A de novo mutation in the KCNJ5 gene causing primary hyperaldosteronism and early-onset hypertension
A de novo mutation in the KCNJ5 gene causing primary hyperaldosteronism and early-onset hypertension
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KCNJ5 基因的从头突变导致原发性醛固酮增多症和早发性高血压
DOI：
10.1097/hjh.0000000000002138
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发表时间：
2019
影响因子：
4.9
通讯作者：
Yang Yan
中科院分区：
文献类型：
--
作者：
Shi Xiaoli;Ma Delin;Li Mengni;Xu Weijie;Hu Shuhong;Yu Xuefeng;Yang Yan
家族性醛固酮增多症是原发性醛固酮增多症的一种罕见形式[1]。已知有四种类型的家族性醛固酮增多症（FH-I 至 FH-IV）[2]。 FH-III是一种由KCNJ5基因突变引起的常染色体显性遗传疾病[3]。迄今为止，已有来自13个家庭的22名FH-III患者携带六种不同的KCNJ5突变（T158A、G151E、G151R、E145Q、I157S和Y152C）的报道[4]。根据迄今为止报告的病例，FH-III 的临床严重程度差异很大，从轻度到重度高血压不等。此外，FH-III 患者对药物治疗的反应也不同。一般来说，所有携带 T158A、I157S 和 E145Q 突变的患者以及大多数携带 G151R 突变的患者均表现出早发性原发性醛固酮增多症的严重表型 [4]。这些患者表现出耐药性高血压、严重低钾血症和大量肾上腺增生。相比之下，携带 G151E 突变的患者表现出轻微的表型和良好的病程。他们的高血压和低钾血症可以通过单药治疗（即螺内酯）轻松控制。此外，在任何G151E突变患者中尚未发现肾上腺肿大[5-7]。与 G151E 突变类似，Y152C 突变也与不太严重的表型相关。特别是，受影响的患者在肾上腺计算机断层扫描（CT）扫描中显示出最小的增生[8]。根据迄今为止报道的有限病例数，高血压的严重程度似乎与肾上腺增生的程度有关。我们研究的目的是描述具有 G151R 突变的新 FH-III 表型，并研究 KCNJ5 突变导致的临床多样性与细胞存活之间的关系。指标患者是一名中国女性，1岁时出现多尿和烦渴。 2岁时，她到同济医院儿科就诊，被查出患有高血压、低钾血症。她的血压 (BP) 为 140/90 mmHg（超过了她年龄的第 99 个身高校正百分位数），血清钾为 2.12 mmol/l。根据血清醛固酮水平升高（518.5 pg/ml；正常范围，59.5-173.9 pg/ml）和正常血浆肾素活性（0.8 ng/ml/h；正常范围，0.05-0.8 ng/ml/h），她被诊断为原发性醛固酮增多症。超声检查未发现肾上腺增生。每日服用20mg螺内酯、13mg硝苯地平和1.5g氯化钾治疗后，她的血压（BP）降至110/80 mmHg，血钾升至3.6 mmol/l。患者9岁时到瑞金医院就诊。她的血压为 150/100 mmHg。她已经近 6 年没有服用螺内酯和硝苯地平了。在未补充钾的情况下，她表现出严重的低钾血症（2.0 mmol/l）。她的血清醛固酮为 690.4 pg/ml（正常范围，3.8–21 pg/ml），血浆肾素活性为 0.23 ng/ml/h（正常范围，0.1–5.5 ng/ml/h）。 CT显示肾上腺未见增大。她再次被诊断为原发性醛固酮增多症，并接受螺内酯（80 毫克/天）、非洛地平（5 毫克/天）和氯化钾治疗。 12岁时，她的血压为140/60 mmHg，血清钾为3.98 mmol/l。腹部 CT 扫描显示左侧肾上腺轻度增大。 17岁时，她出现高血压（血压150/95）和低钾血症（血清钾2.5-3.7毫摩尔/升）。 21岁时，患者被介绍给我们。她已停止螺内酯和非洛地平治疗 4 年。她的血压为 165/91 mmHg，血清钾为 2.22 mmol/l。家族史显示……
Familial hyperaldosteronism is a rare form of primary aldosteronism [1]. Four types of familial hyperaldosteronism (FH-I to FH-IV) are known [2]. FH-III is an autosomal-dominant disease caused by mutations in the KCNJ5 gene [3]. To date, 22 FH-III patients from 13 families carrying six different KCNJ5 mutations (T158A, G151E, G151R, E145Q, I157S, and Y152C) have been reported [4]. On the basis of the cases reported to date, the clinical severity of FH-III varies significantly, ranging from mild-tosevere hypertension. Furthermore, different responses to medical therapy have been observed in patients with FH-III. In general, all patients with the T158A, I157S, and E145Q mutations, and most patients with the G151R mutation, display a severe phenotype with early-onset primary aldosteronism [4]. These patients exhibit drug-resistant hypertension, severe hypokalaemia, and massive adrenal hyperplasia. In contrast, patients with the G151E mutation display a mild phenotype with a favourable disease course. Their hypertension and hypokalaemia can be easily controlled with single-agent treatment (ie spironolactone). Moreover, adrenal enlargement has not been found in any G151E mutation patient [5–7]. Similar to the G151E mutation, the Y152C mutation is also associated with a less severe phenotype. In particular, the affected patient displayed minimal hyperplasia in the adrenal computed tomography (CT) scan [8]. On the basis of the limited number of cases reported to date, the severity of hypertension seems to be related to the degree of adrenal hyperplasia. The objective of our study was to describe a new FH-III phenotype with a G151R mutation, and investigate the relationship between clinical diversity and cell survival because of KCNJ5 mutations. The index patient was a Chinese woman who presented with polyuria and polydipsia at 1 year of age. At the age of 2 years, she visited the paediatric department of Tongji Hospital and was found to suffer from hypertension and hypokalaemia. Her blood pressure (BP) was 140/90 mmHg (this was over the 99th height-corrected percentile for her age) and her serum potassium was 2.12 mmol/l. She was diagnosed with primary aldosteronism based on the elevated serum aldosterone level (518.5 pg/ml; normal range, 59.5–173.9 pg/ml) and normal plasma renin activity (0.8 ng/ml/h; normal range, 0.05–0.8 ng/ml/h). An ultrasound showed no adrenal hyperplasia. After daily treatment with 20mg spironolactone, 13mg nifedipine, and 1.5 g potassium chloride, her blood pressure (BP) decreased to 110/80 mmHg and serum potassium rose to 3.6 mmol/l. At 9 years of age, the patient visited Ruijin Hospital. Her BP was 150/100 mmHg. She had not been taking spironolactone and nifedipine for almost 6 years. She displayed severe hypokalaemia (2.0 mmol/l) without potassium supplementation. Her serum aldosterone was 690.4 pg/ml (normal range, 3.8–21 pg/ml) and her plasma renin activity was 0.23 ng/ml/h (normal range, 0.1–5.5 ng/ml/h). CT revealed no adrenal enlargement. She was again diagnosed with primary aldosteronism and treated with spironolactone (80mg/day), felodipine (5mg/day), and potassium chloride. At the age of 12 years, her BP was 140/60 mmHg and her serum potassium was 3.98 mmol/l. An abdominal CT scan revealed a mildly enlarged left adrenal gland. At the age of 17 years, she developed hypertension (BP 150/95) and hypokalaemia (serum potassium 2.5–3.7 mmol/l). At 21 years of age, the patient was presented to us. She had been off spironolactone and felodipine treatment for 4 years. Her BP was 165/91 mmHg and her serum potassium was 2.22 mmol/l. A family history showed …