Novel mutations of the CYP17A1 gene cause disorders of sex development in two-chromosome karyotype 46,XY infants and a literature review: A case report

doi:10.21203/rs.3.rs-3646997/v1

Background

Congenital adrenal hyperplasia is a group of rare autosomal recessive diseases due to seven different enzyme mutations, and 17ɑ-hydroxylase deficiency is rare in congenital adrenal hyperplasia. The typical clinical manifestations of 17α-OHD are sexual naivety, with vague or feminine apparent definition of the external genitalia; pubescent and adult females present with no pubertal development and primary amenorrhea, and males show vulval dysplasia or femininity.

Case presentation:

The clinical features and laboratory and whole-exon sequencing test results were analysed in the 2 children with the chromosomal karyotype 46,XY 17ɑ-OHD at the ages of 2 months and 20 days (case 1) and 1 year and 2 months (case 2). Case 1 presented with cryptorchidism and a small penis with an external masculinization score of 7. Case 2 showed feminine external genitalia with a score of 4. Decreased morning cortisol levels, normal electrolytes and significantly increased luteinizing hormone and follicle-stimulating hormone were present in both cases. Both patients harboured compound heterozygous mutations in the CYP17A1 gene, and among them, had three novel mutations.

Conclusions

CYP17A1 gene defects in infants can manifest only as gonadal dysplasia and a lack of blood pressure and electrolyte abnormalities, which are easily misdiagnosed. Those with internal and/or external genitalia inconsistent with the chromosome karyotype should be alert to the possibility of 17ɑ-OHD. Adrenal steroid hormones and gene testing can be helpful for a definite diagnosis and early intervention.

Disorders of sex development

17ɑ-Hydrophase deficiency

CYP17A1 gene

Infant

Congenital adrenal hyperplasia (CAH) is a group of rare autosomal recessive diseases that cause cortisol biosynthesis disorders due to seven different enzyme mutations [1]. 17ɑ-Hydrophase deficiency (17ɑ-OHD) is rare in CAH, accounting for approximately 1% of the disease cases in this group, with a neonatal morbidity of 1 in 50000 [2]. 17α-Hydroxylase, also known as P450c17, is encoded by the CYP17A1 gene located on chromosome 10 (10q24.32-q25) and contains eight exons. Proteins consisting of 508 amino acids, namely, 17α-hydroxylase/17,20-carbon chain lyase, are expressed in the gonads and adrenal glands. Due to 17ɑ-hydroxylase or 17,20-carbon chain lyase deficiency, pregnenolone (Preg) and progesterone (Prog) fail to convert to cortisol (F), oestrogen (E), and androgens (Andr). Mutations in CYP17A1 result in complete 17α-OHD or partial 17α-OHD [3]. The typical clinical manifestations of 17α-OHD are sexual naivety, with vague or feminine apparent definition of the external genitalia; pubescent and adult females present with no pubertal development and primary amenorrhea, and males show vulval dysplasia or femininity [2, 4]. Adrenocorticotropic hormone (ACTH) is compensated at a high level, which stimulates the excessive secretion of 11-deoxycorticosterone (11-DOC) and corticosterone (B), causing increased extracellular volume, hypokalaemia, and hypertension [2, 5].

Heretofore, in the literature on the clinical features of 17ɑ-OHD, the consequences of the disease were visible mainly from adolescence or adulthood [5–10], and slightly more than 20 cases [11–14] among infants and toddlers have been published over the last 3 decades. There are only two publications reporting the bone growth characteristics and novel pathogenic variants of the CYP17A1 gene [15, 16], and the scarcity of early reports of these patients could be partially attributable to findings of normal serum electrolyte levels in such patients in contrast to the typical levels seen in early classic CAH [15, 16]. Thus, the possibility for misdiagnosis or missed diagnosis at young ages is high. In this study, we present two cases of 17ɑ-OHD involving infants with novel genetic pathogenic variants and analyse the early clinical characteristics of 17ɑ-OHD in the context of the literature, aiming to support the early diagnosis of 17α-OHD and improve long-term clinical outcomes.

