Practice Essentials
3-Beta–hydroxysteroid dehydrogenase (3BHSD) deficiency is a rare form of congenital adrenal hyperplasia that results in decreased production of all 3 groups of adrenal steroids: mineralocorticoids, glucocorticoids, and sex steroids. In severely affected individuals, 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. This condition is due to defects in type II 3-beta–hydroxysteroid dehydrogenase, an enzyme that occurs almost exclusively in the gonads and adrenal glands. A variety of mutations in the HSD3B2 gene affect the activity of this enzyme, resulting in the extremely variable, phenotypic presentations of 3-beta–hydroxysteroid dehydrogenase deficiency.
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With severe deficiency, the most common presentation is that of a newborn infant with adrenal insufficiency due to both glucocorticoid and mineralocorticoid deficiency and ambiguous genitalia in 46,XY patients. Infants with less severe (non–salt-wasting) forms may be relatively asymptomatic.
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Older patients with mild defects in 3-beta–hydroxysteroid dehydrogenase activity (late-onset or nonclassic variant) may present with premature pubic hair development, hirsutism, irregular menstrual cycles or primary amenorrhea.
Management
Patients with classic salt-losing 3-beta–hydroxysteroid dehydrogenase require initial replacement of glucocorticoids and mineralocorticoid, plus the addition of sex steroids at appropriate, pubertal age.
The need for replacement therapy varies in late-onset (nonclassic) 3-beta–hydroxysteroid dehydrogenase deficiency and depends on the severity of the defect. Hydrocortisone (or other glucocorticoid) replacement therapy may be needed to suppress excess androgen production.
Prognosis is usually good-to-excellent with adequate replacement (as needed) of glucocorticoids, mineralocorticoid, and sex steroid therapy, monitoring and follow-up.
Background
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 image below).
Normal adrenal steroid biosynthesis results in 3 products: mineralocorticoid (aldosterone), glucocorticoids (cortisol), and androgens (androstenedione). Cortisol production is regulated by feedback with adrenocorticotropic hormone (ACTH). ACTH stimulates the enzyme P-450scc (20,22 desmolase) with subsequent increased production of all adrenal steroids.
Congenital adrenal hyperplasia (CAH) is a family of autosomal recessive disorders of adrenal steroid biosynthesis [2] in which activity of one of the enzymes necessary for cortisol production is deficient (see image below). 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). Treatment with exogenous glucocorticoid results in decreased ACTH secretion and subsequent suppression of the overproduced steroids.
Representation of typical congenital adrenal hyperplasia (CAH). In this example, both the mineralocorticoid and glucocorticoid pathways are deficient. Decreased serum cortisol levels stimulate adrenocorticotropic hormone (ACTH) release via negative feedback. Increased ACTH secretion results in overproduction of adrenal steroids preceding the missing enzyme as well as those not requiring the missing enzyme. In this example, a deficiency of 21-hydroxylase results in deficient mineralocorticoid and glucocorticoid production and excessive androgen production.
An 8-kilobase (kb) gene, HSD3B2, located on the p11-13 region of chromosome 1 encodes 3-beta–hydroxysteroid dehydrogenase. [3] 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. Deficiencies of this isoenzyme primarily effect bile acid metabolism and may present with cholestasis, hepatomegaly, steatorrhea, failure to thrive, and low serum levels of the fat soluble vitamins A, E, and D. [4]
Type II 3-beta–hydroxysteroid dehydrogenase occurs almost exclusively in the gonads and adrenal glands [5] and is the focus of this review. Various mutations in the HSD3B2 gene have been shown to be responsible for the varying phenotypic presentations. [6]
Patients with classic 3-beta–hydroxysteroid dehydrogenase deficiency have various nonconservative missense, nonsense, splicing, and frameshift mutations in the type II 3-beta–hydroxysteroid dehydrogenase gene with no mutation in the type I gene. Such mutations of the type II isoenzyme typically occur in gene domains essential for normal enzyme activity, but in vitro enzyme activity does not necessarily correlate with genital phenotype. [7]
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 image below.
3-beta-hydroxysteroid dehydrogenase (3BHSD) is required for the synthesis of all three groups of adrenal steroids: mineralocorticoids, glucocorticoids, and sex steroids. 3BHSD catalyzes the conversion of pregnenolone to progesterone (mineralocorticoid pathway), 17-alpha-hydroxypregnenolone to 17-alpha-hydroxyprogesterone (glucocorticoid pathway), and dehydroepiandrosterone to androstenedione (sex steroid pathway). Complete absence of this enzyme thus impairs all steroid production. 17OH Preg = 17-alpha-hydroxypregnenolone; DHEA = Dehydroepiandrosterone; 17OH Prog = 17-alpha-hydroxyprogesterone; Andros = Androstenedione; DOC = Deoxycorticosterone; Cmp S = Compound S.
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. [8] 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.
