Table 1.

Overview of monogenic disorders of adrenal steroidogenesis with associated effects on steroidogenic pathways and their specific key analytic steroid abnormalities detected with either serum or urinary steroid profiling useful in the diagnosis for each condition

Name	Gene	Effect on MC synthesis	Effect on GC synthesis	Effect on sex steroid synthesis	Key analytic steroid abnormalities	Other
Congenital lipoid adrenal hyperplasia	StAR	Classic: hyperreninemic, hypokalaemic hypotension/neonatal salt-wasting crisis Nonclassic: variable degrees/normal	Classic: neonatal adrenal insufficiency Non-classic: late-onset adrenal insufficiency	Classic: female external genitalia in 46,XY; spontaneous ovarian sex steroid production in 46,XX reported Nonclassic: variable degrees of 46,XY DSD	Absence/reduction of all steroid classes, including precursors	Large adrenals with accumulating cholesterol and cholesterol metabolites Also affects gonadal androgen production
P450 side-chain cleavage deficiency	CYP11A1	As above	As above	As above	As above	Small, hypoplastic adrenals Also affects gonadal androgen production
CAH due to 21-hydroxylase deficiency	CYP21A2	Classic: hyperreninemic, hypokalaemic hypotension/neonatal salt-wasting crisis Nonclassic: variable degrees/normal	Classic: neonatal adrenal insufficiency Nonclassic: various degrees of (partial) adrenal insufficiency; normal	Classic: prenatal androgen excess (46,XX DSD); maybe the only symptom from birth (“simple virilizers”) Nonclassic: various degrees of adrenal androgen excess after birth	Serum: elevated 17OHP and 21-deoxycortisol Urine: elevated metabolites of 17OHP (17OH-pregnanolone [17HP], pregnanetriolone [PT]) and 21-deoxycortisol (pregnanetriolone [P'TONE])	Enlarged adrenals
CAH due to 11-hydroxylase deficiency	CYP11B1	Classic: low renin hypertension with normal aldosterone levels Nonclassic: mild/absent hypertension	Classic: adrenal insufficiency Nonclassic: various degrees of partial adrenal insufficiency; normal	Classic: prenatal androgen excess (46,XX DSD) Nonclassic: various degrees of androgen excess after birth	Serum: elevated 11-deoxycortisol [S] and 11-deoxycorticosterone [DOC] Urine: elevated metabolites of S (tetrahydro-11-deoxycortisol [THS]) and DOC (tetrahydrocorticosterone [THDOC])
CAH due to 17-hydroxylase deficiency	CYP17A1	Low-renin, hypokalaemic hypertension; can be absent in partial defects	Various degrees of adrenal insufficiency, often rarely adrenal crisis (cross-reactivity of MC precursors on GC receptor)	46,XY DSD from birth; absence of secondary sexual characteristics in both sexes	Serum: elevated corticosterone [B] and 11-deoxycorticosterone [DOC]; low androgens Urine: increased ratio of MC over GC metabolites to assess 17-hydroxylase activity; increased ratio of androgens over GC metabolites to assess 17,20 lyase activity	Also affects gonadal androgen production
CAH due to 3ß-hydroxysteroid-dehydrogenase deficiency	HSD3B2	Classic: hyperreninemic, hypokalaemic hypotension/neonatal salt-wasting crisis Nonclassic: variable degrees/normal	Classic: neonatal adrenal insufficiency Nonclassic: various degrees of (partial) adrenal insufficiency; normal	Classic: DSD in both sexes Nonclassic: premature adrenarche, precocious pseudopuberty, irregular menstrual cycles	Serum: increased (stimulated) ratio of Δ4 (progesterone, 17OHP, androstenedione) over 5 steroids (pregnenolone, 17Preg, DHEA) Urine: elevated ratio of DHEA over GC metabolites and 5-pregnenetriol (5PT) over GC metabolites	Also affects gonadal androgen production
CAH due to P450 oxidoreductase deficiency	POR	Some elevation of MC metabolites but overt arterial hypertension has not been reported	Various degrees of GC deficiency in 85% of patients	DSD in both sexes from birth in 75% of patients; delayed puberty in both sexes of various degrees	Serum: unspecific mild elevation of 17OHP; increased pregnenolone, progesterone, 17OHP Urine: combined impairment of diagnostic ratios for CYP17A1 and CYP21A2; distinct accumulation of pregnenolone metabolites (pregnanediol [PD])	Also affects gonadal androgen production; affects bone development: skeletal malformations of the Antley-Bixler phenotype spectrum
Cytochrome b5 deficiency	CYB5A	None	None	46,XY DSD; absence of puberty in 46,XX	Serum: isolated sex steroid deficiency Urine: normal ratio of MC over GC metabolites reflecting normal 17-hydroxylase activity; increased ratio of androgen over GC metabolites reflective of 17,20 lyase activity	Raised methaemoglobin levels; also affects gonadal androgen production
Apparent DHEA sulfotransferase deficiency	PAPSS2	None	None	Premature adrenarche and polycystic ovary syndrome (hyperandrogenemic oligoanovulation)	Serum: very low/undetectable DHEAS and sulfated steroid compounds, with high DHEA and downstream androgens (testosterone, androstenedione) Urine: high androgen metabolites and precursors	Also causes skeletal abnormalities: brachyolmia type 4

MC, mineralocorticoid; GC, glucocorticoid; CAH, congenital adrenal hyperplasia; DSD, disorders of sex development.