Clinical characteristics and mutation analysis of Chinese children with 17α-hydroxylase deficiency: a report on three cases

Introduction

17α-hydroxylase/17,20 lyase deficiency (17-OHD) [Online Mendelian Inheritance in Man (OMIM) #202110] is a rare and autosomal recessive inherited disorder caused by a mutation in the cytochrome P450 17A1 (CYP17A1) gene (1). It accounts for 1% of the congenital adrenal hyperplasia (CAH) cases in world and has an incidence of approximately 1:500,000 (1,2). CYP17A1 is an important cytochrome P450 (CYP) enzyme that catalyzes the 17α-hydroxylation of pregnenolone to 17α-OH pregnenolone and then further converts it to dehydroepiandrosterone (DHEA) and androstenedione (3). Defects in the CYP17A1 gene result in decreased gonadal steroid biosynthesis (4). At puberty, patients with 17-OHD consistently exhibit sexual infantilism. Patients with a karyotype of 46,XX often seek medical consultation for primary amenorrhea at puberty or for infertility at adulthood. Meanwhile, patients with the 46,XY karyotype typically exhibit genital virilization (5). CYP17A1 catalyzes the production of cortisol. When this function is impaired, the level of adrenocorticotropic hormone (ACTH) increases, resulting in cortisol deficiency and the overproduction of mineralocorticoids, especially deoxycorticosterone (DOC). Increased DOC and corticosterone levels cause severe low-renin hypertension and hypokalemia, which is observed in many 17-OHD cases (6,7). Because corticosterone has weak glucocorticoid activity—in contrast to 21-hydroxylase, whose deficiency can be diagnosed early in newborns—patients with 17-OHD are generally diagnosed when delayed puberty becomes apparent (6). This increases this difficulty for clinical physicians to arrive at a timely diagnosis. Therefore, the identification of suitable indicators of 17-OHD is urgently needed.

This report describes and discusses three unrelated patients with Chinese 17-OHD.

Age at diagnosis and presenting features were confirmed through examination of the patients’ history, and Tanner stage was confirmed through physical examination. Body mass index (BMI) was calculated as weight in kilograms divided by the square of height in meters (kg/m²). Blood pressure was measured, and the grade was defined according to the 2017 American Academy of Pediatrics updated definitions for pediatric blood pressure categories. Blood karyotyping was used to determine the gender according to standard techniques. The levels of serum potassium, sodium, and chloride were tested through peripheral blood samples. The levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), progesterone, basal cortisol, 17-hydroxyprogesterone, renin, and ACTH were also determined. Pelvic ultrasound or magnetic resonance imaging (MRI) and adrenal computed tomography (CT) were performed. X-ray images of the phalanx, carpal, and radioulnar bones were used to evaluate the patients’ bone age via the Greulich and Pyle method.

Based on trio-based whole-exome sequencing (trio-WES) and Sanger sequencing, mutation screening was conducted. Peripheral blood samples from the probands and their parents were used to extract the genomic DNA via a blood DNA mini kit. Through use of a DNA nanoball DNBSEQ-T7 sequencer (MGI Tech Co., Ltd., Shenzhen, China), all the exons of CYP17A1 were captured and sequenced. Following alignment to the human reference genome, variants that were most likely to be deleterious were filtered based on factors such as population frequency, gene function, phenotype association, and other conditions. Finally, clinical pathogenic mutations were categorized in accordance with the guidelines for variant classification of the Association of Molecular Pathology (AMP) and the American College of Medical Genetics and Genomics (ACMG). Using the bioinformatics software PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) and MutationTaster (http://www.mutationtaster.org), we analyzed the functional affect and conservation of variants.

With the investigation of their clinical, biochemical, and molecular features, we aimed to identify appropriate indicators to arrive at a timely diagnosis of 17-OHD. We present this article in accordance with the CARE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-359/rc).

