Long-term clinical outcomes of primary adrenal insufficiency caused by homozygous CYP11A1 p.R451W variant

Background: The cytochrome P450 side-chain cleavage enzyme (P450scc), encoded by the CYP11A1 gene, regulates the first and rate-limiting step of steroidogenesis. c.1351C > T (p.R451W) is the most commonly identified pathogenic variant in the CYP11A1 gene, and is associated with a mild P450scc deficiency. Long-term follow-up data of affected individuals are insufficient. Aim: To investigate the long-term growth, pubertal development, and adrenal and gonadal functions of patients with homozygous CYP11A1 c.1351C > T (p.R451W) variant. Method: Retrospective follow-up data were obtained from the medical records of patients managed at tertiary pediatric endocrinology centers. Results: Twenty-two patients (16 males) from 16 families were included. The median age at presentation was 4.8 ± 4.2 years (range: 1-14.6 years), and the mean follow-up period was 7.8 ± 5.2 years (range: 0.5-17.9 years). Primary adrenal insufficiency (PAI) was present in all cases. Three patients were diagnosed during family screening. Mineralocorticoid (MC) deficiency was detected in 20 patients (83%), and recovered in 2 cases during follow-up. One patient with no MC deficiency at presentation had developed a salt-wasting crisis during acute illness. None of the 46,XY cases showed atypical genitalia; 3 had micropenis, 1 had cryptorchidism, and 2 patients required sex steroid therapy because of subsequent hypergonadotropic hypogonadism later. Conclusion: Mild P450scc deficiency due to p.R451W variant in the CYP11A1 gene is associated with late onset PAI with variable MC and sex hormone deficiency. The growth is consistent with genetic potential, and pubertal onset and progression are normal in affected patients, while long-term follow-up is required with regard to the risk of gonadal failure.