17α-hydroxylase/17,20-lyase Deficiency Diagnosed at 45 Years of Age with Hyperaldosteronism

Abstract

17α-hydroxylase deficiency is a type of congenital adrenocortical hyperplasia that is typically diagnosed in childhood or adolescence. It manifests as hypertension with gonadal dysfunction as the primary symptom. We herein report 17α-hydroxylase/17,20-lyase deficiency (17OHD) diagnosed at the age of 45 years. The patient presented with hypertension, irregular menstruation, and hyperaldosteronism. The clinical manifestations of 17OHD vary based on the specific variant pattern of CYP17A1. In this case, the variant was c.157_159 TCC del p. Phe53del, which has been frequently reported in Japan. The enzymatic deficiency due to this variant is partial, leading to a delay in making a correct diagnosis.

Introduction

17α-hydroxylase/17,20-lyase deficiency (17OHD) is a rare disease characterized by hypertension and gonadal dysfunction (1) as the primary clinical symptoms. It accounts for approximately 1% of congenital adrenal hyperplasia (CAH) cases, but it is a relatively frequent type of CAH in Japan, Korea, and Brazil (2,3). 17OHD is caused by a mutation in CYP17A1. To date, over 100 variants have been reported (4), and some patients experience either a complete or partial loss of enzyme activity depending on the position of the variant (5). We herein report a case of 17OHD in a 45-year-old female with menstruation due to partial loss of enzymatic activity of CYP17A1.

Most patients with 17OHD are diagnosed with symptoms of hypogonadism from childhood to puberty, such as undermasculinization of the external genitalia in males and a lack of secondary sexual characteristics such as amenorrhea and breast underdevelopment in females.

However, atypical cases of menstruation have also been reported, wherein the enzyme activity is only partially lost (6,7).

Patients with 17OHD typically present hypoaldosteronism. However, some patients present with hyperaldosteronism and primary aldosteronism is suspected to be the cause of hypertension (8). The patient in this case was initially suspected to have primary aldosteronism. Therefore, 17OHD should be differentiated in adult patients with hypertension.

Case Report

A 45-year-old woman was diagnosed with hypertension at the age of nine and admitted to the pediatric department of a nearby hospital. However, the cause of hypertension was not identified at the first hospitalization, and at 12 years of age, she was re-admitted to a pediatric hospital and examined carefully; however, the cause of hypertension was not identified. Her first menarche occurred late namely, at 18 years of age. Thereafter, her menstrual cycle became more irregular.

She continued to have high blood pressure (BP) and was repeatedly identified during health checkups; however, she did not seek medical attention. At 45 years of age, she was strongly advised to see a referral doctor in the workplace about hypertension.

Subsequently, hyperaldosteronism and hypokalemia were observed at a medical institution, and primary aldosteronism was suspected. The patient was referred to our hospital for a detailed examination of primary aldosteronism.

The blood pressure at the first visit to our hospital was high at BP 178/112 mmHg under the antihypertensive drugs cilnidipine (20 mg) and Amlodipine Besilate (5 mg). Physical examination revealed a mild nail bed pigmentation. The vulva was female, but pubic hair had fallen off. Her breasts were observed to have Tanner stage 3. Blood data showed hypokalemia (K 2.9 mEq/L) and high level of plasma adrenocorticotropic hormone (ACTH 112.0 pg/mL) and hypocortisolemia (cortisol 3.7 μg/dL) (Table 1). A high plasma aldosterone level (PAC 200 pg/mL) and low plasma renin activity (PRA 0.3 ng/mL/h) was also found. Abdominal computed tomography (CT) (Fig. 1) revealed right-dominant (long diameter, 34 mm) bilateral adrenal enlargement.

Table 1.

Bassl Hormone Profile of This Patient.

ACTH	112	pg/mL
Cortisol	3.7	μg/dL
PRA	0.3	ng/mL/h
PAC	200	pg/mL
DHEA-S	6.0	μg/dL
LH	41.5	mIU/mL
FSH	74.6	mIU/mL
Estradiol	<10.0	pg/mL
Progesterone	4.71	ng/mL/h

ACTH: adrenocorticotropic hormone, DHEA-S: dehydroepiandrosterone sulfate, FSH: follicle stimulating hormone, LH: luteinizing hormone, PAC: plasma aldosterone concentration, PRA: plasma renin activity

Figure 1.

An abdominal and pelvic computed tomography scan. Both adrenal glands are enlarged (arrows).

Based on clinical symptoms and laboratory findings, 17OHD was suspected. Her blood steroid metabolite levels were evaluated using commercial laboratory tests.

High levels of corticosterone (B) and deoxycorticosterone (DOC) and low levels of 17OH-progesterone were consistent with CYP17A1 disorders, but were atypical for 17OHD because of the high levels of PAC (Fig. 2). In the synthetic ACTH stimulation test (Table 2), although PAC showed an increase in reactivity, no reaction was observed between 17OHP and cortisol and CYP171A enzyme damage was strongly suspected.

