1. Rare causes of primary adrenal insufficiency: Genetic and clinical characterization of a large nationwide cohort
- Author
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Güran, Tülay, Buonocore, Federica, Saka, Nurçin, Özbek, Mehmet Nuri, Aycan, Zehra, Bereket, Abdullah, Baş, Firdevs, Darcan, Sükran, Bideci, Aysun, Güven, Ayla, Demir, Korcan, Akıncı, Ayşehan, Büyükinan, Muammer, Aydın, Banu Küçükemre, Turan, Serap, Ağladıoğlu, Sebahat Yılmaz, Atay, Zeynep, Abalı, Zehra Yavaş, Çatlı, Gönül, Yüksel, Bilgin, Akçay, Teoman, Yıldız, Metin, Özen, Samim, Doger, Esra, Demirbilek, Hüseyin, Uçar, Ahmet, Işık, Emregül, Özhan, Bayaram, Bolu, Semih, Özgen, İlker Tolga, Suntharalingham, Jenifer P., Achermann, John C., Uludağ Üniversitesi/Tıp Fakültesi/Pediatrik Endokrinoloji ve Diyabet Anabilim Dalı., and Tarım, Ömer
- Subjects
Male ,Genetic procedures ,ABCD1 gene ,Turkey ,Epidemiology ,CYP11A1 gene ,Gene ,Infant, newborn ,Structured questionnaire ,Chain cleavage enzyme ,High throughput sequencing ,MC2R gene ,Missense mutation ,Child ,Endocrinology & metabolism ,Priority journal ,Achalasia Addisonianism Alacrimia Syndrome ,Melanocortin 2 Receptor ,Alacrima ,Nonsense mutation ,Follow-up ,Genetic analysis ,MRAP gene ,Cyp11A1 ,NR0B1 gene ,AAAS gene ,NR5A1 gene ,Acth receptor ,Cohort studies ,Female ,Molecular diagnosis ,Nicotinamide adenine dinucleotide (phosphate) transhydrogenase ,Cohort analysis ,Primary adrenal insufficiency ,Human ,Sequence capture ,Adolescent ,Child, preschool ,Age of onset ,Major clinical study ,Killer-cell deficiency ,Hypoplasia congenita ,Article ,Next generation sequencing ,Frameshift mutation ,NNT gene ,Genetics ,Humans ,Steroidogenic factor-I ,Clinical evaluation ,Genetic variation ,Gene deletion ,Infant ,DNA ,Mutational analysis ,Newborn ,Cholesterol monooxygenase (side chain cleaving) ,Dax-1 nrob1 ,Onset age ,Clinical feature ,Preschool child ,Missense mutations ,Mutation ,Corticotropin ,Genetic variability ,Gene expression ,Familial glucocorticoid deficiency ,Adrenal insufficiency - Abstract
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. Türk Pediatrik Endokrinoloji Araştırma Bursu- UPE-2014-2 Wellcome Trust/European Commission - 098513/Z/12/Z National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London European Commission - PIEF-GA-2012-328959
- Published
- 2016