Skeletal Disorders & Mineral Homeostasis Section, NIDCR, NIH, Bethesda, MD, USA.
Calcilytix Therapeutics, Inc., San Francisco, CA, USA.
J Bone Miner Res. 2022 Oct;37(10):1926-1935. doi: 10.1002/jbmr.4659. Epub 2022 Aug 22.
Autosomal dominant hypocalcemia type 1 (ADH1) is a rare form of hypoparathyroidism due to activating variants of the calcium-sensing receptor gene (CASR). Inherited or de novo activating variants of the CASR alter the set point for extracellular calcium, resulting in inadequate parathyroid hormone (PTH) secretion and inappropriate renal calcium excretion leading to hypocalcemia and hypercalciuria. Conventional therapy includes calcium and activated vitamin D, which can worsen hypercalciuria, resulting in renal complications. A systematic literature review, using published reports from 1994 to 2021, was conducted to catalog CASR variants, to define the ADH1 clinical spectrum, and to determine the effect of treatment on patients with ADH1. There were 113 unique CASR variants reported, with a general lack of genotype/phenotype correlation. Clinical data were available in 191 patients; 27% lacked symptoms, 32% had mild/moderate symptoms, and 41% had severe symptoms. Seizures, the most frequent clinical presentation, occurred in 39% of patients. In patients with blood and urine chemistries available at the time of diagnosis (n = 91), hypocalcemia (99%), hyperphosphatemia (59%), low PTH levels (57%), and hypercalciuria (34%) were observed. Blood calcium levels were significantly lower in patients with severe symptoms compared with asymptomatic patients (6.8 ± 0.7 versus 7.6 ± 0.7 mg/dL [mean ± SD]; p < 0.0001), and the age of presentation was significantly lower in severely symptomatic patients (9.1 ± 15.0 versus 19.3 ± 19.4 years; p < 0.01). Assessments for complications including nephrocalcinosis, nephrolithiasis, renal impairment, and brain calcifications in 57 patients on conventional therapy showed that 75% had at least one complication. Hypercalciuria was associated with nephrocalcinosis, nephrolithiasis, renal impairment, or brain calcifications (odds ratio [OR] = 9.3; 95% confidence interval [CI] 2.4-37.2; p < 0.01). In 27 patients with urine calcium measures before and after starting conventional therapy, the incidence of hypercalciuria increased by 91% (p < 0.05) after therapy initiation. ADH1 is a condition often associated with severe symptomatology at presentation with an increase in the risk of renal complications after initiation of conventional therapy. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
自身显性低钙血症 1 型（ADH1）是一种罕见的甲状旁腺功能减退症，其病因是钙敏感受体基因（CASR）的激活变体。CASR 的遗传或新出现的激活变体改变了细胞外钙的设定点，导致甲状旁腺激素（PTH）分泌不足和肾脏排钙不当，导致低钙血症和高钙尿症。传统治疗包括钙和活性维生素 D，这可能会加重高钙尿症，导致肾脏并发症。对 1994 年至 2021 年期间发表的报告进行了系统的文献回顾，以分类 CASR 变体，定义 ADH1 临床谱，并确定治疗对 ADH1 患者的影响。报告了 113 种独特的 CASR 变体，一般缺乏基因型/表型相关性。在 191 名患者中可获得临床数据；27%的患者无症状，32%的患者有轻度/中度症状，41%的患者有严重症状。癫痫发作是最常见的临床表现，发生在 39%的患者中。在诊断时可获得血液和尿液化学数据的 91 名患者中，观察到低钙血症（99%）、高磷血症（59%）、低 PTH 水平（57%）和高钙尿症（34%）。与无症状患者相比，严重症状患者的血钙水平明显更低（6.8 ± 0.7 与 7.6 ± 0.7 mg/dL [平均值 ± 标准差]；p < 0.0001），且严重症状患者的发病年龄明显更低（9.1 ± 15.0 与 19.3 ± 19.4 岁；p < 0.01）。对 57 名接受常规治疗的患者进行包括肾钙质沉着症、肾结石、肾功能损害和脑钙化在内的并发症评估显示，75%的患者至少有一个并发症。高钙尿症与肾钙质沉着症、肾结石、肾功能损害或脑钙化有关（比值比[OR] 9.3；95%置信区间[CI] 2.4-37.2；p < 0.01）。在 27 名接受常规治疗前后进行尿钙测量的患者中，治疗开始后高钙尿症的发生率增加了 91%（p < 0.05）。ADH1 是一种常伴有严重症状的疾病，在开始常规治疗后，肾脏并发症的风险增加。© 2022 作者。《骨矿盐研究杂志》由 Wiley 期刊出版公司代表美国骨矿盐研究协会（ASBMR）出版。
