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Rare causes of primary adrenal insufficiency: Genetic and clinical characterization of a large nationwide cohort
- Publication Year :
- 2016
- Publisher :
- Endocrine Soc, 2016.
-
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
- 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
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.od......9458..e4c8d91a98822b4699cf16b5bc2c5c5f