Germ cell neoplasia in situ complicating 17β-hydroxysteroid dehydrogenase type 3 deficiency

Abstract

17β-hydroxysteroid dehydrogenase type 3 (17βHSD3) deficiency is an autosomal recessive disorder of male sex development that results in defective testosterone biosynthesis. Although mutations in the cognate HSD17B3 gene cause a spectrum of phenotypic manifestations, the majority of affected patients are genetic males having female external genitalia. Many cases do not present until puberty, at which time peripheral conversion of androgen precursors causes progressive virilization. Measurement of the testosterone-to-androstenedione ratio is useful to screen for 17βHSD3 deficiency, and genetic analysis can confirm the diagnosis. As some individuals with 17βHSD3 deficiency transition from a female sex assignment to identifying as males, providers should ensure stable gender identity prior to recommending irreversible treatments. Gonadectomy is indicated to prevent further virilization if a female gender identity is established. The risk of testicular neoplasia is unknown, a point which should be discussed if patients elect to transition into a male gender role.

Keywords: 17β-hydroxysteroid dehydrogenase type 3 deficiency; 46XY disorder of sex development; Mutations; Puberty; Testosterone; Virilization.

Figure 1.

GCNIS in a patient with 17βHSD3 deficiency. Panel A shows GCNIS via H&E staining of left testicular tissue. Panel B shows IHC staining with positive C-kit/CD117 (OCT4) of left testicular tissue.

Figure 2.

Pathways to DHT and activities of 17βHSD3. Conventional pathways are to the left, and backdoor pathway to the right. Dotted arrow indicating poor activity for the formation of androstenedione, and “±” indicates that effect of cofactor is modest. The Δ⁵, Δ⁴, 5α, and 5α,3α-pathways are indicated with boxed symbols. Abbreviations are as in text, plus 17OH-, 17-hydroxy; 5αR1, 5α-reductase type 1, 5αR2, 5α-reductase type 2; Cyt b₅, cytochrome b₅; 17βHSD6, 17β-hydroxysteroid dehydrogenase type 6. AKR1Cs indicates that the AKR1C isoenzymes that perform this reaction are not known with certainty.

Figure 3.

Location of the HSD17B3 gene on chromosome 9, and sites of known mutations.

Figure 4.

Documented mutations in HSD17B3 gene in patients with 17βHSD3 deficiency. Recurrent mutations are represented in framed boxes. Adapted from Castro et al [32].