Case presentation

Case 1

Patient 1 was a 6-year-old female who was admitted to The First Affiliated Hospital, Zhejiang University School of Medicine, due to rapid growth. Physical examination indicated the presence of female external genitalia. However, a 2-cm long blind pouch instead of a vagina was confirmed (Table 1). The laboratory data showed elevated levels of LH, FSH, and progesterone and decreased levels cortisol and 17-hydroxyprogesterone. However, the levels of serum sodium, potassium, and ACTH were in normal range. She was diagnosed with 17-OHD, and the CYP17A1 genotyping demonstrated two heterozygote variants, c.1459_1467delGACTCTTTC (p.D487_F489 deletion [del]) inherited from her father, and c.985_987AA deletion-insertion (delins) (p.Y329Kfs*90) from her mother (Figure 1). The proband finally received spironolactone and cortisol to control the hypertension. After 2 months, the level of blood pressure decreased to 120/70 mmHg.

Figure 1 Genetic diagnosis and pedigree of the three patients. (A1) Patient 1 inherited the variant in the CYP17A1 gene, c.985_987delinsAA, from her mother. (A2) Patient 1 inherited another variant in the CYP17A1 gene, c.1459_1467delGACTCTTTC, from her father. (B1,B2) Two heterozygous variants in the CYP17A1 gene, c.1459_1467delGACTCTTTC and c.245C>A, were found in patient 2. Her parents refused gene testing. (C1) Patient 3 inherited a novel variant in the CYP17A1 gene, c.50G>A, from her mother. (C2) A heterozygous variant in the CYP17A1 gene, c.1459_1467delGACTCTTTC, was found in patient 3, which was inherited from her father. (D) Pedigree chart showing that patient 1 inherited two heterozygote variants in the CYP17A1 gene from her parents, respectively. (E) Pedigree chart showing that that two variants in the CYP17A1 gene were identified in patient 2. Her parents refused gene testing. The same heterozygous variants were confirmed in her younger sister. (F) Pedigree chart showing that two heterozygous variants in the CYP17A1 gene were confirmed in patient 3, which were inherited from her parents, respectively.

Case 2

Patient 2 was an 11-year-old female who presented to the Ningbo Women & Children Hospital due to growth retardation and had two previous episodes of hypokalemia. Despite being in adolescence, her breast and labia were undeveloped, and hypertrophy of the clitoris was not found (Table 1). Laboratory screening confirmed hypokalemia, hypertension, and hypergonadotropic hypogonadism. The levels of ACTH and progesterone were markedly elevated, while that of cortisol was relatively low. Genotype testing identified two variants in the CYP17A1 gene. The other family members were advised to also undergo gene testing, but her parents refused. The same heterozygous variants were confirmed in her 2-year-old younger sister, but this sister had no symptoms and was ultimately lost to follow-up. The proband’s treatment was based on the cortisol and spironolactone, and the blood pressure was in control. The proband received sex-steroid replacement when she was 13 years old.

Case 3

Patient 3 was a 13-year-old female who attended Fuzhou Children’s Hospital of Fujian Province due to growth retardation. She had primary amenorrhea, and breast development appeared to be absent (Table 1). The clinical data indicated decreased levels of 17-hydroxyprogesterone, DHEA, and cortisol but increased levels of ACTH, LH, FSH, and progesterone. Meanwhile, serum sodium and potassium levels were in the normal range. In the growth hormone (GH) stimulation test, the peak level of GH was 9.1 µg/dL, and the level of insulin-like growth factor-1 (IGF-1) was 474 ng/mL. Her CYP17A1 gene testing indicated two heterozygous variants, c.1459_1467delGACTCTTTC (p.D487_F489del) inherited from her father, and c.50G>A (p.W17*), a novel variant inherited from her mother (Figure 1). She required life-long cortisol replacement, with sex-steroid replacement needed from puberty onward.

Laboratory data of the patients with CYP17A1 variants

The data of clinical and hormonal evaluations are summarized in Tables 1,2. All patients had at least stage II hypertension. All were nonconsanguineous and reared as females. Patient 1 arrived at hospital with rapid growth. In contrast, patients 2 and 3 consulted for growth retardation, and their bone age was much younger than their actual age. However, all the patients’ actual height was markedly taller than that predicted according to their bone age. Physical examination showed they had prepubertal female external genitalia. The karyotype of patients 2 and 3 was 46,XX, and although they were adolescents, their breasts and labia were undeveloped. A prepubertal uterus and visible small ovaries were also observed. However, a uterus and bilateral gonads could be found in patient 1, and her karyotype was 46,XY. No tumor was evident in the patients’ adrenal CT scans.

