CLASSIC CONGENITAL ADRENAL HYPERPLASIA (CAH)

General Overview

• Definition: CAH comprises a group of autosomal recessive disorders characterized by enzyme deficiencies in the cortisol synthetic pathway.
• Pathophysiology:
  • Decreased Cortisol → Lack of negative feedback → ↑ACTH → Adrenal hyperplasia & accumulation of precursor steroids.
  • Depending on the specific enzyme block, there may be loss or excess of mineralocorticoids or androgens.
• Classic vs. Nonclassic:
  • Classic: Severe enzyme deficiencies, typically presenting in infancy.
  • Nonclassic (late-onset): Milder enzyme defects, presenting later in childhood or adulthood.

CONGENITAL LIPOID HYPERPLASIA

(StAR or P450scc Mutation)

1. Enzyme/Protein Defect
   • Mutations in Steroidogenic Acute Regulatory Protein (StAR) or P450 side-chain cleavage enzyme (P450scc).
2. Hormone Deficiency
   • Deficiency in all adrenal and gonadal steroid hormones (glucocorticoids, mineralocorticoids, sex steroids).
3. Pathology
   • Marked accumulation of cholesterol esters in the adrenal cortex (due to ACTH drive with no steroid synthesis).
4. Clinical Presentation
   • Severe adrenal insufficiency in neonates (hypotension, hyponatremia, hyperkalemia, vomiting).
   • In 46,XY infants: No testicular androgens → female external genitalia.
5. Laboratory Findings
   • Low serum cortisol & aldosterone, high ACTH, high plasma renin activity.
6. Outcome and Treatment
   • Lethal if untreated.
   • Glucocorticoid + mineralocorticoid replacement therapy is essential.

3β-HYDROXYSTEROID DEHYDROGENASE DEFICIENCY

(3β-HSD2 Mutation)

1. Function
   • 3β-HSD converts pregnenolone → progesterone, also DHEA → androstenedione.
   • Type 2 isoenzyme (3β-HSD2) is present in adrenal cortex and gonads.
2. Hormone Deficiency
   • Cortisol, aldosterone, gonadal steroid production severely reduced.
   • ↑Δ⁵-steroids (pregnenolone, 17-hydroxypregnenolone, DHEA, DHEA-S).
3. Clinical Presentation
   • Severe deficiency: Neonatal salt-wasting adrenal crisis (cortisol & aldosterone deficiency).
   • Mild virilization in 46,XX infants (excess DHEA).
   • 46,XY phenotype can vary from normal male to ambiguous or female genitalia.
4. Laboratory Findings
   • Low cortisol, low aldosterone, ↑DHEA, DHEA-S, but androstenedione not elevated (needs 3β-HSD).
   • ↑Renin activity (salt-wasting).
5. Treatment
   • Glucocorticoid & mineralocorticoid replacement + sex steroid replacement at puberty if needed.

17α-HYDROXYLASE DEFICIENCY

(CYP17A1 Mutation)

1. Enzyme/Pathway
   • 17α-hydroxylase (P450c17) required for 17-hydroxylation → glucocorticoids & sex steroids.
   • Also has 17,20-lyase activity → androgens.
2. Hormonal Effects
   • ↑Mineralocorticoid precursors (11-deoxycorticosterone, corticosterone) → hypertension, hypokalemia.
   • ↓Androgens & estrogens → lack of pubertal sexual development.
3. Clinical Presentation
   • Often found at puberty due to sexual infantilism.
   • 46,XX: Primary amenorrhea, no secondary sexual characteristics, HTN, hypokalemia.
   • 46,XY: Phenotypic female (externally), but no internal female structures, intraabdominal testes, no puberty, HTN, hypokalemia.
4. Laboratory Findings
   • Hypokalemia, low plasma renin, low aldosterone (corticosterone suffices for MR effect).
   • High DOC, high corticosterone, low 17-hydroxyprogesterone, low cortisol, low sex steroids.
5. Treatment
   • Glucocorticoid replacement to suppress ACTH.
   • Sex steroid replacement for pubertal development.

