A Novel CYP17A1 Mutation in a Compound Heterozygote and Response to Mineralocorticoid Receptor Antagonist Therapy

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SUN 29-49-Congenital Adrenal Hyperplasia & Ectopic Cushing's
Clinical
Sunday, June 16, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SUN-31
Elizabeth Osborne Buschur*1, Jiayan Liu2, Jacqueline L Naffin-Olivos3 and Richard Joseph Auchus1
1University of Michigan, Ann Arbor, MI, 2University of Michigan, 3Brandeis University, Waltham, MA
Background: The hypertension of ACTH-dependent mineralocorticoid excess is often treated with dexamethasone, but mineralocorticoid receptor antagonist (MRA) therapy might be equally effective and cause fewer long-term side effects.

Clinical Case: A 35 YO Caucasian woman presented for evaluation of primary amenorrhea. She had bilateral inguinal hernia repairs and childhood onset, refractory hypertension. She received estrogen replacement for Mullerian and ovarian agenesis since adolescence. The blood pressure (BP) was 130/86 despite metoprolol, amlodipine, hydralazine, and irbesartan. Exam was remarkable for a 2/6 systolic murmur at the left sternal border, bilateral surgical scars in the groin, Tanner 5 breasts, scant axillary hair, Tanner 3 pubic hair with normal external female genitalia, and no clitoral enlargement. Her skin had hyperpigmentation in the palmar creases but no edema, bruising, striae, or thinning. ECG showed left ventricular hypertrophy by voltage. Labs showed K 2.9 mEq/L (n 4-5.2), PRA < 0.6 ng/mL/h (n ≤0.6-4.3), aldosterone 6.2 ng/dL (n ≤21), ACTH 47 pg/mL (n 10-60), cortisol 4.4 mcg/dL (n 7-25), DHEAS <15 mcg/dL (n 44-332), and 46,XY karyotype. Cosyntropin stimulation revealed peak cortisol of 3.9 mcg/dL (n >18) and markedly elevated corticosterone and 11-deoxycorticosterone at 21,981 (n 53-1560) and 368 ng/dL (n <10), respectively.  With informed consent, sequencing of the CYP17A1 gene showed compound heterozygous mutations A398V and F463C, consistent with partial, combined 17-hydroxylase/17,20-lyase deficiency (17OHD). In transiently transfected HEK-293 cells, these mutations retained 13-16% of wild-type 17-hydroxylase and <1% 17,20-lyase activities.

Treatment with spironolactone 25 mg bid normalized BP and K. Her other antihypertensives were gradually discontinued; BP and K remained normal on spironolactone 50 mg bid plus hydrocortisone 10 mg qam, yet she developed orthostasis and exercise intolerance. Spironolactone was changed to eplerenone 50 mg daily, and DHEA 25 mg/d was added, to allow pubic hair progression to Tanner 5. PRA and ECG voltage normalized after 18 months.

Conclusion: This case represents a novel F463C mutation in a young woman with 17OHD and hypertension. Treatment with a MRA allowed subphysiologic hydrocortisone replacement, which avoided glucocorticoid excess. This case suggests that early-onset mineralocorticoid hypertension over time leads to chronic physiologic adaptations, which resolve slowly.

Nothing to Disclose: EOB, JL, JLN, RJA

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm