Serum steroid metabolite profiling by LC-MS/MS in two phenotypic male patients with HSD17B3 deficiency: Implications for hormonal diagnosis.

Abstract

Although 17β-hydroxysteroid dehydrogenase type 3 (HSD17B3) deficiency is diagnosed when a testosterone/androstenedione (T/A-dione) ratio after human chorionic gonadotropin (hCG) stimulation is below 0.8, this cut-off value is primarily based on hormonal data measured by conventional immunoassay (IA) in patients with feminized or ambiguous genitalia. We examined two 46,XY Japanese patients with undermasculinized genitalia including hypospadias (patient 1 and patient 2). Endocrine studies by IA showed well increased serum T value after hCG stimulation (2.91 ng/mL) and a high T/A-dione ratio (4.04) in patient 1 at 2 weeks of age and sufficiently elevated basal serum T value (2.60 ng/mL) in patient 2 at 1.5 months of age. Despite such partial androgen insensitivity syndrome-like findings, whole exome sequencing identified biallelic ″pathogenic″ or ″likely pathogenic″ variants in HSD17B3 (c .188 C>T:p.(Ala63Val) and c .194 C>T:p.(Ser65Leu) in patient 1, and c.139 A>G:p.(Met47Val) and c.672 + 1 G>A in patient 2) (NM_000197.2), and functional analysis revealed reduced HSD17B3 activities of the missense variants (∼ 43% for p.Met47Val, ∼ 14% for p.Ala63Val, and ∼ 0% for p.Ser65Leu). Thus, we investigated hCG-stimulated serum steroid metabolite profiles by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in patient 1 at 7 months of age and in patient 2 at 11 months of age as well as in five control males with idiopathic micropenis aged 1 - 8 years, and found markedly high T/A-dione ratios (12.3 in patient 1 and 5.4 in patient 2) which were, however, obviously lower than those in the control boys (25.3 - 56.1) and sufficiently increased T values comparable to those of control males. The elevated T/A-dione ratios are considered be due to the residual HSD17B3 function and the measurement by LC-MS/MS. Thus, it is recommended to establish the cut-off value for the T/A-dione ratio according to the phenotypic sex reflecting the residual function and the measurement method.

• Authors: Yasuko Fujisawa, Yohei Masunaga, Wataru Tanikawa, Shinichi Nakashima, Daisuke Ueda, Shinichiro Sano, Maki Fukami, Hirotomo Saitsu, Takashi Yazawa, Tsutomu Ogata
• Journal: The Journal of steroid biochemistry and molecular biology (J Steroid Biochem Mol Biol) Vol. 234 Pg. 106403 (11 2023) ISSN: 1879-1220 [Electronic] England
• PMID: 37741351 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 Elsevier Ltd. All rights reserved.

Chemical References

• Testosterone
• 17-Hydroxysteroid Dehydrogenases

Topics

• Humans
• Male
• Chromatography, Liquid
• Tandem Mass Spectrometry
• Disorders of Sex Development
• Androgen-Insensitivity Syndrome
• Testosterone
• 17-Hydroxysteroid Dehydrogenases (genetics)