46,XY Disorder of Sex Development due to 17-Beta Hydroxysteroid Dehydrogenase Type 3 Deficiency in an Infant of Greek Origin

Abstract

17-beta hydroxysteroid dehydrogenase type 3 (17βHSD-3) enzyme catalyzes the conversion of androstenedione (Δ4) to testosterone (T) in the testes of the developing fetus, thus playing a crucial role in the differentiation of the gonads and in establishing the male sex phenotype. Any mutation in the encoding gene (HSD17B3) can lead to varying degrees of undervirilization of the affected male, ranging from completely undervirilized external female genitalia to predominantly male with micropenis and hypospadias. We present here an infant who was referred to our clinic because of ambiguous genitalia at birth. Gonads were palpable in the inguinal canal bilaterally and no Müllerian structures were identified on pelvic ultrasound. Because of a low T/Δ4 ratio after a human chorionic gonadotropin stimulation test, a tentative diagnosis of 17βHSD-3 deficiency was made which was confirmed after genetic analysis of the HSD17B3 gene of the patient. The molecular analysis identified compound heterozygosity of two previously described mutations and could offer some further validation for the idea of a founder effect for 655-1;G→A mutation in the Greek population.

Ablation of the canonical testosterone production pathway via knockout of the steroidogenic enzyme HSD17B3, reveals a novel mechanism of testicular testosterone production

“…Individuals with perturbed HSD17B3 function are under-masculinized at birth, with hypoplastic to normal internal genitalia (epididymis, vas deferens, seminal vesicles, and ejaculatory ducts), but with female external genitalia and the absence of a prostate. [5][6][7] Inadequate testosterone production by the testis reduces the availability of dihydrotestosterone in peripheral tissues leading to under-masculinization of the external genitalia during development. During puberty, increased luteinizing hormone (LH) stimulation of testicular androgen production leads to an increase in production and secretion of androstenedione (the precursor of testosterone).…”

“…The importance of HSD17B3 for testicular testosterone production in humans is highlighted in differences/disorders of sex development involving mutations in HSD17B3 that reduce its function. Individuals with perturbed HSD17B3 function are under‐masculinized at birth, with hypoplastic to normal internal genitalia (epididymis, vas deferens, seminal vesicles, and ejaculatory ducts), but with female external genitalia and the absence of a prostate 5‐7 . Inadequate testosterone production by the testis reduces the availability of dihydrotestosterone in peripheral tissues leading to under‐masculinization of the external genitalia during development.…”

Disorder of Sex Development Due to 17-Beta-Hydroxysteroid Dehydrogenase Type 3 Deficiency: A Case Report and Review of 70 Different HSD17B3 Mutations Reported in 239 Patients

“…Sixty-eight articles reported one or more patients with HSD17B3 mutations ( Supplemental Table S1 ) [ 1 , 3 , 4 , 5 , 9 , 10 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 ...…”

Identification of a Novel Mutation in an Iranian Family With 17-β Hydroxysteroid Dehydrogenase Type 3 Deficiency: A Case Series

“…Affected individuals have female external genitalia with male normal wolffian ducts at birth (4). The incidence of this disorder is estimated at 1 T in 147,000 newborns (5) and is higher in the Arab population of Gaza, and its prevalence is approximately 1 in every 200 to 300 people, which is due to the high rate of consanguineous marriages (6). Pathogenic mutations in the HSD17B3 gene (MIM# 264300) are associated with the impaired sexual development of the 46, XY fetuses.…”

“…Pathogenic mutations in the HSD17B3 gene (MIM# 264300) are associated with the impaired sexual development of the 46, XY fetuses. The mutations may be homozygous or compound heterozygous, leading to 17βHSD-3 deficiency with a wide range of sexual ambiguity in the 46, XY fetuses (7).…”