Özet:
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.IVS3ds1delG 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. (J Clin Endocrinol Metab 101: 284 –292, 2016)
ISSN Pri
