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]

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).

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.

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.

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]

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.

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.

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.

Various clinical presentations occur.

• The first, and most common, is that of a newborn (male or female) with adrenal insufficiency due to both glucocorticoid and mineralocorticoid deficiency. A history of ambiguous genitalia coupled with signs of adrenal insufficiency (ie, circulatory collapse, low serum sodium, high serum potassium) suggests either 3-beta–hydroxysteroid dehydrogenase (3BHSD) deficiency or another error in adrenal biosynthesis. Patients with less severe non–salt-wasting forms may be relatively asymptomatic as infants.

• The second presentation in older patients with an apparent mild defect in 3-beta–hydroxysteroid dehydrogenase activity (late-onset or nonclassic variant) includes premature pubic hair development in young children or irregular menstrual cycles and hirsutism in postpubertal adolescent females. One adolescent female presented with primary amenorrhea.

• One report described 2 sisters with the classic variant (salt wasting in infancy) who were not diagnosed until later in life, when one sibling presented for evaluation of premature pubarche.[14] The second sibling had no pubarche or other signs of virilization. The siblings were first thought to have nonclassical 21-hydroxylase deficiency because of elevated 17 alpha-hydroxyprogesterone. However, gene sequencing of the CYP21 gene found that both sisters were only heterozygotes (V281L mutation). Gene sequencing results, history of salt wasting, and increased dehydroepiandrosterone sulfate levels suggested a variant 3-beta–hydroxysteroid dehydrogenase deficiency.

• Infants may occasionally present with elevated 17-alpha-hydroxyprogesterone levels detected as a result of newborn screening for 21-hydroxylase deficiency.[15, 16]

Physical findings specific to female and male patients are as follows:

• Females

  • Affected 46,XX newborns may appear to have normal anatomy or have varying degrees of clitoromegaly and labial fusion.

  • Signs of mild androgen excess may occur in older children, including acne, premature pubarche,[17] and advanced linear and skeletal growth.

  • Adolescent or older women may present with hirsutism and mild clitoromegaly. Internally, polycystic ovaries may be present.

• Males

  • Most newborn 46,XY individuals are incompletely masculinized and have varying degrees of hypospadias. Testes are usually palpable.

  • Patients with milder defects may present as adolescents with ambiguous genitalia and poor virilization. However, virilization or spontaneous puberty has been reported in some males.

  • Gynecomastia is a common finding in pubertal males.

3-beta–hydroxysteroid dehydrogenase deficiency is inherited as an autosomal recessive trait.

• 3-beta–hydroxysteroid dehydrogenase is encoded by an 8-kb gene located on the p11-13 region of chromosome 1.

• 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 but including the aorta, and type II 3-beta–hydroxysteroid dehydrogenase almost exclusively occurs in the gonads and adrenal glands.

• Type I 3-beta–hydroxysteroid dehydrogenase isoenzyme is normal in patients with type II 3-beta–hydroxysteroid dehydrogenase deficiency. At least 31 different mutations in the type II 3-beta–hydroxysteroid dehydrogenase gene have been identified in 32 unrelated families with 3-beta–hydroxysteroid dehydrogenase deficiency.

• Patients with classic salt-losing 3-beta–hydroxysteroid dehydrogenase deficiency have been shown to have various mutations, including splicing (1 patient), in-frame (1 patient), nonsense (3 patients), frameshift (4 patients), and missense (22 patients) mutations in the type II 3-beta–hydroxysteroid dehydrogenase gene with no mutation in the type I gene.

• No functional 3-beta–hydroxysteroid dehydrogenase type II enzyme is found in the adrenals or gonads of patients with severe salt-losing disease. The non–salt-losing form can occur with a missense mutation causing only partial deficiency in enzyme activity.[18]

• Different missense mutations of the type II 3-beta–hydroxysteroid dehydrogenase gene have been identified in female patients with late-onset 3-beta–hydroxysteroid dehydrogenase deficiency.

No biochemical differences between male and female patients are recognized.

• Classic 3-beta–hydroxysteroid dehydrogenase (3BHSD) deficiency

  • Plasma concentrations of pregnenolone, 17-hydroxypregnenolone, and DHEA are elevated.

