Clinical, hormonal and molecular genetic characteristics of patients with 46,XY disorders of sex development associated with variants in the HSD17B3 gene

BACKGROUND: Deficiency of 17β-hydroxysteroid dehydrogenase type 3 (HSD17B3) is a rare variant of 46,XY disorders of sex development (DSD).
AIM: To give clinical, hormonal and molecular genetic characteristics of cases of 46,XY DSD associated with variants in the HSD17B3 gene.
MATERIALS AND METHODS: The study included 310 patients with 46,XY DSD for the period from 2015 to 2019. The patients underwent a comprehensive examination, including a study of the steroid profile by high-performance liquid chromatography with tandem mass spectrometric detection, as well as a molecular genetic analysis using NGS.
RESULTS: According to the results of molecular genetic studies, biallelic nucleotide substitutions in the HSD17B3 gene were detected in 13 cases, which accounted for 4.2% of the total number of patients with 46,XY DSD. All 13 patients with biallelic variants in the HSD17B3 gene were registered as females. The ratio of androstenedione/testosterone concentrations in the blood in this group ranged from 1.4 to 8.9. 2 variants in the HSD17B3 gene were found in several patients: c.277+4A>T (on 6 chromosomes) and c.729_735del:p.V243fs (on 9 chromosomes). 4 novel variants have been identified. Monoallelic nucleotide substitutions in the HSD17B3 gene were detected in 7 cases, which accounted for 2.3% of the total number of patients with 46,XY DSD. External genitalia in this group corresponded to Prader stages 3–4. In 1 patient, a pathogenic variant c.277+4A>T was detected in the HSD17B3 gene, in other cases variants with uncertain significance were detected.
CONCLUSION: In the structure of 46,XY DSD, patients with biallelic variants in the HSD17B3 gene were identified in 4.2% of cases, with monoallelic variants — in 2.3% of cases. 4 novel variants were found in the HSD17B3 gene.

1. Geissler WM, Davis DL, Wu L, Bradshaw KD, Patel S, et al. Male pseudohermaphroditism caused by mutations of testicular 17 beta-hydroxysteroid dehydrogenase 3. Nat Genet. 1994;7(1):34-9. doi: https://doi.org/10.1038/ng0594-34

2. Andersson S, Geissler WM, Wu L, Davis DL, Grumbach MM, et al. Molecular genetics and pathophysiology of 17 betahydroxysteroid dehydrogenase 3 deficiency. J Clin Endocrinol Metab. 1996;81(1):130-6. doi: https://doi.org/10.1210/jcem.81.1.8550739

3. Forest MG. Inborn errors of testosterone biosynthesis. In Intersex Child (Edited by Josso N.). 1981;8:133-155

4. Hughes IA. Disorders of sex development: a new definition and classification. Best Pract Res Clin Endocrinol Metab. 2008;22(1):119-34. doi: https://doi.org/10.1016/j.beem.2007.11.001

5. Rösler A, Silverstein S, Abeliovich D. A (R80Q) mutation in 17 beta-hydroxysteroid dehydrogenase type 3 gene among Arabs of Israel is associated with pseudohermaphroditism in males and normal asymptomaticfemales. J Clin Endocrinol Metab. 1996;81(5):1827-31. doi: https://doi.org/10.1210/jcem.81.5.8626842

6. Rösler A. Steroid 17β-hydroxysteroid dehydrogenase deficiency in man: an inherited form of male pseudohermaphroditism. J Steroid Biochem Mol Biol. 1992;43(8):989-1002. doi: https://doi.org/10.1016/0960-0760(92)90327-F

7. Kolodkina AA, Kalinchenko NI, Nizhnik AN, Nokel’ MA, Tiul’pakov AN. Clinical, hormonal, and molecular-genetic characteristics of two cases of abnormal sex formation (ASF) in 46XY subjects caused by type 3 17-beta hydroxysteroid dehydrogenase deficiency. Problems of Endocrinology. 2011;57(3):25-30. (In Russ.)] doi: https://doi.org/10.14341/probl201157325-30

8. Ioutsi VA, Panov YuM, Usol’tseva LO, Smolin ES, et al. Analysis of Serum Estrogens Using High-Performance Liquid Chromatography– Tandem Mass Spectrometry Coupled to Differential Ion Mobility Spectrometry. J Anal Chem. 2022;77:1760–1766. doi: https://doi.org/10.1134/S1061934822140027

9. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-24. doi: https://doi.org/10.1038/gim.2015.30

10. Ryzhkova OP, Kardymon OL, Prohorchuk EB, i dr. Rukovodstvo po interpretacii dannyh posledovatel’nosti DNK cheloveka, poluchennyh metodami massovogo parallel’nogo sekvenirovaniya (MPS) (redakciya 2018, versiya 2). Medicinskaya genetika. 2019;18(2) (In Russ.)] doi: https://doi.org/10.25557/2073-7998.2019.02.3-23

