A Chinese girl with delayed puberty due to 17α-hydroxylase deficiency: the diagnosis, treatment and monitoring approach

Background

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders that disrupt adrenal steroidogenesis. 17α-hydroxylase deficiency (17α-OHD) is caused by mutations in cytochrome P450 family 17 subfamily A member 1 (CYP17A1) gene, which encodes 17α-hydroxylase (1). It catalyses two steroidogenic pathways in the adrenal glands and the gonads: 17-α-hydroxylation, which involves in cortisol production, and 17,20-lyase, which involves in sex steroids production. This results in cortisol deficiency and leads to increased production of adrenocorticotropic hormone (ACTH), resulting in the accumulation of deoxycorticosterone (DOC) and corticosterone, which leads to hypertension (2). On the other hand, it also leads to impaired sex steroid production and hence lack of pubertal development in girls and even sex reversal in boys (3). Herein, we report the cass of a 13-year-old Chinese girl with 17α-OHD who presented with delayed puberty and hypertension.

Case presentation

A 13-year-old Chinese girl, who enjoyed good past health, was referred for delayed puberty. She was born to non-consanguineous Chinese parents. She had one elder sister who had given birth to a healthy baby boy, otherwise, there was no family history of stillbirth, unexplained neonatal death, pubertal issues or infertility. On examination, she was not dysmorphic, her height was 158 cm (75th percentile) and body weight was 39.7 kg (25th percentile). She was prepubertal with Tanner stage 1 breast development with absent axillary and pubic hair. She had normal female external genitalia without features of virilisation, and there was no mucocutaneous hyperpigmentation. She was found to have high blood pressure at 173/124 mmHg. On direct questioning, she did complain of intermittent headaches. Cardiovascular examination was unremarkable with no radio-femoral delay. There was no focal neurological sign and fundi examination was normal.

Investigations

Initial investigations were remarkable for hypokalaemia (serum potassium = 3.4 mmol/L) with suppressed plasma renin (<0.07 ng/mL), low plasma aldosterone (<50 pmol/L). The renal function and serum sodium were normal. In view of the finding of hypertension, echocardiogram was performed and showed normal heart structure with no coarctation of the aorta nor left ventricular hypertrophy. She was also found to have hypergonadotropic hypogonadism (luteinising hormone: 26.4 IU/L, follicle stimulating hormone: 66.4 IU/L, oestradiol: <18 pmol/L). She had normal female karyotype (46, XX). She failed standard dose synacthen test (baseline ACTH was elevated at 32.6 pmol/L, cortisol at 0 min: <14 nmol/L, 30 min: 19 nmol/L, 60 min: 17 nmol/L), which was suggestive of primary adrenal insufficiency. Essential laboratory results were summarised in Table 1.

Twenty-four-hour urine steroid profile showed undetectable 17-OH progesterone, 11-deoxycortisol and androstenedione and markedly elevated pregnenolone, progesterone, deoxycorticosterone (DOC) and corticosterone (Fig. 1A).

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Urine steroid profile (USP) chromatogram at diagnosis (A) and after treatment (B). Spike A and B denote internal standards androstanediol and cholesterol butyrate, respectively, for quantitative comparison. There were excess of progesterone, pregnenolone and corticosterone metabolites (spike 1 to 8) at diagnosis, which significantly improved with treatment. Adrenal androgens (grey arrow) were absent at both time points.

Citation: Endocrinology, Diabetes & Metabolism Case Reports 2023, 3; 10.1530/EDM-23-0047

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PCR and Sanger sequencing of all the exons and introns of CYP17A1 gene, as well as gene dosage analysis using multiplex ligation-dependent probe amplification revealed homozygous pathogenic variants in CYP17A1 gene [c.985_987delinsAA (p.Tyr329Lys) in exon 6. Both parents were later confirmed to be carriers. Together with the clinical picture of hypergonadotropic hypogonadism, hypokalaemic hypertension and primary adrenal insufficiency, the diagnosis of 17α-OHD was substantiated. There was no evidence of end-organ damage as a result of hypertension.

Treatment

Partial hydrocortisone replacement (6 mg/m²/day) and spironolactone (100 mg twice daily) were started for hypokalaemic hypertension. Amlodipine (10 mg daily) was later added for better blood pressure control at the age of 14 years. She was started on oral oestradiol for pubertal induction, cyclical progesterone was also added later for regular menstrual flow.

Outcome and follow-up

The patient’s blood pressure, serum potassium and plasma renin normalised. Urinary steroid profile still showed elevated DOC level, though it had been markedly reduced (Fig. 1A and B). At the age of 16 years, she had Tanner stage 4 breast development but absent axillary and pubic hair. She had regular menstrual cycles with cyclical progesterone.

Discussion

We report on a Chinese teenage girl with 17α-OHD who presented with delayed puberty, hypergonadotropic hypogonadism and hypokalaemic hypertension. To the best of our knowledge, this is the first reported case with a complete urine steroid profile comparison before and after treatment.

17α-OHD was first reported by Biglieri et al. in 1966, who described a 35-year-old female patient with hypertension, hypokalaemia and amenorrhoea (4). To date, there are more than 500 reported cases of 17α-OHD reported worldwide (5). It is caused by autosomal recessive mutations in the cytochrome P450c17, encoded by the CYP17A1 gene in chromosome 10q24-q25. In steroid biosynthesis, CYP17A1 enzyme catalyses actions of 17α-hydroxylase and 17, 20-lyase in the adrenal glands and gonads. Therefore, it gives rise to the biochemical picture of primary adrenal insufficiency and primary gonadal insufficiency.

