AUTHOR INFORMATION	Section 1 of 11
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Author: J Paul Frindik, MD, Associate Professor, Department of Pediatrics, University of Arkansas for Medical Sciences

J Paul Frindik, MD, is a member of the following medical societies: American Association of Clinical Endocrinologists, and Endocrine Society

Editor(s): Phyllis Speiser, MD, Professor, Department of Pediatrics, New York University School of Medicine; Chief, Division of Pediatric Endocrinology, Schneider Children's Hospital; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Barry B Bercu, MD, Professor, Departments of Pediatrics, Biochemistry and Molecular Biology, Pharmacology and Therapeutics, University of South Florida; Merrily P M Poth, MD, Professor, Department of Pediatrics and Neuroscience, Uniformed Services University of the Health Sciences; and George P Chrousos, MD, FAAP, MACP, MACE, Professor and Chair, Department of Pediatrics, Athens University Medical School

Disclosure

	INTRODUCTION	Section 2 of 11
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Background: 3-Beta-hydroxysteroid dehydrogenase (3B HSD) deficiency is a rare genetic disorder of steroid biosynthesis resulting 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 exists in the clinical presentation of this disorder. Although first described in male infants with ambiguous genitalia and severe salt wasting, 3B HSD 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.

Pathophysiology: Anatomically, the adrenal gland can be divided into 3 zones, (1) the zona glomerulosa, which produces predominately mineralocorticoid, (2) the zona fasciculata, which produces predominately glucocorticoid, and (3) the zona reticularis, which produces predominantly 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 stimulated directly by high serum potassium concentrations. By contrast, cortisol synthesis and secretion is regulated by adrenocorticotrophic 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 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 Image 2). Treatment with exogenous glucocorticoid results in decreased ACTH secretion and subsequent suppression of the overproduced steroids.

An 8-kilobase (kb) gene located on the p11-13 region of chromosome 1 encodes 3B HSD. Two isoenzymes of 3B HSD have been described, differing by only 23 amino acids. Type I 3B HSD isoenzyme occurs in the peripheral tissues, primarily the liver, and type II 3B HSD occurs almost exclusively in the gonads and adrenal glands. Patients with classic 3B HSD deficiency have been shown to have nonconservative missense, nonsense, splicing, and frameshift mutations in the type II 3B HSD gene with no mutation in the type I gene. Missense mutations in the type II gene have been described in nonclassic late-onset 3B HSD deficiency. A variety of 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 3B HSD. The adrenal steroids are mineralocorticoids, glucocorticoids, and sex steroids. 3B HSD 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 3.

Absence of this enzyme, therefore, impairs all steroid production. Low levels of cortisol result in increased ACTH stimulation of steroids prior to the 3B HSD 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 3B HSD 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 3B HSD isoenzyme. Rarely, the gonads and adrenal glands may be discordant for 3B HSD activity. One report exists of a patient in whom partial 3B HSD activity was demonstrated in the testes coupled with complete absence of adrenal 3B HSD activity.

Frequency:

• Internationally: Most (80-90%) individuals world wide with CAH have 21-hydroxylase deficiency. The incidence of classic 21-hydroxylase deficiency varies by population and ranges from 1 in 5000-15,000 live births to as high as 1 in 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 3B HSD deficiency.

  The true frequency of mild 3B HSD 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 3B HSD II gene. For example, in 1996, Sakkal-Alkaddour et al reported normal type II 3B HSD gene sequences in 15 infants and children with premature pubarche and mildly elevated DHEA levels. Among 30 women with hirsutism and elevated baseline (unstimulated or random) DHEA levels, none had ACTH-stimulated increases in 17-alpha-hydroxypregnenolone and DHEA levels consistent with elevations typically observed in genetically proven classic 3B HSD deficiency.

Mortality/Morbidity: 3B HSD 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 exists with 3B HSD deficiency. The most severely affected patients may have fatal salt-losing adrenal crises in infancy. By contrast, some patients with classic 3B HSD 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	Section 3 of 11
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History: Various clinical presentations occur.

• The first, and more 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 (3B HSD) 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 3B HSD 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.

• A recent 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 (Johannsen, 2005). 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 3B HSD 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, 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 usually are 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: 3B HSD deficiency is inherited as an autosomal recessive trait.

• 3B HSD is encoded by an 8-kb gene located on the p11-13 region of chromosome 1.

• Two isoenzymes of 3B HSD have been described, differing by only 23 amino acids. Type I 3B HSD isoenzyme occurs in the peripheral tissues, primarily the liver but including the aorta, and type II 3B HSD almost exclusively occurs in the gonads and adrenal glands.

• Type I 3B HSD isoenzyme is normal in 3B HSD deficiency, whereas at least 31 different mutations in the type II 3B HSD gene have been identified in 32 unrelated families with 3B HSD deficiency. Patients with classic salt-losing 3B HSD deficiency have been shown to have a variety of mutations, including splicing (1 patient), in-frame (1 patient), nonsense (3 patients), frameshift (4 patients), and missense (22 patients) mutations in the type II 3B HSD gene with no mutation in the type I gene. No functional 3B HSD type II enzyme is found in the adrenals or gonads of patients with severe salt-losing disease. The non–salt-losing form results from missense mutations causing only partial deficiency in enzyme activity. Different missense mutations of the type II 3B HSD gene have been identified in female patients with late-onset 3B HSD deficiency.

	DIFFERENTIALS	Section 4 of 11
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Adrenal Insufficiency
Congenital Adrenal Hyperplasia
Dehydration
Familial Glucocorticoid Deficiency
Hypospadias
Precocious Pseudopuberty

Other Problems to be Considered:

Male pseudohermaphroditism