 200mg，口服，持续 2 个月。
该患者 CYP24A1 基因的序列显示有两个典型的剪接突变。对家族成员的分析显示，表型与一个或两个突变相关，提示为常染色体显性遗传，该特征存在部分外显率。酮康唑治疗后，尿钙显著降低至正常范围。血清 1,25-二羟维生素 D 和钙浓度降低，甲状旁腺激素浓度升高至正常范围，但差异无统计学意义。
在间歇性高钙血症、高钙尿症、1,25-二羟维生素 D 升高、24,25-二羟维生素 D 浓度不可检测、CYP24A1 基因剪接突变和特征常染色体显性遗传的综合征中，酮康唑治疗可有效降低尿钙。