Figure 2.

Steroid metabolism map for the blood steroid profile. The blood steroid hormone levels were measured using the conventional RIA. PAC was measured using aldosterone kits (Fujirebio, and the normal range in women. CYP: cytochrome P450, DHEA: dehydroepiandrosterone, DHEA-S: dehydroepiandrosterone sulfate, DOC: deoxycorticosterone, 17-OH pregnenolone: 17-hydroxypregnenolone, 17-OH progesterone: 17-hydroxyprogesterone, 17βHSD: 17β-hydroxysteroid dehydrogenase, 3βHSD: 3β-hydroxysteroid dehydrogenase

Table 2.

Loading Tests of Patient.

Captopril suppressing test
	Before	60min	90min
PAC (pg/mL)	173	173	267
PRA (ng/mL/h)	0.3	0.3	0.3
ARR (PAC/PRA)	576.7	576.7	890.0
Synthetic ACTH stimulation test
	Before	30min	60min
PAC (pg/mL)	202	307	354
17OHP (ng/mL)	1.03	1.13	1.32
Cortisol (μg/dL)	3.6	3.9	4.3

ACTH: adrenocorticotropic hormone, ARR: aldosterone-renin ratio, PAC: plasma aldosterone concentration, PRA: plasma renin activity, 17OHP: 17-hydroxyprogesterone

On the contrary, the urinary free cortisol was relatively maintained at 57.3 μg/day, and secondary sexual characteristics and menstruation was present. These findings indicate that the CYP171A enzyme activity was partial, and incomplete.

Owing to atypical findings for 17OHD, such as menstruation and hyperaldosteronism, the samples were sent to Keio University Hospital for urinary steroid metabolite analysis to make a definitive diagnosis. The urinary steroid profile results (Fig. 3) showed that B metabolites were 4.4 times the upper limit and 17OH steroids, dehydroepiandrosterone, and androstenedione metabolites were less than the lower limit of 20%; consistent results were obtained for 17OHD. With the patient's consent, genetic analysis was performed and a homozygous mutation of c.157_159 TCC del p. Phe53del, which is a known mutation in the causative gene CYP17A1, was detected (Fig. 4).

Figure 3.

Steroid metabolism map for the urine steroids profile. Urinary steroid metabolisms were measured by the gas chromatography method. An: androsterone, CYP: cytochrome P450, DOC: deoxycorticosterone, DHEA: dehydroepiandrosterone, DHEA-S: dehydroepiandrosterone sulfate, Et: ethiocholanolone, E1: estrone, E2: estradiol, E3: estriol, PD: pregnanediol, PTS: 3α-17α-20α pregnanetriol, THAld: tetrahydroaldosterone, THDOC: tetrahydro-11-deoxycorticosterone, α+β THB: α+β tetrahydrocorticosterone, 3βHSD: 3β-hydroxysteroid dehydrogenase, 5αβTHF: 5αβ tetrahydrocortisol, 5βTHS: 5β-tetrahydro-11-deoxy cortisol, 16OHOS: 16α-hydroxypregnenolone, 17-OH pregnenolone: 17-hydroxypregnenolone, 17-OH progesterone: 17-hydroxyprogesterone, 17βHSD: 17β-hydroxysteroid dehydrogenase, 20αPT: 5β-20α pregnanetriol

Figure 4.

Genetic analysis results. The sequence analysis of the CYP17A1 gene of the patient identified a CTT deletion at codon 157-159 of exon 1 (arrow).

The oral administration of 0.5 mg/day of dexamethasone was initiated, hypokalemia and hypertension improved, and the ACTH level decreased to the normal range. However, estimated glomerular filtration rate decreased from 61 to 42 mL/min after dexamethasone administration, and a decreased renal function was observed.

As it turned out later, it was highly likely that the paternal and maternal grandmothers were third-degree relatives (aunt and niece relationships) in the present case.

Discussion

17OHD is a CAH disease clinically characterized by hypertension and gonadal dysfunction due to decreased activity of the steroidogenic enzyme P450cl7 caused by genetic variation in CYP17A1 (9). As it is an autosomal recessive inherited disease, familial confirmation through detailed medical interviews can be an important step in making an accurate diagnosis. To date, more than 500 cases of 17OHD and 100 CYP17A1 variants causing 17OHD have been reported. Hotspots of this variant have not yet been reported for CYP17A1 (4,10). One-third of 17OHD cases have been reported in Japan (9). CYP17A1 variant sites are biased by region and country; however, the reason for this remains unclear (3).

In this case, the identified CYP17A1c.157_159 TCC del (p. Phe53del) mutation was a frequently reported variant, especially among Japanese patients.

