ESPE Abstracts (2019) 92 P1-162

Evaluation of Molecular Characteristics and Steroid Metabolomics in a Large Cohort of Children with 3β-Hydroxysteroid Dehydrogenase 2 Deficiency

Tulay Guran1, Cengiz Kara2, Melek Yildiz3, Eda C. Bitkin2, Goncagul Haklar4, Jen-Chieh Lin5, Lorna C. Gilligan6, Lise Barnard7, Mehmet Keskin8, Ahmet Anik9, Gonul Catli10, Ayla Guven11, Birgul Kirel 12, Filiz Tutunculer13, Hasan Onal 3, Serap Turan1, Teoman Akcay3, Zeynep Atay1, Elizabeth S. Baranowski6, Gulay C. Yilmaz2, Jamala Mamadova2, Azad Akbarzade1, Onder Sirikci4, AghaRza Aghayev14, Afra Alkan15, Cedric H.L. Shackleton6, Karl H. Storbeck7, Tugba Baris16, Wiebke Arlt6,17, Bon-Chu Chung5, Abdullah Bereket1


1Marmara University, School of Medicine, Department of Pediatric Endocrinology and Diabetes, Istanbul, Turkey. 2Ondokuz Mayis University, Department of Pediatric Endocrinology and Diabetes, Samsun, Turkey. 3Kanuni Sultan Suleyman Training and Research Hospital, Department of Pediatric Endocrinology and Diabetes, Istanbul, Turkey. 4Marmara University, School of Medicine, Department of Biochemistry, Istanbul, Turkey. 5Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan. 6Institute of Metabolism and Systems Research (IMSR), College of Medical & Dental Sciences, University of Birmingham, Birmingham, United Kingdom. 7Stellenbosch University, Department of Biochemistry, Western Cape, South Africa. 8Gaziantep University, Department of Pediatric Endocrinology and Diabetes, Gaziantep, Turkey. 9Adnan Menderes University, School of Medicine, Department of Pediatric Endocrinology and Diabetes, Aydin, Turkey. 10Katip Celebi University, School of Medicine, Department of Pediatric Endocrinology and Diabetes, Izmir, Turkey. 11Health Science University, Faculty of Medicine, Zeynep Kamil Women and Children Diseases Education and Research Hospital, Pediatric Endocrinology, Istanbul, Turkey. 12Eskisehir Osmangazi University, Department of Pediatric Endocrinology, Eskisehir, Turkey. 13Department of Pediatrics, Division of Pediatric Endocrinology, Trakya University School of Medicine, Edirne, Turkey. 14Istanbul Faculty of Medicine, Department of Medical Genetics, Istanbul, Turkey. 15Yildirim Beyazit University, School of Medicine, Department of Medical Bioinformatics and Biostatistics, Ankara, Turkey. 16Gelisim Genetik Tani Merkezi, Istanbul, Turkey. 17Cenre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, United Kingdom


Context: Deficiency of 3β-hydroxysteroid dehydrogenase 2 (3βHSD2) causes a very rare form of congenital adrenal hyperplasia (CAH) known as 3βHSD2 deficiency, which is a consequence of biallelic HSD3B2 gene defects. The estimated prevalence is less than 1/1,000,000 live births. Knowledge of comprehensive steroid metabolome patterns in 3βHSD2 deficiency is scarce.

Objective: We aimed to investigate phenotypical, molecular, and biochemical characteristics, as well as the genotype-phenotype relationship in patients with 3βHSD2 deficiency. We evaluated steroid hormone profiles in individuals with homozygous and heterozygous HSD3B2 gene defects, mutation-negative "functional 3βHSD2 deficiency", and patients with 21-hydroxylase deficiency (21-OHD).

Setting: Multi-centre, cross-sectional study in nine tertiary pediatric endocrinology clinics in Turkey

Patients or Other Participants: Children with homozygous 3βHSD2 deficiency (n=31), individuals with heterozygous 3βHSD2 deficiency (n=31), children with classical 21-OHD (n=57), functional 3βHSD2 deficiency (n=18), and healthy controls (n=172).

Main Outcome Measures: A structured questionnaire was used to assess clinical and biochemical phenotype data. Genetic analysis of HSD3B2 was performed using Sanger sequencing. We measured Δ5-to-Δ4 steroids and 11-oxygenated C19 androgens in serum and urine by mass spectrometry. Novel HSD3B2 mutations were studied in silico and by in vitro enzyme kinetic assays.

Results: We have identified 11 homozygous HSD3B2 mutations (7 missense-4 novel, 2 novel deletions, 2 novel insertion variants) in 31 children from 24 families (19 male/12 female; mean age: 8.4±5 yrs). The missense variants >5% of wild-type 3βHSD2 activity in vitro were associated with non-salt losing clinical phenotype. There was a strong genotype-phenotype-steroid metabolome correlation in patients with 3βHSD2 deficiency. The plasma ratio of (17OH-Pregnenolone+Pregnenolone+DHEA)/(17OH-Progesterone+Progesterone+Androstenedione+ Cortisol) was superior to (17OH-Pregnenolone/Cortisol) to discriminate 3βHSD2 deficiency from the other groups. Heterozygote carriers and functional 3βHSD2 deficiency patients showed higher Δ5-to-Δ4 steroids than controls. 11-oxygenated androgens were significantly lower in patients with 3βHSD2 deficiency.

Conclusions: This largest pediatric cohort of patients with 3βHSD2 deficiency will be of importance to gain a deeper understanding of the steroid metabolome and underlying molecular pathogenesis of 3βHSD2 deficiency as well as the disease-specific complications of specific molecular genetic variants.

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