7β-Hydroxysteroid Dehydrogenase III Deficiency

17β-Hydroxysteroid dehydrogenase III deficiency is a rare autosomal recessive disorder of sexual development that leads to 46,XY disorder of sex development (46,XY DSD). The reduced testosterone production by 17β-hydroxysteroid dehydrogenase III (17β-HSD III) results in atypical genitalia in affected males.

Signs and symptoms

17-β-Hydroxysteroid dehydrogenase III deficiency causes 46,XY disorder of sex development (46,XY DSD) in males, with varying impacts on genitalia that may appear completely or mostly female, often with a blind vaginal pouch. Testes are typically located in the inguinal canal or within a bifid scrotum. Wolffian structures such as the epididymides, vas deferens, seminal vesicles, and ejaculatory ducts are present.

This autosomal recessive deficiency is due to homozygous or compound heterozygous mutations in the HSD17B3 gene, which encodes the 17β-hydroxysteroid dehydrogenase III enzyme, disrupting the conversion of 17-keto to 17-hydroxysteroids. This enzyme plays a role in the final stage of steroidogenesis, converting androstenedione to testosterone and estrone to estradiol. Virilization of affected males still occurs at puberty.

Genetics

17β-Hydroxysteroid dehydrogenase III deficiency is caused by mutations in the 17β-HSD III (17BHSD3) gene. It is an autosomal recessive disorder.

Mechanism

Androstenedione is produced in the testis and the adrenal cortex. It is synthesized from dehydroepiandrosterone (DHEA) or 17-hydroxyprogesterone.

A deficiency in the HSD17B3 gene is biochemically characterized by reduced testosterone levels, leading to inadequate dihydrotestosterone formation during fetal development. At puberty, there is an increase in plasma luteinizing hormone and testicular secretion of androstenedione, causing a clinically significant higher ratio of androstenedione to testosterone.

Diagnosis

For diagnosing 17β-hydroxysteroid dehydrogenase III deficiency, consider the following:

• Increased androstenedione:testosterone ratio

• Thyroid dyshormonogenesis

• Genetic testing