Case 1

This child was the first-born child of both parents and was delivered at 38 weeks of gestation with a birth weight of 2.95 kg. He was hospitalized at 2 months and 20 days of age due to a "small penis and empty scrotum after birth". The gender was male, and the family history was normal. Physical examination showed the following: body length of 63 cm (+ 1 SD ~ + 2 SD), weight of 6.9 kg (+ 1 SD ~ + 2 SD), and blood pressure of 79/50 mmHg (systolic reference range 75 ~ 106 mmHg, diastolic reference range 43 ~ 67 mmHg) at the time of admission. The body was symmetrical, with no special facial features, no skin pigmentation, no thyroid enlargement, and no heart murmur. The lungs and abdomen were normal. The bilateral breasts were Tanner stage B1, the male external genitalia and stretched penis length were 2 cm (<-1 SD), the testis was not palpable in the scrotum, and the external masculinization score (EMS) was 7 (Fig. 1). The chromosome karyotype was 46, XY. Ultrasound of the genitals showed no obvious testicular echo in the right scrotum and right inguinal region, suspicious testicular tissue was seen in the left inguinal canal, both epididymes were unclear, and there was no obvious abnormality in either adrenal gland. Due to the young age of the patient, an ACTH stimulation test was not performed. Laboratory tests indicated that FSH and LH were elevated, and testosterone and blood free cortisol were decreased (Table 1). Treatment with oral hydrocortisone (10 mg/m²) was started at diagnosis. At age one, he underwent laparoscopic exploration for cryptorchidism under general anaesthesia and resection of the spermatic cord lesion (bilateral end of the spermatic cord resection). During the operation, both sides of the testicles were absent. The pathological results showed a luminal structure lined with epithelial cells at the ends of both spermatic cords, with focal small vessel congestion. He was thereafter regularly followed up at paediatric endocrine clinics (Table 2).

Case 2

The child was the first-born child of both parents and was a full-term infant with a birth weight of 2.85 kg. The girl was hospitalized at 1 year and 2 months of age due to a "chromosomal karyotype inconsistent with gender" in a local hospital examination. Her gender was female. When the child was born, the labia vulva was full like the scrotum, and the umbilical cord blood karyotype was 46,XY. The family history was normal. The physical examination was as follows: body length of 83.5 cm (+ 1 SD ~ + 2 SD), body weight of 10.5 kg (median) and blood pressure of 93/62 mmHg (systolic blood pressure at the 50th to 90th percentile, diastolic blood pressure at the 95th to 99th percentile). A proportionate physique, ordinary facial features, no skin pigmentation abnormalities, no thyroid enlargement, and heart murmur were observed. The lungs and abdomen were normal. The female external genital appearance, large clitoris, and labia majora fully resembled the scrotum, Tanner stage 1, and the EMS score was 4 points (Fig. 2). Ultrasound showed suspicious testicular tissue of approximately 9.3×4.7×5.5 mm in the lower left pelvic cavity with an unclear blood supply; a suspicious testicular tissue echo of approximately 10.6×3.2×6.2 mm was found in the lower right pelvic cavity, and a small amount of blood flow signal was observed. The bilateral epididymis was not clearly identified, and no obvious focal lesions were observed in the adrenal ultrasound on either side. Laboratory tests indicated elevated serum FSH and LH levels and a decrease in blood free cortisol (Table 1). Plasma ACTH and the serum Prog level were increased, and ACTH challenge test results suggested that blood free cortisol could increase but to a much lower-than-normal value. The 17ɑ-OH Prog level did not change significantly (Table 3). Treatment with oral hydrocortisone (10 mg/m²) was given at diagnosis, and regular follow-up at the paediatric endocrine specialist clinic was indicated (Tables 3 and 4).

