Background: 3β-Hydroxysteroiddehydrogenase (3β-HSD) is a key enzyme in steroidogenesis, responsible for the conversion of Δ5- to Δ4-steroids. Deficiency in 3β-HSD results in congenital adrenal hyperplasia (CAH). The molecular etiology of 3β-HSD deficiency lies in a defect in HSD3B2 gene.
Clinical case: A healthy newborn girl was admitted on day of life (DOL) 8 due to increased 17-OH-progesterone (17OHP) in newborn screening. She was in no physical distress, feeding well, and gaining weight appropriately. External genitalia were female without virilization nor palpable gonads. Ultrasound revealed female internal genitalia. Labs: increased ACTH (549 ng/l), low cortisol (92 nmol/l), increased 17OHP (124 nmol/l), normal DHEA and 11-desoxycortisol, and increased renin (116 pg/ml). The patient was immediately started on hydrocortisone (HC). The following day, she developed salt loss (Na of 129 mmol/l, K of 6.1 mmol/l) and was therefore started on fludrocortisone (FC) and NaCl. Further evaluation at 7 months of age, 36 h after discontinuing HC and FC: increase in ACTH and renin, low cortisol and aldosterone, no increase in 17OHP, DHEA, Δ4A, 11-desoxycortisol and testosterone, confirming glucocorticoid (GC), mineralocorticoid (MC) and androgen deficiency.
Molecular analysis: Compound heterozygote for two mutations in HSD3B2: a previously described c.512G>A (W171X) mutation in the paternal allele, and a novel frameshift mutation c.503delC (A168Vfs*6) in the maternal allele.
Conclusion: Our patient is compound heterozygote for two mutations in HSD3B2 causing two shorter and aberrant peptides. This clinically causes a severe loss of 3β-HSD II activity, leading to a nearly complete deficiency in GCs, MCs and sex steroids in our phenotypically non-virilized female CAH patient. One of the mutations is novel: c.503delC (A168Vfs*6).
20 - 22 Sep 2014
European Society for Paediatric Endocrinology