Liddle's syndrome

Liddle's syndrome, also called Liddle syndrome and pseudoaldosteronism, is an autosomal dominant disorder characterized by early, and frequently severe, hypertension associated with low plasma renin activity, metabolic alkalosis due to hypokalemia, and normal to low levels of aldosterone. Liddle syndrome involves abnormal kidney function, with excess reabsorption of sodium and loss of potassium from the renal tubule, and is treated with a combination of low sodium diet and potassium-sparing diuretic drugs (e.g., amiloride). It is extremely rare, with fewer than 30 pedigrees or isolated cases having been reported worldwide as of 2008.

Etiology
This syndrome is caused by dysregulation of an epithelial sodium channel (ENaC) due to a genetic mutation at the 16p13-p12 locus. These channels are found at the surface of certain cells called epithelial cells found in the kidneys, lungs, and sweat glands. The ENaC channel transports sodium into cells. 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. Therefore, there is increased activity of this channel leading to increased sodium reabsorption. The increased sodium reabsorption leads to hypertension due to an increase in extracellular volume.



Signs and symptoms
Children with Liddle syndrome are frequently asymptomatic. The first indication of the syndrome often is the incidental finding of hypertension during a routine physical exam. Because this syndrome is rare, it may only be considered by the treating physician after the child's hypertension does not respond to antihypertensive agents.

Adults could present with nonspecific symptoms of hypokalemia, which can include weakness, fatigue, palpitations or muscular weakness (dyspnea, constipation/abdominal distention or exercise intolerance). Additionally, long-standing hypertension could become symptomatic.

Diagnosis
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 reduced, 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 (adenoma) or adrenal hyperplasia. Aldosterone levels are high in hyperaldosteronism, whereas they are low to normal in Liddle syndrome.

A genetic study of the ENaC sequences can be requested to detect mutations (deletions, insertions, missense mutations) and get a diagnosis.

Treatment
The treatment is with a low sodium (low salt) diet and a potassium-sparing diuretic that directly blocks the sodium channel. Potassium-sparing diuretics that are effective for this purpose include amiloride and triamterene; spironolactone is not effective because it acts by regulating aldosterone and Liddle syndrome does not respond to this regulation.