Table 1

The laboratory examination results of the 2 cases with 17ɑ-OHD
Laboratory examination	Case 1	Case 2	Reference range
Chromosomal karyotype	46,XY	46,XY	/^a
Potassium (mmol·L^-1)	5.18	4.89	3.5 ~ 5.3
Sodium (mmol·L^− 1)	136.0	137.0	137 ~ 147
Chlorine (mmol · L^− 1)	103.7	106.8	96 ~ 108
ACTH (pg·mL^− 1)	30.61	185.62	7.2 ~ 63.4
F (nmol·L^− 1)	107.66	11.17	137.95 ~ 689.75
Prog (nmol ·L^− 1)	2.36	19.95	0.95 ~ 2.67
17ɑ-OHProg (ng ·m L^− 1)	1.94	0.19	2 months ~ 1 years old 0.82 ~ 16.63; 1 ~ 13 years old < 2.32;
DHEA (µmol ·L^− 1)	3.7	0.1	0.95 ~ 11.67
Andro (ng·mL^− 1)	< 0.3	< 0.3	0.6 ~ 3.1
Tes (nmol·L^− 1)	0.00	0.00	0 ~ 6 years old, 0.10 ~ 1.11
E2 (pmol·L^− 1)	0.00	50	< 220.26
AMH (ng·mL^− 1)	< 0.06	/^a	38.00-332.00
Aldo (pg·m L^− 1)	/^a	406.412	Decumbent position 10 ~ 160;
FSH (U·L^− 1)	137.9	32.68	0 ~ 11.1
LH (U·L^− 1)	9.16	11.73	0 ~ 7.6
Renin activity (pg · mL^− 1)	/^a	19.38	Decumbent position 4 ~ 24
Note: ^a. literature data are missing, ACTH (adrenocorticotropic hormone), F (cortisol), Prog (progesterone), 17ɑ-OHProg (17ɑ-hydroxyprogesterone), DHEA (dehydroepiandrosterone), Andro (androstenedione), Tes (testosterone), E2 (oestradiol), AMH (anti-Müllerian hormone), Aldo (aldosterone), PRL (prolactin), FSH (follicle-stimulating hormone), LH (luteinizing hormone).

Table 2

Changes in posttreatment laboratory indicators over time in the 2 cases
Item	Case 1				Case 2				Reference range
Item	3 months	9 months	1 years	2 years	3 months	9 months	1 years	2 years	Reference range
E2 (pmol·L^− 1)	73	12	0.00	0.00	45.00	58.00	/^a		< 220.26
FSH (U·L^− 1)	142.93	106.09	129.05	57.58	25.02	/^a	54.22	/^a	0 ~ 11.1
LH (U·L^− 1)	9.89	4.37	19.81	0.64	5.58	4.69	24.32	/^a	0 ~ 7.6
Tes (nmol·L^− 1)	0.00	0.00	0.00	0.00	0.00	0.00	/^a		0.1 ~ 1.11
F (nmol·L^− 1)	/^a	169.49	240.99	187.83	315.88	398.44	36.51	66.17	137.95ཞ689.75
Prog (nmol·L^− 1)	0.00	/^a		0.85	/^a				0.95 ~ 2.67
AMH (ng·mL^− 1)	/^a		0.02	0.099	/^a		12.86	/^a	0.32 ~ 7.88
K (mmol·L^− 1)	3.93	4.26	4.04	3.97	4.46	4.93	4.83	4.93	3.5 ~ 5.3
Na (mmol·L^− 1)	141.00	138.68	138.12	139.43	136.00	136.66	136.80	137.57	137 ~ 147
DHEA (µmol·L^− 1)	/^a			0.00	0.00	0.00	/^a		0.95 ~ 11.67
Andro (ng·mL^− 1)	/^a			< 0.30	/a	< 0.30	/^a		0.6 ~ 3.1
17ɑ-OHProg (ng·mL-1)	/^a			0.28	0.37	1.58	/^a		1 ~ 13 years old < 2.32
ACTH (pg·mL^− 1)	/^a				222.52	18.58	66.63	72.83	7.2 ~ 63.4
Note: ^a. literature data are missing; ACTH (Adrenocorticotropic hormone); F (Cortisol); Prog (Progesterone); 17ɑ-OHProg (17ɑ-hydroxyprogesterone); DHEA (Dehydroepiandrosterone); Andro (Androstenedione); Tes (Testosterone); E2 (Oestradiol); AMH (Anti-Müllerian hormone); FSH (Follicle-stimulating hormone); LH (Luteinizing hormone).

