17-α-Hydroxylase deficiency: An unusual case with primary amenorrhea and hypertension.

A 14-year-old girl presented with acute onset quadriparesis and newly detected hypertension. Parental consanguinity, delayed puberty with normal stature form the additional information. Hypokalemia with metabolic alkalosis, low cortisol, high ACTH and FSH pointed to the possibility of CAH with 17α hydroxylase deficiency. 46XX karyotype and high progesterone supported this. Normalization of hypokalemia and hypertension with glucocorticoid treatment confirmed the diagnosis. In summary, the possibility of 17 OHD should be suspected in patients with hypokalemic myopathy, Hypertension and hypogonadism so that appropriate therapy can be implemented.

INTRODUCTION

17-α-Hydroxylase deficiency (17OHD) is a rare form of congenital adrenal hyperplasia resulting from mutation in CYP17 gene.[1] The gene is expressed in adrenal gland and gonads but not in placenta and ovarian granulosa cells.[2] It is an autosomal recessive defect leading to deficiency in glucocorticoid, adrenal androgen, and sex steroid synthesis with concomitant mineralocorticoid excess. Patients present with hypertension and hypokalemia with undervirilized state in males and delayed puberty in females. It has an estimated incidence of approximately 1 in 50,000 individuals.[3] To date approximately 150 cases of 17-α-hydroxylase deficiency have been reported.[4] Here we report one female case with clinical, hormonal, and metabolic characteristics typical of 17OHD.

CASE REPORT

A 14-year-old girl presented with acute onset quadriparesis and hypertension. Parental consanguinity, primary amenorrhea, and absent breast development form the additional information. On examination, BP was 150/100 mmHg without significant asymmetry or postural variation with palpable pulses in all extremities. Her height was 157 cm and weight was 45 kg. There was generalized skin fold and knuckle pigmentation without mucosal pigmentation. Sexual maturity rating was B1 PH1.[5] Axillary hairs were absent. Muscle power was grade 3 with normal deep tendon reflexes and intact sensory, bladder, and bowel functions. Rest of the systemic examination was normal. Investigations revealed hypokalemia (serum potassium, 1.9 meq/L), low 24 h urine potassium (7 meq/day) with metabolic alkalosis (pH, 7.6, HCO3, 30 mmol/L, PaCO2 40 mmHg). Other positive investigations were low serum cortisol (1.5 mcg/dL), high ACTH (513 pg/mL), and high FSH (45 mIU/L). Her karyotype was 46XX and serum progesterone was elevated (8.5 ng/mL, normal < 1.5 ng/mL).

Combination of hypergonadotropic hypogonadism (primary amenorrhea, breast B1 stage with high FSH) adrenal insufficiency (low cortisol with high ACTH) and hypertension with metabolic alkalosis (signifying mineralocorticoid excess) in a girl of pubertal age led to the provisional diagnosis of 17OHD. Serum progesterone being the immediate proximal hormone, prior to 17-α-hydroxylase was elevated confirming the diagnosis of 17OHD. She was prescribed potassium supplementation, prednisolone 10 mg at bedtime, ethinyl estradiol 10 μg, and amlodepin 5 mg daily. Quadriparesis resolved over 1 day. After 2 weeks amlodepin and potassium supplements could be withdrawn without recurrence of hypokalemia and hypertension. Two months later, after stopping prednisolone for 4 days, her tests showed: plasma renin activity < 0.1 ng/mL/h and aldosterone 428.8 pg/mL (normal: 40-480 pg/mL). Prednisolone 10 mg and ethinyl estradiol 10 μg/day were continued. After 3 months due to cushingoid facial features, bedtime prednisolone was replaced with 0.5 mg of dexamethasone.

DISCUSSION

The classical presentation of 17OHD is hypertension, hypokalemia, and delayed puberty with lack of secondary sexual characteristics in a female of pubertal age group.[6] Our patient had all the classical features. Males present with varying degrees of ambiguous genitalia with lack of secondary sexual characteristics.[7] Approximately 90% patients are hypertensive or hypokalemic at presentation.

In humans 17-α-hydroxylase has two functions: (i) it hydroxylates pregnenolone and progesterone in the 17 position; and (ii) cleaves the steroid side-chains from 17-hydroxypregnenolone (17, 20 lyase activity) to convert it to the C-19 androgen precursor, DHEA.[8] Deficiencies in CYP17 result in decreased synthesis of cortisol, C-19 androgens (dihydroepiandrosterone and androstenedione) and sex hormones. Adrenal insufficiency (due to decreased cortisol synthesis) does not manifest as classical Addison's disease because of increased production of corticosterone, a weaker glucocorticoid. Our patient also did not manifest with all the features of Addison's disease except having increased skin fold and knuckle pigmentation. This results in an increase in ACTH secretion, which in turn leads to increased synthesis of steroid intermediates, such as progesterone, 17-α-deoxysteroids (deoxycorticosterone [DOC] and corticosterone).[9] DOC has a potent mineralocorticoid action and causes retention of sodium and water, hypokalemia, alkalosis, and hypertension. In consequence, the renin-angiotensin system is usually suppressed, resulting in decreased aldosterone synthesis leading to a state of hyporeninemic hypoaldosteronism.[3] The low 24 h urine potassium at the baseline in our patient could be attributed to hypoaldosteronism. DOC levels are high in patients with 17-α-OHD, but could not be checked in our patient. High progesterone, the immediate proximal hormone alone could explain the block at 17-α-hydroxylase step [Figure 1].

Figure 1

Steroidogenic pathway defects at various levels in 17OHD and relevant hormonal and clinical manifestations

Hypertension and hypokalemia responded to glucocorticoid treatment. Glucocorticoids suppress the high ACTH-induced mineralocorticoid excess.[10] Mineralocorticoid antagonist, such as spironolactone and calcium channel blockers can be added to the regimen for better control of BP.[1112] Quadriparesis resolved with correction of hypokalemia, so no imaging was done.

Although the approach to a case with hypertension and hypokalemia requires initial measurements of plasma renin and aldosterone, in view of the current scenario with associated findings of hypergonadotropic hypogonadism, low cortisol with high ACTH, elevated progesterone, testing of renin and aldosterone was postponed. However, to complete the workup, plasma renin and aldosterone levels were checked 2 months later (after stopping prednisolone for 4 days, intended toward tapering the effect of glucocorticoid on renin-angiotensin axis). In our patient, findings of low renin and normal aldosterone could be related to gradual reversal of DOC-induced suppression of renin angiotensin axis by glucocorticoid therapy for 8 weeks.

Our patient had primary amenorrhea without any pubertal features and ambiguous genitalia with 46XX karyotype. Deficient estrogen production (exemplified by absent breast development) explains hypergonadotropic hypogonadism. Absence of adrenal androgens explains absent pubic and axillary hairs in our patient. Estrogen therapy is given for induction of puberty and could be required with progesterone in later life to prevent osteoporosis.

CONCLUSION

17-α-Hydroxylase deficiency is a rare cause of CAH; however, it should be considered when 46XY sex reversal or 46XX pubertal failure occurs in association with hypokalemic hypertension, so that appropriate therapy can be implemented. A failure to do so will result in uncontrolled arterial hypertension and its sequelae.