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

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dc.authoridTuran, Serap/0000-0002-5172-5402
dc.authoridAycan, Zehra/0000-0003-4584-2976
dc.authoridAkinci, Aysehan/0000-0001-7267-9444
dc.authoridAchermann, John/0000-0001-8787-6272
dc.authoridBas, Firdevs/0000-0001-9689-4464
dc.authoridbereket, abdullah/0000-0002-6584-9043
dc.authoridAchermann, John/0000-0001-8787-6272
dc.authorwosidDemirbilek, Huseyin/AAK-6434-2021
dc.authorwosidTuran, Serap/U-7195-2018
dc.authorwosidDemirbilek, Huseyin/JCF-0692-2023
dc.authorwosidAycan, Zehra/AAQ-9537-2020
dc.authorwosidAkinci, Aysehan/AAC-6847-2021
dc.authorwosidCatli, Gönül/AFT-1499-2022
dc.authorwosidAchermann, John/C-5476-2008
dc.contributor.authorGuran, Tulay
dc.contributor.authorBuonocore, Federica
dc.contributor.authorSaka, Nurcin
dc.contributor.authorOzbek, Mehmet Nuri
dc.contributor.authorAycan, Zehra
dc.contributor.authorBereket, Abdullah
dc.contributor.authorBas, Firdevs
dc.date.accessioned2024-08-04T20:41:27Z
dc.date.available2024-08-04T20:41:27Z
dc.date.issued2016
dc.departmentİnönü Üniversitesien_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 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 Community [PIEF-GA-2012-328959]; Wellcome Trust [098513/Z/12/Z] Funding Source: Wellcome Trusten_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.2015-3250
dc.identifier.endpage291en_US
dc.identifier.issn0021-972X
dc.identifier.issn1945-7197
dc.identifier.issue1en_US
dc.identifier.pmid26523528en_US
dc.identifier.scopus2-s2.0-84954515152en_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/11616/97128
dc.identifier.volume101en_US
dc.identifier.wosWOS:000377212700036en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_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.subjectFamilial Glucocorticoid Deficiencyen_US
dc.subjectSteroidogenic Factor-Ien_US
dc.subjectChain Cleavage Enzymeen_US
dc.subjectKiller-Cell Deficiencyen_US
dc.subjectHypoplasia Congenitaen_US
dc.subjectMissense Mutationsen_US
dc.subjectActh Receptoren_US
dc.subjectDax-1 Nr0b1en_US
dc.subjectFollow-Upen_US
dc.subjectCyp11a1en_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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