Table 4

Determination of the adrenal steroid mass spectrum in case 2
Item	1 year	2 years	Reference range
pregnenolone	26.85	44.03	< 140.00
17-hydroxypregnenolone	< 10.00	< 20.00	≤ 487.00
corticosterone	2477.84	232.46	18.00-1970
estrone	< 10.00	< 10.00	≤ 34.00
11-dehydrocortisol	54.92	< 2.00	< 344.00
21-dehydrocortisol	3.52	< 0.50	< 5.00
Andro	129.88	< 5.00	/a
dihydrotestosterone	51.83	< 25.00	/a
DHEA	< 0.10	< 0.10	< 2.30
E2	< 10.00	< 10.00	/a
17ɑ-OHProg	< 5.00	68.46	≤ 134.00
Prog	0.47	0.25	≤ 0.50
Aldo	14,52	< 1.00	2.00–37.00
corticosterone	0.77	1.81	3.00–25.00
11-dehydrocortisterone	47.14	20.64	< 30.00
Note: ^a. Literature data are missing; Prog (Progesterone); 17ɑ-OHProg (17ɑ-hydroxyprogesterone); DHEA (Dehydroepiandrosterone); E2 (oestradiol); Andro (Androstenedione); Aldo (Aldosterone).

Genetics findings

Whole-exome sequencing (SureSelectXT Human All Exon Kit V6, Agilent Technologies, CA, USA) was applied, and data were analysed via WuXiNextCODE analysis software. The sequencing fragments were compared with the UCSC hg19 reference genome by BWA; the variation data were annotated by VEP software and an annotation program, and the known pathogenic variants were screened by ClinVar and the Human Gene Mutation Database (HGMD). All pathogenicity analyses were carried out according to the guidelines for the interpretation of variation published by the American Society of Medical Genetics and Genomics (ACMG). Both children harboured point pathogenic gene variants in the CYP17A1 gene (NM_000102). In case 1, the exon 8 c.1482G > C(p. K494N) variant was present and had a paternal origin, whereas the exon 7 c.1209G > C(p. E403D) variant had its origin in the maternal compound heterozygous mutation (Fig. 3). In case 2, exon 6 c.985_987delTACinsAA(p.Y329fs) had a maternal origin, and exon 7 c.1243 + 1G > A originated from a paternal compound heterozygous mutation (Fig. 4). According to the variant interpretation guideline rules issued by the ACMG [17], the variant in case 1 is likely pathogenic and that in case 2 is pathogenic. Here, we report the first two Chinese 46,XY infants to be diagnosed with 17α-hydroxylase deficiency and harbour gene mutations at 3 novel gene loci (c.1482G > C, c.1209G > C, exon 7 c.1243 + 1G > A). We also report that a heterozygous variant in exon 6 (c.985_987delTACinsAA(p.Y329fs)) in case 2 is the most common mutation in the Chinese sick population of 17ɑ-OHD [18]. Although the proportion of carriers of this mutation in the healthy control population ranges from 1/1000 to 1/2000 [19], the results of the enzyme activity test show the complete elimination of cytochrome P450c17 activity [18]. The main manifestations of the patients are abnormal sexual development without significant manifestations of decreased cortisol, hypokalaemia, and hypertension.

