History
Various clinical presentations occur.
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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.
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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.
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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.
Physical
Physical findings specific to female and male patients are as follows:
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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.
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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.
Causes
3-beta–hydroxysteroid dehydrogenase deficiency is inherited as an autosomal recessive trait.
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3-beta–hydroxysteroid dehydrogenase is encoded by an 8-kb gene located on the p11-13 region of chromosome 1.
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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.
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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.
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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.
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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]
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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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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.
