HSD3B2 – Congenital Adrenal Hyperplasia

HSD3B2 encodes the type II 3β-hydroxysteroid dehydrogenase (3β-HSD2) enzyme expressed in the adrenal cortex and gonads. Bi-allelic loss-of-function variants cause autosomal recessive congenital adrenal hyperplasia (CAH), presenting with salt-wasting crises, primary adrenal insufficiency, and variable degrees of genital ambiguity in genetic males and females (PMID:12428206).

The inheritance is autosomal recessive. More than 56 affected individuals from 44 unrelated families have been reported, with segregation of pathogenic HSD3B2 variants confirmed in multi-family studies (PMID:12428206; PMID:10599696).

Case reports include two siblings harboring a paternal missense variant c.385G>A (p.Gly129Arg) and a maternal splice-affecting variant in intron III, both in trans, who presented with salt-wasting and 46,XY undervirilization (PMID:7962268). A founder frameshift variant c.818_819del (p.Lys273fs) has been described in Afghan/Pakistani kindreds with classical CAH (PMID:8004103).

Functional assays of recombinant mutant enzymes demonstrate markedly reduced catalytic efficiencies. The p.Gly129Arg variant retained only 2–4.7% of wild-type activity for pregnenolone and DHEA, respectively, correlating with clinical severity. Broader functional characterization of 25 HSD3B2 mutations confirmed that most missense and truncating variants abolish enzyme activity, whereas hypomorphic alleles show residual function insufficient to prevent salt loss (PMID:10599696).

The mechanism of pathogenicity is loss of HSD3B2 enzymatic activity leading to impaired Δ⁵-to-Δ⁴ steroid conversion. Genetic and experimental concordance across multiple studies support a definitive gene–disease relationship. Biochemical screening followed by targeted HSD3B2 sequencing is essential for diagnosis, family counseling, and newborn screening algorithms.

Key Take-home: HSD3B2 deficiency is a definitive autosomal recessive cause of CAH; early molecular diagnosis guides hormonal replacement and prevents adrenal crises.

References

• Seminars in reproductive medicine • 2002 • Congenital adrenal hyperplasia due to 3beta-hydroxysteroid dehydrogenase/Delta(5)-Delta(4) isomerase deficiency PMID:12428206
• The Journal of clinical endocrinology and metabolism • 1994 • Molecular basis of congenital adrenal hyperplasia in two siblings with classical nonsalt-losing 3 beta-hydroxysteroid dehydrogenase deficiency PMID:7962268
• Human molecular genetics • 1994 • Congenital adrenal hyperplasia caused by a novel homozygous frameshift mutation 273 delta AA in type II 3 beta-hydroxysteroid dehydrogenase gene (HSD3B2) in three male patients of Afghan/Pakistani origin PMID:8004103
• The Journal of clinical endocrinology and metabolism • 1999 • New insight into the molecular basis of 3beta-hydroxysteroid dehydrogenase deficiency: identification of eight mutations in the HSD3B2 gene PMID:10599696

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