Rare Causes of Primary Adrenal Insufficiency: Genetic and Clinical Characterization of a Large Nationwide Cohort.
Rare Causes of Primary Adrenal Insufficiency: Genetic and Clinical Characterization of a Large Nationwide Cohort.
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DOI：
10.1210/jc.2015-3250
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发表时间：
2016-01
期刊：
影响因子：
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通讯作者：
Achermann JC
中科院分区：
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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
原发性肾上腺皮质功能不全(PAI)是一种危及生命的疾病，通常是由于儿童的单基因原因造成的。虽然先天性肾上腺增生症很常见，但也有其他几个重要的分子原因被报道，通常具有重叠的临床和生化特征。这些疾病的相对患病率尚不清楚，但做出特定的诊断可能对管理具有重要意义。这项研究的目的是调查全国范围内病因不明的PAI儿童的临床和分子遗传学特征。使用结构化问卷对临床、生化和影像数据进行评估。基因分析使用Halopex捕获和下一代测序。排除先天性肾上腺增生症、肾上腺脑白质营养不良、自身免疫性肾上腺功能不全或明显症状性PAI。这项研究是在19个三级儿科内分泌诊所进行的。95名患有不明原因PAI的儿童(48名女性，0-18岁，8名家族性)参与了这项研究。77例患者(81%)获得了基因诊断。病因依次为MC2R(n=25)、NR0B1(n=12)、STAR(n=11)、Cyp11a1(n=9)、MRAP(n=9)、NNT(n=7)、ABCD1(n=2)、NR5A1(n=1)和AAAS(n=1)。MC2R中的c.560delT、Cyp11a1中的p.R451W和MRAP中的c.IVS3ds+1delG等基因均发生了反复突变。出现了几个重要的临床和分子方面的见解。这是对儿童PAI分子遗传学进行的最大规模的全国性研究。在80%以上的儿童中实现分子诊断对于咨询家庭、症状前诊断、个性化治疗(如盐皮质激素替代治疗)、预测合并症(如神经、青春期/生育)以及针对未来的临床基因测试具有重要的翻译影响。
Primary adrenal insufficiency (PAI) is a life-threatening condition that is often due to monogenic causes in children. Although congenital adrenal hyperplasia occurs commonly, several other important molecular causes have been reported, often with overlapping clinical and biochemical features. The relative prevalence of these conditions is not known, but making a specific diagnosis can have important implications for management. The objective of the study was to investigate the clinical and molecular genetic characteristics of a nationwide cohort of children with PAI of unknown etiology. A structured questionnaire was used to evaluate clinical, biochemical, and imaging data. Genetic analysis was performed using Haloplex capture and next-generation sequencing. Patients with congenital adrenal hyperplasia, adrenoleukodystrophy, autoimmune adrenal insufficiency, or obvious syndromic PAI were excluded. The study was conducted in 19 tertiary pediatric endocrinology clinics. Ninety-five children (48 females, aged 0–18 y, eight familial) with PAI of unknown etiology participated in the study. A genetic diagnosis was obtained in 77 patients (81%). The range of etiologies was as follows: MC2R (n = 25), NR0B1 (n = 12), STAR (n = 11), CYP11A1 (n = 9), MRAP (n = 9), NNT (n = 7), ABCD1 (n = 2), NR5A1 (n = 1), and AAAS (n = 1). Recurrent mutations occurred in several genes, such as c.560delT in MC2R, p.R451W in CYP11A1, and c.IVS3ds+1delG in MRAP. Several important clinical and molecular insights emerged. This is the largest nationwide study of the molecular genetics of childhood PAI undertaken. Achieving a molecular diagnosis in more than 80% of children has important translational impact for counseling families, presymptomatic diagnosis, personalized treatment (eg, mineralocorticoid replacement), predicting comorbidities (eg, neurological, puberty/fertility), and targeting clinical genetic testing in the future.