373- What is the clinical relevance of “backdoor pathway” in CAH?
P450 oxidoreductase is required for the electron transfer to 17α-hydroxylase
(CYP17A1), 21α-hydroxylase (CYP21B1), and aromatase (CYP19A1).
Therefore, 46,XY individuals with CAH due to POR defi ciency manifest with
under virilization of external genitalia and cortisol defi ciency. However, 46,XX
individuals with POR defi ciency also have genital ambiguity in addition to cor-
tisol defi ciency. The presence of genital ambiguity in patients with 46,XX indi-
viduals can be explained by androgen synthesis through “backdoor pathway.”
In addition, “backdoor pathway” has also been shown to be functional in new-
borns and children with 21α-hydroxylase defi ciency. This may partly explain
the variability between genotype and phenotype (virilization of external genita-
lia) in these patients.- What are the characteristics of CAH due to 3β-HSD2 defi ciency?
The enzyme 3β-HSD is required for the conversion of ∆ 5 steroids to ∆ 4 ste-
roids and is expressed in all three layers of adrenal cortex. There are two
isoforms of enzyme in humans, 3β-HSD1 and 3β-HSD2. The enzyme
3 β-HSD1 is expressed in the placenta, skin, breast, and adipocytes, whereas
3 β-HSD2 is expressed in the adrenal, testes, and ovary. Classical CAH due
to 3β-HSD2 manifests with salt-wasting and genital ambiguity in both gen-
ders; however, genital ambiguity is rare and less severe (isolated mild clito-
romegaly) in females. Therefore, girls with classical CAH due to 3β-HSD2
may succumb to salt-wasting crisis as the diagnosis is not considered due to
lack of genital ambiguity. This is in contrast to CAH due to 21α-hydroxylase
defi ciency wherein boys are underdiagnosed due to the absence of genital
ambiguity. The diagnosis of CAH due to 3β-HSD2 is established by an
ACTH-stimulated serum 17-hydroxypregnenolone >100 nmol/L or elevated
∆ 5 to ∆ 4 steroid ratio.- What are the causes of glucocorticoid-remediable hypertension?
Glucocorticoid excess, whether endogenous or exogenous, is associated with
hypertension. On the contrary, in certain disorders, hypertension associated
with “mineralocorticoid excess/activity” resolves with glucocorticoids. These
disorders include congenital adrenal hyperplasia (CAH) due to 11β-hydroxylase
and 17α-hydroxylase defi ciency, glucocorticoid resistance syndrome (GRS),
familial hyperaldosteronism type 1 (glucocorticoid- remediable aldosteronism,
GRA/FH type 1), and apparent mineralocorticoid excess syndrome (AME).
The defects in these disorders include increased ACTH drive either due to cor-
tisol defi ciency (e.g. CAH) or resistance (e.g. GRS), or increased ACTH sensi-
tivity (e.g. familial hyperaldosteronism type 1) or specifi city-spillover of
cortisol action on mineralocorticoid receptor (e.g. AME).10 Congenital Adrenal Hyperplasia