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
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.
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
*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
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: firstname.lastname@example.org
issue | Search journal |
Archived issues | Classifieds
| Hotline (free ads)
Subscribe | Contribute | Advertise | Contact Us | Copyright | Other Journals