46,XY 17 alpha-hydroxylase/17,20 lyase deficiency with breast development: A case report and literature review

Abstract

Individuals with the 46,XY karyotype and 17 alpha-hydroxylase/17,20 lyase deficiency (17OHD) may develop disorders/differences of sex development (DSD) accompanied by delayed puberty or primary amenorrhea. Glucocorticoid replacement is required to normalize hypertension in 17OHD, which highlights the importance of appropriate diagnostics for the selection of relevant treatment. A 16-year-old female with primary amenorrhea was found to have the 46,XY karyotype. Since the patient had spontaneous breast development, she was initially diagnosed with complete androgen insensitivity syndrome (CAIS). However, CAIS was subsequently ruled out due to an extremely low testosterone level, and 17OHD was suspected because of hypertension with low plasma renin activity, an elevated adrenocorticotropic hormone (ACTH) level, and decreased cortisol level. Two variants in CYP17A1, which were previously reported to be pathogenic, were detected and eventually confirmed the diagnosis of 17OHD. We reviewed 198 reported cases of 46,XY with 17OHD, and found spontaneous breast development in 9 of 129 (7.0%) individuals with typical female external genitalia. Although gonadal hormone production is impaired in 17OHD, 17OHD needs to be considered in differential diagnostics of 46,XY DSD even with spontaneous breast development.

Introduction

17 Alpha-hydroxylase/17,20 lyase deficiency (17OHD) is a rare form of congenital adrenal hyperplasia that promotes the development of disorders/differences of sex development (DSD) in individuals with the 46,XY karyotype [1, 2]. It is caused by biallelic pathogenic variants in the CY17A1 gene encoding P450c17α [1, 3], which is expressed in the adrenal cortex, testis, and ovary [3]. This enzyme catalyzes 17α-hydroxylation and 17,20 lysis reactions [3]; the former is fundamental in the synthesis of both cortisol and gonadal hormones [3, 4].

The synthesis of gonadal hormones is impaired in 46,XY cases with 17OHD and the female phenotype; therefore, spontaneous pubertal development is considered to be unlikely [5]. However, breast development has been reported in approximately 5% of 46,XY cases with 17 OHD [1], which poses a diagnostic challenge, particularly in differentiating 17OHD from a number of conditions, such as complete androgen insensitivity syndrome (CAIS). Since the severity of the enzyme deficiency may be associated with the severity of the failure to masculinize the external genitalia in XY cases with 17 OHD [6], the impairment of sex hormone production may be more severe in XY cases with complete female external genitalia. Therefore, spontaneous breast development is less likely in XY cases with 17OHD that develop complete female external genitalia. However, further investigations are warranted to clarify the actual incidence.

The first case of 17OHD was described in 1966, with the manifestations of hypertension, hypokalemia, and hypogonadism [4]. Patients with 17OHD have a decreased cortisol level and elevated deoxycorticosterone (DOC) and corticosterone levels [4]. Since DOC exerts mineralocorticoid effects, excessive DOC results in hypertension [4]. Glucocorticoid replacement suppresses the excessive production of adrenocorticotropic hormone (ACTH), and the subsequent inhibition of DOC production normalizes blood pressure [1, 6]. 17OHD rarely causes adrenal insufficiency despite insufficient cortisol levels due to elevated levels of corticosterone, which exhibits mild glucocorticoid activity [7-9]. Symptoms of adrenal insufficiency rarely manifest in 17OHD, which often results in delayed clinical diagnostics, typically at pubertal age or later, leading to prolonged hypertension [10, 11].

We herein report a 46,XY case with 17OHD raised as female who was initially diagnosed with CAIS due to the presence of spontaneous breast development and a detectable level of estradiol. This case highlights the diagnostic challenges posed by the rare presentation of 17OHD, particularly when spontaneous breast development is observed.

Case Presentation

The patient had been raised as female and her gender identity was female. She had not developed obvious adrenal insufficiency, even during fever. However, she sometimes became fatigued after vigorous exercise. She had a healthy older sister who had menarche at the age of 12 years.

