What are the causes of hypertension in infants due to defects in the renin‑angiotensin‑aldosterone system (RAAS) pathway?

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Last updated: November 3, 2026 • View editorial policy

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Hypertension in Infants Due to RAAS Pathway Defects

Monogenic hypertension caused by RAAS pathway defects in infants includes Liddle syndrome, pseudohypoaldosteronism type II (Gordon syndrome), apparent mineralocorticoid excess, familial hyperaldosteronism, familial glucocorticoid resistance, and congenital adrenal hyperplasia. 1

Primary Monogenic Causes

The 2017 AAP Clinical Practice Guideline identifies specific genetic disorders affecting the RAAS pathway that cause infant hypertension 1:

Core Monogenic Disorders

  • Liddle syndrome: Activating mutations in epithelial sodium channel (SCNN1G gene)
  • Gordon syndrome (Pseudohypoaldosteronism type II): Increased distal tubule sodium absorption
  • Apparent mineralocorticoid excess: Loss of function mutations in HSD11B2 gene
  • Familial hyperaldosteronism type I (FH-I): Also called glucocorticoid-remediable aldosteronism; confirmed in 3% of select hypertensive children without known etiology
  • Familial glucocorticoid resistance: Loss of function glucocorticoid receptor mutations (NR3C1 gene)
  • Congenital adrenal hyperplasia: Adrenal cortical dysfunction

Unifying Pathophysiology

All these disorders share a common mechanism: suppressed plasma renin activity (PRA) with increased sodium absorption in the distal tubule. 1 This creates a characteristic biochemical signature that helps distinguish monogenic hypertension from other causes.

Clinical Presentation Features

Look for these specific findings that suggest RAAS-related monogenic hypertension:

  • Electrolyte abnormalities: Particularly serum potassium disturbances (hypokalemia in most forms)
  • Metabolic acid-base disturbances: Variable patterns depending on specific disorder
  • Abnormal plasma aldosterone concentrations: Despite suppressed renin
  • Early-onset hypertension: Often presenting in infancy or early childhood
  • Abnormal sexual development: May occur with congenital adrenal hyperplasia
  • Family history: Positive for early-onset hypertension

Critical caveat: Clinical presentations can be highly variable even within the same genetic disorder, making diagnosis challenging without genetic testing 1.

Developmental RAAS Defects

Beyond genetic mutations, in utero exposure to RAAS inhibitors (ACE inhibitors or AT1 receptor blockers) causes severe developmental kidney defects that manifest as neonatal hypertension 2, 3:

  • Renal agenesis or tubular dysgenesis
  • Kidney failure
  • Skull ossification defects (hypocalvaria)
  • Low bone mineralization
  • Sustained activation of RAAS after birth: Marked elevation of plasma renin and aldosterone 3

This "RAS blockage syndrome" occurs even with first-trimester exposure, not just second and third trimester 3. The paradoxical hypertension results from abnormal kidney development with impaired sodium excretion and salt-sensitive mechanisms 4.

Structural Kidney Abnormalities

Congenital renal dysplasia (such as multicystic dysplastic kidney) causes hypertension through abnormal RAAS activation 5:

  • Abnormal vascular structures with wall thickening
  • Irregular renin localization in proximal tubules and immature glomeruli
  • Parenchymal destruction with gathered immature glomeruli
  • Poor response to ACE inhibitors due to structural abnormalities

These infants may require nephrectomy when medical management fails, with gradual normalization of renin and aldosterone levels post-surgery 5.

Diagnostic Approach

When evaluating infant hypertension for RAAS defects:

  1. Measure plasma renin activity and aldosterone: Suppressed PRA is the hallmark
  2. Check serum potassium and acid-base status: Specific patterns suggest particular disorders
  3. Obtain detailed perinatal history: Maternal medication use (especially RAAS inhibitors), pregnancy complications, gestational age, birth weight
  4. Document umbilical catheter placement: Associated with renal vascular injury
  5. Perform targeted genetic testing: Next-generation sequencing for suspected monogenic forms 6

Treatment Implications

Recognition of specific RAAS-related monogenic hypertension is critical because certain readily available medications are highly effective 6:

  • Thiazide diuretics: First-line for Liddle syndrome and Gordon syndrome
  • Low-dose corticosteroids: Specific treatment for glucocorticoid-remediable aldosteronism
  • Amiloride or triamterene: Epithelial sodium channel blockers for Liddle syndrome

These targeted therapies prevent serious complications including cerebrovascular events, making accurate genetic diagnosis essential rather than empiric antihypertensive therapy 6.

References

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