A multidisciplinary approach to the diagnosisand treatment of isolated 17,20-lyase deficiency:a case report
PRACTICAL NOTES
Abstract
Isolated 17,20-lyase deficiency is an extremely rare form of congenital adrenal hyperplasia caused by mutations in the CYP17A1 gene, characterized by impaired androgen synthesis with preserved cortisol production. The clinical picture is often subtle, leading to delayed diagnosis. The description of clinical cases is crucial for understanding the features of this pathology. The article presents a detailed clinical description and analysis of the diagnostic pathway in a 13-year-old female patient with primary amenorrhea and delayed puberty. The examination included assessment of the hormonal profile, pelvic imaging, cytogenetic study, and molecular genetic Sanger sequencing of the CYP17A1 gene with verification of findings in the parents. The patient with a 46,XX karyotype was found to have hypergonadotropic hypogonadism, cystic transformation of the ovaries, and an abnormally elevated level of 17-OH-progesterone. Genetic analysis revealed compound heterozygous pathogenic variants in the CYP17A1 gene: c.1039C>T (inherited from the mother) and c.1319G>A (inherited from the father), confirming the diagnosis of isolated 17,20-lyase deficiency. Prescription of combined therapy with low doses of dexamethasone and estradiol valerate led to positive dynamics: the appearance and progression of secondary sexual characteristics, menarche, normalization of the hormonal profile, and regression of ovarian cysts. This case demonstrates the successful diagnosis of an extremely rare isolated form of 17,20-lyase deficiency, which requires a multidisciplinary approach and targeted genetic testing. The combination of pathogenic variants c.1039C>T and c.1319G>A in the CYP17A1 gene leading to this form of congenital adrenal hyperplasia is described for the first time. Personalized therapy aimed at suppressing the ACTH-dependent pathway and replacing estrogen deficiency proved to be highly effective clinically and in laboratory findings, ensuring normal pubertal development.
References
1. Finkielstain G.P., Vieites A., Bergadá I., Rey R.A. Disorders of sex development of adrenal origin. Front Endocrinol. 2021;12:770782. https://doi.org/10.3389/fendo.2021.770782.
2. Singh H., Kumar R., Mazumder A., Salahuddin Mazumder R., Abdullah M.M. insights into interactions of human cytochrome P450 17A1: A review. Curr Drug Metab. 2022;23(3):172–187. https://doi.org/10.2174/1389200223666220401093833.
3. Lee S.G., Kim V., Lee G.H., Kim C., Jeong E., Guengerich F.P., Kim D. Hydroxylation and lyase reactions of steroids catalyzed by mouse cytochrome P450 17A1 (Cyp17a1). J Inorg Biochem. 2023;240:112085. https://doi.org/10.1016/j.jinorgbio.2022.112085.
4. Maheshwari M., Arya S., Lila A.R., Sarathi V., Barnabas R., Rai K. et al. 17α-hydroxylase/17,20-lyase deficiency in 46,XY: our experience and review of literature. J Endocr Soc. 2022;6(3):bvac011. https://doi.org/10.1210/jendso/bvac011.
5. Willemsen A.L., Torpy D.J., De Sousa S., Falhammar H., Rushworth R.L. 17α-hydroxylase/17,20-lyase deficiency (17-OHD): A meta-analysis of reported cases. J Clin Endocrinol Metab. 2025;110(4):e1261–e1271. https://doi.org/10.1210/clinem/dgae773.
6. Lee H.I., Kwon A., Suh J.H., Choi H.S., Song K.C., Chae H.W., Kim H.S. Two cases of 17α-hydroxylase/17,20-lyase deficiency caused by the CYP17A1 mutation. Ann Pediatr Endocrinol Metab. 2021;26(1):66–70. https://doi.org/10.6065/apem.2040184.092.
7. Zhao Y., Wang C., Guo Z., Yi C., Zhang W. Severe hypertension caused by 17α-hydroxylase deficiency: A case report. Heliyon. 2023;9(3):e14062. https://doi.org/10.1016/j.heliyon.2023.e14062.
