Liddle's syndrome

Liddle's syndrome
OMIM	177200
DiseasesDB	7471

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Liddle's Syndrome is an autosomal dominant disorder that mimics hyperaldosteronism. It involves problems with excess resorption of sodium and loss of potassium from the renal tubule. Hypertension begins at a very early age, often in infancy.

Pathophysiology

This syndrome is caused by dysregulation of an epithelial Na+ channel (ENaC) due to a genetic mutation at the 16p12-p13 locus. The mutation changes a domain in the channel so it is no longer degraded correctly by the Ubiquitin Proteasome system. Specifically the PY motif in the protein is deleted or altered so the E3 ligase (Nedd4) no longer recognizes the channel.

Differentiating Liddle's Syndrome from other diseases

Liddle's syndrome should be differentiated from other diseases causing hypertension and hypokalemia for example:

• Renal artery stenosis
• Cushing's syndrome
• Congenital adrenal hyperplasia (CAH)
  • 17 alpha hydroxylase deficiency
  • 11 beta hydroxylase deficiency
• Primary hyperaldosteronism
• Diuretic use
• Licorice ingestion
• Renin-secreting tumors

Hypertension and Hypokalemia

Plasma renin activity

Normal or High (Plasma Renin/Aldosterone ratio <10

Suppressed (Plasma Renin/Aldosterone ratio >20

*Renin-secreting tumors *Diuretic use *Renovascular hypertension *Coarctation of aorta *Malignant phase hypertension

Urinary aldosterone

Elevated

Normal

Low

Conn's syndrome (Primary aldosteronism)

Profound K+ depletion

• 17 alpha hydroxylase deficiency • 11 beta hydroxylase deficiency • Liddle's syndrome • Licorice ingestion • Deoxycortisone producing tumor

Add Mineralocrticoid antagonist for 8 weeks

BP response

No BP response

• Deoxycorticosterone excess( Tumor, 17 alpha hydroxylase and 11 beta hydroxylase deficiency) • Licorice ingestion •Glucocorticoid resistance

Liddle's syndrome)

Differential Diagnoses	Clinical features											History Findings	Laboratory Findings
	Headache and hypertension	Nausea and vomiting	Palpitations	Shortness of breath	Diminished pulses	Fatigue	Constipation	Visual abnormalities	Pruritis	Polyuria	Ambiguous genitalia
Renin-Secreting tumors	✔ (Due to hypertension)	✔	✔	✔	-	-	-	-	-	-	-	Drug-resistant hypertension Chronic headaches	Normal renal function tests Normal liver function tests Metabolic alkalosis (pH > 7.45) Hypokalemia Plasma renin-aldosterone ratio <10
Coarctation of aorta	✔	✔	✔	✔	✔	✔	-	-	-	-	-	Young patients (neonates) may have history of: Failure to thrive Poor feeding Lethargy Turner's syndrome Familial predisposition Ventricular septal defects Adults may have a history of: Claudication Epistaxis	Bicuspid aortic valves Notching of ribs Metabolic alkalosis (pH > 7.45) Hyperkalemia Plasma renin-aldosterone ratio <10
11-beta hydroxylase deficiency	✔ (Hypertensive crisis due to increased 11-deoxycorticosterone-11-DOC)	✔	✔	-	-	✔	-	-	-	-	✔	Females: Clitoral enlargement Labioscrotal fusion Males: Penile enlargement (If not diagnosed at birth, may present as premature adrenarche, developing body odor with axillary and pubic hair development)	Hypokalemia Increased 11-DOC levels Increased androgens Low urinary aldosterone level
17-alpha hydroxylase deficiency	✔	✔	✔	-	-	-	-	-	-	-	✔	Phenotypically females at birth Lack of pubertal development in females Incompletely developed external genitalia in males	Increased serum mineralocorticoids Decreased androgen levels Hypokalemia Low urinary aldosterone level
Uremia		✔	✔	✔	-	✔	✔	-	✔	-	-	Patients have chronic kidney disease and maybe on dialysis Features of uremic neuropathy: Autonomic features with postural hypotension, Impaired sweating Diarrhea Impotence Paraesthesia Delayed deep tendon reflexes Muscle wasting Encephalopathy	Increased blood urea nitrogen (BUN) and creatinine (Cr) Hyperkalemia Decreased serum vitamin 1,25 dihydroxy vitamin D3 level
Liddle's syndrome	✔	✔	✔	-	-	-	✔	-	-	-	-	Family history of Liddle's syndrome (autosomal dominant inheritance) Nephropathy Arrythmias SCNN1B or SCNN1G gene mutation	Hyporeninemic hypoaldosteronism Hypertension Hypokalemia Enhanced erythrocyte sodium influx  Low urinary aldosterone

Epidemiology and Demographics

This syndrome is rare and may only be considered by the treating physician after the child's hypertension is found to be recalcitrant to antihypertensive agents.

Diagnosis

Symptoms

Children and aliens with Liddle's syndrome are frequently asymptomatic.

Physical Examination

Vitals

The first indication of the disease is often the incidental finding of hypertension during a routine physical exam.

Laboratory Studies

Evaluation of the pediatric hypertensive patient usually involves analysis of blood electrolytes and an aldosterone level, as well as other tests. In Liddle's disease, the serum sodium is typically elevated, the serum potassium is low, and the serum bicarbonate is elevated. These findings are also found in hyperaldosteronism, another rare cause of pediatric hypertension. Primary hyperaldosteronism (also known as Conn's syndrome), is due to an aldosterone-secreting adrenal tumor or adrenal hyperplasia.

Treatment

The treatment is with a low-salt diet and a potassium-sparing diuretic that directly blocks the sodium channel, such as amiloride or triamterene. Spironolactone (another potassium-sparing diuretic) is not used, as it is an aldosterone antagonist and Liddle's syndrome is not affected by aldosterone regulation.

References

de:Liddle-Syndrom it:Sindrome di Liddle fi:Liddlen syndrooma