Final Report Summary - AA (Adrenal Androgens)
Recently, important insights into human sexual differentiation have been gained from P450 oxidoreductase deficiency (ORD), a novel congenital adrenal hyperplasia (CAH) variant with apparent combined 17-hydroxylase and 21-hydroxylase deficiency. POR transfers electrons from NADPH to all microsomally located cytochrome P450 (CYP) enzymes, including 17-hydroxylase and 21-hydroxylase and therefore exerts crucial, albeit indirect effects on steroidogenesis. We have recently shown that specific mutations within the POR molecule might have differential effects on the enzymatic activity of P450 enzymes requiring electron transfer from POR.
Whilst all other CAH variants manifest with either 46,XX DSD or 46,XY disordered sex development (DSD), ORD can manifest with both. Affected boys may present with 46,XY DSD, i.e. undervirilization of their external genitalia, which appears logic as the POR mutations lead to a partial loss of 17-hydroxylase deficiency and thus to sex steroid deficiency. However, whilst circulating androgens are invariably low in both males and females, affected girls often present with virilised genitalia at birth, i.e. 46,XX DSD, indicating prenatal androgen excess.
Whilst all other CAH variants manifest with either 46,XX DSD or 46,XY disordered sex development (DSD), ORD can manifest with both. Affected boys may present with 46,XY DSD, i.e. undervirilization of their external genitalia, which appears logic as the POR mutations lead to a partial loss of 17-hydroxylase deficiency and thus to sex steroid deficiency. However, whilst circulating androgens are invariably low in both males and females, affected girls often present with virilised genitalia at birth, i.e. 46,XX DSD, indicating prenatal androgen excess.