SUN-204 Case of Non-Classic Congenital Adrenal Hyperplasia with Compound CYP21A2 Mutations Combined with CYP11B1 Mutation

Introduction: Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder, caused by a deficiency in one of the enzymes involved in adrenal steroid synthesis. Homozygotes usually have a severe classical CAH phenotype. Heterozygotes, carrying only one abnormal copy of the gene, are thought to be generally asymptomatic, although could be associated with hyperandrogenism, decreased fertility, adrenal incidentalomas. 21-hydroxylase deficiency (21OHD) accounts for 90% of all CAH cases, while 11 β-hydroxylase deficiency (11OHD) accounts for 4–8% of CAH cases. The nature and mechanism of a combined enzymatic defect are unknown. The coincidental presence of gene mutation for both 21OHD and 11OHD CAH in a single individual is very unlikely to occur. Clinical case: A 22-year old female with no significant past medical history presented to endocrinologist for evaluation of facial hirsutism. Patient had menarche at age 11, and menstrual cycle was regular since. No concerns for virilization of external genitalia. She was not sexually active, no pregnancies. No Family history of infertility or genetic conditions. Patient’s father was Jewish, and mother was Slavic. Physical examination revealed female phenotype, normal Blood pressure and BMI, acne on the back and upper arm, Ferriman-Gallwey hirsutism score 5. Labs: AM cortisol, CMP, CBC and TSH were normal. Total testosterone 68 ng/dL (2–45), free testosterone 7 pg/mL (0.1 - 6.4), FSH 5.7 mIU/mL (2.5–10.2), LH 10.6 mIU/mL (1.9–12.5), Progesterone 2.1 ng/mL (<1), Estradiol 51 pg/mL (19–144), 17-OH Progesterone 6728 ng/dL (45–285), Androstenedione 710 ng/dL (35–250), DHEA 1216 ng/dL (102 - 1185), 11-Deoxycortisol 204 ng/dL (<107), Pregnenolone 661 ng/dL(22–237), DHEAS 435 ng/dL (18–391). Elevated 11-Deoxycortisol level raised a suspicion for 11-OHD CAH, or adrenal vs ovarian hormone-producing mass. Abdominal CT and pelvic US were negative for adrenal or ovarian masses. 3-day dexamethasone suppression test completely normalized all biochemical abnormalities the patient had. Genetic testing showed: CYP21A2 c.844G>T (non-classic 21OHD CAH mutation), CYP21A2 c.923dupT (classic 21OHD CAH mutation), CYP11B1 c.953C>G mutation. Thus diagnosis of non-classic 21OHD CAH, and carrier status of 11OHD CAH was made. She was started on oral Dexamethasone 0.25 mg every other day. 11-Deoxycortisol elevation could not be explained by 21OHD alone. Her carrier state of the CYP11B1 mutation also cannot cause elevated 11-Deoxycortisol level. We hypothesize that 11-Deoxycortisol was elevated either from extra adrenal conversion of 17-hydroprogesterone to 11-Deoxycortisol, or from 11 β-hydroxylase inhibition by excess intra-adrenal androgens. Conclusion: Our case reports a rare finding of both CYP21A2 and CYP11B1 mutations in the same individual, which has implications for relatives, family planning and partner genetic screening.