Eight novel KCNJ1 variants and parathyroid hormone overaction or resistance in 5 probands with Bartter syndrome type 2
Eight novel KCNJ1 variants and parathyroid hormone overaction or resistance in 5 probands with Bartter syndrome type 2
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DOI：
10.1016/j.cca.2020.10.002
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发表时间：
2020-12-01
影响因子：
5
通讯作者：
Shao, Leping
中科院分区：
文献类型：
--
作者：
Zuo, Jianxin;Guo, Wencong;Shao, Leping
目的：Bartter综合征2型（Bartter syndrome type 2，BS 2）是一种由KCNJ 1基因突变引起的常染色体隐性遗传性肾小管疾病。本研究分析并描述5例中国BS 2先证者的基因型和临床特征。方法：采用新一代测序技术鉴定KCNJ 1基因变异，并根据2015年美国医学遗传学与基因组学学会（ACMG）标准和指南评价其突变效应。共发现10种KCNJ 1基因变异，其中8种为新变异，最常见的是错义变异。常见症状和体征由高到低依次为：多饮多尿（5/5），其中1例（1/5）出现尿崩症;孕妇羊水过多和早产（4/5）;生长发育迟缓（3/5）。两名患者表现为低血糖性代谢紊乱和低钾血症，而其他患者则无酸碱失衡。1例患者有明显的甲状旁腺激素（PTH）抵抗（低钙血症，高磷血症和PTH水平明显升高），3例出现PTH过度反应（高钙血症，低磷血症和PTH水平轻度升高），1例显示正常血钙和磷浓度，PTH水平正常偏高。所有患者均有肾钙质沉着和/或高钙尿，其中1例合并肾结石。吲哚美辛对生长迟缓、多饮和多尿有显著的治疗作用，治疗后尿钙排泄减少，电解质紊乱和PTH参数正常化。结论：在5名中国先证者中发现了10种KCNJ 1基因变异。这些患者具有非典型BS表型，缺乏明显的代谢性碱中毒和/或表现为甲状旁腺激素作用过度/抵抗，这提醒临床医生仔细区分BS 2与其他甲状旁腺疾病。这是首次从中国人群中发现BS 2。
Purpose: Bartter syndrome type 2 (BS2) is an autosomal recessive renal tubular disorder, which is caused by the mutations in KCNJ1. This study was designed to analyze and describe the genotype and clinical features of five Chinese probands with BS2.Methods: Identify KCNJ1 gene variants by the next generation sequencing and evaluate their mutation effects according to 2015 American College of Medical Genetics and Genomics (ACMG) standards and guidelines.Results: Ten variants including eight novel ones of KCNJ1 gene were found, the most common type was missense variant. The common symptoms and signs from high to low incidence were: polydipsia and polyuria (5/5), one of them (1/5) presented with diabetes insipidus; maternal polyhydramnios and premature delivery (4/5); growth retardation (3/5). Two patients presented with hypochloremic metabolic alkalosis and hypokalemia; whereas the acid-base disturbance was absent in the others. One patient had evident parathyroid hormone (PTH) resistance (hypocalcemia, hyperphosphatemia and markedly elevated PTH levels), three presented with PTH overacting (hypercalcemia, hypophosphatemia and mild elevated PTH levels), and one showed normal blood calcium and phosphorus concentrations with high-normal PTH levels. All patients had nephrocalcinosis and/or hypercalciuria, and one of them complicated with nephrolithiasis. Indomethacin has significant therapeutic effect on the growth retardation, polydipsia and polyuria and treatment was associated with a decrease in urine calcium excretion, normalization of electrolyte disturbance and PTH parameters.Conclusions: Ten variants of KCNJ1 gene were identified in five Chinese probands. These patients had atypical BS phenotype lacking evident metabolic alkalosis and/or manifesting with PTH overaction/resistance, which reminds clinicians to carefully differentiate BS2 with other parathyroid disorders. This is the first report of BS2 from Chinese populations.