	Table of contents

	Current issue

	Search journal

	Archived issues

	NZMJ Obituaries

	Classifieds

	Hotline (free ads)

	How to subscribe

	How to contribute

	How to advertise

	Contact Us

	Copyright

	Other journals

Journal of the New Zealand Medical Association, 25-May-2012, Vol 125 No 1355

Delayed puberty from partial 17-alpha hydroxylase enzyme deficiency

Michael Croxson, C Megan Ogilvie, Stella Milsom, John Lewis, James Davidson, Gill Rumsby

Abstract

An 18-year-old woman with primary amenorrhoea and pubertal delay was investigated for mild labile hypertension and secondary hypogonadism. Low renin and normal aldosterone levels combined with evidence of primary adrenal insufficiency suggested partial 17-alpha hydroxylase enzyme deficiency. The diagnosis was confirmed by measurement of 24-hour urine steroid metabolites and whole gene sequencing of CYP17A1 that demonstrated c.160_162delTTC (p.Phe54del) homozygous mutation. Ultrasound showed bilateral small ovaries with multiple cysts. The serum anti-Mullerian hormone concentration was unremarkable at 6.6 (normal <12.6 ng/ml) but the outlook for her future ovulatory potential is uncertain. Dexamethasone 0.25 mg pre-bed and hydrocortisone 5 mg on waking normalised her hormonal profile and her blood pressure without side-effects.

Failure of puberty to progress to onset of menarche by age 15 in young women usually requires further investigation. The distinctive triad of hypogonadism, low-renin hypertension and primary hypocortisolism in a young woman suggested the presence of congenital adrenal hyperplasia caused by partial deficiency of 17α (alpha) hydroxylase enzyme.

Case report

An 18-year-old daughter of unrelated Indian parents was referred for further endocrine assessment of primary amenorrhoea and pubertal delay. Early growth had been unremarkable with height on the 50th percentile, BMI 18 kg/m2. Breast development as well as axillary and pubic hair had begun 3 years earlier but progressed only to Tanner Stage II. She was found to have normal external genitalia and vaginal appearances.

Ultrasound showed bilateral small ovaries with multiple cysts and a normal uterus. Serum gonadotrophins were not raised, her karyotype was 46XX normal as was a pituitary CT scan. Her blood pressure ranged from 120/80 to 150/100 mmHg and she had occasional migraine-type headaches. A raised plasma ACTH and low basal serum cortisol indicated primary hypocortisolism but plasma active renin level was undetectable, suggesting mineralocorticoid excess rather than deficiency. Basal hormone values and the response to 250 mcg Synachthen (tetracosactide) are shown in Table 1.

Table 1. Pre and post-glucocorticoid treatment steroid, peptide and blood pressure measurements indicate primary adrenal insufficiency. Serum progesterone and corticosterone levels are raised, active renin is suppressed and there is pre-treatment hypertension

Serum values	Pre-treatment	Post-treatment	Normal range
Cortisol	178, basal 0800 186, 1 hr post-ACTH		>550 nmol/l
ACTH	28	5.0	2–11 pmol/l
Corticosterone	731		<40 nmol/l
Progesterone*	12.2	6.4	<6 nmol/l
Aldosterone	414		<850 pmol/l
Active renin	<2		4–46 mU/l
Testosterone	1		0–1.8 nmol/l
Estradiol*	66		<220 pmol/l
DHEAS	<0.4		0.3–6.2 umol/l
FSH	5.6		3–10 IU/l
LH	4.3		2–8 IU/l
Anti-Mullerian hormone	6.6		<12.6 ng/ml
Blood pressure*	130–150/80–100	98/70	<120/80 mmHg

*Normal reference ranges for age, weight and Tanner Stage II.

Hydrocortisone replacement led to increased wellbeing and a slight fall of blood pressure to 130/90. Measurement of urinary steroids and further investigation of a possible CYP17A1 mutation were carried out by Dr Gill Rumsby at UCL Hospitals, London. 24-hour urine adrenal steroids and metabolites were measured by gas chromatography mass spectrometry.

Cortisol and metabolites were reduced while intermediate mineralocorticoid precursors proximal to 17α hydroxylase action were increased, consistent with 17α hydroxylase enzyme deficiency. Whole gene sequencing of CYP17A1 demonstrated c.160_162delTTC (p.Phe54del) homozygous mutation.