Reported gene mutation information for the CYP7A1 gene was retrieved from the HGMD database, and the search time frame was from database establishment to May 30, 2023. A total of 673 articles associated with 17ɑ-OHD and CYP17A1 mutations were retrieved. Among them, 179 articles reported 449 cases of 17ɑ-OHD confirmed by genetic testing, a total of 168 mutations were involved, and 109 mutations were included in the HGMD database. Consistent with the chromosome karyotype of 46,XY and CYP17A1 genetic testing-confirmed 17ɑ-OHD cases reported here, there have been 170 cases included in 96 articles. Among these patients, 12.94% (22 patients) were male, 87.06% (148 patients) were female, 63.53% had a female genital appearance, 11.17% had undefined external genitalia, 8.24% had a small penis, 37.50% had anorchia, 55.68% had different degrees of cryptorchidism or testicular heterotopia, 9.09% had testicular dysplasia, and 8.82% had hypospadias. In addition to abnormal gonadal development, there was hypertension in 35.29% of cases and hypokalaemia in 39.41% of cases (Table 5).

Table 5

The clinical manifestations of 17ɑ-OHD in 46,XY patients
Items	Clinical phenotype
Social sex	Male (22/170, 12.94%)	Female (148/170, 87.06%)	/^a
Reason for the visit	Primary amenorrhea/Sexual developmental disorders (43/170,25.29%)	Hypertension (60/170, 35.29%)	Hypokalaemia (67/170, 39.41%)
Breast stage	B1 stage (75/95, 78.95%)	B2-4 stage (17/95,17.89%)	B5 stage (3/95,3.16%)
The pubic hair stage	Infantile type (P1) (68/89, 76.40%)	Intermediate type (P2-P4) (16/89, 17.98%)	Adult type (P5) (2/89, 2.25%)
External genitalia	Micropenis (14/170, 8.24%)	Clitorism (14/170, 8.24%)	Hypospadias (15/170,8.82%)
External genitalia	Blurred genitalia (19/170, 11.17%)	Feminization (108/170, 63.53%)	/^a
Testis imaging	Anorchia (31/88, 37.50%)	Cryptorchidism (labia majora/pelvic/inguinal canal) (49/88, 55.68%)	Testicular hypoplasia (8/88, 9.09%)
Adrenal imaging	No abnormality (10/54, 18.52%)	Adrenal nodules/Adenoma/Lipoma/Myeloma(14/54, 25.93%)	Adrenal hyperplasia (30/54, 55.55%)
Nervous system	Headache/Dizziness (10/170, 5.38%)	Feeble/Decreased muscle strength (22/170, 12.94%)	Cerebral haemorrhage (4/170, 3.46%)
Skin mucosa	Chromatosis (15/170, 8.82%)	/^a
Skeletal system	Osteoporosis (18/170, 10.59%)	Retardation of bone age (34/170, 20.00%)	Skeletal development abnormalities (6/170, 3.53)
Other	Surgery for inguinal hernia (10/170, 5.88%)	Polydipsia and polyuria (4/170,2.35%)	Recurrent infection (10/170,5.88%)
Note: ^a Literature data are missing.

