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.

The lack of HSD17B3 in male mice results in disturbed Leydig cell maturation and endocrine imbalance akin to humans with HSD17B3 deficiency

“…In line with the disrupted conversion of A‐done to T, the mRNAs for several enzymes related to steroid and cholesterol biosynthesis were found to be upregulated in the mutant testes, including Cyp11a1 , Cyp17a1 , Cyp51 , Nsdhl , and Hsd17b7 . In patients with HSD17B3 deficiency, the serum T levels start to increase at puberty and extragonadal tissues have been considered to be the source for the increase in circulating T . However, our data on the tissue/serum ratio in the HSD17B3KO mice indicate that their serum T is mainly of testicular origin.…”

“…HSD17B3 deficiency is a rare disease with unknown worldwide prevalence. However, several patients have been reported with the highest incidence in the consanguineous Arab population in Gaza, while for example in the USA less than 20 cases have been reported to date . The deficiency causes a 46,XY DSD with abnormal hormonal profile, including high serum levels of A‐dione and low to the normal level of T, resulting in T/A ratio below 0.8, even in the presence of high serum LH .…”

“…However, there has been only one report on Leydig cell adenoma and one on Leydig cell tumor . Similarly, there are only isolated reports on germ cell malignancies among HSD17B3 deficient patients; one report where histological findings of spermatogonia were consistent with testicular malignancy, one report of 30‐years‐old patient with metastatic teratocarcinoma‐seminoma and reports of 16‐years‐ and 4‐years‐old patients with OCT4 staining positive germ cell neoplasia in situ (GCNIS) . In contrast, Leydig cell hyperplasia is a common finding in patients with HSD17B3 mutations .…”

“…However, the patients completely lack Müllerian‐derived structures and instead present with Wolffian‐derived male internal genitalia, including epididymides, vasa deferentia, and seminal vesicles, and their testes are often located in the inguinal canal . These patients are usually diagnosed at the time of puberty either due to primary amenorrhea or sudden onset of virilization . The phenotype of the patients is variable and clinically indistinguishable from other causes of 46,XY DSD such as partial androgen insensitivity syndrome (AIS) and 5a‐reductase 2 deficiency.…”

“…Several inactivating HSD17B3 mutations have been discovered in humans. They cause a rare 46, XY disorder of sex development (DSD) resulting from homozygous or compound heterozygous mutations in the HSD17B3 gene . Due to the rarity of the condition, the worldwide prevalence is unknown, but the estimated incidences vary from 1:147 000 in The Netherlands to 1:100‐150 in the Arab population of the Gaza strip .…”