3 beta-hydroxysteroid dehydrogenase deficiency

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mehrian Jafarizade, M.D [2]

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Overview

3 beta-hydroxysteroid dehydrogenase deficiency is a rare disease due to congenital adrenal hyperplasia. It is characterized by impaired biosynthesis pathway of progestins, mineralocorticoids, glucocorticoids, and androgens. As a result of cortisol absence, corticotropin (ACTH) secretion increases and leads to produce 3-hydroxy-delta-5-steroids pregnenolone, 17-hydroxypregnenolone, and dehydroepiandrosterone (DHEA), also their sulfates. In peripheral tissues the conversion of DHEA sulfate (DHEAS) to testosterone, is responsible for virilization in females. 3 beta-hydroxysteroid dehydrogenase deficiency is caused by a mutation in the HSD3B2 gene. Symptoms of 3 beta-hydroxysteroid dehydrogenase deficiency may include symptoms of both cortisol and aldosterone deficiency such as feeding difficulties, vomiting, volume depletion, undervirilization in newborn males, and mild virilization and clitoromegaly in newborn female. Diagnosis for 3 beta-hydroxysteroid dehydrogenase deficiency is based on delta-5-17-hydroxypregnenolone high levels in serum laboratory tests. The mainstay of therapy for this disease is hydrocortisone and fludrocortisone acetate. The reconstruction surgery for ambiguous genitalia in genetically male patients may be applied.

Historical Perspective

3 beta-hydroxysteroid dehydrogenase deficiency was first time described in 1962, in a patient with ambiguous genitalia and salt wasting.

Classification

There are two types of 3 beta-hydroxysteroid dehydrogenase deficiency:

• Salt-wasting
• Non-salt-wasting

Pathophysiology

The pathogenesis of 3 beta-hydroxysteroid dehydrogenase deficiency is characterized by impaired pathway of biosynthesis of progestins, mineralocorticoids, glucocorticoids, and androgens. As a result of cortisol absence, corticotropin (ACTH) secretion increases the production of 3-hydroxy-delta-5-steroids pregnenolone, 17-hydroxypregnenolone, and dehydroepiandrosterone (DHEA). ACTH secretion also increases the production of their sulfates. In peripheral tissues the conversion of DHEA sulfate (DHEAS) to testosterone is responsible for virilization in females.

Causes

3 beta-hydroxysteroid dehydrogenase deficiency is caused by a mutation in the HSD3B2 gene.

Differentiating 3 beta-hydroxysteroid dehydrogenase deficiency from other Diseases

3 beta-hydroxysteroid dehydrogenase deficiency must be differentiated from diseases that cause ambiguous genitalia:

Disease name	Steroid status		Important clinical findings
	Increased	Decreased
3 beta-hydroxysteroid dehydrogenase deficiency	Dehydroepiandrosterone 17-hydroxypregnenolone Pregnenolone	Cortisol Aldosterone	Vomiting, volume depletion, hyponatremia, and hyperkalemia 46-XY infants often show undervirilization, due to a block in testosterone synthesis
Classic type of 21-hydroxylase deficiency	17-hydroxyprogesterone Progesterone Androstenedione DHEA	Aldosterone Corticosterone (salt-wasting) Cortisol (virilization)	Ambiguous genitalia in female Virilization in female Salt-wasting Hypotension and hyperkalemia
11-β hydroxylase deficiency	Deoxycorticosterone 11-Deoxy-cortisol 17-hydroxyprogesterone (mild elevation)	Cortisol Corticosterone Aldosterone	Ambiguous genitalia in female Hypertension and hypokalemia Virilization
17-α hydroxylase deficiency	Deoxycorticosterone Corticosterone Progesterone	Cortisol Aldosterone	Ambiguous genitalia in male Hypertension Primary amenorrhea Absence of secondary sexual characteristics Minimal body hair
Gestational hyperandrogenism	Maternal serum androgen concentrations (usually testosterone and androstenedione) are high If virilization is caused by exogenous hormone administration, the values may be low because the offending hormone is usually a synthetic steroid not measured in assays for testosterone or other androgens		Androgen excess in mother History of androgen containing medication consumption during pregnancy in mother Virilization in a 46,XX individual with normal female internal anatomy Causes include maternal luteoma or theca-lutein cysts, and placental aromatase enzyme deficiency

