原发性肾上腺皮质功能减退的罕见病因：全国大型队列的遗传学与临床特征分析
Rare Causes of Primary Adrenal Insufficiency: Genetic and Clinical Characterization of a Large Nationwide Cohort.
作者信息
Guran Tulay, Buonocore Federica, Saka Nurcin, Ozbek Mehmet Nuri, Aycan Zehra, Bereket Abdullah, Bas Firdevs, Darcan Sukran, Bideci Aysun, Guven Ayla, Demir Korcan, Akinci Aysehan, Buyukinan Muammer, Aydin Banu Kucukemre, Turan Serap, Agladioglu Sebahat Yilmaz, Atay Zeynep, Abali Zehra Yavas, Tarim Omer, Catli Gonul, Yuksel Bilgin, Akcay Teoman, Yildiz Metin, Ozen Samim, Doger Esra, Demirbilek Huseyin, Ucar Ahmet, Isik Emregul, Ozhan Bayram, Bolu Semih, Ozgen Ilker Tolga, Suntharalingham Jenifer P, Achermann John C
机构信息
Department of Pediatric Endocrinology and Diabetes (T.G., Z.A., A.B., S.T.), Marmara University, Istanbul 34899, Turkey; Institute of Metabolism and Systems Research (T.G.), University of Birmingham, Birmingham B15 2TT, United Kingdom; Department of Genetics and Genomic Medicine (F.B., J.S., J.C.A.), University College London Institute of Child Health, University College London, London WC1N 1EH, United Kingdom; Department of Pediatric Endocrinology and Diabetes (N.S., F.B., B.K.A., Z.Y.A.), Istanbul Faculty of Medicine, Istanbul University, 34452 Istanbul, Turkey; Clinics of Pediatric Endocrinology (M.N.O., H.D.), Diyarbakir Children's Hospital, 21100 Diyarbakir, Turkey; Clinics of Pediatric Endocrinology (Z.A., S.Y.A.), Dr Sami Ulus Obstetrics and Gynecology, Children's Health and Disease Training and Research Hospital, 06100 Ankara, Turkey; Department of Pediatric Endocrinology and Diabetes (S.D., S.O.), Ege University, 35040 Izmir, Turkey; Department of Pediatric Endocrinology and Diabetes (A.B., E.D.), Gazi University, 06550 Ankara, Turkey; Pediatric Endocrinology Clinic (A.G., M.Y.), Goztepe Educational and Research Hospital, 34810 Istanbul, Turkey; Department of Pediatrics (A.G.), Amasya University Medical Faculty, 05189 Amasya, Turkey; Pediatric Endocrinology Clinic (K.D.), Dr Behçet Uz Children's Hospital, Izmir, Turkey; Department of Pediatric Endocrinology and Diabetes (A.A.), Inonu University, Malatya, Turkey; Clinics of Pediatric Endocrinology (M.B.), Konya Training and Research Hospital, 42100 Konya, Turkey; Department of Pediatric Endocrinology and Diabetes (O.T.), Uludag University, 16059 Bursa, Turkey; Department of Pediatric Endocrinology and Diabetes (G.C.), Eylul University, 35210 Izmir, Turkey; Department of Pediatric Endocrinology and Diabetes (B.Y.), Cukurova University, 01330 Adana, Turkey; Clinics of Pediatric Endocrinology (T.A.), Kanuni Sultan Suleyman Education and Research Hospital, 34303 Istanbul, Turkey; Pediatric Endocrinology Clinic
出版信息
J Clin Endocrinol Metab. 2016 Jan;101(1):284-92. doi: 10.1210/jc.2015-3250. Epub 2015 Nov 2.
CONTEXT
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.
OBJECTIVE
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.
DESIGN
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.
SETTING
The study was conducted in 19 tertiary pediatric endocrinology clinics.
PATIENTS
Ninety-five children (48 females, aged 0-18 y, eight familial) with PAI of unknown etiology participated in the study.
RESULTS
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.
CONCLUSION
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.
背景
原发性肾上腺皮质功能减退症（PAI）是一种危及生命的疾病，在儿童中通常由单基因病因引起。虽然先天性肾上腺增生症很常见，但也有其他一些重要的分子病因被报道，其临床和生化特征往往重叠。这些疾病的相对患病率尚不清楚，但做出明确诊断对治疗具有重要意义。
目的
本研究的目的是调查全国范围内病因不明的PAI患儿队列的临床和分子遗传学特征。
设计
使用结构化问卷评估临床、生化和影像学数据。采用Haloplex捕获和下一代测序进行基因分析。排除先天性肾上腺增生症、肾上腺脑白质营养不良、自身免疫性肾上腺皮质功能减退症或明显综合征性PAI患者。
地点
该研究在19家三级儿科内分泌诊所进行。
患者
95名病因不明的PAI患儿（48名女性，年龄0至18岁，8名有家族史）参与了本研究。
结果
77名患者（81%）获得了基因诊断。病因范围如下：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）。几个基因出现了复发性突变，如MC2R中的c.560delT、CYP11A1中的p.R451W和MRAP中的c.IVS3ds+1delG。出现了一些重要的临床和分子见解。
结论
这是全国范围内开展的关于儿童PAI分子遗传学的最大规模研究。在超过80%的儿童中实现分子诊断对为家庭提供咨询、症状前诊断、个性化治疗（如盐皮质激素替代）、预测合并症（如神经、青春期/生育）以及未来靶向临床基因检测具有重要的转化意义。
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