Early Risk Stratification in Non-Classical Congenital Adrenal Hyperplasia Based on Newborn 17-OHP Screening Values, Hormonal Findings, and Genotype

Background/Objectives: Non-classical congenital adrenal hyperplasia (NCCAH) due to 21-hydroxylase deficiency represents the mildest form of congenital adrenal hyperplasia and is frequently diagnosed only after the onset of clinical signs in childhood. Newborn screening programs for CAH are primarily designed to detect classical forms and show limited sensitivity for NCCAH. The clinical significance of neonatal 17-hydroxyprogesterone (17-OHP) values below recall thresholds remains incompletely defined. Methods: We retrospectively analyzed clinical, auxological, hormonal, and genetic data from pediatric patients diagnosed with NCCAH between 2018 and 2023 at a tertiary referral center. Neonatal screening 17-OHP concentrations, basal and ACTH-stimulated 17-OHP levels at diagnosis, bone age advancement, pubertal status, and hydrocortisone treatment were evaluated. Correlations between hormonal parameters, age at onset, and treatment dose were assessed. Results: Thirty-five patients (30 females) were included, with a mean age at clinical onset of 7.52 ± 0.36 years for females and 6.25 ± 0.29 years for males. Premature pubarche was the most frequent presenting sign (94.3%), and central precocious puberty was diagnosed in 31.4% of cases. The mean neonatal screening 17-OHP level was 4.53 ± 0.7 ng/mL; only two patients exceeded the screening recall cut-off. At diagnosis, mean basal and ACTH-stimulated 17-OHP levels were 15.1 ± 3.35 and 55.2 ± 11.3 ng/mL, respectively. Age at clinical onset was inversely correlated with both basal and stimulated 17-OHP levels, while hydrocortisone dose correlated positively with biochemical severity. Bone age advancement was observed in all patients. Conclusions: Most children with NCCAH display mildly elevated neonatal 17-OHP values that do not trigger screening recall. Higher biochemical severity is associated with earlier clinical presentation and higher glucocorticoid requirements. Neonatal 17-OHP concentrations, even when below cut-off values, may represent an early indicator of disease severity and warrant further investigation.