She presented with primary amenorrhea at a clinic at the age of 16 years and 1 month and was referred to a local Gynecology department. Pelvic magnetic resonance imaging showed the absence of a uterus and ovaries; however, gonads (smaller than 2 cm) were detected bilaterally in the inguinal region. The patient’s karyotype was 46,XY. She was referred to the gynecology department of our hospital. Her height was 159.6 cm (0.40 SD as female) and her weight was 53.0 kg (0.18 SD as female). A clinical examination revealed female external genitalia and a blind vagina. The puberty stage of breast development was Tanner II, while that of pubic hair was Tanner I. Since the patient was initially diagnosed with CAIS due to breast development and a detectable level of estradiol at the age of 16 years and 1 month (Table 1), gonadectomy was planned without glucocorticoid replacement. However, the diagnosis of CAIS was subsequently ruled out because of an extremely low testosterone level (Table 1). Due to the elevated level of ACTH and decreased level of dehydroepiandrosterone sulfate, DSD with adrenal insufficiency was suspected. Her bone age was approximately 12.4 years (as female) at the chronological age of 16 years and 5 months. Dual-energy X-ray absorptiometry showed that bone density was low (0.573 g/cm² at the lumbar spine, –5.3 SD as female). The patient did not respond to the human chorionic gonadotropin (hCG) test or human menopausal gonadotropin test (Table 1). The cortisol response was blunted in the ACTH stimulation test at the age of 16 years and 11 months. The patient was prescribed estradiol transdermal patches from this visit.

Table 1 Laboratory test results before daily hydrocortisone replacement

Age	16y1m	16y10m	16y11m	17y0m*	17y3m*	Reference range
						Male	Female
Blood test
LH (mIU/mL)	14.8		21.00	<0.30	NE	0.79–5.72	follicular phase 1.76–10.24 ovulatory phase 2.19–88.33 luteal phase 1.13–14.22
FSH (mIU/mL)	17.57		22.40	0.43	<0.3	2.00–8.30	follicular phase 3.01–14.72 ovulatory phase 3.21–16.60 luteal phase 1.47–8.49
Estradiol (pg/mL)	15.4		8.4	161.0	199.0	14.6–48.8	follicular phase 28.8–196.8 ovulatory phase 36.4–525.9 luteal phase 44.1–491.9
Testosterone (ng/dL)	<3		<3	<3	NE	28–1,110	10–50
Progesterone (ng/mL)	4.28		4.18	NE	NE	0.16–0.57	follicular phase <0.28 ovulatory phase <5.69 luteal phase 2.05–24.2
ACTH (pg/mL)	99.1		103.0	44.2	35.4	7.2–63.3	7.2–63.3
Dehydroepiandrosterone sulfate (ng/mL)	55		46	22	34	16y: 525–3,610, 17y: 619–4,060	16y: 557–3,690 17y: 657–4,190
Cortisol (μg/dL)	0.8		1.2	0.7	0.8	6–22	6–22
17 alpha-hydroxy progesterone (ng/mL)	NE		NE	NE	<0.1	0.5–2.9	follicular phase 0.2–2.8 luteal phase 0.4–3.1
Aldosterone (ng/dL)	NE		NE	<0.40	<0.40	0.3–8.21	0.3–8.21
Plasma renin activity (ng/mL/hr)	NE		<0.2	<0.2	0.2	0.2–2.3	0.2–2.3
Na (mEq/L)	141		143	NE	139	138–145	138–145
K (mEq/L)	3.6		3.9	NE	3.6	3.6–4.8	3.6–4.8
hCG stimulation test
Stimulated testosterone (ng/dL)		12					>100 (in males)
hMG stimulation test
Stimulated estradiol (pg/mL)		<5.0					300–1,500 (in females)
ACTH stimulation test
Basal Cortisol/Peak Cortisol (μg/dL)	NE		1.2/1.8	0.7/1.6	NE	6–22/>18	6–22/>18

* Using an estradiol transdermal patch at 0.72 mg

m, months; y, years ; NE, not evaluated

To make a definite diagnosis, the patient was referred to our pediatric department at the age of 17 years. Her height and weight were 163.2 cm (1.01 SD as female) and 52.7 kg (0.68 SD as female), respectively. Her blood pressure was high (147/101 mmHg). She had mild hyperpigmentation, particularly at the external genitalia. The concentrations of metabolites of pregnenolone, progesterone, DOC, and corticosterone were elevated in the urinary steroid profile (Keio University School of Medicine), which suggested 17OHD (Table 2). Computed tomography did not show obvious adrenal enlargement. We identified two variants in CYP17A1 (NM_000102.4:c.160_162del(;)1118A>T and NP_000093.1:p.Phe54del(;)His373Leu) by next-generation sequencing (Kazusa DNA Research Institution). Her parents did not consent to their own genetic analysis. The same combination of variants was previously reported to be pathogenic in patients with17OHD [12]. Her clinical symptoms and test results were consistent with 17OHD, indicating compound heterozygous variants. We initiated hydrocortisone therapy.

