3-Beta-Hydroxysteroid Dehydrogenase Deficiency

3-beta–hydroxysteroid dehydrogenase (3BHSD) deficiency is a rare genetic disorder of steroid biosynthesis that results in decreased production of all 3 groups of adrenal steroids, which include mineralocorticoids, glucocorticoids, and sex steroids. Decreased mineralocorticoid secretion results in varying degrees of salt wasting in both males and females, and deficient androgen production results in ambiguous genitalia in 46,XY males. Much heterogeneity is observed in the clinical presentation of this disorder. Although first described in male infants with ambiguous genitalia and severe salt wasting, 3-beta–hydroxysteroid dehydrogenase deficiency also occurs in 46,XX female infants (who may have mild clitoromegaly), as well as in older patients who present with a milder or so-called late-onset variant.1

Pathophysiology
Anatomically, the adrenal gland can be divided into 3 zones, (1) the zona glomerulosa, which predominately produces mineralocorticoid, (2) the zona fasciculata, which predominately produces glucocorticoid, and (3) the zona reticularis, which predominantly produces androgens. Think of the zona glomerulosa and the zonae fasciculata and reticularis as 2 separate endocrine organs because they are under separate control. Aldosterone (mineralocorticoid) synthesis and secretion is regulated via the renin-angiotensin system, which is responsive to the state of electrolyte balance and the plasma volume. Aldosterone secretion is also directly stimulated by high serum potassium concentrations. By contrast, cortisol synthesis and secretion is regulated by adrenocorticotropic hormone (ACTH), which stimulates the enzyme P-450scc (20,22 desmolase), with subsequent increased production of all adrenal steroids in both the zona fasciculata and the zona reticularis (see Media file 1).

Congenital adrenal hyperplasia (CAH) is a family of autosomal recessive disorders of adrenal steroid biosynthesis in which activity of one of the enzymes necessary for cortisol production is deficient. Decreased serum cortisol levels stimulate ACTH release via negative feedback. The adrenal glands undergo hypertrophy, apparently because of ACTH-stimulated production of insulinlike growth factor–2 (IGF-2). Increased ACTH secretion also produces overproduction of both the adrenal steroids preceding the missing enzyme and those not requiring the missing enzyme (ie, build-up of compounds both before the block and “sideways” from the block). See Media file 2. Treatment with exogenous glucocorticoid results in decreased ACTH secretion and subsequent suppression of the overproduced steroids.

An 8-kilobase (kb) gene, HSD3B2, located on the p11-13 region of chromosome 1 encodes 3-beta–hydroxysteroid dehydrogenase.2 Two isoenzymes of 3-beta–hydroxysteroid dehydrogenase have been described, differing by only 23 amino acids. Type I 3-beta–hydroxysteroid dehydrogenase isoenzyme occurs in the peripheral tissues, primarily the liver, and type II 3-beta–hydroxysteroid dehydrogenase occurs almost exclusively in the gonads and adrenal glands.

Patients with classic 3-beta–hydroxysteroid dehydrogenase deficiency have been shown to have nonconservative missense, nonsense, splicing, and frameshift mutations in the type II 3-beta–hydroxysteroid dehydrogenase gene with no mutation in the type I gene. Missense mutations in the type II gene have been described in nonclassic late-onset 3-beta–hydroxysteroid dehydrogenase deficiency. Various mutations have been described in the type II gene, including T259M and G129R/P222Q mutations in female patients and P222Q in a male patient with salt-wasting.

The synthesis of all 3 groups of adrenal steroids requires 3-beta–hydroxysteroid dehydrogenase. The adrenal steroids are mineralocorticoids, glucocorticoids, and sex steroids. 3-beta–hydroxysteroid dehydrogenase catalyzes the 3-beta-dehydrogenation and isomerization of the double bond of the steroid B ring to the steroid A ring, converting pregnenolone to progesterone (mineralocorticoid pathway), 17-alpha-hydroxypregnenolone to 17-alpha-hydroxyprogesterone (glucocorticoid pathway), and dehydroepiandrosterone (DHEA) to androstenedione (sex steroid pathway). See Media file 3.

Therefore, absence of this enzyme impairs all steroid production. Low levels of cortisol result in increased ACTH stimulation of steroids prior to the 3-beta–hydroxysteroid dehydrogenase step, producing increased accumulation and secretion of pregnenolone, 17-alpha-hydroxypregnenolone, and DHEA. Adrenal insufficiency occurs secondary to aldosterone and cortisol deficiency. Reduced sex steroid production leads to ambiguous external genitalia in 46,XY individuals; some virilization may occur in 46,XX infants or in older children of either sex because of excessive DHEA production.

Affected 46,XX infants appear normal or may have mild-to-moderate clitoromegaly due to either direct androgen effects of elevated DHEA or peripheral conversion of excess DHEA to testosterone via peripheral type I 3-beta–hydroxysteroid dehydrogenase isoenzyme. Effects of excessive androgen activity in older 46,XX children include acne, premature pubarche, and advanced linear and skeletal growth.

By contrast, 46,XY infants present with varying degrees of ambiguous genitalia due to defective androgen production. 46,XY individuals with milder defects may present as adolescents with ambiguous genitalia, poor virilization, and gynecomastia. Virilization or spontaneous puberty has been reported in occasional male patients secondary to either direct effects of DHEA or to sufficient conversion of DHEA to testosterone via peripheral type I 3-beta–hydroxysteroid dehydrogenase isoenzyme. 3-beta–hydroxysteroid dehydrogenase activity may vary in the gonadal, adrenal, and peripheral tissues within the same individual.3 At least one patient has been reported with partial 3-beta–hydroxysteroid dehydrogenase activity in the testes coupled with complete absence of adrenal 3-beta–hydroxysteroid dehydrogenase activity.