Akademik Veri Yönetim Sistemi
Therapeutic Advances in Endocrinology and Metabolism, cilt.16, 2025 (SCI-Expanded)
Objective: Recent guidelines about Non-classical Congenital Adrenal Hyperplasia (NCCAH) indicate that if the peak cortisol response to the adrenocorticotropic hormone (ACTH) stimulation test is <14–18 µg/dL (monoclonal/polyclonal assay), it may be essential to augment the hydrocortisone dosage during significant stress events. In the current setting, when genetic diagnoses are increasingly widespread in NCCAH, there is a paucity of studies concerning cortisol responses to prevalent mutations. Aims: Our objectives are to investigate the outcomes of ACTH stimulation tests in children with NCCAH, delineate the biallelic mutations associated with insufficient cortisol responses, and evaluate the frequency of cortisol insufficiency in individuals with the V281L genotype. Our secondary objective is to assess the necessity of the ACTH stimulation test based on these results. Methods: Reviewing the retrospective medical records of 45 individuals diagnosed with NCCAH based on exacerbated clinical and biochemical findings, the mean age was 9.8 years (range: 2.4–17.9 years). Study participants had stimulated 17-hydroxyprogesterone (17-OHP) >10 ng/dL and had been investigated for 11 common CYP21A2 mutations. A peak cortisol response below 18 µg/dL was insufficient for our polyclonal assay. The cases were divided into two groups: Inadequate/low cortisol response group (LCR; n: 11) and adequate/normal response group (n: 25). We correlated biallelic genotype and cortisol response. Genotypes were classified as mild/mild (M/M), mild/severe (M/S), and heterozygous on a single allele based on the genotype’s effect on enzyme activity. P30L, V281L, P453S, and R339H are mild NCCAH mutations, whereas Q318X, R356W, exon 6 cluster mutations, Intron2A, and 8 bp deletions were severe. All cohorts with the V281L variant were separated into three groups (M/M, M/S, mild/undefined) and evaluated separately. Results: Almost one-third of patients had inadequate cortisol reserve. In the LCR group, 17-OHP 0’ levels were greater, but cortisol 0’ levels were lower, with no difference in stimulated responses (15.4 ± 10.5 vs 7.8 ± 6.2, p: 0.016 for basal 17-OHP; 40.7 ± 48.6 vs 32.3 ± 26.4, p: 0.63 for stimulated 17-OHP). The 17-OHP cutoff values were found to be 4.2 and 30.4 ng/dL, with 100% specificity for both groups. In 36% of the LCR group, mild–mild mutations were found. ACTH, cortisol (0’ and peak), and 17-OHP (0’ and peak) levels were similar in mild/mild and mild/severe groups. The V281L mutation was present in 86.1% of our cohort, with inadequate cortisol response in 29% of cases with V281L mutation. Differences were observed between the 0’ and peak cortisol levels in the V281L groups, with post hoc analysis indicating a difference between one allele heterozygous (mild/undefined) and mild/severe group. Conclusion: Our findings emphasize that a significant portion of patients with the mild/mild V281 mutation exhibit inadequate cortisol responses, highlighting the importance of the ACTH stimulation test in diagnosis and the need for careful monitoring in clinical treatment, as well as consideration of genotype variations.