Abstract
INTRODUCTION: Suboptimal cortisol levels after ACTH stimulation have been recently reported in approximately 30% of patients with nonclassic congenital adrenal hyperplasia (NCCAH). There is little information on the role of genotype on cortisol secretion in NCCAH. The aim of this study is to investigate the association between genotype (i.e compound heterozygote for one mild and one severe CYP21A2 variant vs. homozygous for two mild variants) and peak cortisol response after ACTH stimulation in a pediatric population with NCCAH. METHODS: Retrospective chart review to identify children with NCCAH who had 1) CYP21A2 genetic information 2) high dose ACTH stimulation test and 3) serum cortisol measurements by LC-MS/MS. The cohort was divided into 2 groups mild/mild (M/M) genotype (mild variants associated with NCCAH include V281L, P30L, P453S) and mild/severe (M/S) genotype (severe variants associated with classic CAH include gene deletion, Q318X, R356W, In2G, I172N) and peak cortisol concentrations were compared. IRB approved. RESULTS: The cohort included 23 children - 12 M/M and 11 M/S diagnosed at 6.6 years old (SD 3.6, range 0.25-15). Peak cortisol levels were lower in the M/S group compared to M/M (mean +/- SD, 13.2 +/- 3.3 vs. 19 +/- 3.6 mcg/dL, p=0.001). The overall prevalence of adrenal insufficiency (AI) using cortisol cutoff of <15 mcg/dL (based on recent literature) was 9/23 (39%) and was higher in M/S vs. M/M (8/11, 73% vs. 1/12, 8%, p=0.003). CONCLUSION: The data suggest higher rates of suboptimal cortisol response in children with NCCAH who have mild/severe genotype compared to mild/mild.