Table 2 Urinary steroid profile at the age of 17 years and 3 months

		Range from the 2.5th to 97.5th percentile in females aged 15 to 17 years
Metabolites of pregnenolone
16α-hydroxypregnenolone and 21-hydroxypregnenplone (mg/g creatinine)	2.046	0.045–0.294
Metabolites of progesterone
pregnanediol (mg/g creatinine)	3.284	0.112–1.182
Metabolites of deoxycorticosterone
tetrahydro-11-deoxycorticosterone (mg/g creatinine)	0.292	0.004–0.037
Metabolites of corticosterone
5α-tetrahydrocorticosterone	18.481	0.172–0.423
5β-tetrahydrocorticosterone	3.677	0.000–0.188
Metabolites of androstenedione
androsterone	0.015	0.735–2.901
etiocholanolone	0.006	0.448–2.295

Values above the reference ranges are in bold font, while those below the reference ranges are underlined.

Bilateral gonadectomy was performed at the age of 18 years and 5 months. The maximum diameters of the excised masses were 12 and 11 mm. The histopathology of the bilateral gonads revealed immature testes, which had both immature Sertoli cells and Leydig cells. No malignant changes were detected. The patient still had hypertension during hospitalization (range, 140/86 to 174/115 mmHg). Therefore, we prescribed dexamethasone instead of hydrocortisone to sufficiently suppress mineralocorticoid function, resulting in marked improvement in blood pressure (113/51 mmHg).

Literature Review

We searched the PubMed database in January 2025 using the keywords “(17-hydroxylase deficiency) OR (17,20-lyase deficiency)” and identified 198 cases with the XY karyotype aged 14 years or older (Supplementary Fig., Supplementary Table 1). We extracted 25 cases with spontaneous breast development including gynecomastia (Supplementary Table 2). “Lack of secondary sexual characteristics” was considered to be ‘no breast development.’ Cases for which breast development information was reported only after estradiol replacement were classified as “Not available.” Thirteen of 17 (76.5%) socially male cases had gynecomastia, while 9 of 129 (7.0%) socially female cases with female external genitalia spontaneously developed breasts (Table 3). Estradiol and testosterone levels varied in cases exhibiting typical female genitalia with and without breast development (Supplementary Table 2, Table 4).

Table 3 Breast development in XY cases with 17 OHD (older than 14 years old)

Social sex	External genitalia	Breast development			Total number
		Yes	No	NA
Female (n = 181)	Female	9	120	23	152
	Atypical/Ambiguous	3	3	1	7
	NA	0	18	4	22
Male (n = 17)	Male	3	0	3	6
	Atypical/Ambiguous	9	0	1	10
	NA	1	0	0	1

NA, not available

Table 4 Clinical characteristics of XY cases with typical female external genitalia

	Present case	breast development (+) n = 9	breast development (–) n = 120	Reference range
				male	female
Estradiol (pg/mL)	15.4	range (n = 5): UD–34.64 number of UD: 3	median: 6 range (n = 71): UD–47.8 number of UD: 24	14.6–48.8	follicular phase 28.8–196.8 ovulatory phase 36.4–525.9 luteal phase 44.1–491.9
Testosterone (ng/dL)	<3	range (n = 8): UD–40 number of UD: 2	median: 3 range (n = 82): UD–70 number of UD:29	28–1,110	10–50
Progesterone (ng/mL)	4.28	range (n = 7): 0.29–7.45 number of UD: 0	median: 6.64 range (n = 73): 0.06–100 number of UD: 0	0.16–0.57	follicular phase <0.28 ovulatory phase <5.69 luteal phase 2.05–24.2
Dehydroepiandrosterone sulfate (ng/mL)	55	range (n = 6): UD–244 number of UD: 4	median 176 range (n = 55): UD–620 number of UD: 21	16y: 525–3,610 17y: 619–4,060	16y: 557–3,690 17y: 657–4,190

UD, undetectable.

