Liddle syndrome (ORPHA:526)
A rare genetic form of low-renin hypertension characterized by hypertension associated with decreased plasma levels of potassium and aldosterone.
Epidemiology
Liddle syndrome prevalence is unknown. The condition is considered rare with less than 80 families reported worldwide.
Clinical description
The disease can be clinically heterogeneous, ranging from mild to severe. Most patients are diagnosed in young adulthood, although the diagnosis may be made as early as in infancy, especially when family screening of an affected patient is performed. The typical clinical features are resistance to treatment with conventional anti-hypertensives, salt-sensitive arterial hypertension, hypokalemia and metabolic alkalosis often associated with a family history of early-onset hypertension and sudden death. Associated manifestations of hypokalemia may include muscular weakness, polyuria/polydipsia. Sudden death due to stroke or myocardial infarction or associated with malignant arrhythmias elicited by severe hypokalemia has been reported. Mild forms with essential normal plasma electrolytes have also been reported.
Etiology
Liddle syndrome is due to gain-of-function mutations in the genes SCNN1A (16p13), SCNN1B (16p12.2-p12.1) and SCNN1G (16p12.2), encoding, respectively, the alpha, beta and gamma subunits of the epithelial sodium channel (ENaC), a key protein involved in sodium reabsorption in the distal renal tubules. Physiologically, ENaC channel abundance is regulated by aldosterone. The gain-of-function mutations causing Liddle syndrome impair the retrieval from the apical membrane and subsequent degradation of ENaC by the ubiquitin proteasome pathway. The prolonged tenancy of mutated ENaC in the membrane results in increased sodium reabsorption independent of aldosterone with consequent hypertension.
Diagnostic methods
Diagnosis is suspected by the detection of hypertension, associated with hypokalemic alkalosis and suppressed renin and aldosterone, especially in the presence of a relevant family history. It can be confirmed by genetic testing.
Differential diagnosis
Liddle syndrome needs to be distinguished from other forms of hypertension with hypokalemic alkalosis. The suppressed renin and aldosterone levels separate it from primary and secondary forms of hyperaldosteronism, such as Conn syndrome or renovascular hypertension. A family history consistent with dominant inheritance, a urine steroid profile and genetic testing can separate it from apparent mineralocorticoid excess and glucocorticoid remediable hypertension.
Genetic counseling
The pattern of inheritance is autosomal dominant, the risk to offspring of inheriting the mutation from an affected parent is 50%. Given the variable phenotype reported in some families, genetic screening should be performed in first-degree relatives of a mutation carrier.
Management and treatment
Treatment is based on administration of potassium-sparing diuretics, such as amiloride or triamterene, which act by blocking ENaC activity. This results in reduction of blood pressure and correction of hypokalemia and metabolic alkalosis. Conventional antihypertensive therapies are not effective. Patients must also follow a low sodium diet.
Prognosis
With adequate treatment, prognosis is good. Without treatment, cardiovascular and renal complications usually occur.

                            Last update: 
                            May 2020


                            - Expert reviewer(s): 
                            Pr Detlef BÖCKENHAUER | ERKNet*


                                * European Reference Network