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.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology