SUN-406 Post-ACTH Peak Cortisol Response is Associated with Genotype in Children with Nonclassic Congenital Adrenal Hyperplasia

Abstract Disclosure: A. Dayno: None. M.J. Kilberg: None. M.G. Vogiatzi: Research support from Neurocrine, Spruce and Adrenas. Consultant for Spruce, Eton and Crinetics. Introduction: Children with nonclassic congenital adrenal hyperplasia (NCCAH) are considered low risk for cortisol deficiency. Current guidelines do not recommend screening for adrenal insufficiency (AI) or stress dose coverage; however, recent studies have shown rates of AI on stimulation testing ranging from 15-60%. There is little information whether genotype correlates with cortisol response to ACTH stimulation. The aim of this study is to investigate the association between genotype and peak cortisol response in a pediatric population with NCCAH. Methods: This IRB approved retrospective chart review sought to identify children presenting with NCCAH between 2007-2024. Inclusion criteria include: 1) NCCAH confirmed by genetic testing and 2) high dose ACTH stimulation test (i.e. 250 mcg) available for review with serum cortisol measurements by LC-MS/MS. Electronic medical records were reviewed and clinical details abstracted. The cohort was divided into 2 groups mild/mild (M/M) genotype (mild mutations include V281L, P30L, P453S) and mild/severe (M/S) genotype (severe mutations include deletion, Q318X, R356W, In2G, I172N). Peak cortisol levels in response to high dose ACTH stimulation and rates of AI were compared between groups using ANOVA and Fishers exact test on STATA. Results: The cohort included 23 children - 12 (52%) M/M and 11 (48%) M/S diagnosed at 6.5 years old (SD 3.7, range 0-15). Peak cortisol levels were lower in the M/S group (n=11) compared to M/M (n=12) (mean +/- SD, 13.2 +/- 3.3 vs. 19 +/- 3.6 mcg/dL, p=0.0006). The overall prevalence of 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). Statistical significance remains when using the traditional cortisol cutoff of <18 mcg/dL: overall prevalence of AI was 13/23 (57%) and was higher in M/S vs. M/M (10/11, 91% vs. 3/12, 25%, p=0.003). Conclusion: The data suggest higher rates of AI in children with NCCAH who have M/S genotype compared to M/M. The majority of children with M/S genotype had a sub-optimal cortisol response to ACTH stimulation (i.e. <15 mcg/dL), indicating need for screening for AI. More studies are needed to confirm these findings and determine the association between genotype and other disease outcomes, such as growth abnormalities, in these children. Genetic testing may be useful in predicting more severe biochemical outcomes, need for stimulation testing and stress dose coverage in children with NCCAH. Presentation: Sunday, July 13, 2025