HSD3B2 – 3β-HSD Deficiency-Related Congenital Adrenal Hyperplasia

HSD3B2 encodes the type II 3β-hydroxysteroid dehydrogenase (3β-HSD2) enzyme required for conversion of Δ5 to Δ4 steroids in the adrenal cortex and gonads. Biallelic loss-of-function variants result in autosomal recessive congenital adrenal hyperplasia (CAH) due to 3β-HSD deficiency, characterized by salt-wasting crises, ambiguous genitalia in 46,XY individuals, and variable virilization in females. Early hormonal assessment reveals elevated 17-hydroxypregnenolone and Δ5 steroids relative to cortisol.

Case reports identified three unrelated male infants of Afghan/Pakistani descent homozygous for the founder c.818_819del (p.Lys273fs) variant, all presenting with severe salt-wasting and adrenal crisis, with carrier status confirmed in multiple family members (PMID:8004103). Additional sib-pairs and parental segregation analyses further support autosomal recessive inheritance.

In a cohort of 11 patients from seven new families, eight novel HSD3B2 mutations were described, raising the total to 31 distinct alleles (1 splicing, 1 in-frame deletion, 3 nonsense, 4 frameshift, 22 missense) and confirming complete loss of enzymatic activity for severe salt-wasting forms (PMID:10599696). A multicenter study of 31 children identified 11 homozygous and compound heterozygous variants, correlating residual in vitro activity (>5% WT) with non-salt-losing phenotypes (PMID:31950145). Altogether >42 probands have been documented.

Variant spectrum includes common missense changes such as c.244G>A (p.Ala82Thr) associated with non-salt-losing CAH, recurrent nonsense (c.385G>A p.Gly129Arg) and frameshift alleles, and deep-intronic or splice site defects. Founder and population-specific variants underscore the importance of targeted genetic screening in high-risk ethnic groups.

Functional assays in transiently transfected HEK293 cells demonstrate absent or severely reduced Δ5→Δ4 conversion for type II 3β-HSD mutants, with Northern/Western blot and in vitro translation revealing protein instability as a key pathogenic mechanism (PMID:10599696). A novel transactivation assay using progesterone- and androgen-responsive reporters confirms the relationship between enzymatic activity and patient phenotype (PMID:39415787).

Some heterozygous missense variants (e.g., p.Ser213Thr, p.Ser284Arg) were identified in patients with idiopathic hypospadias but without a steroidogenic profile of CAH, indicating that partial activity reductions may be insufficient to cause clinical disease (PMID:14764821).

Overall, the genetic and functional concordance, extensive segregation data, and consistent biochemical phenotype establish a definitive gene–disease relationship. Comprehensive HSD3B2 sequencing and steroid profiling enable early diagnosis, guide hormone replacement therapy, and inform genetic counseling.

Key Take-home: HSD3B2 loss-of-function variants cause autosomal recessive 3β-HSD deficiency with salt-wasting CAH; genetic testing and functional assays are essential for precise diagnosis and management.

References

• 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 eleven patients from seven new families and comparison of the functional properties of twenty-five mutant enzymes. PMID:10599696
• The Journal of clinical endocrinology and metabolism • 2020 • Revisiting Classical 3β-hydroxysteroid Dehydrogenase 2 Deficiency: Lessons from 31 Pediatric Cases PMID:31950145
• The Journal of clinical endocrinology and metabolism • 2004 • Molecular study of the 3 beta-hydroxysteroid dehydrogenase gene type II in patients with hypospadias. PMID:14764821
• Frontiers in endocrinology • 2024 • Evaluation of 3β-hydroxysteroid dehydrogenase activity using progesterone and androgen receptors-mediated transactivation PMID:39415787

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