Finally, a deficiency in the related 3-alpha-hydrozysteroid dehydrogenase may also play a role in hirsutism. 3-alpha HSD is encoded by the AKR1C2 gene and is required for normal metabolism of dihydrotestosterone (DHT) in peripheral tissues. Deficient 3-alpha HSD activity may lead to increased tissue levels of DHT and subsequent hirsutism. [9]
Epidemiology
Most individuals worldwide with CAH have 21-hydroxylase deficiency (80-90%). The incidence of classic 21-hydroxylase deficiency varies by population and ranges from 1 case per 5000-15,000 live births to as high as 1 case per 300-700 births in Alaskan Yupik Eskimos. The next most common type of CAH, 11-beta-hydroxylase deficiency, has an incidence of about 1 in 100,000 persons. Less than 5% of all patients worldwide with CAH have 3-beta–hydroxysteroid dehydrogenase deficiency. In one study of 81 children with ambiguous genitalia, only 2 were found to have 3-beta–hydroxysteroid dehydrogenase deficiency. [10] The incidence is higher in some populations; 3-beta–hydroxysteroid dehydrogenase deficiency is relatively common in the Old Order Amish in North America associated with a HSD3B2 c.35G, a founder mutation. [11]
Mild 3-beta–hydroxysteroid dehydrogenase defects are probably rare because most children with premature appearance of pubic hair (pubarche) or older women with irregular menstrual cycles and hirsutism and mildly elevated DHEA or 17-hydroxypregnenolone levels only rarely have mutations in the 3-beta–hydroxysteroid dehydrogenase II gene. For example, in 1996, Sakkal-Alkaddour et al reported normal type II 3-beta–hydroxysteroid dehydrogenase gene sequences in 15 infants and children with premature pubarche and mildly elevated DHEA levels. [12] Among 30 women with hirsutism and elevated baseline (unstimulated or random) DHEA levels, none had ACTH-stimulated increases in 17-alpha-hydroxypregnenolone and had DHEA levels consistent with elevations typically observed in genetically proven classic 3-beta–hydroxysteroid dehydrogenase deficiency.
Prognosis
3-Beta–hydroxysteroid dehydrogenase is required for the synthesis of all 3 groups of adrenal steroids, which are mineralocorticoids, glucocorticoids, and sex steroids. Therefore, absence of this enzyme impairs all steroid production, and adrenal insufficiency occurs secondary to aldosterone and cortisol deficiency.
A great deal of heterogeneity is observed with 3-beta–hydroxysteroid dehydrogenase deficiency. The most severely affected patients may have fatal salt-losing adrenal crises in infancy. By contrast, some patients with classic 3-beta–hydroxysteroid dehydrogenase deficiency do not have salt-losing crises; milder or late-onset variants have also been described in which patients do not present until later childhood or adolescence.
Prognosis is usually good-to-excellent with adequate replacement glucocorticoid and mineralocorticoid (if needed) therapy and monitoring.
Sex steroid replacement may be necessary for the development of secondary sexual characteristics in both males and females and cyclic menstrual bleeding in females. Decreased spermatogenesis may occur in affected males. [13] In postpubertal females with late-onset 3-beta–hydroxysteroid dehydrogenase deficiency, menstrual irregularity and infertility may correct with glucocorticoid replacement alone.
Patient Education
Patients with complete 3-beta–hydroxysteroid dehydrogenase deficiency are at risk for acute adrenal insufficiency when ill. Patients and their families should be instructed in the use of stress doses of glucocorticoids for acute illness (eg, temperature ≥101°F) or major trauma. If medication can be taken orally, the patient should double or triple the usual dose of glucocorticoid for 3 days. Mineralocorticoid doses do not need to be increased. If the patient cannot take the medication orally because of vomiting, altered state of consciousness, or surgery, parenteral glucocorticoids, preferably hydrocortisone, should be administered.
Patients should wear MedicAlert identification and be taken to their local health care provider as soon as possible when acutely ill for evaluation.
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Normal adrenal steroid biosynthesis results in 3 products: mineralocorticoid (aldosterone), glucocorticoids (cortisol), and androgens (androstenedione). Cortisol production is regulated by feedback with adrenocorticotropic hormone (ACTH). ACTH stimulates the enzyme P-450scc (20,22 desmolase) with subsequent increased production of all adrenal steroids.
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Representation of typical congenital adrenal hyperplasia (CAH). In this example, both the mineralocorticoid and glucocorticoid pathways are deficient. Decreased serum cortisol levels stimulate adrenocorticotropic hormone (ACTH) release via negative feedback. Increased ACTH secretion results in overproduction of adrenal steroids preceding the missing enzyme as well as those not requiring the missing enzyme. In this example, a deficiency of 21-hydroxylase results in deficient mineralocorticoid and glucocorticoid production and excessive androgen production.
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3-beta-hydroxysteroid dehydrogenase (3BHSD) is required for the synthesis of all three groups of adrenal steroids: mineralocorticoids, glucocorticoids, and sex steroids. 3BHSD catalyzes the conversion of pregnenolone to progesterone (mineralocorticoid pathway), 17-alpha-hydroxypregnenolone to 17-alpha-hydroxyprogesterone (glucocorticoid pathway), and dehydroepiandrosterone to androstenedione (sex steroid pathway). Complete absence of this enzyme thus impairs all steroid production. 17OH Preg = 17-alpha-hydroxypregnenolone; DHEA = Dehydroepiandrosterone; 17OH Prog = 17-alpha-hydroxyprogesterone; Andros = Androstenedione; DOC = Deoxycorticosterone; Cmp S = Compound S.
