Gordon Syndrome

Gordon syndrome (familial hyperkalaemic hypertension, pseudohypoaldosteronism type 2) is a rare inherited disorder of the distal convoluted tubule. The thiazide sensitive sodium chloride cotransporter is overactive. This causes hypertension, hyperkalaemia and hyperchloraemic metabolic acidosis, with a normal glomerular filtration rate and low renin.

It results from variants in WNK1 (intronic deletions that increase expression), WNK4, KLHL3 or CUL3, which regulate degradation of WNK kinases and the cotransporter. Inheritance is autosomal dominant for WNK1, WNK4 and CUL3 (and some KLHL3 variants) and recessive for most KLHL3 variants. CUL3 variants cause the most severe and earliest disease.

Prevalence is unknown but the disease is rare, often diagnosed in young adulthood or later. It responds dramatically to thiazide diuretics. Aldosterone levels are inappropriately low or normal for the degree of hyperkalaemia.

Pathophysiology.

• Overactivity of the sodium chloride cotransporter reduces sodium delivery to the collecting duct and reduces the driving force for potassium and hydrogen secretion.
• Chloride retention causes volume expansion, hypertension and suppressed renin.
• The renal outer medullary potassium channel is also inhibited by WNK4 variants.

• Hypertension from childhood or young adulthood, often salt sensitive and sometimes resistant to usual agents.
• Hyperkalaemia (potassium 5.5 to 7.5 mmol/L) with normal GFR, mild hypercalciuria, low bicarbonate (16 to 22 mmol/L).
• Hypercalciuria, bone disease and short stature in some; muscle weakness, periodic paralysis.
• Family history of hypertension and hyperkalaemia, early stroke.
• CUL3 forms: severe hypertension, short stature and learning difficulty in childhood.

Red flags

• Hyperkalaemia with severe hypertension at a young age.
• Hyperkalaemia with ECG changes.
• Failure of hypertension to respond to ACE inhibitors, with rise in potassium.
• Family history of early cardiovascular disease and hyperkalaemia.

• Sodium, potassium (repeated, non-haemolysed), chloride (high), bicarbonate (low), anion gap (normal), creatinine, eGFR, calcium, magnesium, urate, blood gas.
• Plasma renin (low) and aldosterone (low to normal for potassium level), cortisol; urine sodium, potassium, calcium, chloride; transtubular potassium gradient (low).
• Blood pressure measurement by ambulatory monitoring; echocardiography for hypertensive heart disease; urinary sodium and 24-hour sodium excretion.
• Response to thiazide: hydrochlorothiazide 25 mg daily normalises potassium and blood pressure within days.
• Genetic testing: WNK1, WNK4, KLHL3, CUL3.

Differential diagnosis

• Hyporeninaemic hypoaldosteronism, drug induced hyperkalaemia (ACE inhibitors, trimethoprim, calcineurin inhibitors), chronic kidney disease, Liddle syndrome (hypokalaemia), primary aldosteronism, pseudohypoaldosteronism type 1, volume expansion states, Addison disease.

First line: thiazide diuretic

• Hydrochlorothiazide 12.5 to 25 mg daily (usual maximum 50 mg), or chlortalidone 12.5 to 25 mg daily (maximum 50 mg), or indapamide 1.25 to 2.5 mg daily.
• Effects on potassium and blood pressure occur within 3 to 7 days. Check sodium, potassium, magnesium, calcium, urate and creatinine at 1 week and 4 weeks.
• Children: hydrochlorothiazide 1 to 2 mg/kg daily in 2 divided doses (maximum 50 mg).
• Dietary sodium under 1.5 to 2 g daily (the response improves with salt restriction); avoid potassium rich supplements and salt substitutes.

Alternative and add on

• Loop diuretic furosemide 40 to 80 mg once or twice daily when eGFR is under 30 or thiazide response is partial.
• Amiloride is not helpful and may worsen hyperkalaemia; avoid potassium sparing diuretics, trimethoprim and NSAIDs.
• Sodium bicarbonate 500 mg to 1 g two to three times daily if acidosis persists after thiazide.
• Hypertension not controlled: add amlodipine 5 to 10 mg daily; avoid ACE inhibitors and angiotensin receptor blockers unless potassium is controlled.

Emergency: hyperkalaemia with ECG changes

• Calcium gluconate 10% 10 mL intravenously over 10 minutes.
• Insulin 10 units with glucose 25 g.
• Salbutamol 10 to 20 mg nebulised.
• Sodium zirconium cyclosilicate 10 g three times daily for up to 48 hours, then 5 to 10 g daily (maximum 15 g).
• Thiazide or loop diuretic if still passing urine.

Monitoring. Potassium, sodium, bicarbonate, magnesium and creatinine every 3 months in the first year, then every 6 months. Ambulatory blood pressure yearly; calcium and bone health; echocardiography every 2 to 3 years.

Referral and escalation. Nephrology or endocrinology for every confirmed patient; genetics for family testing; urgent for ECG changes or severe hypertension.

Special groups

• Pregnancy: use methyldopa 250 mg three times daily increasing to 500 mg three times daily (maximum 3 g) or labetalol 100 to 200 mg twice daily (maximum 800 mg twice daily). Thiazides are used with caution and potassium monitored closely.
• Children: early treatment prevents growth failure and cardiovascular damage.
• Older adults with thiazide induced hyponatraemia or hypokalaemia: use the lowest dose that normalises potassium and monitor sodium and magnesium.