Discussion

In this case of 17OHD, spontaneous breast development delayed a diagnosis. The combination of female external genitalia, spontaneous breast development, and the absence of a uterus led this 46,XY case with 17OHD to initially be diagnosed as CAIS despite the extremely low level of testosterone. Although CAIS was initially considered, the diagnosis was later ruled out based on the markedly low testosterone levels and absence of response to hCG stimulation. Nevertheless, the mechanism underlying spontaneous breast development in this present case may resemble the mechanism by which estrogen action predominates over androgen action in CAIS or pubertal gynecomastia. This similarity refers to pathophysiological dynamics —namely, the imbalance between estrogen and androgen action—, not to the diagnostic category itself. In CAIS, the lack of androgen effects in the presence of estrogen converted by peripheral aromatase activity may lead to breast development [13, 14]. A similar imbalance between the effects of androgens and estrogens has been implicated in gynecomastia in patients with Kallmann syndrome and normal pubertal males [15]. Although androgen production and subsequent peripherally converted estrogen in XY cases with 17OHD and complete female external genitalia may be severely impaired, testosterone and estradiol levels widely varied among cases in our literature review, ranging from undetectable to 70 ng/dL and from undetectable to 47.6 pg/mL, respectively (Supplementary Table 1). Among the 181 reported XY cases with 17OHD who were reared as female, 9 exhibited spontaneous breast development (Table 2). Testosterone and estradiol levels also varied in these patients (ranging from undetectable to 40 ng/dL and from undetectable to 34.64 pg/mL, respectively) (Supplementary Table 2, Table 4). Although statistical analyses were not performed due to the small number of patients in the breast development group, testosterone and estradiol levels varied widely among cases, observing no consistent trend differentiating those with and without breast development. However, this observation should be interpreted cautiously due to missing data and potential publication bias (Table 4). The prevalence of breast development (or gynecomastia) was higher in XY cases with 17OHD showing ambiguous external genitalia or male external genitalia than in cases with female external genitalia as expected (Table 3). Although spontaneous breast development is uncommon in 46,XY cases with 17OHD, 17OHD needs to be considered as a diagnosis for 46,XY DSD even with breast development or a detectable level of estradiol. Spontaneous breast development and a detectable estradiol level may be associated with Leydig cell hyperplasia [16]. However, the present case was unresponsive to the hCG loading test, which indicated that testosterone was not being produced by Leydig cells. Additionally, a pathological examination revealed the absence of Leydig cell hyperplasia. This result suggests that other mechanisms, such as peripheral aromatase activity converting a small amount of adrenal androgen precursors into estrogen, resulting in the superiority of estradiol to androgens, may have contributed to spontaneous breast development. The hCG loading test was not performed for the nine other 17OHD cases with breast development and female external genitalia (Supplementary Table 2). Further studies are needed to identify the source of androgens and estrogens contributing to spontaneous breast development in XY cases with 17OHD and typical female external genitalia.

Low-renin hypertension and the results of other biochemical tests suggested that our patient had 17OHD, which was subsequently confirmed by next-generation sequencing. Although diagnostic guidelines have not yet been established for 17OHD, hypertension, hypokalemia, a low cortisol level, and a high ACTH level need to be considered [6]. Elevated progesterone, DOC, and corticosterone levels also suggest 17OHD [1]. In Japan, DOC and corticosterone measurements are not covered by the national health insurance system; therefore, progesterone is a useful alternative marker for the detection of steroid overproduction. The present case exhibited a high progesterone level as an individual without ovaries (Table 1). A total of 88.9% of young 46,XY individuals with 17OHD were previously reported to have hypertension [1]. Glucocorticoid replacement to suppress the excess production of DOC is important for the attenuation of hypertension in patients with 17OHD [10, 11]. Delayed diagnostics or inadequate blood pressure management may lead to permanent hypertension or even death due to hypertensive encephalopathy [11]. Therefore, the detection of 17OHD in patients with delayed puberty or primary amenorrhea is crucial for the initiation of glucocorticoid replacement and blood pressure control. Blood pressure needs to be measured in patients with amenorrhea in order to detect 17OHD.

In clinical practice to evaluate a 46,XY case with female external genitalia and spontaneous breast development without uterus, initial workup should include not only measurement of serum testosterone, estradiol, LH and FSH, but also progesterone, and blood pressure. Furthermore, absent response to hCG stimulation would deny the possibility of CAIS and prompt consideration of 17OHD. Genetic analysis can help confirming the diagnosis.

In conclusion, the present case highlights the importance of considering 17OHD as a differential diagnosis in 46,XY DSD cases with spontaneous breast development. The results of the literature review further confirmed that testosterone and estradiol levels widely vary among 46,XY cases with 17OHD and typical female genitalia, with no clear distinction between those with and without breast development (Graphical Abstract).

Graphical Abstract 

Acknowledgments

We thank the patient and her family for participating in our study. We would also like to thank Dai Suzuki and Takayuki Musashi for their clinical support. We thank Tomonobu Hasegawa and Keiko Honma for conducting the urinary steroid profile.

Disclosure

The authors declare no conflicts of interest.

Informed Consent

Written informed consent was obtained from the patient for the publication of this case report.

Funding

This study did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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