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Abstract：
BACKGROUND: 17α-Hydroxylase/17,20-lyase deficiency (17OHD) caused by mutations in the CYP17A1 gene is a rare form of congenital adrenal hyperplasia typically characterised by cortisol deficiency, mineralocorticoid excess and sex steroid deficiency.
OBJECTIVE: To examine the phenotypic spectrum of 17OHD by clinical and biochemical assessment and corresponding in silico and in vitro functional analysis.
METHODS: Case series.
RESULTS: We assessed eight patients with 17OHD, including four with extreme 17OHD phenotypes: two siblings presented with failure to thrive in early infancy and two with isolated sex steroid deficiency and normal cortisol reserve. Diagnosis was established by mass spectrometry-based urinary steroid profiling and confirmed by genetic CYP17A1 analysis, revealing homozygous and compound heterozygous sequence variants. We found novel (p.Gly111Val, p.Ala398Glu, p.Ile371Thr) and previously described sequence variants (p.Pro409Leu, p.Arg347His, p.Gly436Arg, p.Phe53/54del, p.Tyr60IlefsLys88X). In vitro functional studies employing an overexpression system in HEK293 cells showed that 17,20-lyase activity was invariably decreased while mutant 17α-hydroxylase activity retained up to 14% of WT activity in the two patients with intact cortisol reserve. A ratio of urinary corticosterone over cortisol metabolites reflective of 17α-hydroxylase activity correlated well with clinical phenotype severity.
CONCLUSIONS: Our findings illustrate the broad phenotypic spectrum of 17OHD. Isolated sex steroid deficiency with normal stimulated cortisol has not been reported before. Attenuation of 17α-hydroxylase activity is readily detected by urinary steroid profiling and predicts phenotype severity.
CONCLUSIONS: Here we report, supported by careful phenotyping, genotyping and functional analysis, a prismatic case series of patients with congenital adrenal hyperplasia due to 17α-hydroxylase (CYP17A1) deficiency (17OHD). These range in severity from the abolition of function, presenting in early infancy, and unusually mild with isolated sex steroid deficiency but normal ACTH-stimulated cortisol in adult patients. These findings will guide improved diagnostic detection of CYP17A1 deficiency.
OBJECTIVE: To examine the phenotypic spectrum of 17OHD by clinical and biochemical assessment and corresponding in silico and in vitro functional analysis.
METHODS: Case series.
RESULTS: We assessed eight patients with 17OHD, including four with extreme 17OHD phenotypes: two siblings presented with failure to thrive in early infancy and two with isolated sex steroid deficiency and normal cortisol reserve. Diagnosis was established by mass spectrometry-based urinary steroid profiling and confirmed by genetic CYP17A1 analysis, revealing homozygous and compound heterozygous sequence variants. We found novel (p.Gly111Val, p.Ala398Glu, p.Ile371Thr) and previously described sequence variants (p.Pro409Leu, p.Arg347His, p.Gly436Arg, p.Phe53/54del, p.Tyr60IlefsLys88X). In vitro functional studies employing an overexpression system in HEK293 cells showed that 17,20-lyase activity was invariably decreased while mutant 17α-hydroxylase activity retained up to 14% of WT activity in the two patients with intact cortisol reserve. A ratio of urinary corticosterone over cortisol metabolites reflective of 17α-hydroxylase activity correlated well with clinical phenotype severity.
CONCLUSIONS: Our findings illustrate the broad phenotypic spectrum of 17OHD. Isolated sex steroid deficiency with normal stimulated cortisol has not been reported before. Attenuation of 17α-hydroxylase activity is readily detected by urinary steroid profiling and predicts phenotype severity.
CONCLUSIONS: Here we report, supported by careful phenotyping, genotyping and functional analysis, a prismatic case series of patients with congenital adrenal hyperplasia due to 17α-hydroxylase (CYP17A1) deficiency (17OHD). These range in severity from the abolition of function, presenting in early infancy, and unusually mild with isolated sex steroid deficiency but normal ACTH-stimulated cortisol in adult patients. These findings will guide improved diagnostic detection of CYP17A1 deficiency.