The hormonal data of all patients showed that the levels of basal FSH, estradiol (E2), and progesterone were higher than the normal range. The levels of aldosterone, 8:00 AM cortisol (cortisol_8AM), 17-OHP, estradiol, androstenedione, and testosterone were decreased in the three patients. The ACTH levels were increased in patients 2 and 3 but not in patient 1. The level of plasma renin activity (PRA) was markedly lower than normal reference range in patient 1, but her level of serum K⁺ was normal. In comparison, although the level of PRA was at the lower limit of the normal range, patients 2 and 3 had hypokalemia. For patient 1, ACTH stimulation testing showed decreased levels of cortisol_8AM (<1.00 µg/dL), androstenedione (<0.30 ng/mL), DHEA sulfate (18 µg/dL), and 17-OHP (0.08 nmol/L). After 3 days of human chorionic gonadotropin (HCG) injection at a dose of 1,000 U per day in the HCG stimulation test (8), the level of testosterone decreased (0.82 ng/dL).

Genetic diagnosis of CYP17A1

Sanger sequencing verified compound heterozygote variants of CYP17A1 gene in three patients (Figure 1). All patients carried the variant, c.1459_1467delGACTCTTTC, which was located in exon 8, indicating that it is a hotspot (9). Patient 1’s mother carried the c.985_987delinsAA heterozygous frameshift variant, while her father carried c.1459_1467delGACTCTTTC heterozygous deletion, and she inherited these two heterozygous variants of CYP17A1. The c.985_987delinsAA variant led to p.Y329Kfs*90, which caused truncated protein (10). The c.1459_1467delGACTCTTTC deletion resulted in p.D487_F489del, which has been reported to occur in patients with 17α-hydroxylase/17,20 lyase deficiency by Zhu et al. (9). These two variants were in different exons. For patient 2, two heterozygous variants in CYP17A1 gene were also identified, including c.245C>A, as well as c.1459_1467delGACTCTTTC variants. The c.245C>A variant led to p.A82D [Human Gene Mutation Database (HGMD) ID CM113863]. Genotype testing confirmed the presence of the same CYP17A1 variants in her younger sister. Patient 3 carried both c.1459_1467delGACTCTTTC and c.50G>A heterozygous variants of CYP17A1, inherited from her father and mother, respectively, with c.50G>A being a novel variant. It caused a stop codon and decreased the length of the CYP17A1 protein to 17 amino acids. MutationTaster predictive analysis showed that the p.W17* variant might be pathogenic.

Ethical considerations

All procedures described in this report were performed in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of The First Affiliated Hospital, Zhejiang University School of Medicine (approval No. IIT20230364B-R2). All participating hospitals were informed of and agreed to the study. Written informed consent was obtained from the parents of the patients for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

Diagnosis of 17-OHD was established based on typical clinical characteristics, hormonal data, and the molecular feature of the patients. Patient 1 could also be diagnosed with 46,XY disorder of sex development (DSD). Laboratory findings (Table 2) showed that all patients had hypertension; elevated gonadotropin and progesterone levels; and reduced aldosterone, cortisol, 17-OHP, estradiol, androstenedione, and testosterone levels. Hormonal data indicated mineralocorticoid excess and suppressed renin activity. These results suggest that the function of 17-hydroxylation enzymatic activity was impaired. Moreover, all patients had elevated progesterone levels, which implies that an elevated serum progesterone level may be a highly sensitive indicator for the diagnosis of 17-OHD (11).