11. Engeli RT, Rhouma BB, Sager CP, Tsachaki M, Birk J, et al. Biochemical analyses and molecular modeling explain the functional loss of 17β-hydroxysteroid dehydrogenase 3 mutant G133R in three Tunisian patients with 46, XY Disorders of Sex Development. J Steroid Biochem Mol Biol. 2016;155(Pt A):147-54. doi: https://doi.org/10.1016/j.jsbmb.2015.10.023

12. Boehmer AL, Brinkmann AO, Sandkuijl LA, Halley DJ, Niermeijer MF, et al. 17Beta-hydroxysteroid dehydrogenase-3 deficiency: diagnosis, phenotypic variability, population genetics, and worldwide distribution of ancient and de novo mutations. J Clin Endocrinol Metab. 1999;84(12):4713-21. doi: https://doi.org/10.1210/jcem.84.12.6174

13. Phelan N, Williams EL, Cardamone S, Lee M, Creighton SM, Rumsby G, Conway GS. Screening for mutations in 17β-hydroxysteroid dehydrogenase and androgen receptor in women presenting with partially virilised 46,XY disorders of sex development. Eur J Endocrinol. 2015;172(6):745-51. doi: https://doi.org/10.1530/EJE-14-0994

14. Hassan HA, Mazen I, Gad YZ, Ali OS, Mekkawy M, Essawi ML. Mutational Profile of 10 Afflicted Egyptian Families with 17-β-HSD-3 Deficiency. Sex Dev. 2016;10(2):66-73. doi: https://doi.org/10.1159/000445311

15. Eggers S, Sadedin S, van den Bergen JA, Robevska G, Ohnesorg T, Hewitt J, et al. Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort. Genome Biol. 2016;17(1):243. doi: https://doi.org/10.1186/s13059-016-1105-y

16. Saez JM, De Peretti E, Morera AM, David M, Bertrand J. Familial male pseudohermaphroditism with gynecomastia due to a testicular 17-ketosteroid reductase defect. I. Studies in vivo. J Clin Endocrinol Metab. 1971;32(5):604-10. doi: https://doi.org/10.1210/jcem-32-5-604

17. Labrie F, Luu-The V, Lin SX, Simard J, Labrie C. Role of 17 betahydroxysteroid dehydrogenases in sex steroid formation in peripheral intracrine tissues. Trends Endocrinol Metab. 2000;11(10):421-7. doi: https://doi.org/10.1016/s1043-2760(00)00342-8

18. Werner R, Kulle A, Sommerfeld I, Riepe FG, Wudy S, et al. Testosterone synthesis in patients with 17β-hydroxysteroid dehydrogenase 3 deficiency. Sex Dev. 2012;6(4):161-8. doi: https://doi.org/10.1159/000336605

19. Imperato-McGinley J. Male pseudohermaphroditism. In: Adashi EY, Rock JA, Rosenwaks Z, editors. Reproductive endocrinology, surgery, and technology. Philadelphia: Lippincott-Raven; 1996:936–955

20. Neher R, Kahnt FW. Gonadal steroid biosynthesis in vitro in four cases of testicular feminization; in normal and pathological conditions. International Congress Series No101. Excerpta Medica, Ammsterdam. 1965:130

21. Gonçalves CI, Carriço J, Bastos M, Lemos MC. Disorder of Sex Development Due to 17-Beta-Hydroxysteroid Dehydrogenase Type 3 Deficiency: A Case Report and Review of 70 Different HSD17B3 Mutations Reported in 239 Patients. Int J Mol Sci. 2022;23(17):10026. doi: https://doi.org/10.3390/ijms231710026

22. Alikasifoglu A, Hiort O, Gonc N, Demirbilek H, Isik E, Kandemir N. 17beta- hydroxysteroid dehydrogenase type 3 deficiency as a result of a homozygous 7 base pair deletion in 17betaHSD3 gene. J Pediatr Endocrinol Metab. 2012;25(5-6):561-3. doi: https://doi.org/10.1515/jpem-2012-0009

23. Mazen I, Mekkawy M, Kamel A, Essawi M, Hassan H, et al. Advances in genomic diagnosis of a large cohort of Egyptian patients with disorders of sex development. Am J Med Genet A. 2021;185(6):1666-1677. doi: https://doi.org/10.1002/ajmg.a.62129

24. Hughes LA, McKay-Bounford K, Webb EA, Dasani P, Clokie S, et al. Next generation sequencing (NGS) to improve the diagnosis and management of patients with disorders of sex development (DSD). Endocr Connect. 2019;8(2):100-110. doi: https://doi.org/10.1530/EC-18-0376