21-HYDROXYLASE DEFICIENCY

(CYP21A2 Mutation)

1. Incidence
   • >90% of CAH cases, autosomal recessive.
2. Hormone Effects
   • Defect in conversion:
     • Progesterone → 11-deoxycorticosterone (mineralocorticoid branch).
     • 17-hydroxyprogesterone → 11-deoxycortisol (glucocorticoid branch).
   • Excess: 17-hydroxyprogesterone, progesterone, adrenal androgens.
3. Clinical Presentation
   • Classic Salt-Wasting: Severe deficiency → life-threatening neonatal salt-losing crisis, ambiguous genitalia in 46,XX.
   • Classic Simple Virilizing: Some mineralocorticoid function preserved; virilization but no salt-wasting.
   • Nonclassic (late-onset): Milder, partial enzyme defect.
4. Laboratory Findings
   • ↑17-hydroxyprogesterone (often > 6x normal).
   • Low cortisol, low aldosterone in salt-wasters, ↑ACTH, ↑renin.
   • ↑Androstenedione, ↑testosterone, decreased 11-deoxycortisol.
5. Diagnosis
   • Newborn screening (17-hydroxyprogesterone test).
6. Treatment
   • Glucocorticoid & mineralocorticoid replacement.
   • Surgical correction of ambiguous genitalia if needed.

11β-HYDROXYLASE DEFICIENCY

(CYP11B1 Mutation)

1. Enzyme/Pathway
   • Converts 11-deoxycortisol → cortisol in fasciculata, and 11-deoxycorticosterone (DOC) → corticosterone in glomerulosa.
2. Hormonal Effects
   • ↑11-deoxycortisol, ↑DOC, ↑adrenal androgens.
   • DOC has mineralocorticoid activity → hypertension, hypokalemia, suppressed renin, low aldosterone.
3. Clinical Presentation
   • Severe deficiency: Neonatal virilization (46,XX ambiguous genitalia), salt retention (HTN).
   • Partial deficiency: Hypertension, possible precocious puberty, or young adult onset of HTN, hirsutism, oligomenorrhea.
4. Laboratory Findings
   • ↑11-deoxycortisol, ↑DOC, ↑DHEA, DHEA-S, androstenedione, testosterone.
   • Hypokalemia, low renin, low aldosterone, high ACTH.
5. Treatment
   • Glucocorticoid replacement ± mineralocorticoid considerations (though often suppressed renin–aldosterone axis already).

APPARENT MINERALOCORTICOID EXCESS

(11β-HSD2 Deficiency)

1. Enzyme
   • 11β-hydroxysteroid dehydrogenase type 2 normally inactivates cortisol → cortisone in kidney.
2. Pathophysiology
   • Decreased 11β-HSD2 → cortisol not inactivated → binds mineralocorticoid receptor → HTN, hypokalemia, metabolic alkalosis, low renin, low aldosterone, normal cortisol levels.
   • May be hereditary or from licorice (glycyrrhizic acid) ingestion.
3. Diagnosis
   • Abnormal 24-hour urinary ratio of cortisol : cortisone (>10:1).
   • Also seen in ectopic ACTH with massive cortisol production overwhelming 11β-HSD2.
4. Clinical
   • Severe HTN, hypokalemia, suppressed RAAS.
   • Treated with mineralocorticoid receptor antagonists (e.g., spironolactone) or correct the underlying cause.

MAJOR BLOCKS IN ABNORMAL STEROIDOGENESIS (SUMMARY)

1. Congenital Lipoid Hyperplasia (StAR or P450scc)
2. 3β-HSD Deficiency
3. 17α-Hydroxylase Deficiency (CYP17A1)
4. 21-Hydroxylase Deficiency (CYP21A2)
5. 11β-Hydroxylase Deficiency (CYP11B1)

Additional Points

• Aldosterone Synthase (P450c11AS) in zona glomerulosa converts corticosterone → aldosterone (via 18-hydroxylation).
• Zona Glomerulosa lacks 17α-hydroxylase, cannot synthesize cortisol.
• Zona Reticularis: high cytochrome b5 → strong 17,20-lyase activity → DHEA production.
• Interconversion: 11β-HSD1 (liver) → cortisone → cortisol; 11β-HSD2 (kidney) → cortisol → cortisone.