Rare Causes of Primary Adrenal Insufficiency: Genetic and Clinical Characterization of a Large Nationwide Cohort

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dc.contributor.authorGüran, Tülay
dc.contributor.authorBuonocore, Federica
dc.contributor.authorSaka, Nurçin
dc.contributor.authorÖzbek, Mehmet Nuri
dc.contributor.authorAycan, Zehra
dc.contributor.authorBereket, Abdullah
dc.contributor.authorAchermann, John C.
dc.date.accessioned2020-04-30T23:31:33Z
dc.date.available2020-04-30T23:31:33Z
dc.date.issued2016
dc.departmentDÜ, Tıp Fakültesi, Dahili Tıp Bilimleri Bölümüen_US
dc.descriptionAchermann, John/0000-0001-8787-6272; Turan, Serap/0000-0002-5172-5402; GUVEN, AYLA/0000-0002-2026-1326; Achermann, John/0000-0001-8787-6272; Buyukinan, Muammer/0000-0002-2937-823X; Ucar, Ahmet/0000-0001-8144-8437; yuksel, bilgin/0000-0003-4378-3255; Demir, Korcan/0000-0002-8334-2422en_US
dc.descriptionWOS: 000377212700036en_US
dc.descriptionPubMed: 26523528en_US
dc.description.abstractContext: 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.en_US
dc.description.sponsorshipTurkish Pediatric Endocrinology Research Grant [UPE-2014-2]; Wellcome TrustWellcome Trust [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 CommunityEuropean Community (EC) [PIEF-GA-2012-328959]en_US
dc.description.sponsorshipThis work was supported by Turkish Pediatric Endocrinology Research Grant UPE-2014-2. J.C.A. is a Wellcome Trust Senior Research Fellow in Clinical Science (Grant 098513/Z/12/Z), with support from the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. T.G. is a European Community, Marie-Curie research fellow (Grant PIEF-GA-2012-328959).en_US
dc.identifier.doi10.1210/jc.2015-3250en_US
dc.identifier.endpage291en_US
dc.identifier.issn0021-972X
dc.identifier.issn1945-7197
dc.identifier.issue1en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.startpage283en_US
dc.identifier.urihttps://doi.org/10.1210/jc.2015-3250
dc.identifier.urihttps://hdl.handle.net/20.500.12684/4307
dc.identifier.volume101en_US
dc.identifier.wosWOS:000377212700036en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakPubMeden_US
dc.indekslendigikaynakScopusen_US
dc.language.isoenen_US
dc.publisherEndocrine Socen_US
dc.relation.ispartofJournal Of Clinical Endocrinology & Metabolismen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.titleRare Causes of Primary Adrenal Insufficiency: Genetic and Clinical Characterization of a Large Nationwide Cohorten_US
dc.typeArticleen_US

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