A novel form of human mendelian hypertension featuring nonglucocorticoid-remediable aldosteronism
A novel form of human mendelian hypertension featuring nonglucocorticoid-remediable aldosteronism
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DOI：
10.1210/jc.2008-0594
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发表时间：
2008-08-01
影响因子：
5.8
通讯作者：
Lifton, Richard P.
中科院分区：
文献类型：
--
作者：
Geller, David S.;Zhang, Junhui;Lifton, Richard P.
内容：原发性醛固酮增多症是继发性高血压（HTN）的主要原因，但其机制的特点，不依赖于肾素分泌的aldosterone.Objectives：我们报告了一个新的家族形式的醛固酮增多症的父亲和两个女儿。所有人在7岁时被诊断为严重的HTN，对药物治疗无效。我们进行了各种临床，生化和遗传研究，试图澄清潜在的分子default.Results：生化研究显示低肾素血症，高醛固酮血症，和非常高水平的18-氧代皮质醇和18-羟基皮质醇，类固醇，反映类固醇17-α羟化酶和醛固酮合成酶的氧化。这些酶通常分别在肾上腺束状体和肾小球中区室化。地塞米松的管理未能抑制醛固酮或皮质醇的分泌，这些研究结果区分这种临床综合征的糖皮质激素可补救的醛固酮增多症，另一种常染色体显性遗传形式的HTN，并提出了一个全球性的缺陷，在调节肾上腺类固醇的生产。遗传学研究排除了醛固酮合成酶位点的突变，进一步将这种疾病与糖皮质激素可治疗的醛固酮增多症区分开来。由于持续的HTN，所有三名受试者都接受了双侧肾上腺切除术，在每种情况下都纠正了HTN。肾上腺显着增大，成对肾上腺重量高达82 g。组织学发现大量增生和细胞肥大的一个单一的皮质室，肾上腺束状体或过渡区的功能，与萎缩glomerulosa.Conclusion：这些研究结果定义了一种新的遗传形式的醛固酮增多症，并建议识别潜在的缺陷将提供洞察调节肾上腺类固醇生物合成的正常机制。
Context: Primary aldosteronism is a leading cause of secondary hypertension (HTN), but the mechanisms underlying the characteristic renin-independent secretion of aldosterone remain unknown in most patients.Objectives: We report a new familial form of aldosteronism in a father and two daughters. All were diagnosed with severe HTN refractory to medical treatment by age 7 yr. We performed a variety of clinical, biochemical, and genetic studies to attempt to clarify the underlying molecular defect.Results: Biochemical studies revealed hyporeninemia, hyperaldosteronism, and very high levels of 18-oxocortisol and 18-hydroxycortisol, steroids that reflect oxidation by both steroid 17-alpha hydroxylase and aldosterone synthase. These enzymes are normally compartmentalized in the adrenal fasciculata and glomerulosa, respectively. Administration of dexamethasone failed to suppress either aldosterone or cortisol secretion; these findings distinguish this clinical syndrome from glucocorticoid-remediable aldosteronism, another autosomal dominant form of HTN, and suggest a global defect in the regulation of adrenal steroid production. Genetic studies excluded mutation at the aldosterone synthase locus, further distinguishing this disorder from glucocorticoid-remediable aldosteronism. Because of unrelenting HTN, all three subjects underwent bilateral adrenalectomy, which in each case corrected the HTN. Adrenal glands showed dramatic enlargement, with paired adrenal weights as high as 82 g. Histology revealed massive hyperplasia and cellular hypertrophy of a single cortical compartment that had features of adrenal fasciculata or a transitional zone, with an atrophic glomerulosa.Conclusion: These findings define a new inherited form of aldosteronism and suggest that identification of the underlying defect will provide insight into normal mechanisms regulating adrenal steroid biosynthesis.