3-Beta-Hydroxysteroid Dehydrogenase Deficiency Clinical Presentation

Updated: Jun 16, 2016
  • Author: J Paul Frindik, MD, FACE; Chief Editor: Stephen Kemp, MD, PhD  more...
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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.