Authored by 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
Edited by Phyllis Speiser, MD, Director, Division of Pediatric Endocrinology, Children’s Health Network of North Shore/LIJ Health System, Clinical Professor, Department of Pediatrics, New York University School of Medicine; Robert Konop, PharmD, Clinical Assistant Professor, Department of Pharmacy, Section of Clinical Pharmacology, University of Minnesota; Barry B Bercu, MD, Professor, Departments of Pediatrics and Pharmacology and Therapeutics, University of South Florida and All Children’s Hospital; Merrily Poth, MD, Professor, Department of Pediatrics, Uniformed Services University of the Health Sciences; and George P Chrousos, MD, FAAP, FACP, MACE, Chief, Pediatric and Reproductive Endocrinology Branch, Program Director, Pediatric Endocrinology, NICHD/NIH; Clinical Professor, Department of Pediatrics, Georgetown University Medical School
eMedicine Journal, January 7 2002, Volume 3, Number 1
 | INTRODUCTION | Section 2 of 11    |
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 includes 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. It is convenient to think of the zona glomerulosa and the zonae fasciculata and reticularis as 2 separate endocrine organs, since 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 also is 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 zona reticularis (see Picture 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 due to 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 Picture 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 non-conservative 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.
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 Picture 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 dehydroepiandrosterone (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 due to 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, gonad and adrenal may be discordant for 3B HSD activity. There has been one report 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: The majority (80-90%) of individuals world wide with congenital adrenal hyperplasia (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 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, since 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, Sakkal-Alkaddour et al demonstrated 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.
There is a great deal of heterogenicity 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 also have been described that do not present until later childhood or adolescence.
History: Two 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 (circulatory collapse, low serum sodium, high serum potassium) suggests either 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, presenting complaints 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.
Physical: Physical findings specific to female and male patients are as follows:
- 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.
- 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, 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 |
3-beta-hydroxysteroid Dehydrogenase Deficiency
Adrenal Insufficiency
Congenital Adrenal Hyperplasia
Dehydration
Familial Glucocorticoid Deficiency
Hypospadias
Precocious Pseudopuberty
Other Problems to be Considered:
Male pseudohermaphroditism
Lab Studies:
- No biochemical differences exist between male and female patients.
- Classic 3B HSD deficiency: Plasma concentrations of pregnenolone, 17-hydroxypregnenolone, and DHEA are elevated. 17-Hydroxyprogesterone (17-OHP) levels may be increased due to conversion of 17-hydroxypregnenolone to 17-OHP by peripheral type I 3B HSD isoenzyme; nonetheless, the plasma ratio of 17-hydroxypregnenolone to 17-OHP is elevated markedly in affected patients. Plasma cortisol, aldosterone, and androstenedione levels are low.
- ACTH levels are elevated due to 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 3B HSD deficiency: Baseline (unstimulated) measurements of pregnenolone, 17-hydroxypregnenolone, and DHEA may be unremarkable in patients with late-onset or nonclassic 3B HSD deficiency. In such patients, diagnosis is based on an excessive response of pregnenolone, 17-hydroypregnenolone, and/or DHEA to ACTH stimulation, usually about ten-fold above the age specific upper normal limit of the assay.
Imaging 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.
| | TREATMENT | Section 6 of 11 |
Medical Care: - Classic 3B HSD deficiency: Patients with classic, salt-losing 3B HSD require replacement of glucocorticoids, mineralocorticoids, and sex steroids.
- Exogenous, orally administered hydrocortisone (or other glucocorticoid) suppresses ACTH secretion and decreases plasma concentrations of pregnenolone, 17-hydroxypregnenolone, and DHEA.
- Mineralocorticoid replacement is achieved by 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 3B HSD deficiency will 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) 3B HSD 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.
| | MEDICATION | Section 7 of 11 |
Drug Category: Glucocorticoids -- Exogenous glucocorticoid therapy suppresses ACTH secretion, decreasing pregnenolone, 17-hydroxypregnenolone, and 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. Drug Name
| 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. |
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| Pediatric Dose | 15 mg/m2/d PO divided tid initially; adjust long-term dose on an individual basis |
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| Contraindications | Documented hypersensitivity |
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| Interactions | Corticosteroid clearance may decrease with estrogens; may increase digitalis toxicity secondary to hypokalemia |
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| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
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| Precautions | Administer with meals to decrease GI upset; early-onset side effects include glucose intolerance, hypertension, agitation and indigestion; late-onset side effects seen in patients on large glucocorticoid doses include immune suppression and increased susceptibility to sepsis, hypertension, urinary calcium loss and osteopenia, and gastric irritation and bleeding (the above-listed side effects usually are not seen with the dosages used for physiological replacement in 3B HSD deficiency) |
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Drug Category: Mineralocorticoids -- Exogenous mineralocorticoid therapy is required in patients with salt-losing variants of congenital adrenal hyperplasia (21 hydroxylase deficiency and 3B HSD deficiency). Plasma renin levels are elevated in untreated salt-losing patients, 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. Drug Name
| 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. |
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| Adult Dose | 0.1-0.2 mg/d PO |
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| Pediatric Dose | 0.05-0.1 mg/d PO as a starting dose. This dose may be sufficient in patients with milder forms of the disease. Other patients with more severe defects may require higher doses, ie, 0.1-0.2 mg/d. If doses higher than 0.1 mg per day are required, the dose may be divided bid. The addition of NaCl to the diet may also be required in patients with severe salt losing. |
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| Contraindications | Documented hypersensitivity |
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| Interactions | Antagonizes effects of anticholinergics; rifampin, hydantoins, and barbiturates decrease effects of fludrocortisone; decreases salicylate levels |
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| Pregnancy | C - Safety for use during pregnancy has not been established. |
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| Precautions | Can cause elevation in blood pressure, salt and water retention, and excessive excretion of potassium |
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| | FOLLOW-UP | Section 8 of 11 |
Further Outpatient Care:
- Follow-up with infants and young children about every 3-4 months for evaluation of height and weight, blood pressure, and laboratory monitoring (pregnenolone, 17-hydroxypregnenolone, DHEA, plasma renin levels). Individualize adjustment of hydrocortisone and fludrocortisone acetate dosages based on the results of the physical exam 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 3B HSD deficiency. Because commercial estrogen preparations in the US 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.
