Phenotypic spectrum and diagnostic challenges in non-21-alpha-hydroxylase deficiency congenital adrenal hyperplasia: a case series from a tertiary care center

<b>Objectives.</b> The aim of the present study was 1) to describe the phenotypic spectrum of non-21-alfa-hydroxylase deficiency (non-21-OHD) congenital adrenal hyperplasia (CAH) encountered in a tertiary care endocrine center; 2) to identify the key biochemical, hormonal, and genetic markers that aid in differentiating non-21-OHD CAH subtypes; 3) to highlight the diagnostic challenges faced in distinguishing non-21-OHD CAH from classic 21OHD CAH and other adrenal disorders; and 4) to discuss the clinical implications and management challenges associated with non-21-OHD CAH. <b>Methods.</b> A retrospective analysis identified 13 cases of non-21-OHD CAH out of 87 CAH patients between 2008 to 2022. Clinical, biochemical, imaging and genetic data were analyzed. The diagnosis was confirmed by hormonal assays and next-generation sequencing (NGS)-based genetic analysis. <b>Results.</b> Of the 13 cases, six patients had 11β-hydroxylase deficiency (11β-OHD), primarily presenting with precocious puberty, hypertension, and hyperpigmentation, with elevated ACTH, 17-hydroxyprogesterone (17-OHP), and suppressed renin levels. Three patients with 3β-hydroxysteroid dehydrogenase type 2 (3β-HSD2) deficiency were diagnosed in early infancy following salt-wasting crises. 17α-hydroxylase deficiency (17α-OHD) was diagnosed in three adolescent females presenting with primary amenorrhea, tall stature, hypertension, and elevated gonadotropins. One case of StAR deficiency was diagnosed at 45 days of life, presenting with adrenal crisis and severe adrenal insufficiency. <b>Conclusion.</b> Non-21-OHD CAH presents diagnostic challenges due to its varied clinical spectrum. Hypertension and hypokalemia are key differentiators for 11β-OHD and 17α-OHD, while steroid profiling (LC-MS) aids in diagnosing 3β-HSD2 deficiency. However, the most crucial aspect is the early diagnosis, which is a significant factor in preventing complications like hypertensive cardiomyopathy and adrenal crises.