HSD17B3 – 17β-HSD3 Deficiency

17β-Hydroxysteroid dehydrogenase type 3 (17β-HSD3) is encoded by HSD17B3 and catalyzes the reduction of Δ4-androstenedione to testosterone in Leydig cells. Pathogenic biallelic variants in HSD17B3 result in an autosomal recessive 46,XY disorder of sex development characterized by undervirilization at birth and spontaneous virilization at puberty. Molecular confirmation of HSD17B3 deficiency is essential given the overlap in biochemical and phenotypic features with other forms of 46,XY DSD.

Inheritance is autosomal recessive, with segregation demonstrated in multiple consanguineous pedigrees and compound heterozygotes. Over 70 distinct HSD17B3 variants have been reported in 239 patients from 187 families, including recurrent missense alleles at codon 80 and the splice-site mutation c.277+4A>T. Familial co-segregation has been observed in 14 affected relatives across seven pedigrees, supporting pathogenicity ([PMID:17466011]).

The variant spectrum comprises missense (55%), splice-site (29%), small indels (7%), nonsense (5%), and multi-exon deletions/duplications (2%). Founder effects include p.Cys206Ter in Tunisian cohorts and p.Arg80Gln globally. Population studies estimate a minimal incidence of 1:147 000 with a carrier frequency of 1:135 in The Netherlands ([PMID:10599740]).

Functional assays consistently demonstrate loss of enzyme activity for pathogenic variants: p.Cys268Tyr abolishes steroid conversion in recombinant assays ([PMID:11158067]); c.277+4A>G disrupts normal splicing in minigene studies ([PMID:29176693]); p.Gly133Arg impairs NADPH binding in HEK-293 models ([PMID:26545797]). Murine knockout studies reveal compensation by HSD17B12 and HSD17B7, highlighting species-specific plasticity ([PMID:40336300]).

Biochemical testing using stimulated testosterone/androstenedione ratios may yield false negatives, particularly with residual enzyme function. Reliance on D4/T ratios alone can misclassify cases as AIS; molecular analysis remains the gold standard for diagnosis ([PMID:25536660], [PMID:17466011]).

Overall, definitive genetic and experimental evidence—239 patients with segregation, robust in vitro and in vivo functional concordance—establish HSD17B3 as the causal gene for 17β-HSD3 deficiency. Molecular diagnosis informs clinical management, sex assignment decisions, and targeted genetic counseling. Key take-home: HSD17B3 variant analysis provides definitive diagnosis and guides personalized care in 46,XY DSD.

References

• The Journal of clinical endocrinology and metabolism • 1999 • 17Beta-hydroxysteroid dehydrogenase-3 deficiency: diagnosis, phenotypic variability, population genetics, and worldwide distribution of ancient and de novo mutations. PMID:10599740
• The Journal of clinical endocrinology and metabolism • 2001 • Substitution mutation C268Y causes 17 beta-hydroxysteroid dehydrogenase 3 deficiency. PMID:11158067
• Scientific reports • 2017 • A study of splicing mutations in disorders of sex development. PMID:29176693
• The Journal of steroid biochemistry and molecular biology • 2016 • Biochemical analyses and molecular modeling explain the functional loss of 17β-hydroxysteroid dehydrogenase 3 mutant G133R in three Tunisian patients. PMID:26545797
• The Journal of steroid biochemistry and molecular biology • 2017 • Novel cases of Tunisian patients with mutations in the gene encoding 17β-hydroxysteroid dehydrogenase type 3 and a founder effect. PMID:26956191
• Journal of pediatric endocrinology & metabolism • 2015 • Pitfalls in hormonal diagnosis of 17-beta hydroxysteroid dehydrogenase III deficiency. PMID:25536660
• Clinical endocrinology • 2007 • Phenotypic variability in 17beta-hydroxysteroid dehydrogenase-3 deficiency and diagnostic pitfalls. PMID:17466011
• Endocrinology • 2025 • Functional Analysis of HSD17B3-Deficient Male Mice Reveals Roles for HSD17B7 and HSD17B12 in Testosterone Biosynthesis. PMID:40336300

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