eMedicine Specialties > Pediatrics: General Medicine > Endocrinology

3-Beta-Hydroxysteroid Dehydrogenase Deficiency

Author: J Paul Frindik, MD, FACE, Associate Professor, Department of Pediatrics, University of Arkansas for Medical Sciences
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Updated: Sep 18, 2008

Introduction

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 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.

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.⁴

Frequency

International

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 1% of all patients with CAH have 3-beta–hydroxysteroid dehydrogenase deficiency.

The true frequency of mild 3-beta–hydroxysteroid dehydrogenase defects is 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.⁵  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.

Mortality/Morbidity

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 heterogenicity 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.

Clinical

History

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.⁶ 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.

Physical

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

• Females
  • Affected 46,XX newborns may appear normal or have varying degrees of clitoromegaly and labial fusion.
  • Signs of mild androgen excess may occur in older children, including acne, premature pubarche,⁷ 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 males 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.

Causes

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 3-beta–hydroxysteroid dehydrogenase deficiency, whereas 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.⁸
• 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.

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