An Unusual Case of Non-classical 21-Hydroxylase Deficiency Presenting with Hypercortisolemia and Hyperandrogenemia: A Case Report

Abstract Background Non-classical 21-hydroxylase deficiency (NC-21OHD) typically presents with hyperandrogenemia and low-to-normal cortisol levels. However, elevated cortisol levels are exceedingly rare and may lead to diagnostic confusion with Cushing's syndrome. Case Presentation: We report a 25-year-old woman who presented with a three-month history of menstrual irregularities. Physical examination revealed a full-moon face, hirsutism, male-pattern pubic hair distribution, and clitoral hypertrophy. Laboratory investigations demonstrated hypercortisolemia (serum cortisol: 27.98 µg/dL at 8 AM; urinary free cortisol: 264.38 µg/24h) and hyperandrogenemia (testosterone: 1.25 ng/mL; DHEA-S: 1025 µg/dL). Enhanced computed tomography revealed bilateral adrenal thickening. Although these findings initially suggested Cushing's syndrome, low-dose dexamethasone suppression testing markedly suppressed both cortisol (15.88 → 0.63 µg/dL) and testosterone (1.25 → 0.63 ng/mL), effectively excluding Cushing's syndrome and indicating an adrenal source of hyperandrogenemia. Notably, basal 17-hydroxyprogesterone (17-OHP) was within the normal range (0.77 ng/mL), but cosyntropin stimulation elevated 17-OHP to 11.54 ng/mL. Subsequent genetic testing confirmed CYP21A2 mutations, establishing the diagnosis of NC-21OHD. Glucocorticoid therapy with prednisone (2.5 mg nightly) normalized menstrual cycles and androgen levels within one month, with follow-up imaging showing significant adrenal size reduction at six months. Conclusions This case highlights that hypercortisolemia can occur in NC-21OHD and may coexist with features mimicking Cushing's syndrome. The combination of low-dose dexamethasone suppression testing—to simultaneously exclude Cushing's syndrome and confirm adrenal-derived hyperandrogenemia—followed by ACTH stimulation testing and genetic confirmation, represents a critical diagnostic pathway. Clinicians should maintain heightened awareness of this atypical presentation to avoid misdiagnosis.