17-beta-hydroxysteroid dehydrogenase deficiency

17-beta-hydroxysteroid dehydrogenase deficiency (17β-HSD deficiency) is a rare genetic disorder affecting steroidogenesis, leading to an imbalance in sex steroids. This condition is part of a group of disorders termed congenital adrenal hyperplasia (CAH), which affects the adrenal glands' ability to produce cortisol and aldosterone, as well as affecting sex hormone production. 17β-HSD deficiency specifically impacts the enzyme 17β-hydroxysteroid dehydrogenase, which is crucial in the biosynthesis of estrogens and androgens, the female and male sex hormones, respectively.

Etiology and Pathophysiology

17β-HSD deficiency is caused by mutations in the HSD17B3 gene, which encodes the 17β-hydroxysteroid dehydrogenase type 3 enzyme. This enzyme is primarily involved in the conversion of androstenedione (a weak androgen) to testosterone (a potent androgen) in the testes. In individuals with this deficiency, the reduced activity of the enzyme leads to decreased levels of testosterone and an excess of androstenedione. In genetic males (XY), this can result in undermasculinization of the external genitalia at birth, leading to ambiguous genitalia. In genetic females (XX), the condition may go unnoticed or may present with signs of virilization due to excess androgens.

Clinical Presentation

The clinical presentation of 17β-HSD deficiency can vary significantly. In genetic males, symptoms can range from ambiguous genitalia to completely female external genitalia, often leading to incorrect sex assignment at birth. In less severe cases, affected individuals may present later in life with micropenis, cryptorchidism (undescended testes), or infertility. Genetic females typically have normal female external genitalia at birth. However, they may exhibit signs of virilization, such as hirsutism (excessive hair growth) or menstrual irregularities, during puberty.

Diagnosis

Diagnosis of 17β-HSD deficiency involves a combination of clinical evaluation, biochemical assays, and genetic testing. Biochemical assays focus on measuring the levels of sex steroids in the blood, particularly the ratio of testosterone to androstenedione. Elevated levels of androstenedione relative to testosterone are indicative of the deficiency. Genetic testing can confirm the diagnosis by identifying mutations in the HSD17B3 gene.

Treatment

Treatment of 17β-HSD deficiency is tailored to the individual's symptoms and may involve endocrinological and surgical intervention. Hormone replacement therapy (HRT) with testosterone or estrogen may be necessary to induce and maintain secondary sexual characteristics. In cases of ambiguous genitalia or incorrect sex assignment, surgical correction may be considered. Fertility issues are addressed on a case-by-case basis, with assisted reproductive technologies being an option for some individuals.

Prognosis

With appropriate medical and surgical management, individuals with 17β-HSD deficiency can lead a normal life. However, ongoing monitoring and treatment are often necessary to manage symptoms of virilization, optimize growth and development, and address fertility concerns.

See Also

• Congenital adrenal hyperplasia
• Intersex
• Steroidogenesis
• Genetic counseling