ADRENOCORTICOTROPIN RECEPTOR GENE-MUTATIONS IN FAMILIAL GLUCOCORTICOID DEFICIENCY - RELATIONSHIPS WITH CLINICAL-FEATURES IN 4 FAMILIES
ADRENOCORTICOTROPIN RECEPTOR GENE-MUTATIONS IN FAMILIAL GLUCOCORTICOID DEFICIENCY - RELATIONSHIPS WITH CLINICAL-FEATURES IN 4 FAMILIES
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DOI：
10.1210/jc.80.1.65
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发表时间：
1995-01-01
影响因子：
5.8
通讯作者：
CLARK, AJL
中科院分区：
文献类型：
--
作者：
WEBER, A;TOPPARI, J;CLARK, AJL
家族性糖皮质激素缺乏症是一种肾上腺对ACTH无反应的常染色体隐性综合征，其特征是糖皮质激素缺乏，血浆ACTH水平升高，肾素-醛固酮轴正常。ACTH受体缺陷被认为是一个可能的原因，我们以前在一些但不是全部病例中报道了一些新的ACTH受体基因突变，提示家族性糖皮质激素缺乏症可能具有异质性的分子病因学。在此，我们报告了来自不同家族的四例患者的临床特征和ACTH受体基因分析。我们发现2例患者是S74I和R128C突变的复合杂合子(患者A)和I44M和L192fs移码突变的复合杂合子(患者B)。另外两名患者(C和D)具有不同的种族血统，但都是R146H突变纯合子。家庭内部的隔离研究显示，父母和其他几个家庭成员存在杂合性。在患者A和B的父母中，人类CRH试验显示S74I、R128C和I44M杂合子的皮质醇和ACTH反应正常，而L192fs杂合子的皮质醇和ACTH反应被夸大，提示本试验诱导的生理性ACTH增加并未揭示亚临床ACTH抵抗的证据，该试验在确定杂合性方面可能没有价值。
Familial glucocorticoid deficiency is an autosomal recessive syndrome of adrenal unresponsiveness to ACTH characterized by glucocorticoid deficiency, high plasma ACTH levels, and a normal renin-aldosterone axis. Defects of the ACTH receptor have been suggested as a possible cause, and we have previously reported a number of novel mutations of the ACTH receptor gene in some, but not all, cases, suggesting that familial glucocorticoid deficiency may have a heterogeneous molecular etiology. Here we report the clinical features and ACTH receptor gene analysis in four patients from different families. We found that two patients were compound heterozygotes for the S74I and R128C mutations (patient A) and I44M and L192fs frame shift mutations (patient B). The other two patients (C and D) were of different ethnic ancestry, but were both homozygous for a R146H mutation. Segregation studies within families revealed heterozygosity in the parents and several other family members. Human CRH tests in the parents of patients A and B showed normal cortisol and ACTH responses in the S74I, R128C, and I44M heterozygotes and exaggerated cortisol and ACTH responses in the L192fs heterozygote, suggesting that the physiological ACTH increment induced in this test did not reveal evidence of subclinical ACTH resistance, and that this test may not be of value in ascertaining heterozygosity.