摘要：
背景：由CYP17A1基因突变引起的17α-羟化酶/17,20-裂解酶缺乏症（17OHD）是一种罕见的先天性肾上腺增生，通常以皮质醇缺乏症为特征，盐皮质激素过量和性类固醇缺乏症。
目的：通过临床和生化评估以及相应的计算机和体外功能分析来检查17OHD的表型谱。
方法：案例系列。
结果：我们评估了8例17OHD患者，包括四个极端的17OHD表型：两个兄弟姐妹在婴儿期早期未能茁壮成长，两个患有孤立的性类固醇缺乏症和正常的皮质醇储备。诊断通过基于质谱的尿类固醇分析建立，并通过遗传CYP17A1分析证实，揭示纯合和复合杂合序列变体。我们发现小说（p。Gly111Val,p.Ala398Glu,p.Ile371Thr）和先前描述的序列变体（p。Pro409Leu,p.Arg347His,p.Gly436Arg,p.Phe53/54del,p.Tyr60IlefsLys88X)。在HEK293细胞中使用过表达系统的体外功能研究表明，在两名具有完整皮质醇储备的患者中，17,20-裂解酶活性总是降低，而突变体17α-羟化酶活性保留了高达14％的WT活性。反映17α-羟化酶活性的尿皮质酮与皮质醇代谢产物的比率与临床表型严重程度密切相关。
结论：我们的发现说明了17OHD的广泛表型谱。以前没有报道过具有正常刺激的皮质醇的孤立性类固醇缺乏症。17α-羟化酶活性的减弱很容易通过尿类固醇谱分析来检测，并预测表型的严重程度。
结论：这里我们报告，由仔细的表型支持，基因分型和功能分析，由17α-羟化酶（CYP17A1）缺乏症（17OHD）引起的先天性肾上腺增生患者。这些范围的严重性从功能的废除，出现在婴儿早期，在成年患者中，孤立的性类固醇缺乏症异常温和，但ACTH刺激的皮质醇正常。这些发现将指导CYP17A1缺乏症的改进诊断检测。
目的：通过临床和生化评估以及相应的计算机和体外功能分析来检查17OHD的表型谱。
方法：案例系列。
结果：我们评估了8例17OHD患者，包括四个极端的17OHD表型：两个兄弟姐妹在婴儿期早期未能茁壮成长，两个患有孤立的性类固醇缺乏症和正常的皮质醇储备。诊断通过基于质谱的尿类固醇分析建立，并通过遗传CYP17A1分析证实，揭示纯合和复合杂合序列变体。我们发现小说（p。Gly111Val,p.Ala398Glu,p.Ile371Thr）和先前描述的序列变体（p。Pro409Leu,p.Arg347His,p.Gly436Arg,p.Phe53/54del,p.Tyr60IlefsLys88X)。在HEK293细胞中使用过表达系统的体外功能研究表明，在两名具有完整皮质醇储备的患者中，17,20-裂解酶活性总是降低，而突变体17α-羟化酶活性保留了高达14％的WT活性。反映17α-羟化酶活性的尿皮质酮与皮质醇代谢产物的比率与临床表型严重程度密切相关。
结论：我们的发现说明了17OHD的广泛表型谱。以前没有报道过具有正常刺激的皮质醇的孤立性类固醇缺乏症。17α-羟化酶活性的减弱很容易通过尿类固醇谱分析来检测，并预测表型的严重程度。
结论：这里我们报告，由仔细的表型支持，基因分型和功能分析，由17α-羟化酶（CYP17A1）缺乏症（17OHD）引起的先天性肾上腺增生患者。这些范围的严重性从功能的废除，出现在婴儿早期，在成年患者中，孤立的性类固醇缺乏症异常温和，但ACTH刺激的皮质醇正常。这些发现将指导CYP17A1缺乏症的改进诊断检测。
