Steroid Hormone Profiles and Molecular Diagnostic Tools in Pediatric Patients With non-CAH Primary Adrenal Insufficiency

SEVEN MENEVŞE T., Demirkol Y. K. , GÜRPINAR TOSUN B., Bayramoglu E., YILDIZ M., Acar S., ...More

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, vol.107, no.5, 2022 (Journal Indexed in SCI) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 107 Issue: 5
  • Publication Date: 2022
  • Doi Number: 10.1210/clinem/dgac016
  • Keywords: adrenal insufficiency, children, LC-MS, MS, steroid profile, non-CAH primary adrenal insufficiency, MUTATIONS CAUSE, MANAGEMENT, DEFICIENCY, VARIANTS, ETIOLOGY, CHILDREN


Context There is a significant challenge of attributing specific diagnoses to patients with primary adrenal insufficiency of unknown etiology other than congenital adrenal hyperplasia (non-CAH PAI). Specific diagnoses per se may guide personalized treatment or may illuminate pathophysiology. Objective This work aimed to investigate the efficacy of steroid hormone profiles and high-throughput sequencing methods in establishing the etiology in non-CAH PAI of unknown origin. Methods Pediatric patients with non-CAH PAI whose etiology could not be established by clinical and biochemical characteristics were enrolled. Genetic analysis was performed using targeted-gene panel sequencing (TPS) and whole-exome sequencing (WES). Plasma adrenal steroids were quantified by liquid chromatography-mass spectrometry and compared to that of controls. This study comprised 18 pediatric endocrinology clinics with 41 patients (17 girls, median age: 3 mo, range: 0-8 y) with non-CAH PAI of unknown etiology. Results A genetic diagnosis was obtained in 29 (70.7%) patients by TPS. Further molecular diagnosis could not be achieved by WES. Compared to a healthy control group, patients showed lower steroid concentrations, most statistically significantly in cortisone, cortisol, and corticosterone (P < .0001, area under the receiver operating characteristic curve: .96, .88, and .87, respectively). Plasma cortisol of less than 4 ng/mL, cortisone of less than 11 ng/mL, and corticosterone of less than 0.11 ng/mL had a greater than 95% specificity to ensure the diagnosis of non-CAH PAI of unknown etiology. Conclusion Steroid hormone profiles are highly sensitive for the diagnosis of non-CAH PAI of unknown etiology, but they are unlikely to point to a specific molecular diagnosis. TPS is an optimal approach in the molecular diagnosis of these patients with high efficacy, whereas little additional benefit is expected from WES.