Abnormalities of genitalia in 17α-hydroxylase/17,20-carbon chain lyase defects are atypical and diverse. In case 1, in which the EMS score was 7 points, a misdiagnosis of partial androgen insensitivity or 5α-reductase deficiency would be easy. The gender in case 2 was female after birth due to the relatively low EMS score. 17α-Hydroxylase/17,20-carbon chain lyase and 3β-hydroxysteroid dehydrogenase have a shared role in the development and maturation of the adrenal gland and gonads. When the above enzyme is deficient, both adrenal and gonad steroids (androgens and oestrogen), including DHEA, Andro and their precursors (17α-OHPreg and 17α-OHProg), are impaired in their synthesis [20]. Foetal testosterone production is crucial for normal male sex differentiation. The production of testosterone secreted by foetal testicular interstitial cells can stabilize the Wolffian ducts, and testicular Sertoli cells continuously produce anti-Müllerian hormone, leading to the degeneration of Müllerian tubes [21]. The epididymis, ductus deferens, ejaculate tubes and seminal vesicles fail to develop normally when testosterone synthesis is impaired [22], resulting in loss or dysplasia of internal genitals [23]. In the absence of testosterone and dihydrotestosterone, the inability to promote the fusion of urethral folds and the formation of cavernosum and penile urethra, the labia cannot fuse to form the scrotum, the external genital develops into the clitoris, vagina and labia, and the urethra and vagina lead to the perineum [22]. Therefore, the early correct scoring of the internal and external genitalia also has a very important role. According to the literature, approximately 19.40% of “female” patients developed breast development after receiving oestrogen treatment for “sexual development delay or amenorrhea” or underwent breast prosthesis implantation for cosmetic purposes. There are also occasional reports that patients lack the feedback inhibition effect of testosterone, and oestrogen synthesis in vivo causes breast development [20]. Another 4.62% of “female” patients may undergo surgical treatment to remove the testicle due to misdiagnosis of inguinal hernia caused by abdominal groin swelling, which increases the difficulty of diagnosis. To date, knowledge of the long-term effects of early diagnosis and hormonal replacement in children is still pending.

In healthy male infants, a drop in steroid levels caused by placental circulation in the first few days after birth leads to a lack of negative feedback in the pulsatile release of gonadotropin-releasing hormone in the newborn. Activity in the hypothalamic-pituitary axis appears, with LH levels increasing approximately 10-fold within minutes of delivery and reaching levels in the range of adolescence by one week of age. FSH levels gradually decrease to prepubertal levels within 4 months of age [24, 25]. The secretion pattern of Tes is similar to that of LH secretion, with lower Tes in cord blood, gradually increasing to a peak between 1 and 3 months of age and then decreasing to prepubertal levels between 6 and 9 months of age [26]. Boas et al. [27] found penile length to be positively correlated with serum Tes, with a peak increase from birth to 3 months of age, and the growth rate from birth to 3 years old was 3.49 ± 0.4 cm (mean ± SD). During the process of testicular volume increase, from birth to 5–6 months of age, the testicular volume increased from 0.27 cm³ to 0.44 cm³ and then decreased to 0.31 cm³ at 9 months of age.

In case 2, typical high levels of gonadotropins, high levels of progesterone, decreased levels of glucocorticoids, androgen, and the ACTH compensatory rise were present at 1 year and 2 months of age, as were female genitalia features on physical examination, location of the testis in the pelvic cavity, and smaller testicular smaller than that of normal male infants, consistent with the 17ɑ-OHD manifestation. In case 1, at 2 months of age, FSH and LH levels were significantly elevated, but Tes levels were low. This did not match the healthy male infant who was experiencing ‘mini puberty’. The child exhibited mainly a small penis, and missing bilateral testicles were confirmed by abdominal exploration at one year of age. Laboratory tests showed high levels of gonadotropin and decreased levels of cortisol, but ACTH, Prog, and 17ɑ-OHProg were normal. Therefore, the child was considered to have partial 17ɑ-OHD. At the same time, we should be vigilant about whether the child is an extremely rare independent 17,20-lyase-deficient patient whose 17ɑ-hydroxylase activity is basically intact and is able to produce enough glucocorticoids, with no increase in mineralocorticoid production, partial or complete loss of 17,20-carbon chain cleavage enzyme activity, and impaired synthesis of androgen precursors [20]. The clinical manifestations in these two cases are related mainly to sexual developmental abnormalities. During the subsequent 2-year follow-up, both cortisol and potassium were well maintained at normal levels; however, the patients are still young, and subsequent development remains to be observed.

