ESPE Abstracts (2019) 92 P2-253

Complexities of Diagnosis in 17-Beta-Hydroxysteroid Dehydrogenase Deficiency and Implementation of Next Generation Sequencing in Guiding Management Decisions – Case Series of Six Patients

Tashunka Taylor-Miller1, John S Barton1, Christine P Burren1, Mark Woodward2, Julie Alderson3, Elizabeth C Crowne1


1Department of Paediatric Endocrinology, Bristol Royal Hospital for Children, University Hospitals Bristol NHS Foundation Trust, Bristol, United Kingdom. 2Department of Paediatric Urology, Bristol Royal Hospital for Children, University Hospitals Bristol NHS Foundation Trust, Bristol, United Kingdom. 3Psychological Health Services, Bristol Royal Hospital for Children, University Hospitals Bristol NHS Foundation Trust, Bristol, United Kingdom


17-beta-hydroxysteroid dehydrogenase (17-beta-HSD3) deficiency is an autosomal recessive 46XY disorder of sex development (DSD), which results in impaired gonadal androstenedione conversion to testosterone. The phenotype ranges from female to ambiguous genitalia, with wolffian-duct structures and testes. HCG stimulation tests assess testosterone biosynthesis, though biochemical results in confirmed 17-beta-HSD3 deficiency may overlap with gonadal dysgenesis making diagnosis challenging. Therefore, additional molecular genetic diagnostics will help guide surgery and sex of rearing discussions.

We report six 46XY DSD patients with confirmed 17-beta-HSD3 deficiency. Four patients were diagnosed <12months of age: one identified antenatally due to discordant karyotype and ultrasonography, two identified at delivery due to ambiguous genitalia, and one identified aged three months during elective herniotomy. The two adolescent patients presented with progressive virilisation, causing significant emotional distress, and primary amenorrhoea.

Of the four patients identified <12months, baseline immunoassay testosterone ranged between 1.1-12nmol/L.Three demonstrated low T:A ratio after HCG stimulation: (0.11, 0.7 and 0.84 respectively). Case 6's T:A ratio of >0.8 is discordant with literature stating that HCG-stimulated ratio <0.8 is consistent with 17-beta-HSD3 deficiency.

The time taken between initial identification of DSD and molecular genetic diagnosis ranged between 6weeks – 22months. Significantly longer times were experienced by patients presenting prior to 2014, when the 32 gene next generation sequencing (NGS) panel for DSD became available. Patients presenting during 2016-18 had a 4-5 month interval between presentation and molecular genetic diagnostic confirmation. The most recent cases in 2019 had the diagnosis confirmed within 9 weeks of presentation.

Decisions around sex of rearing in the infants and surgery (including gonadectomy) involved multidisciplinary team discussions. In two, parents elected to undergo bilateral gonadectomy. Unilateral gonadectomy was performed on case 2 during a herniotomy procedure when gonadal vessels and vas were inadvertently divided, the gonad removed and sent for histopathology. The two adolescent patients elected to defer gonadectomy and were initially treated with combined GnRH analogue and oestrogen. One subsequently underwent gonadectomy three years later. All 6 patients have been raised female, and neither of the two adolescent cases have voiced gender dysphoria/disturbance concerns.

We highlight the difficulty interpreting both baseline and HCG stimulated plasma hormone levels, and how molecular genetic diagnosis through NGS is becoming integral to providing timely diagnostic information to patients and their families. Complex decisions regarding sex of rearing, gonadectomy and consideration for genital corrective surgery are best managed by an expert multidisciplinary team.

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