Endocrine Abstracts

Background/Aims: 11β-hydroxylase deficiency (11β-OHD) is the second most common form of congenital adrenal hyperplasia and an important cause of virilized 46,XX differences of sex development (DSD). It is typically characterized by prenatal virilization, androgen excess, and hypertension due to accumulation of 11-deoxycorticosterone. However, early biochemical findings may be inconsistent with the classic phenotype. We report two 46,XX patients with genetically confirmed 11β-OHD who demonstrated atypical biochemical profiles.

Methods: A retrospective review of two patients evaluated at a tertiary DSD center. Clinical data, serum and urinary steroid profiles, ACTH stimulation testing, imaging studies, and molecular analyses were assessed.

Results: Case 1: A neonate presented with Prader stage 3–4 virilization, including clitoromegaly, fused labioscrotal folds, and a single urogenital opening. No gonads were palpable; pelvic ultrasound revealed a uterus and ovaries. Electrolytes were normal. ACTH stimulation demonstrated impaired cortisol response (251 nmol/l) with markedly elevated 11-deoxycortisol and adrenal androgens. Hydrocortisone was initiated. Notably, plasma renin and aldosterone were repeatedly elevated rather than suppressed. Genetic testing identified two pathogenic CYP11B1 variants (likely in trans), confirming the diagnosis. Case 2: A newborn with Prader stage 4 virilization had normal electrolytes and no hyperpigmentation. Initial ACTH stimulation showed apparently sufficient cortisol secretion (621 nmol/l). Early serum steroid measurements showed only mild or borderline elevation of 11-deoxycortisol (including one normal value) with elevated 17-hydroxyprogesterone. Pelvic imaging did not clearly identify Müllerian structures or gonads. Diagnostic clarification was achieved through urinary steroid profiling, which demonstrated accumulation of upstream precursors consistent with 11β-OHD. Repeat imaging and later laparoscopy confirmed normal internal female anatomy. Serial ACTH testing demonstrated preserved cortisol reserve until 3 years of age, when impaired response (408 nmol/l), androgen excess, and advanced bone age emerged. Hydrocortisone therapy resulted in biochemical control and normal growth. Molecular testing confirmed 11β-OHD.

Conclusion: 11β-OHD may present with normal electrolytes, borderline or fluctuating steroid abnormalities, preserved early cortisol reserve, and non-suppressed renin–aldosterone profiles. Comprehensive steroid profiling, including urinary analysis, and timely genetic testing are essential for accurate diagnosis. These cases underscore the biochemical heterogeneity of 11β-OHD and the need for continued endocrine surveillance, even when early findings appear reassuring.