  • 17-Hydroxyprogesterone levels may be increased because of conversion of 17-hydroxypregnenolone to 17-hydroxyprogesterone by peripheral type I 3-beta–hydroxysteroid dehydrogenase isoenzyme and may be detected by neonatal screening for 21-hydroxylase deficiency.[15, 16]

  • Peripheral type I 3-beta–hydroxysteroid dehydrogenase activity may also increase androstenedione levels.[15] However, in 3-beta–hydroxysteroid dehydrogenase deficiency, the plasma ratio of 17-hydroxypregnenolone to 17-hydroxyprogesterone is markedly elevated. Plasma cortisol and aldosterone levels are low in 3-beta–hydroxysteroid dehydrogenase.

  • Adrenocorticotropic hormone (ACTH) levels are elevated because of the lack of cortisol secretion, and gonadotropin follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are elevated secondary to deficient sex steroid production.

• Late-onset or nonclassic 3-beta–hydroxysteroid dehydrogenase deficiency: Baseline (unstimulated) measurements of pregnenolone, 17-hydroxypregnenolone, and dehydroepiandrosterone (DHEA) may be unremarkable in patients with late-onset or nonclassic 3-beta–hydroxysteroid dehydrogenase deficiency. In such patients, diagnosis is based on an excessive response of 17-hydroxypregnenolone (delta 5-17Preg) and delta 5-17Preg-to-F ratios at or greater than 201 nmol/L and 487 nmol/L, respectively; this is equivalent to or greater than 36 standard deviations (SD) and 52 SD above matched control mean, respectively.[19]

• Carriers: Carriers of type II 3-beta–hydroxysteroid dehydrogenase deficiency can have hormone profiles (both stimulated and unstimulated) within the reference range and, therefore, can only be detected by genotype studies.

Imaging studies may reveal polycystic ovaries in older patients or enlarged adrenal glands; such findings are nonspecific and not diagnostic for any particular type of enzyme deficiency.

Genotyping is not routinely required for diagnosis but may be helpful if hormone testing is inconclusive. Molecular genetic studies are indicated, as noted above, to detect carriers as well as for genetic counseling of the individual and family.[20]

Classic 3-beta–hydroxysteroid dehydrogenase (3BHSD) deficiency: Patients with classic salt-losing 3-beta–hydroxysteroid dehydrogenase require replacement of glucocorticoids, mineralocorticoids, and sex steroids.

• Exogenous orally administered hydrocortisone (or other glucocorticoid) is used to suppress adrenocorticotropic hormone (ACTH) secretion and decreases plasma concentrations of pregnenolone, 17-hydroxypregnenolone, and dehydroepiandrosterone (DHEA). Dose requirements are variable. Some patients require larger-than-normal glucocorticoid doses and may still not achieve adequate androgen suppression.[11]

• Hydrocortisone tablets are the preferred glucocorticoid choice for treatment. Tablets may be crushed in liquid immediately prior to dosing for infants and small children. Premixed, oral suspensions of hydrocortisone should be avoided, as should long-acting glucocorticoid preparations in pediatric patients.[20]

• Mineralocorticoid replacement is achieved with the oral administration of fludrocortisone acetate (9-alpha-fluorohydrocortisone, Florinef). Patients with non–salt-losing variants do not require mineralocorticoid replacement.

• At puberty, patients with complete 3-beta–hydroxysteroid dehydrogenase deficiency require sex steroid replacement, including testosterone in males and cyclic estrogen-progesterone therapy in females. Such therapy promotes development of secondary sexual characteristics in both males and females, and cyclic menstrual bleeding in 46,XX females.

Late-onset (nonclassic) 3-beta–hydroxysteroid dehydrogenase deficiency: The need for replacement therapy varies, depending on the severity of the defect. Hydrocortisone (or other glucocorticoid) replacement suppresses excess androgens in children with premature pubarche and may correct menstrual irregularities and decrease hirsutism and acne in pubertal and postpubertal females.

Although the literature and experience regarding treatment of pediatric patients is extensive, little has been published regarding treatment of adults with congenital adrenal hormone deficiencies.[21, 22]  Treatment in adults is aimed at preventing adrenal insufficiency and suppressing excess androgens, while avoiding the extremes of overtreatment and undertreatment.[20]

A survey in the United Kingdom demonstrated that the most widely used glucocorticoid in adult patients was hydrocortisone, followed by dexamethasone and prednisolone.[23]  Sixty percent of physicians surveyed used larger doses of glucocorticoids at night (reverse circadian pattern) to achieve adrenocorticotropic hormone (ACTH) suppression, and only 16% of treating physicians used body weight or surface area to determine dosage.

