SAT-441 Cognitive Performance in Classical Congenital Adrenal Hyperplasia: Multicenter Analysis of Age, Glucocorticoid Dose, and Genotype Severity

Abstract Disclosure: N.L. Yamashita: None. B. Jafar: None. S. Dettweiler: None. T.A. Pickering: None. B.P. Hoffman-Kipp: None. A. Mockler: None. E.A. Deras: None. S.H. O'Neil: None. G. Simon: None. M.J. Kilberg: None. M.E. Geffner: Up To Date, Adrenas, Diurnal, Neurocrine Biosciences, Novo Nordisk, Spruce Biosciences, Aeterna Zentaris, Ascendis, Eton Pharmaceuticals, Theratechnologies, Inc., Tolmar, Inc., McGraw-Hill. M.G. Vogiatzi: Neurocrine Biosciences, Spruce Biosciences, Adrenas Therapeutics, Crinetics Pharmaceuticals, Eton Pharmaceuticals. M.S. Kim: Diurnal, Adrenas, Neurocrine Biosciences, Spruce Biosciences, Eton Pharmaceuticals, Up To Date. Background: Classical congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency results in cortisol deficiency and androgen excess starting in utero. Over a lifetime, individuals with CAH may experience comorbidities, including differences in cognitive function and brain structure, though these are not fully understood. Adults with CAH exhibit deficits in working memory, along with reduced corticolimbic structures and white matter abnormalities, while adolescents show decreased inhibitory control and similar brain changes. Additional research is needed to clarify the links between these cognitive differences, brain development, and clinical factors such as age, treatment, and disease severity. Methods: We conducted a cross-sectional, observational study in patients with classical CAH due to 21-hydroxylase deficiency at two national Comprehensive Care Centers for CAH. All participants completed iPad-based cognitive testing using the NIH Toolbox Cognition Battery, assessing inhibitory control (Flanker), cognitive flexibility (Dimensional Change Card Sort), working memory (List Sort), and processing speed (Pattern Comparison). Patient scores were compared to normative means of 100 using Welch’s t test. Within the CAH cohort, Spearman’s correlation was used to assess relationships between cognition scores and age or glucocorticoid dose (mg/m²/day). Disease severity was categorized by CYP21A2 genotype as Null (0% enzyme activity, including deletions and large gene conversions) or Non-Null (< 1% or 1-2% enzyme activity), with severity groups compared via t test. Data are reported as mean ± SD. Results: In 105 patients with CAH (3-23 years old, 10.8 ± 5.4 years; 54% female), scores for inhibitory control (94.4 ± 17), working memory (94.1 ± 21), and processing speed (94.9 ± 12) were significantly lower than normative means (p’s < 0.05), but remained within the average range. In the CAH cohort, inhibitory control (R = -0.6), cognitive flexibility (R = -0.3), and processing speed (R = -0.3) were inversely correlated with age (p’s < 0.01). Additionally, cognitive flexibility (R = -0.3) and processing speed (R = -0.3) were inversely correlated with glucocorticoid dose (p’s < 0.05). Among 68 patients with genotype data, 41% (28/68) had Null genotypes and showed reduced cognitive flexibility (91.0 ± 8) compared to Non-Null (100.0 ± 10; p < 0.05). Conclusions: In a large cohort of patients with classical CAH, we observed lower cognitive function compared to controls, worsening with age and higher glucocorticoid doses. Additionally, patients with the most severe genotypes exhibited lower cognitive functioning. Future longitudinal studies are essential to explore the implications of these cognitive impairments and their relationship to developmental trajectories in patients with CAH. Presentation: Saturday, July 12, 2025