Genetic Analysis of Pediatric Primary Adrenal Insufficiency of Unknown Etiology: 25 Years' Experience in the UK.
Genetic Analysis of Pediatric Primary Adrenal Insufficiency of Unknown Etiology: 25 Years' Experience in the UK.
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DOI：
10.1210/jendso/bvab086
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发表时间：
2021-08-01
影响因子：
4.1
通讯作者：
Achermann JC
中科院分区：
文献类型：
--
作者：
Buonocore F;Maharaj A;Qamar Y;Koehler K;Suntharalingham JP;Chan LF;Ferraz-de-Souza B;Hughes CR;Lin L;Prasad R;Allgrove J;Andrews ET;Buchanan CR;Cheetham TD;Crowne EC;Davies JH;Gregory JW;Hindmarsh PC;Hulse T;Krone NP;Shah P;Shaikh MG;Roberts C;Clayton PE;Dattani MT;Thomas NS;Huebner A;Clark AJ;Metherell LA;Achermann JC
虽然儿童和年轻人的原发性肾上腺功能不全（PAI）通常是由于先天性肾上腺增生（CAH）或自身免疫引起的，但也有其他遗传原因。人们对这些疾病的相对患病率了解甚少。我们调查了25年来儿童和年轻人PAI的遗传原因。在1993年至2018年期间，英国三个主要研究中心对155名年轻人进行了病因不明的PAI遗传分析，回顾了未发表和已发表的数据。我们预先排除了CAH、自身免疫或代谢原因的患者。我们从NR0B1 （DAX-1）临床检测中心获得了额外的数据。遗传分析包括候选基因方法（1993年以后）或下一代测序（NGS；目标面板，外显子组）（2013-2018年）。103/155（66.5%）的个体得到遗传诊断。5例患儿肾上腺功能不全消失，未发现遗传原因。致病性变异发生在11个基因中：MC2R（促肾上腺皮质激素受体，30/155,19.4%）、NR0B1 （DAX-1, 7.7%）、CYP11A1（7.7%）、AAAS（7.1%）、NNT（6.5%）、MRAP（4.5%）、TXNRD2（4.5%）、STAR（3.9%）、SAMD9（3.2%）、CDKN1C（1.3%）和NR5A1/类固醇生成因子-1 （SF-1, 0.6%）。此外，51名男孩通过临床测试鉴定出NR0B1变异。虽然发病年龄、治疗方法、祖先背景和出生体重可以提供诊断线索，但通常需要基因检测来确定病因。儿童和年轻人的PAI通常具有遗传基础。确定具体的病因可以影响这种终身疾病的管理。当涉及许多潜在的候选基因时，NGS方法提高了诊断率。
Although primary adrenal insufficiency (PAI) in children and young people is often due to congenital adrenal hyperplasia (CAH) or autoimmunity, other genetic causes occur. The relative prevalence of these conditions is poorly understood. We investigated genetic causes of PAI in children and young people over a 25 year period. Unpublished and published data were reviewed for 155 young people in the United Kingdom who underwent genetic analysis for PAI of unknown etiology in three major research centers between 1993 and 2018. We pre-excluded those with CAH, autoimmune, or metabolic causes. We obtained additional data from NR0B1 (DAX-1) clinical testing centers. Genetic analysis involved a candidate gene approach (1993 onward) or next generation sequencing (NGS; targeted panels, exomes) (2013-2018). A genetic diagnosis was reached in 103/155 (66.5%) individuals. In 5 children the adrenal insufficiency resolved and no genetic cause was found. Pathogenic variants occurred in 11 genes: MC2R (adrenocorticotropin receptor; 30/155, 19.4%), NR0B1 (DAX-1; 7.7%), CYP11A1 (7.7%), AAAS (7.1%), NNT (6.5%), MRAP (4.5%), TXNRD2 (4.5%), STAR (3.9%), SAMD9 (3.2%), CDKN1C (1.3%), and NR5A1/steroidogenic factor-1 (SF-1; 0.6%). Additionally, 51 boys had NR0B1 variants identified through clinical testing. Although age at presentation, treatment, ancestral background, and birthweight can provide diagnostic clues, genetic testing was often needed to define the cause. PAI in children and young people often has a genetic basis. Establishing the specific etiology can influence management of this lifelong condition. NGS approaches improve the diagnostic yield when many potential candidate genes are involved.
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DOI：
10.1210/jc.2015-3250
发表时间：
2016-01
期刊：
The Journal of clinical endocrinology and metabolism
影响因子：
--
作者：
Guran T;Buonocore F;Saka N;Ozbek MN;Aycan Z;Bereket A;Bas F;Darcan S;Bideci A;Guven A;Demir K;Akinci A;Buyukinan M;Aydin BK;Turan S;Agladioglu SY;Atay Z;Abali ZY;Tarim O;Catli G;Yuksel B;Akcay T;Yildiz M;Ozen S;Doger E;Demirbilek H;Ucar A;Isik E;Ozhan B;Bolu S;Ozgen IT;Suntharalingham JP;Achermann JC
通讯作者：
Achermann JC
影响因子：
3.2
作者：
Chung TT;Chan LF;Metherell LA;Clark AJ
通讯作者：
Clark AJ
影响因子：
5.8
作者：
Bornstein, Stefan R.;Allolio, Bruno;Torpy, David J.
通讯作者：
Torpy, David J.
影响因子：
30.8
作者：
Arboleda VA;Lee H;Parnaik R;Fleming A;Banerjee A;Ferraz-de-Souza B;Délot EC;Rodriguez-Fernandez IA;Braslavsky D;Bergadá I;Dell'Angelica EC;Nelson SF;Martinez-Agosto JA;Achermann JC;Vilain E
通讯作者：
Vilain E
影响因子：
3.2
作者：
Chan LF;Metherell LA;Krude H;Ball C;O'Riordan SM;Costigan C;Lynch SA;Savage MO;Cavarzere P;Clark AJ
通讯作者：
Clark AJ