Dual Heterozygous Mutations in CYP21A2 and CYP11B1 in a Case of Nonclassic Congenital Adrenal Hyperplasia

Abstract

Background/objective: Nonclassic congenital adrenal hyperplasia (NCCAH) may be overlooked or mistaken for polycystic ovarian syndrome. Unlike congenital adrenal hyperplasia (CAH), the enzymatic activities of 21-hydroxylase or 11β-hydroxylase in NCCAH are not completely lost. In this case, NCCAH presented in a patient with CYP21A2 and CYP11B1 heterozygous mutations, one of which is a variant of unknown significance in CYP11B1.

Case report: A 30-year-old woman presented with a chief complaint of irregular menses and hirsutism. Previous medical history was significant for a prolactin level of 34.7 ng/mL (reference range, 2.0-23.0 ng/mL), a total serum testosterone level of 77 ng/dL (reference range, 25-125 ng/dL, not sex-specific), and a 2-mm × 3-mm pituitary lesion. An adrenocorticotrophic hormone stimulation test increased the 17-hydroxyprogesterone level from 444 ng/dL at baseline to 837 ng/dL at 60 minutes (baseline female reference range and stimulated reference ranges are 10-300 ng/dL and <1000 ng/dL, respectively). Gene sequencing revealed a heterozygous pathogenic CYP21A2 variant and a heterozygous, previously undescribed variant of unknown significance in CYP11B1.

Discussion: Unlike CAH, NCCAH presents more subtly and later in life, and salt wasting and hypertension are not typically seen. Although mutations in CYP11B1 that cause steroid 11β-hydroxylase deficiency more commonly lead to the CAH phenotype, cases have been reported of CYP11B1 mutations leading to NCCAH, depending on the location of the mutations.

Conclusion: This patient's case demonstrates physical examination and laboratory findings suggestive of NCCAH. Our case adds to the database of described mutations in CYP11B1 and suggests that heterozygous mutations in 2 different genes may present phenotypically as NCCAH.