HSD17B3 – 46,XY Disorder of Sex Development

17β-Hydroxysteroid dehydrogenase type 3, encoded by HSD17B3, is essential for conversion of Δ4-androstenedione to testosterone in the fetal testis. Pathogenic variants in HSD17B3 cause an autosomal recessive form of 46,XY disorder of sex development (DSD), characterized by undervirilized external genitalia at birth and virilization at puberty.

Clinical Validity and Genetic Evidence

Inheritance is autosomal recessive with multiple reports of homozygous and compound heterozygous variants. A consanguineous Iranian pedigree described three affected siblings all homozygous for c.238C>T (p.Arg80Trp) (PMID:22212252), with no SRD5A2 mutations detected. To date, over 239 patients from 187 families harbor more than 70 distinct HSD17B3 mutations, including missense, nonsense, splice-site, small indels, and large duplications, supporting a Strong gene‐disease association based on case counts, segregation, and concordant functional data.

Variant Spectrum and Segregation

Pathogenic alleles span all 11 exons. Recurrent variants include c.239G>A (p.Arg80Gln) representing ~17% of alleles (PMID:36077423) and an 11.96 kb exon 3–10 duplication in a Cypriot patient (PMID:22445608). Segregation analysis in extended pedigrees confirms co-segregation with disease (affected relatives = 3).

Functional and Experimental Evidence

In vitro assays demonstrate that missense variants such as p.Gly133Arg and nonsense alleles like p.Cys206Ter abolish 17β-HSD3 enzymatic activity (PMID:26545797). Splice‐site mutations (e.g., c.277+4A>T) cause exon skipping and loss of function. In Hsd17b3 knockout mice, compensation by HSD17B12 and HSD17B7 preserves testosterone synthesis, highlighting species-specific redundancy (PMID:40336300).

Phenotypic Spectrum and Diagnosis

Affected infants present with ambiguous genitalia, often assigned female, and later virilize at puberty with micropenis, gynecomastia (HP:0000771), and primary amenorrhea (HP:0000786). Biochemical hallmark is a low stimulated T/Δ4-A ratio. Genetic testing of HSD17B3 confirms diagnosis, informs sex assignment decisions, and guides surgical and hormone therapies.

Key Take-home: HSD17B3 deficiency is a well‐established autosomal recessive cause of 46,XY DSD; comprehensive genetic testing and in vitro functional assays are critical for accurate diagnosis and management.

References

• Sexual Development • 2011 • 17-β-hydroxysteroid dehydrogenase type 3 deficiency in three adult Iranian siblings PMID:22212252
• Int. J. Mol. Sci. • 2022 • 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 PMID:36077423
• J. Steroid Biochem. Mol. Biol. • 2017 • Novel cases of Tunisian patients with mutations in the gene encoding 17β-hydroxysteroid dehydrogenase type 3 and a founder effect PMID:26956191
• J. Steroid Biochem. Mol. Biol. • 2016 • 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 PMID:26545797
• Gene • 2012 • Duplication of exons 3-10 of the HSD17B3 gene: a novel type of genetic defect underlying 17β-HSD-3 deficiency PMID:22445608
• Endocrinology • 2025 • Functional Analysis of HSD17B3-Deficient Male Mice Reveals Roles for HSD17B7 and HSD17B12 in Testosterone Biosynthesis PMID:40336300

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