In/Out Patient Meds:
- Approximately 15 milligrams of PO hydrocortisone per square meter of body surface area per day, divided tid, 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 micrograms (newborns and infants) to 200 micrograms (older children) per day, will also be required in patients with salt-losing variants of 3B HSD deficiency. Adjust long-term dosages on an individual basis.
- Exogenous glucocorticoid therapy suppresses 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.
Prognosis:
- Prognosis usually is 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. In postpubertal females with late-onset 3B HSD deficiency, menstrual irregularity and infertility may correct with glucocorticoid replacement alone.
Patient Education:
- Patients with complete 3B HSD 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, fever of 101 F or greater) 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, either because of vomiting, altered state of consciousness, or surgery, they should receive parenteral glucocorticoids, preferably hydrocortisone.
- Patients should wear medical alert identification and be taken to their local health care provider as soon as possible when acutely ill for evaluation.
| | MISCELLANEOUS | Section 9 of 11 |
Medical/Legal Pitfalls:
- Failure to recognize ambiguous genitalia or mild clitoromegaly in newborn infants: Ambiguous genitalia should be obvious on initial physical examination, but less severe abnormalities of the genitals in newborns (such as first degree hypospadias or mild clitoromegaly) also may indicate possible adrenal abnormalities.
- Failure to diagnosis adrenal insufficiency in a sick patient: The combination of circulatory collapse plus ambiguous genitalia, low serum sodium, high potassium, and/or low glucose suggests adrenal insufficiency requiring exogenous steroid administration in addition to standard resuscitation.
| | PICTURES | Section 10 of 11 |
| | BIBLIOGRAPHY | Section 11 of 11  |
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- Adler JN, Hughes LA, Vivilecchia R: Effect of skin pigmentation on pulse oximetry accuracy in the emergency department. Acad Emerg Med 1998 Oct; 5(10): 965-70[Medline].
- Bentsen D, Schwartz DS, Carpenter TO: Sonography of congenital adrenal hyperplasia due to partial deficiency of 3beta-hydroxysteroid dehydrogenase: a case report. Pediatr Radiol 1997 Jul; 27(7): 594-5[Medline].
- Grumbach MM, Conte FA: Disorders of sex differentiation. In: Williams Textbook of Endocrinology. 8th ed. 1992: 853-951.
- Marui S, Castro M, Latronico AC: Mutations in the type II 3 beta-hydroxysteroid dehydrogenase gene can casue premature pubarche in girls. Clin Endocrinol 2000; 52: 67-75[Medline].
- Moisan AM, Ricketts ML, Tardy V: New insight into the molecular basis of 3beta-hydroxysteroid dehydrogenase deficiency: identification of eight mutations in the HSD3B2 gene eleven patients from seven new families and comparison of the functional properties of twenty-five mutant enzym. J Clin Endocrinol Metab 1999 Dec; 84(12): 4410-25[Medline].
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- Rosler A, Levine LS, Schneider B: The interrelationship of sodium balance, plasma renin activity and ACTH in congenital adrenal hyperplasia. J Clin Endocrinol Metab 1977 Sep; 45(3): 500-12[Medline].
- Sakkal-Alkaddour H, Zhang L, Yang X: Studies of 3 beta-hydroxysteroid dehydrogenase genes in infants and children manifesting premature pubarche and increased adrenocorticotropin-stimulated delta 5-steroid levels. J Clin Endocrinol Metab 1996 Nov; 81(11): 3961-5[Medline].
- Sanchez R, Rheaume E, Laflamme N: Detection and functional characterization of the novel missense mutation Y254D in type II 3 beta-hydroxysteroid dehydrogenase (3 beta HSD) gene of a female patient with nonsalt-losing 3 beta HSD deficiency. J Clin Endocrinol Metab 1994 Mar; 78(3): 561-7[Medline].
- Schneider G, Genel M, Bongiovanni AM: Persistent testicular delta5-isomerase-3beta-hydroxysteroid dehydrogenase (delta5-3beta-HSD) deficiency in the delta5-3beta-HSD form of congenital adrenal hyperplasia. J Clin Invest 1975 Apr; 55(4): 681-90[Medline].
| NOTE: |
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| Medicine is a constantly changing science and not all therapies are clearly established. New research changes drug and treatment therapies daily. The authors, editors, and publisher of this journal have used their best efforts to provide information that is up-to-date and accurate and is generally accepted within medical standards at the time of publication. However, as medical science is constantly changing and human error is always possible, the authors, editors, and publisher or any other party involved with the publication of this article do not warrant the information in this article is accurate or complete, nor are they responsible for omissions or errors in the article or for the results of using this information. The reader should confirm the information in this article from other sources prior to use. In particular, all drug doses, indications, and contraindications should be confirmed in the package insert. FULL DISCLAIMER |
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