3 beta-hydroxysteroid dehydrogenase deficiency must be differentiated from diseases that cause virilization and hirsutism in female:

Disease name	Steroid status	Other laboratory	Important clinical findings
Non-classic type of 21-hydroxylase deficiency	Increased: 17-hydroxyprogesterone Exaggerated Androstenedione, DHEA, and 17-hydroxyprogesterone in response to ACTH	Low testosterone levels	No symptoms in infancy and male Virilization in females
11-β hydroxylase deficiency	Increased: DOC 11-Deoxy-Cortisol Decreased: Cortisol Corticosterone Aldosterone	Low testosterone levels	Hypertension and hypokalemia Virilization
3 beta-hydroxysteroid dehydrogenase deficiency	Increased: DHEA 17-hydroxypregnenolone Pregnenolone Decreased: Cortisol Aldosterone	Low testosterone levels	Salt-wasting adrenal crisis in infancy Mild virilization of genetically female infants Undervirilization of genetically male infants, making it the only form of CAH which can cause ambiguous genitalia in both genetic sexes.
Polycystic ovary syndrome	High DHEAS and androstenedione levels	Low testosterone levels	Polycystic ovaries in sonography Obesity PCOS is the most common cause of hirsutism in women No evidence another diagnosis
Adrenal tumors	Variable levels depends on tumor type	Low testosterone level	Older age Rapidly progressive symptoms
Ovarian virilizing tumor	Variable levels depends on tumor type	Testosterone is high	Older age Rapidly progressive symptoms
Cushing's syndrome	Increase cortisol & metabolites Variable other steroids	Variable mineralocorticoid excess	Cushingoid appearance
Hyperprolactinemia	Normal levels of most of steroids	Increased prolactin	Infertility, galactorrhea

Epidemiology and Demographics

The prevalence of 3 beta-hydroxysteroid dehydrogenase deficiency is unknown. At least 60 affected individuals have been reported.

Risk Factors

Common risk factors in the development of 3 beta-hydroxysteroid dehydrogenase deficiency is family history of this disease.

Diagnosis

Symptoms

Symptoms of 3 beta-hydroxysteroid dehydrogenase deficiency may include symptoms of both cortisol and aldosterone deficiency such as feeding difficulties, vomiting, volume depletion, muscle weakness, undervirilization in male newborns, and mild virilization and clitoromegaly in newborn female.

Physical Examination

Physical examination may be remarkable for:

• Undervirilization in newborn males
• Mild virilization and clitoromegaly in newborn female.

Laboratory Findings

Diagnosis for 3 beta-hydroxysteroid dehydrogenase deficiency is based on delta-5-17-hydroxypregnenolone high levels. Other laboratory findings are included hyponatremia, hyperkalemia.

Treatment

Medical Therapy

The mainstay of therapy for 3 beta-hydroxysteroid dehydrogenase deficiency is hydrocortisone and fludrocortisone acetate adiminstration. Gender-appropriate replacement of androgens or estrogens with progestins is necessary at the puberty time. The goal of therapy is:

• Correct the effects of mineralocorticoid excess
• Prevent glucocorticoid deficiency
• Restore desired secondary sexual characteristics

• Treatment for 3 beta-hydroxysteroid dehydrogenase deficiency is by the use of glucocorticoids such as:
  • Preferred regimen (1): Hydrocortisone 10 to 25 mg/m2 body surface area/day PO.
  • Preferred regimen (2): Prednisolone 0.1 mg/kg/day PO.
  • Preferred regimen (3): Dexamethasone up to 0.5 mg/day PO.

Surgery

The reconstruction surgery for ambiguous genitalia in genetically male patients may be applied.