Nonclassic Adrenal Hyperplasia (NCAH) due to 21-hydroxylase deficiency: A cohort of 78 patients

Diagnosis of nonclassic adrenal hyperplasia (NCAH) due to 21-hydroxylase deficiency (21-OHD) may be challenging due to its occult manifestations. To characterize clinical and molecular features of NCAH patients due to 21-hydroxylase deficiency, we retrospectively included 78 NCAH patients. Their phenotype and genotype were presented and compared. The transcription activities of novel CYP21A2 promoter variants were investigated using a dual-reporter luciferase assay system. This cohort included 53 females (68 %) and 25 males (32 %). The median of onset age was 13 years old (female: 13 range from 7 to 38; male: 11 range from 6 to 71). Menstrual cycle disorder was the most common complaint in females (62 %, n = 33) and for males, it was adrenal incidentalomas (52 %, n = 13). A total of 17 (22 %) patients complained of infertility. The most frequently variant was p.Ile173Asn (20 %, n = 31). Importantly, five variants in the promoter region including - 103/- 126 and 196/- 296 were found in 21 (27 %) patients. Patients with promoter variants showed older onset age and less impaired hormone levels of 17-hydroxyprogesterone, ACTH, progesterone, and androstenedione. Compared with the wild-type promoter, the basic transcription activity of - 103/- 126 and - 196/- 296 promoter variants were reduced by 57% and 25%, respectively. Therefore, females with menstrual cycle disorders or infertility and males with adrenal incidentaloma should be considered of NCAH due to 21-OHD. When genotyping patients with NCAH, the promoter region of the CYP21A2 gene should be also investigated.

Automated summary

We retrospectively analyzed the clinical and molecular features of 78 nonclassic adrenal hyperplasia (NCAH) patients and found associations between certain gene variants and onset age and hormone levels.