Due to the weaker glucocorticoid activity of corticosterone, increased corticosterone can prevent adrenal crisis in patients with 17-OHD. However, it also results in a delayed time of diagnosis (6). The children described in this report had common characteristics of hypertension, hypokalemia, and hypergonadotropic hypogonadism, and these indicators were useful to arriving at a diagnosis of 17-OHD. However, unusual growth velocity is not necessarily an obvious feature of children with 17-OHD. All three children with 17-OHD described in this report exhibited delayed growth. Bolu et al. reported short stature at presentation in four out of five patients (80%) with 17-OHD, which was attributed to the absence of a pubertal growth spurt due to a lack of sex steroids (6). However, among our cases, patient 1 was diagnosed at prepuberty because of rapid growth, and patients 2 and 3 were diagnosed at puberty due to growth retardation. Although their growth velocity differed, they all had a younger bone age, and their height was greater than their bone age-matched expectation. This might have been due to a lack of estrogen and subsequent delayed epiphyseal closure; nonetheless, they can be expected to reached an above average, tall stature. In a study that examined 100 children with CAH who were regularly monitored for bone age from birth, it was found that bone age was a reliable follow-up indicator in the treatment of these patients (12). Therefore, unusual growth velocity matched to the bone age may be a useful indicator among patients with 17-OHD, especially when it is difficult for clinical physicians to perform gene testing.

Patient 1 had a 46,XY karyotype, and pelvic ultrasound and MRI showed no uterus or bilateral gonads. The HCG stimulation test, a standard assay of Leydig-cell function and testosterone production in children, failed to increase her testosterone level. This result indicated an absence of Leydig-cell activity and a lack of viable testicular tissue (8). In patients with 46,XY CAH, early diagnosis and surveillance are essential to prevent malignant transformation of dysplastic testes (13). Regular pelvic imaging is therefore warranted, and gonadectomy should be considered if gonads are detected. Management of 17-OHD relies on adequate glucocorticoid replacement combined with spironolactone to control hypertension and hypokalemia. All three patients in our series had stage II hypertension. After glucocorticoid and spironolactone administration was initiated, both hypertension and hypokalemia resolved in all three patients. From puberty onward, sex-steroid replacement will be required to induce and maintain secondary sexual characteristics.

17-hydroxylase deficiency cannot be detected in newborn screening programs, while testing based on immunoassays from blood spots may facilitate faster diagnosis and treatment for CAH (1). The human CYP17A1 gene is a single-copy gene, encoding a 508-amino acid protein for 17α-hydroxylase and 17,20-lyase activities. The gene consists of eight exons and seven introns, is located on chromosome 10q.24.32, and also encodes the P450c17 enzyme (14). More than 100 variants of the CYP17A1 gene are described in the HGMD, including missense mutations, splice site variants, insertions, and deletions (https://www.hgmd.cf.ac.uk/ac/index.php) (5). Different variants of CYP17A1 reduce P450c17 enzyme activity and result in a cascade of functional impairment.

For our cases, genetic testing confirmed p450c17 deficiency and revealed compound heterozygosity in CYP17A1 (Figure 1). We detected one novel and three known variants: c.1459_1467delGACTCTTTC (p.D487_F489del), c.985_987delinsAA (p.Y329Kfs90), c.245C>A (p.A82D), and c.50G>A (p.W17). All three patients carried p.D487_F489del in exon 8, a mutation common in the Chinese population. It is also one of the most prevalent mutations in the Asian population (28%) (15). The p.Y329Kfs*90 variant in exon 6 is likewise frequent among Han Chinese, with an allele frequency of about 70% in heterozygous or homozygous form. Both variants abolish 17α-hydroxylase and 17,20-lyase activity, reflecting a founder effect in East Asia (10,15,16). Therefore, targeted real-time quantitative polymerase chain reaction and Sanger sequencing of exons 6 and 8 can serve as a rapid first-line test for 17-OHD in Han Chinese patients.

Conclusions

This study identified a novel variant and three reported variants of the CYP17A1 gene among three children with 17-OHD. The findings from these cases suggest that for patients with unusual growth velocity, absence of secondary sexual characteristics, hypertension, and hypokalemia, 17α-hydroxylase/17,20 lyase deficiency should be suspected, and gene testing can be further conducted to confirm this diagnosis.

Acknowledgments

We would like to thank all the medical staff who were involved in our study.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-359/rc

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-359/prf

Funding: This study was supported by the National Natural Science Foundation of China (No. 82270837), and the Key Research and Development Program of Zhejiang Province (No. 2020C03121).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-359/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of The First Affiliated Hospital, Zhejiang University School of Medicine (No. IIT20230364B-R2). All participating hospitals were informed of and agreed to the study. Written informed consent was obtained from the parents of the patients for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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