Long-term Clinical Outcomes of Primary Adrenal Insufficiency Caused by Homozygous CYP11A1 p.R451W Variant
Atilla Cayir, Huseyin Demirbilek, Ilknur Kurt, Ayberk Turkyilmaz, Serkan Bilge Koca, Mehmet Nuri Ozbek, Murat Karaoglan, Hamdi Cihan Emeksiz, Ismail Dundar, Esra Disci, Ayse Sena Donmez, Gonul Catlı, Bumin N Dundar, Serpil Albayrak, Merve Nur Hepokur, Ayse Ozden, Semra Cetinkaya, Tulay GuranAbstract
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 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%) which was 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; three had micropenis, one had cryptorchidism, and two 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 mineralocorticoid 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.