Liddle Syndrome

A 16-year-old boy presents with persistent hypertension detected during a school health examination. He reports muscle cramps and weakness. Blood pressure is 160/100 mm Hg. Laboratory studies show normal serum sodium, hypokalemia, low plasma renin activity, and low plasma aldosterone. Genetic testing identifies a pathogenic variant affecting the β subunit of the epithelial sodium channel. Diagnosis?

The diagnosis is Liddle syndrome.

1. Definition

Liddle syndrome is a rare autosomal dominant monogenic form of hypertension caused by a gain-of-function abnormality of the epithelial sodium channel (ENaC) in the distal nephron. It causes excessive renal sodium reabsorption, volume-dependent hypertension, suppressed renin and aldosterone, and often hypokalemic metabolic alkalosis.

2. Etiology and Genetics

1.      Classic Liddle syndrome is most commonly caused by pathogenic variants in:

o    SCNN1B, encoding the β subunit of ENaC

o    SCNN1G, encoding the γ subunit of ENaC

2.      Exceptionally rare gain-of-function variants involving SCNN1A, encoding the α subunit, have also been reported and may increase ENaC activity through mechanisms distinct from PY-motif disruption

3.      The disorder is usually inherited in an autosomal dominant pattern

4.      Most pathogenic SCNN1B and SCNN1G variants disrupt or truncate the C-terminal PY motif, impairing binding of the NEDD4-2 ubiquitin ligase and reducing ENaC internalization and degradation

5.      In this patient, the variant affecting the β subunit corresponds to SCNN1B

3. Pathophysiology

1.      ENaC is located on the apical membrane of principal cells in the distal nephron

2.      Normally, the NEDD4-2 ubiquitin ligase binds to the ENaC PY motif and promotes channel internalization and degradation

3.      Liddle-associated variants increase ENaC activity by mechanisms that include:

o    Reduced ENaC internalization and degradation

o    Increased ENaC expression or activity at the apical membrane

4.      Increased ENaC activity causes excessive sodium reabsorption

5.      Sodium retention produces extracellular volume expansion and hypertension

6.      Volume expansion suppresses:

o    Renin

o    Aldosterone

7.      Increased ENaC-mediated sodium uptake makes the tubular lumen more electronegative, promoting:

o    Potassium secretion from principal cells

o    Hydrogen ion secretion by α-intercalated cells

8.      This produces hypokalemia and metabolic alkalosis

9.      Serum sodium is often normal despite increased total-body sodium, because compensatory mechanisms limit overt hypernatremia

4. Clinical Features

1.      Early-onset hypertension

o    May be severe or treatment resistant

2.      Hypokalemia

o    May cause muscle weakness

o    Muscle cramps

o    Fatigue

o    Palpitations in severe cases

3.      Metabolic alkalosis

4.      Low plasma renin

5.      Low plasma aldosterone

6.      Peripheral edema is usually absent despite volume expansion

7.      Phenotypic expression is variable, and some affected individuals may have normal potassium levels or relatively mild hypertension

5. Diagnosis

5.1 Clinical and Laboratory Pattern

1.      Suspect Liddle syndrome in a child or young adult with:

o    Early-onset hypertension

o    Suppressed renin

o    Suppressed aldosterone

o    Hypokalemia with or without metabolic alkalosis

2.      The combination of low renin and low aldosterone distinguishes Liddle syndrome from primary aldosteronism

5.2 Genetic Testing

1.      Identification of a pathogenic or likely pathogenic gain-of-function variant in an ENaC subunit gene confirms the molecular diagnosis

2.      A variant of uncertain significance does not by itself confirm Liddle syndrome

3.      Pathogenic variants most commonly involve SCNN1B or SCNN1G

4.      Once a causative variant is identified, genetic counseling and targeted evaluation of first-degree relatives should be considered because of autosomal dominant inheritance and variable phenotypic expression

5.3 Additional Evaluation

1.      Assess:

o    Serum potassium

o    Serum bicarbonate

o    Renal function

o    Renin and aldosterone

2.      Evaluate for hypertension-mediated target-organ damage, particularly when hypertension is severe or longstanding

3.      Adrenal imaging is not required to diagnose Liddle syndrome and does not establish the diagnosis

6. Differential Diagnosis

1.      Primary aldosteronism

o    Low renin

o    High aldosterone

2.      Apparent mineralocorticoid excess

o    Low renin and low aldosterone

o    Caused by impaired cortisol inactivation, classically due to 11β-HSD2 deficiency

o    A similar phenotype may occur with excessive licorice ingestion

3.      Congenital adrenal hyperplasia due to 11β-hydroxylase or 17α-hydroxylase deficiency

o    Hypertension and low renin

o    Increased mineralocorticoid precursors such as deoxycorticosterone

4.      Geller syndrome

o    Activating variant of the mineralocorticoid receptor

5.      Gordon syndrome

o    Hypertension with hyperkalemia and metabolic acidosis, rather than hypokalemic alkalosis

7. Management

7.1 First-Line Therapy

1.      Amiloride is the preferred targeted treatment

2.      Triamterene is an alternative

3.      These medications directly block ENaC, reducing sodium reabsorption and correcting hypertension and hypokalemia

7.2 Dietary Therapy

1.      Dietary sodium restriction enhances the antihypertensive effect of ENaC blockade

7.3 Therapies That Are Ineffective

1.      Spironolactone and other mineralocorticoid receptor antagonists are generally ineffective as targeted therapy

2.      This is because ENaC activation in Liddle syndrome is independent of aldosterone, which is already suppressed

7.4 Monitoring

1.      Monitor:

o    Blood pressure

o    Serum potassium

o    Renal function

2.      Additional antihypertensive therapy may be required if blood pressure remains above target despite adequate ENaC blockade and sodium restriction

8. Complications

Untreated or inadequately controlled hypertension may cause:

1.      Left ventricular hypertrophy

2.      Premature cardiovascular disease

3.      Stroke

4.      Heart failure

5.      Chronic kidney disease

6.      Severe hypokalemia may predispose to cardiac arrhythmias

9. Key Clinical Insight

Early-onset hypertension with hypokalemia, suppressed renin, suppressed aldosterone, and a pathogenic ENaC variant is characteristic of Liddle syndrome. The hypertension results from aldosterone-independent ENaC overactivity and is treated specifically with an ENaC blocker such as amiloride.

References

1.      Gallegos FR, Delahunty MP, Hu J, et al. Decoding Monogenic Hypertension: A Review of Rare Hypertension Disorders. Am J Hypertens. 2025;38(6):333-351. doi:10.1093/ajh/hpaf005.

2.      Singh V, Van Why SK. Monogenic Etiology of Hypertension. Med Clin North Am. 2024;108(1):157-172. doi:10.1016/j.mcna.2023.06.005.

3.      Granhøj J, Nøhr TK, Hinrichs GR, Rasmussen M, Svenningsen P. Reverse Phenotypes of Patients with Genetically Confirmed Liddle Syndrome. Clin J Am Soc Nephrol. 2024;19(5):610-619. doi:10.2215/CJN.0000000000000430.