Benign testicular adrenal rest tumors are found in adult men in association with poorly controlled congenital adrenal hyperplasia (CAH). Such men may have gonadal dysfunction and infertility, perhaps due to obstruction of seminiferous tubules.[24]

High-resolution ultrasonography has recently been used to estimate the prevalence of testicular adrenal rest tumors in male children with CAH, with a reported incidence ranging from 21-24%.[25, 24]

Although the testes are by far the most common location for such rest tumors, ectopic adrenal rest tumors may be present elsewhere.[26]

Follow up with infants and young children about every 3-4 months for evaluation of height and weight, blood pressure, and laboratory monitoring (ie, pregnenolone, 17-hydroxypregnenolone, dehydroepiandrosterone [DHEA], plasma renin levels). Individualize adjustment of hydrocortisone and fludrocortisone acetate dosages based on the results of the physical examination and laboratory studies.

A left-hand radiograph may be obtained yearly for evaluation of skeletal maturation.

Sex hormone replacement may be required at the time of expected puberty in patients with complete 3-beta–hydroxysteroid dehydrogenase (3BHSD) deficiency. Because commercial estrogen preparations in the United States contain high doses of estradiol that induce rapid epiphyseal maturation, replacement therapy is often delayed until the bone age is 12 years or more to preserve linear growth. Ideally, testosterone or estrogen should begin at very low doses and gradually increase as the child ages and matures.

Patients with classic salt-losing 3-beta–hydroxysteroid dehydrogenase require replacement of glucocorticoids, mineralocorticoids, and sex steroids.

For late-onset (nonclassic) 3-beta–hydroxysteroid dehydrogenase deficiency, the need for replacement therapy varies, depending on the severity of the defect. Hydrocortisone (or other glucocorticoid) replacement suppresses excess androgens in children with premature pubarche and may correct menstrual irregularities and decrease hirsutism and acne in pubertal and postpubertal females.

Approximately 15 mg/m2/d of oral hydrocortisone divided 3 times daily may be used as an initial dose. Hydrocortisone is the drug of choice in infants and children. Longer-acting preparations, such as prednisone and dexamethasone, are difficult to titrate and can lead to overtreatment and growth suppression. Fludrocortisone acetate, 50 mcg (newborns and infants) to 200 mcg (older children) per day, is also required in patients with salt-losing variants of 3-beta–hydroxysteroid dehydrogenase deficiency. Adjust long-term dosages on an individual basis.

Exogenous glucocorticoid therapy suppresses adrenocorticotropic hormone (ACTH) secretion and decreases pregnenolone, 17-hydroxypregnenolone, and DHEA levels. Exogenous mineralocorticoid therapy normalizes both renin and ACTH levels. Combination therapy of mineralocorticoid plus glucocorticoid replacement reduces total glucocorticoid dose required and improves statural growth.

Class Summary

Exogenous glucocorticoid therapy suppresses adrenocorticotropic hormone (ACTH) secretion, decreasing pregnenolone, 17-hydroxypregnenolone, and dehydroepiandrosterone (DHEA) levels. Doses used are somewhat empirical and must be individualized based on clinical findings, growth and skeletal maturation, and hormonal data, including monitoring of pregnenolone, 17-hydroxypregnenolone, and DHEA levels.

Hydrocortisone (A-Hydrocort, Cortef, Hydrocort)

Longer-acting preparations, such as prednisone and dexamethasone, are difficult to titrate and can lead to overtreatment and growth suppression.

Class Summary

Exogenous mineralocorticoid therapy is required in patients with salt-losing variants of CAH (21-hydroxylase deficiency and 3-beta–hydroxysteroid dehydrogenase [3BHSD] deficiency). Plasma renin levels are elevated in patients with untreated salt-losing variants, and the addition of mineralocorticoid replacement normalizes both renin and ACTH levels. Combination therapy of mineralocorticoid plus glucocorticoid replacement reduces total glucocorticoid dose required and improves statural growth.

Fludrocortisone acetate (Florinef)

Only drug available in this category. Promotes increased reabsorption of sodium and loss of potassium renal distal tubules. Dosages are adjusted to achieve suppressed plasma renin levels.