In the steroid metabolism pathway, the mineralocorticoid pathway is not affected by 17ɑ-hydroxylase and 17,20-carbon chain cleavage enzymes. Patients may not show hypertension or hypokalaemia. However, according to the relevant literature, patients with 17α-OHD have a higher proportion of hypertension (35.29%) and hypokalaemia (39.41%) at their first medical visit. The possible reason is that the deficiency of this enzyme causes adrenal corticosteroid and androgen steroid metabolism disorders. ACTH is attenuated by feedback inhibition, stimulating the elevation of cortisone and deoxycorticosterone levels in the mineralocorticoid pathway [28], in which deoxycorticosterone can increase by 1,000 times [29] and act on the mineralocorticoid receptor, causing water and sodium retention and potassium loss, increasing blood volume to inhibit the renin-angiotensin system and decreasing aldosterone synthesis, manifesting as hyporeninemia and hypoaldosteronism or hyporeninemic normal aldosteronism. In the absence of glucocorticoid supplementation, patients present with resistant malignant hypertension, and antihypertensive drugs alone (such as atenolol, lisinopril, and thiazides) may also affect the distribution of sodium, potassium and hydrogen ions in the kidney [23], further affecting blood pressure control. In addition, due to the influence of upstream mineralocorticoids, patients show long-term hypokalaemia, decreased muscle strength, fatigue, activity impairment, and even cardiac arrest [30], all of which pose a threat to the lives of patients.

In case 1, the plasma ACTH level was in the normal range, the intermediate substances of the mineralocorticoid pathway had not been stimulated over the long term, and excessive secretion occurred, so the blood pressure and serum potassium levels did not change. The blood pressure situation in case 2 should be noted. The patient’s plasma ACTH level and systolic blood pressure were increased to the 50th -90th percentile for the same age and height, and diastolic blood pressure was increased to the 95th -99th percentile for the same age and height, which was high. Therefore, long-term follow-up of ACTH and serum potassium levels and the observation of dynamic changes in blood pressure play a very important role in the diagnosis and treatment of patients.

The laboratory examination of two children indicated that androgen was in a low-level state, reducing the feedback inhibition of the central system, and serum gonadotropin continued at a high level on the dysplastic testes, which could aggravate the gonadal decline or malignant lesions. In a study [31] of 30 patients with the 46,XY chromosome and 17α-OHD who underwent laparoscopic gonadectomy under general anaesthesia, 26 patients (86.7%) had bilateral gonads located at the inner port of the intraperitoneal inguinal canal, and 4 patients (13.3%) had testes located at the inguinal canals. Pathological examination showed that all testes were dysplastic testicular tissue, and 2 patients (6.7%) developed gonadal tumours, including Leydig cell tumours and Sertoli cell adenomas. The study also showed that the incidence of gonadal malignancy with Y chromosome material in “female” patients increased with age. All of the above findings indicate that laparoscopic gonadal resection or surgical treatment should be performed as soon as possible to prevent gonadal degeneration, which has clinical significance in preventing tumour occurrence [31, 32].

In 17α-hydroxylase/17,20-carbon chain lyase deficiency, the intermediate products in the pathway of Preg and Prog conversion to androgens and corticosteroids, 17α-OHProg and 17α-OHPreg generation were decreased. Therefore, the disease could not be detected early by neonatal screening of 17α-OHProg. Because the external genitalia of patients at birth are often feminine, there may be no electrolyte disturbances or hypertension in the early stages, and the condition may not be accompanied by skin pigmentation or other clinical manifestations. Therefore, patients often seek medical attention during puberty without gonad development, severe hypertension or electrolyte disturbances. At the same time, it is also easily diagnosed as androgen-insensitivity syndrome, primary aldosteronism and other diseases [33]. The current treatment plan for 17α-OHD patients is to administer supplementary physiological doses of glucocorticoids, oestrogen or androgen. Two patients were treated with physiological doses of hydrocortisone for 2 years, and their serum potassium levels were normal, but the high gonadotropin-induced hypogonadism did not improve. In case 2, neither laparoscopic exploration nor orchiectomy was performed. During this period, AMH was found to be elevated, so we should pay attention to the occurrence of testicular lesions. If necessary, orchiectomy should be performed in a timely manner. During follow-up in case 2, adrenal steroid mass spectrometry was monitored once a year. We found that after supplementation with hydrocortisone, aldosterone levels gradually decreased and remained within the normal range. Therefore, for diagnosed infants and toddlers, the long-term physiological effect and effectiveness of corticoid replacement therapy need to be further studied, and it is speculated that it will have positive significance for the prevention of hypertension.

