Abstract

Ashraf T. Soliman*, Vincenzo De Sanctis, Fawzia Alyafei, Shayma Elsayed, Dina Fawzy, Ahmed Elawwa, Nada Alaaraj, Noor Hamed, Nada Soliman and Ahmed Khalil

ABSTRACT

Background: Congenital genital adrenal hyperplasia (CAH) caused by 21-hydroxylase deficiency (21-OHD) is a difficult endocrine condition. This results in decreased secretion of cortisol and aldosterone, accompanied by an increase in adrenal androgen secretion as a compensatory mechanism. CAH presents with a wide range of clinical manifestations. Although glucocorticoid (GC) and mineralocorticoid (MC) treatment regimens have been proven to be effective, many patients still struggle to strike a balance between managing their condition and avoiding overtreatment side effects such as slow linear growth and an elevated risk of developing metabolic syndrome. New treatments and increased diagnostic accuracy could revolutionize CAH management strategies. Objectives: The objectives of this mini-review are to: (a) assess the diagnostic precision of traditional hormonal biomarkers such as 17-hydroxyprogesterone (17-OHP), androstenedione, testosterone, and DHEAS; (b) provide an overview of recent developments in steroid-sparing medications and gene-targeted therapies and (c) assess their clinical influence on the Prognosis of children with CAH. Methods:. Using PubMed, Scopus, Web of Science, and Clinical Trials. gov databases, a systematic literature review was carried out. The inclusion criteria included research on children and adolescents with genetically and/or clinically confirmed 21-OHD, conducted between 2000 and 2025. Research was considered eligible if it included information on hormone levels, treatment results, and emergent treatment trial design. Editorials, case reports and non-human research were among the exclusion criteria. The data are presented as a narrative review. Results: To maximize treatment, hormone monitoring with 17-OHP, androstenedione and testosterone is crucial. The most consistent and dependable biomarker for disease management is androstenedione. Age-appropriate norms for testosterone androstenedione (0. 3–1. 5 nmol/L) and 17-OHP (12–36 nmol/L) are all considered adequate treatment ranges. Corticotropin-releasing factor receptor 1 antagonists (CRF-1) such as crinecerfont and tildacerfont have been shown to minimize glucocorticoid exposure and significantly reduce ACTH-driven adrenal androgen production. In pediatric trials, the recently FDA-approved crinecerfont demonstrated a strong ability to lower 17O-HP and androstenedione. Gene-targeted treatments have advanced to preclinical or early clinical stages, including mRNA–LNP platforms, CRISPR/Cas9 editing, and AAV–CYP21A2 vectors. Despite the limited effectiveness of BBP-631 gene therapy, recent research supports the potential for adrenal-directed gene correction. Conclusion: Advances in steroid-sparing agents and modified biomarker-guided monitoring are improving the precision of CAH management. More clinical value can be obtained from androstenedione as a monitoring tool. While gene therapy may offer future curative potential, CRF1 antagonists show promise in the near term to lessen the burden of GC. For kids and teenagers with CAH, a shift to customized mechanism-targeted treatment plans is essential to enhancing endocrine stability and growth outcomes.