As illustrated in Fig. 2, patients with 17α-OHD had glucocorticoid deficiencies. This stimulates excess ACTH secretion, and because of the enzymatic blockage, it further drives DOC and corticosterone production. DOC is a potent mineralocorticoid and, in excess amounts, causes hypokalaemic hypertension and suppresses renin and aldosterone secretion. Interestingly, hypertension tends not to occur in infancy, as the kidneys of infants are insensitive to mineralocorticoids (2). On the other hand, corticosterone carries glucocorticoid effects. Therefore, with high corticosterone levels, adrenal crisis is rare (2). The lack of androgen metabolites causes absent pubic hair and axillary hair in females, as in our patient. In males, they may present with sex reversal, absent pubic hair and axillary hair (3). The phenotypes of the disease are heterogeneous, it has been estimated that 10–15% of cases are normotensive and some patients even had normal serum potassium level (1). These heterogeneities are even observed in cases with the same mutation and in those with total enzymatic deficiency. This suggests that other disease modifiers may play a role in the exact clinical phenotype (6).

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CYP17A1 enzyme catalyses actions of 17α-hydroxylase and 17, 20-lyase in the adrenal glands and gonads. In patients with 17α-OHD, the enzymatic block results in glucocorticoid deficiencies, which stimulates excess ACTH secretion and further drives DOC and corticosterone production.

Citation: Endocrinology, Diabetes & Metabolism Case Reports 2023, 3; 10.1530/EDM-23-0047

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The general prevalence of the gene mutation in the Chinese population is unknown. Based on multiple studies from Mainland China, c.985_987delinsAA (p.Tyr329Lys) and c.1459_1467 (p.487_489del) are the two commonest mutations amongst the Chinese population (6, 7). In this report, our patient also carried one of these hotspot mutations. Among non-Chinese patients, more than 90% of patients carried mutations other than the two aforementioned mutations (5). This suggests the genetic mutations among patients with 17α-OHD vary with ethnicity.

Treatment of 17α-OHD mainly includes partial glucocorticoid supplementation, blood pressure control and sex hormone replacement. While classical CAH due to 21-hydroxylase deficiency is a condition of glucocorticoid deficiency, it is not the case in 17α-OHD, as the high corticosterone concentrations in 17α-OHD would compensate for glucocorticoid deficiency. Therefore, patients with 17α-OHD are not at risk for adrenal crisis. Indeed, glucocorticoid treatment could even cause adrenal suppression and consequently prevent an appropriate glucocorticoid (corticosterone) response during physiological stress or acute illness (2). However, glucocorticoids could ameliorate ACTH elevation that helps to lower DOC level and control hypertension and potassium level. As a compromise, partial replacement can lower DOC yet mitigate the long-term consequences of glucocorticoid therapy (2). Mineralocorticoid antagonists such as eplerenone and spironolactone should be added when partial glucocorticoid supplementation is not sufficient to achieve satisfactory blood pressure control. Calcium channel blockers and angiotensin II receptor blockers are sometimes used for adjunct blood pressure control (2). In our patient, hypertension was only partially controlled with hydrocortisone replacement and spironolactone. Amlodipine added as eplerenone was not available in our institution at that juncture. Subsequently, blood pressure normalised and hence she was continued with amlodipine. On the other hand, for 46, XX patients, oestrogen replacement would be needed for pubertal induction and cyclical progesterone replacement would be added after 2–3 years to induce cyclical withdrawal bleeding and prevent endometrial hyperplasia. For 46, XY patients who are raised as female, oestrogen alone would be prescribed to induce female secondary sexual characteristics. However, if the patient is raised as a male, testosterone replacement therapy, genital reconstructive surgery and gonadectomy to avoid malignant changes in intra-abdominal cryptorchidism, would be needed. Theoretically, patients remain infertile due to an irreversible steroidogenesis defect that impairs spermatogenesis and folliculogenesis (8). However, with advancement in reproductive medicine, successful live birth in a 46, XX individual with 17α-OHD with in vitro fertilisation frozen-thawed embryo transfer had been reported (9).

In general, patients should be monitored clinically, including blood pressure, growth and pubertal development, and biochemically by serum potassium and plasma renin. Plasma renin level reflects the degree of mineralocorticoid receptor antagonism. However, it might take months or even years to normalise (2). The serial change in urine steroid profile in patients with 17α-OHD at diagnosis and after treatment was seldom reported. In our patient, a reduction of DOC in the urinary steroid profile was observed after treatment. However, it is generally not recommended to use urine steroid profile alone for disease monitoring, as the test only provides semi-quantitative data and there is a lack of target level for the steroid markers (10). Nevertheless, this could serve as another marker for disease control.

A high incidence of hypertension-mediated organ damage in patients with 17α-OHD has been reported and is postulated to be related to undiagnosed and hence untreated or partially treated hypertension of long duration (7); this, fortunately, was not observed in our patient. This highlights the importance of early recognition and timely treatment for this rare disease entity.

When assessing a child with delayed puberty, blood pressure and electrolytes should constitute an essential part of the investigation. In girls with hypergonadotropic hypogonadism, after exclusion of more common conditions, e.g. Turner syndrome, even with normal blood pressure and electrolytes, it is also recommended to perform steroidogenic investigation, including urinary steroid profiling, to rule out 17α-OHD as a rare yet important differential diagnosis.

Declaration of interest

There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

Patient consent

Written informed consent for publication of their clinical details was obtained from the patient.

Author contribution statement

GCY drafted the manuscript and JYT supervised and revised the manuscript. All authors critically reviewed and endorsed the content of the manuscript.