Gordon’s Syndrome, also known as Pseudohypoaldosteronism Type II (PHA II) or Familial Hyperkalemic Hypertension, is a rare, inherited disorder. It affects the kidneys’ ability to manage salt and water balance, disrupting the normal regulatory processes that control blood pressure and electrolyte levels. This genetic disturbance leads to the inappropriate retention of salts, which subsequently drives the characteristic symptoms of the syndrome.
Defining Gordon’s Syndrome and Its Clinical Presentation
The primary features of Gordon’s Syndrome are early-onset hypertension and hyperkalemia (abnormally high potassium levels in the blood). Patients often present with high blood pressure starting in childhood or young adulthood, which is frequently resistant to conventional therapies. This elevation results directly from the kidneys retaining excess sodium chloride (salt), causing the body to hold onto more water.
The retention of salt and water expands the circulating blood volume, forcing the heart to pump against greater resistance and causing hypertension. The kidney’s inability to effectively excrete potassium simultaneously leads to hyperkalemia, which can cause muscle weakness or, in extreme cases, affect heart rhythm. These electrolyte imbalances are often accompanied by hyperchloremic metabolic acidosis, where the blood becomes slightly more acidic due to an excess of chloride ions. Overall kidney function, measured by the glomerular filtration rate, typically remains normal.
The physiological state of the kidneys in Gordon’s Syndrome causes the activity of the renin-angiotensin-aldosterone system (RAAS), the body’s primary blood pressure and fluid regulator, to be suppressed. This suppression is a reflex response to the body’s volume overload and the high potassium levels.
Genetic Basis and Underlying Causes
Gordon’s Syndrome follows an autosomal dominant inheritance pattern, meaning only one copy of the mutated gene is needed to develop the disorder. The underlying cause traces back to mutations in one of four genes: WNK1, WNK4, CUL3, or KLHL3. These genes encode proteins that act as molecular switches in the kidney’s distal convoluted tubule, the final segment where fine-tuning of salt and water occurs.
The fundamental molecular defect involves the overactivity of the renal sodium-chloride cotransporter (NCC), a protein responsible for moving salt back into the bloodstream from the forming urine. Normally, WNK proteins regulate the NCC, ensuring only the necessary amount of salt is reabsorbed. However, mutations in WNK1 and WNK4 lead to the accumulation or overactivity of these kinases, which excessively stimulate the NCC.
The CUL3 and KLHL3 genes encode proteins that form a complex whose normal function is to tag the WNK proteins for destruction. When these genes are mutated, WNK proteins are not broken down efficiently and accumulate, leading to persistent, unregulated activation of the NCC. This overactive NCC transporter forces the kidney to reclaim too much sodium chloride and water, explaining the resulting hypertension and volume expansion. This excessive salt reabsorption also disrupts the electrochemical gradient necessary for potassium excretion, directly causing hyperkalemia.
Diagnosis and Treatment Approaches
Diagnosis typically begins by identifying the characteristic combination of hypertension and hyperkalemia in a patient with otherwise normal kidney function. Standard blood tests reveal elevated potassium levels, hyperchloremic metabolic acidosis, and often suppressed plasma renin activity and aldosterone concentration, reflecting the body’s attempt to compensate for the volume overload. This unique biochemical profile is highly suggestive of the condition, especially when a family history of similar symptoms exists.
Imaging studies, such as renal ultrasound, are often used to rule out secondary causes of hypertension or electrolyte imbalance, ensuring the underlying kidney structure is normal. The definitive confirmation of Gordon’s Syndrome relies on genetic testing, which analyzes the patient’s DNA for pathogenic mutations in the WNK1, WNK4, CUL3, or KLHL3 genes. Identifying the specific mutation not only confirms the diagnosis but can also offer prognostic information, as some mutations are associated with a more severe presentation.
The treatment for Gordon’s Syndrome is straightforward and effective, focusing on correcting the functional defect in the kidney tubules. The first-line therapy involves thiazide diuretics, such as hydrochlorothiazide or chlorthalidone. These specific diuretics work by directly inhibiting the overactive NCC transporter in the distal convoluted tubule.
By blocking the NCC, thiazide diuretics force the kidney to excrete excess sodium chloride and water, reducing the expanded blood volume and lowering blood pressure. This action corrects the electrolyte imbalance by restoring the proper conditions for potassium excretion, normalizing serum potassium levels and resolving metabolic acidosis. When properly managed with thiazide therapy, the prognosis for individuals with Gordon’s Syndrome is excellent, leading to a typical life expectancy and quality of life.