We have reported two cases of 46,XY infants with 17α-OHD and three unreported gene mutations. The clinical features include significantly elevated LH and FSH levels and significant abnormalities in the external genitalia, although electrolyte disorders are not significant at this age. However, domestic and foreign literature reviews suggest that a feminine genital appearance, small penis, testicular loss, or cryptorchidism are often more common in this disease. High-throughput second-generation sequencing and the determination of the adrenal steroid mass spectrum are helpful for early detection of the disease. Moreover, determination of the adrenal steroid mass spectrum can also be used to monitor the treatment effect [34]. Further research on early detection and intervention for 17α-OHD is needed to determine patient prognosis.

CAH: congenital adrenal hyperplasia;

17ɑ-OHD: 17ɑ-hydroxylase deficiency;

ACTH: Adrenocorticotropic hormone;

F: Cortisol;

Prog: Progesterone;

Preg: Pregnenolone;

17ɑ-OHProg: 17ɑ-hydroxyprogesterone;

DHEA: Dehydroepiandrosterone;

Andro: Androstenedione;

Tes: Testosterone;

E2: Oestradiol;

AMH: Anti-Müllerian hormone;

Aldo: Aldosterone;

PRL: Prolactin;

FSH: follicle-stimulating hormone;

LH: Luteinizing hormone;

Prog: progesterone;

11-DOC: 11-deoxycorticosterone;

B: corticosterone;

EMS: external masculinization score.

Ethics approval and consent to participate

The study was approved by the Ethics Committee of the Children’s Hospital of Fudan University. Permission to access the clinical data used in the research was provided by the Ethics Committee of the Children’s Hospital of Fudan University. Written informed consent for the study was obtained from all of the patients’ parents. A copy of the consent form is available for review by the Editor of this journal.

Consent for publication

Written informed consent for the publication of personal and clinical details was obtained from all of the patients’ parents. A copy of the consent form is available for review by the Editor of this journal.

Availability of data and materials

Relevant genetic polymorphisms have been submitted to NCBI ClinVar (http://www.ncbi.nlm.nih.gov/clinvar/advanced). Transcript data were downloaded from UCSC Genome Brower (http://genome.ucsc. edu/cgi-bin/hgGateway), accession number: NM_000102.4.

Competing interests

The authors declare that they have no conflicts of interest related to this work.

Funding

The study was supported by the Children’s Hospital of Fudan University. The funding body played no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

Authors’ contributions

FL designed and supervised the study and critically reviewed and revised the manuscript. DY performed the entire study, collected the data and drafted the manuscript. XL, CR, ZM, ZZ, XC and LQ cared for the patients, helped collect data, and reviewed and revised the manuscript. All authors have read and approved the final manuscript.

Acknowledgements

The authors thank Dr. Luo Feihong for helping with the article. The authors are grateful to all the patients for their invaluable contribution to this study. The authors wish to gratefully acknowledge the patients and their parents for allowing us to publish this case report.

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No competing interests reported.

Novel mutations of the CYP17A1 gene cause disorders of sex development in two-chromosome karyotype 46,XY infants and a literature review: A case report

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Abstract

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Case presentation:

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Background

Case presentation

Genetics findings

Discussion and conclusions

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Version 1