Genotype-phenotype analysis in congenital adrenal hyperplasia due to P450 oxidoreductase deficiency.
Genotype-phenotype analysis in congenital adrenal hyperplasia due to P450 oxidoreductase deficiency.
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DOI：
10.1210/jc.2011-0640
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发表时间：
2012-02
期刊：
影响因子：
--
通讯作者：
Arlt W
中科院分区：
文献类型：
--
作者：
Krone N;Reisch N;Idkowiak J;Dhir V;Ivison HE;Hughes BA;Rose IT;O'Neil DM;Vijzelaar R;Smith MJ;MacDonald F;Cole TR;Adolphs N;Barton JS;Blair EM;Braddock SR;Collins F;Cragun DL;Dattani MT;Day R;Dougan S;Feist M;Gottschalk ME;Gregory JW;Haim M;Harrison R;Olney AH;Hauffa BP;Hindmarsh PC;Hopkin RJ;Jira PE;Kempers M;Kerstens MN;Khalifa MM;Köhler B;Maiter D;Nielsen S;O'Riordan SM;Roth CL;Shane KP;Silink M;Stikkelbroeck NM;Sweeney E;Szarras-Czapnik M;Waterson JR;Williamson L;Hartmann MF;Taylor NF;Wudy SA;Malunowicz EM;Shackleton CH;Arlt W
P450氧化还原酶缺乏症（PORD）是一种独特的先天性肾上腺皮质增生症，表现为糖皮质激素缺乏、性发育障碍（DSD）和骨骼畸形。没有关于高加索患者基因型-表型相关性的全面数据。本研究的目的是在一个大型PORD队列中建立基因型-表型相关性。该研究的设计是对来自11个国家的30名PORD患者进行临床、生化和遗传评估，包括多重连接依赖探针扩增（MLPA）。我们确定了23个P450氧化还原酶（POR）突变（14个新的），包括外显子缺失和MLPA检测到的部分重复。只有22%的无关患者携带纯合子POR突变。p.A287P是最常见的突变（43%的不相关等位基因）;未发现其他热点。尿类固醇分析显示特征性PORD代谢组，17α-羟化酶和21-羟化酶存在不同程度的损伤。短促肾上腺皮质激素试验显示89%的肾上腺功能不全。DSD存在于18 46，XX和12 46，XY个体中的15和7。p.A287P纯合性总是与46，XX DSD相关，但在46，XY个体中与正常生殖器相关。通过一种新的评分系统评估，大多数轻度至中度骨骼畸形患者为错义突变的复合杂合子，而几乎所有重度畸形患者在其中一个受影响的等位基因上均存在严重的功能缺失缺陷。我们报告了一个大型PORD队列的临床、生化和遗传学发现，并表明MLPA是POR突变分析的一个有用补充。高加索人中最常见的突变p.A287P的纯合性可以预测生殖器表型和中度畸形。肾上腺功能不全是常见的，容易被忽视，但很容易发现促肾上腺素试验。
P450 oxidoreductase deficiency (PORD) is a unique congenital adrenal hyperplasia variant that manifests with glucocorticoid deficiency, disordered sex development (DSD), and skeletal malformations. No comprehensive data on genotype-phenotype correlations in Caucasian patients are available. The objective of the study was to establish genotype-phenotype correlations in a large PORD cohort. The design of the study was the clinical, biochemical, and genetic assessment including multiplex ligation-dependent probe amplification (MLPA) in 30 PORD patients from 11 countries. We identified 23 P450 oxidoreductase (POR) mutations (14 novel) including an exonic deletion and a partial duplication detected by MLPA. Only 22% of unrelated patients carried homozygous POR mutations. p.A287P was the most common mutation (43% of unrelated alleles); no other hot spot was identified. Urinary steroid profiling showed characteristic PORD metabolomes with variable impairment of 17α-hydroxylase and 21-hydroxylase. Short cosyntropin testing revealed adrenal insufficiency in 89%. DSD was present in 15 of 18 46,XX and seven of 12 46,XY individuals. Homozygosity for p.A287P was invariably associated with 46,XX DSD but normal genitalia in 46,XY individuals. The majority of patients with mild to moderate skeletal malformations, assessed by a novel scoring system, were compound heterozygous for missense mutations, whereas nearly all patients with severe malformations carried a major loss-of-function defect on one of the affected alleles. We report clinical, biochemical, and genetic findings in a large PORD cohort and show that MLPA is a useful addition to POR mutation analysis. Homozygosity for the most frequent mutation in Caucasians, p.A287P, allows for prediction of genital phenotype and moderate malformations. Adrenal insufficiency is frequent, easily overlooked, but readily detected by cosyntropin testing.
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