HSD3B2

HSD3B2 is the gene that encodes the enzyme 3β-hydroxysteroid dehydrogenase type II, a key enzyme in human steroidogenesis. The enzyme catalyzes the conversion of Δ5-steroids to Δ4-ketosteroids in the adrenal cortex and gonads, enabling the synthesis of all classes of steroid hormones. Substrates include pregnenolone and 17-hydroxypregnenolone, which are converted to progesterone and 17-hydroxyprogesterone, respectively, and DHEA, which is converted to androstenedione. Through these reactions, HSD3B2 supports the production of glucocorticoids, mineralocorticoids, and sex steroids.

Expression and isoforms: HSD3B2 is the predominant 3β-HSD isoform in adrenal and gonadal tissues. A related isoform, HSD3B1, is expressed in other tissues such as the placenta. The enzyme’s activity is essential for normal cortisol, aldosterone, and androgen synthesis, and its disruption impairs steroidogenesis across multiple pathways.

Clinical significance: Mutations in HSD3B2 cause congenital adrenal hyperplasia due to 3β-hydroxysteroid dehydrogenase deficiency (CAH type II), inherited in an autosomal recessive pattern. Affected individuals may present in infancy with salt-wasting and signs of adrenal insufficiency, including dehydration and hypotension. Sexual development can be variably affected, with undervirilization or atypical development in genetic males and normally feminized genitalia in many genetic females. Hormone profiles typically show accumulation of Δ5 steroids such as pregnenolone, 17-hydroxypregnenolone, and DHEA, with reduced downstream steroids including progesterone, 17-hydroxyprogesterone, androstenedione, cortisol, and aldosterone.

Diagnosis and management: Diagnosis relies on clinical and hormonal assessment and confirmation by genetic testing for HSD3B2 mutations. Management includes lifelong glucocorticoid replacement to address cortisol deficiency and ACTH excess, and mineralocorticoid replacement for salt-wasting; acute care addresses dehydration and electrolyte imbalances, with ongoing monitoring of growth and development.