8. Habib A., Shojazadeh A., Molayemat M., Jafari Khamirani H., Zoghi S., Dastgheib S.A., Habib A. A single-amino-acid in-frame deletion in CYP17A1 results in combined 17-hydroxylase and 17,20-lyase deficiency in an Iranian family despite the protein mutation site. Hum Genome Var. 2021;8(1):31. https://doi.org/10.1038/s41439-021-00160-y.
9. Yamagata S., Kageyama K., Usui T., Saito K., Takayasu S., Usutani M., Terui K., Daimon M. Identification of a homozygous c.1039C>T (p.R347C) variant in CYP17A1 in a 67-year-old female patient with partial 17α-hydroxylase/17,20-lyase deficiency. Endocr J. 2022;69(2):115–120. https://doi.org/10.1507/endocrj.EJ21-0266.
10. Siklar Z., Camtosun E., Bolu S., Yildiz M., Akinci A., Bas F. et al. 17α-hydroxylase/17,20 lyase deficiency: clinical features and genetic insights from a large Turkey cohort. Endocrine. 2024;85(3):1407–1416. https://doi.org/10.1007/s12020-024-03962-6.
11. Li J., Zhang Q., Chen J., Fu X., Yang J., Liu L. Case report: 17α-hydroxylase deficiency due to a hotspot variant and a novel compound heterozygous variant in the CYP17A1 gene of five Chinese patients. Front Pediatr. 2022;10:935191. https://doi.org/10.3389/fped.2022.935191.
12. Gomes L.G., Bachega T.A.S.S., Mendonca B.B. Classic congenital adrenal hyperplasia and its impact on reproduction. Fertil Steril. 2019;111(1):7–12. https://doi.org/10.1016/j.fertnstert.2018.11.037.
13. Xia Y., Shi P., Xia J., Zhang H., Xu L., Kong X. Novel mutations of the CYP17A1 gene in four Chinese 46,XX cases with partial 17α-hydroxylase/17,20-lyase deficiency. Steroids. 2021;173:108873. https://doi.org/10.1016/j.steroids.2021.108873.
14. Tateishi Y., Webb S.N., Li B., Liu L., Lindsey Rose K., Leser M., Patel P, Guengerich F.P. Proteomics, modeling, and fluorescence assays delineate cytochrome b5 residues involved in binding and stimulation of cytochrome P450 17A1 17,20-lyase. J Biol Chem. 2024;300(3):105688. https://doi.org/10.1016/j.jbc.2024.105688.
15. Saltarelli M.A., Ferrante R., Marcello F.D., David D., Valentinuzzi S., Pilenzi L. et al. A novel heterozygous mutation of the CYP17A1 Gene in a child with a micropenis and isolated 17,20-lyase deficiency. Int J Environ Res Public Health. 2022;19(11):6880. https://doi.org/10.3390/ijerph19116880.
16. Kurnaz E., Kartal Baykan E., Türkyılmaz A., Yaralı O., Yavaş Abalı Z., Turan S. et al. Genotypic sex and severity of the disease determine the time of clinical presentation in steroid 17α-hydroxylase/17,20-lyase deficiency. Horm Res Paediatr. 2020;93(9-10):558–566. https://doi.org/10.1159/000515079.
17. Sun M., Mueller J.W., Gilligan L.C., Taylor A.E., Shaheen F., Noczyńska A. et al. The broad phenotypic spectrum of 17α-hydroxylase/17,20-lyase (CYP17A1) deficiency: a case series. Eur J Endocrinol. 2021;185(5):729–741. https://doi.org/10.1530/EJE-21-0152.
18. Van Den Akker E.L., Koper J.W., Boehmer A.L., Themmen A.P., Verhoef-Post M., Timmerman M.A., Otten B.J., Drop S.L., De Jong F.H. Differential inhibition of 17alpha-hydroxylase and 17,20-lyase activities by three novel missense CYP17 mutations identified in patients with P450c17 deficiency. J Clin Endocrinol Metab. 2002;87(12):5714–5721. https://doi.org/10.1210/jc.2001-011880.