17α and 17-20 enzyme activities decreased to 23% and 5%, respectively, for this mutation (11). Because the activity of each enzyme is only partially inactivated, female 17αOHD patients with this mutation are clinically characterized by a low frequency of gonadal dysfunction, including menstrual abnormalities (9). Some patients are diagnosed with 17OHD after adulthood because of infertility and hypertension (12-14). In the present case, hypertension was identified in childhood, and the patient underwent multiple hospitalizations for detailed examination. However, making a definitive diagnosis of 17OHD takes a long time because symptoms of typical hypogonadism in 17OHD are scarce. Although primary aldosteronism is suspected in adults with hypertension and hypokalemia, some cases of 17OHD show partial residual CYP171A activity, as observed in the present case. Physicians should also note that there are cases in which hypertension and hypokalemia occur, but hypogonadism is not conspicuous in 17OHD.

For the treatment of 17OHD, suppressing DOC production by suppressing ACTH secretion using dexamethasone is important. Aldosterone production is typically suppressed in 17OHD; however, many 17OHD cases with high aldosterone levels have been reported in Japanese patients (9). The mechanism underlying aldosterone levels that vary from low to high in 17OHD remains unknown. Yamakita et al. reported that the higher the impairment of 17α-hydroxylase activity, the higher the aldosterone level (15).

A significant limitation in the interpretation of aldosterone levels in our case was due to the fact that the blood steroid hormone levels were quantified using a radioimmunoassay (RIA). The aldosterone levels ascertained via RIA are prone to cross-reactivity with DOC and corticosterone (B) (7,16), thus potentially leading to artificially elevated readings. Regrettably, the plasma samples from this patient were not preserved, thus precluding us from presenting the results of aldosterone, DOC, and B measurements obtained using liquid chromatography-tandem mass spectrometry (LC/MS-MS). The metabolites of urinary aldosterone, as measured by gas chromatography, were found to be low relatively to the blood aldosterone levels measured by RIA. Conversely, the levels of urinary B metabolites measured using gas chromatography were high (Fig. 3). Consequently, it is hypothesized that the elevated blood aldosterone levels, as measured using RIA in this case, can be attributed to cross-reactivity with B and DOC.

Currently, the methodology for quantifying aldosterone in Japan has transitioned from RIA to the chemiluminescent enzyme immunoassay (CLEIA), thus leading to decreased cross-reactions with DOC and B. This transition to the CLEIA method resulted in diminished aldosterone levels compared with those ascertained using the RIA method in patients diagnosed with primary hyperaldosteronism. Consequently, the diagnostic criteria for primary hyperaldosteronism have become a topic of ongoing scholarly debate (17,18). In patients with 17OHD, renin is suppressed by the mineralocorticoid action of DOC and B, even in the absence of a significant elevation in aldosterone levels. As previously mentioned, a substantial number of 17OHD cases with elevated aldosterone levels have been documented in Japan (9). Therefore, we emphasize the necessity of not hastily dismissing 17OHD in adult patients with hypertension who present with hypokalemia and hyperaldosteronism.

In the present case, the administration of dexamethasone (0.5 mg) suppressed ACTH, normalized the aldosterone levels measured using RIA, and improved hypokalemia and hypertension. However, after dexamethasone administration, the patient developed renal dysfunction that closely resembled acute kidney injury following adrenalectomy for primary aldosteronism (Table 3). In cases such as ours, where 17OHD had not been diagnosed until adulthood and was exposed to high aldosterone or DOC and B levels for a long period of time, hyperfiltration due to the mineralocorticoid action of aldosterone or DOC and B may mask any deterioration of the renal function. Prolonged exposure to hypertension also contributes to renal impairment. Attention should be paid to the changes in renal function after the initiation of dexamethasone. It should be noted that even in 17OHD patients with low aldosterone levels, those diagnosed in adulthood may experience a similar course owing to the aldosterone-like effects of DOC and B. The possibility of 17OHD should therefore be considered when examining patients, and by shortening the duration of hypertension, renal dysfunction can be avoided, as in this case.

Table 3.

Renal Function Changes before and after Treatment.

	Before treatment	After treatment
BP (mmHg)	178/112	135/99
ACTH (pg/mL)	112.0	14.5
K (mEq/L)	2.9	4.4
BUN (mg/dL)	14.2	23.6
Cr (mg/dL)	0.81	1.14
eGFR (mL/min/1.73 m2)	60.8	42.0

ACTH: adrenocorticotropic hormone, BP: blood pressure, Cr: serum creatinine, eGFR: estimated glomerular filtration rate, K: serum potassium

Conclusion

17OHD shows various clinical symptoms, depending on the site of the gene variant. The c.157_159 TCC del p. Phe53del variant, which is common in Japanese people, may cause menstruation, and therefore it is important for such patients to consult an internal medicine doctor with the chief complaint of hypertension in adulthood. At that time, if hypertension, hypokalemia, hyperaldosteronism, and hyporeninemia are present, but accompanied by high ACTH levels, there is a possibility of 17OHD rather than primary aldosteronism. As 17OHD diagnosed in adulthood is associated with a long period of hypertension, renal function deterioration may become apparent when treatment with dexamethasone is initiated.

The authors state that they have no Conflict of Interest (COI).