Figure 1 illustrates the hormonal consequences of the partial enzyme deficiency.

On confirmation of the diagnosis, her glucocorticoid supplements were modified to maintain diurnal ACTH suppression using dexamethasone 0.25 mg pre-bed and hydrocortisone 5 mg on waking. Her blood pressure fell further to 90/60 and both serum progesterone and ACTH also fell appropriately. Weekly percutaneous oestradiol was added to advance puberty. Additional radiology showed epiphyseal closure but osteopenia with a t score of -2.6 prior to beginning estradiol replacement.

Figure 1. Illustration of the measured hormones decreased or increased in relation to the partial enzyme deficiency

Discussion

Congenital adrenal hyperplasia due to 17α hydroxylase deficiency is a rare form of congenital adrenal hyperplasia with less than 200 cases reported and approximately 50 different mutations of the CYP17A gene identified.1 Partial CYP17A1 deficiency associated with the homozygous phenylalanine 53 or 54 deletion was first described by Yanese et al2 who showed <37% wild type 17α hydroxylase activity and < 8% 17,20 lyase activity in a cell expression system.

The first case was initially reported as an example of dexamethasone suppressible aldosteronism.3 Three 46XX women with the Phe53 deletion had no sexual abnormalities on physical examination and regular or irregular menstruation .

Gonadotrophin levels were normal. One 46XY phenotypic male had hypospadias and cryptorchidism. Hypospadias or microphallus has been reported in a further two phenotypic 46XY males due to partial loss of function mutation at the same site (p.Phe54del) in CYP17.4 Overt cortisol deficiency and adrenal crises are rare because the increased corticosterone production has glucocorticoid activity.

The finding of low renin hypertension with normal aldosterone levels reflects the mineralocorticoid activity of corticosterone and deoxycorticosterone. Delay in recognition of hypertension may occur unless normative childhood values are used for comparison. With hindsight, unexpected elevation of serum progesterone was a clue to the presence of increased steroid precursors and the true diagnosis. Both parents are normotensive and her 24-year-old brother has a normal male phenotype and normal steroid values, but mildly elevated plasma corticosterone and corticosterone/cortisol ratios both basally and after ACTH stimulation, as has recently been shown in genotype-proven heterozygous individuals.5 The outlook for her future fertility remains uncertain.

Author information: Michael Croxson, Endocrinologist, Auckland Hospital, Auckland; C Megan Ogilvie, Endocrinologist, Auckland Hospital, Auckland; Stella Milsom, Endocrinologist, Auckland Hospital, Auckland; John Lewis, Scientific Officer, Steroid Laboratory, Christchurch Hospital, Christchurch; James Davidson, Chemical Pathologist, Auckland Hospital, Auckland; Gill Rumsby, Consultant Biochemist, Department of Clinical Biochemistry, University College London Hospitals, London, England

Correspondence: Michael Croxson, Endocrinology Department, Greenlane Clinical Centre, Private Bag 92189, Auckland, New Zealand. Fax +64 (0)9 3074993; email: michaelc@adhb.govt.nz

References:

Yanase T, Simpson ER, Waterman MR. 17 alpha-hydroxylase/17,20-lyase deficiency: from clinical investigation to molecular definition. Endocr Rev. 1991; 12(1):91–108.
Yanase T, Kagimoto M, Suzuki S, et al. Deletion of a phenylalanine in the N-terminal region of human cytochrome P-450(17 alpha) results in partial combined 17 alpha-hydroxylase/17,20-lyase deficiency. J Biol Chem. 1989; 264(30):18076–82.
Miura K, Yasuda K, Yanase T, et al. Mutation of cytochrome P-45017 alpha gene (CYP17) in a Japanese patient previously reported as having glucocorticoid-responsive hyperaldosteronism: with a review of Japanese patients with mutations of CYP17. J Clin Endocrinol Metab. 1996; 81(10):3797–801.
Lin L, Rumsby G, Honour JW, et al. Micropenis or hypospadias due to a partial loss of function mutation (F54del) in CYP17. Proceedings of the American Endocrine Society, New Orleans 2004 P1–490.
Qiao J, Chen X, Zuo CL, et al. Identification of steroid biosynthetic defects in genotype-proven heterozygous individuals for 17alpha-hydroxylase/17,20-lyase deficiency. Clin Endocrinol. 2010 ; 72(3):312-9.