Pseudohypoaldosteronism

Pseudohypoaldosteronism type 1 is a rare inherited disorder of aldosterone resistance. It presents in the neonatal period with severe salt wasting, hyponatraemia, hyperkalaemia and metabolic acidosis despite very high plasma renin and aldosterone. Incidence is about 1 in 80 000 births.

There are two forms.

• The renal (autosomal dominant) form results from heterozygous loss of function variants in NR3C2, the mineralocorticoid receptor. It is milder, limited to the kidney, and improves with age.
• The systemic (autosomal recessive) form results from loss of function variants in SCNN1A, SCNN1B or SCNN1G, which encode the three subunits of the epithelial sodium channel. It affects the kidney, colon, sweat and salivary glands and lungs, is life long, and carries a high mortality in infancy without treatment.

Secondary (transient) pseudohypoaldosteronism occurs with urinary tract infection and obstructive uropathy in infants, and with drugs that block the sodium channel.

Type 2 pseudohypoaldosteronism is Gordon syndrome and is a different disorder (hypertension and hyperkalaemia with low renin).

Pathophysiology. Failure of aldosterone signalling or of the epithelial sodium channel prevents distal sodium reabsorption and potassium and hydrogen secretion. Volume depletion raises renin and aldosterone while salt wasting persists.

• Neonates: poor feeding, vomiting, dehydration, weight loss, failure to thrive, lethargy, hypotension, arrhythmia from hyperkalaemia, usually in the first 1 to 2 weeks.
• Laboratory: sodium 110 to 130 mmol/L, potassium 7 to 11 mmol/L, bicarbonate under 15 mmol/L, high urinary sodium loss despite volume depletion.
• Systemic form: recurrent lower respiratory tract infection and cough (excess airway fluid), sweat chloride raised (similar to cystic fibrosis), miliaria rubra and rash, high sodium loss in sweat and saliva, and hyperkalaemia that worsens in intercurrent illness.
• Renal form: salt wasting and growth failure in infancy that improves by 2 to 3 years, with later normal growth.
• Normal genitalia and normal 17-hydroxyprogesterone (distinguishes it from congenital adrenal hyperplasia).

Red flags

• Neonatal hyperkalaemia with hyponatraemia and shock.
• Arrhythmia, wide QRS or bradycardia in an infant.
• Persistent salt wasting despite hydrocortisone and fludrocortisone.
• Recurrent chest infections with raised sweat chloride and normal cystic fibrosis genotype.

• Sodium, potassium, bicarbonate, chloride, glucose, creatinine, venous blood gas, ECG.
• Plasma renin activity and aldosterone (both very high; aldosterone usually over 100 times the age matched normal), cortisol, 17-hydroxyprogesterone (normal), ACTH.
• Urine sodium (inappropriately high), potassium (low), urinary tract ultrasound and urine culture to exclude secondary forms.
• Sweat chloride (raised in systemic form, often over 60 mmol/L), cystic fibrosis genotype (normal).
• Genetic testing: NR3C2 (dominant), SCNN1A, SCNN1B, SCNN1G (recessive).

Differential diagnosis

• Congenital adrenal hyperplasia (21-hydroxylase deficiency), adrenal haemorrhage or hypoplasia, aldosterone synthase deficiency, urinary tract infection or obstruction with transient pseudohypoaldosteronism, cystic fibrosis, Gordon syndrome, Bartter syndrome (opposite pattern: low potassium).

Emergency: hyperkalaemia and shock in an infant

• 0.9% sodium chloride 10 to 20 mL/kg intravenously over 15 to 30 minutes, repeated as needed, then maintenance fluids with added sodium.
• Hydrocortisone 2 mg/kg intravenously (maximum 100 mg) until adrenal insufficiency is excluded.
• Hyperkalaemia with ECG changes: calcium gluconate 10% 0.5 mL/kg intravenously over 10 minutes (maximum 20 mL); insulin 0.1 unit/kg with glucose 0.5 g/kg over 30 minutes; salbutamol 2.5 mg nebulised (5 mg over 5 years); sodium bicarbonate 1 to 2 mmol/kg for acidosis. Use dialysis (peritoneal or haemodialysis) if refractory.

Long term treatment

• Sodium chloride supplements: 10 to 20 mmol/kg daily (0.6 to 1.2 g/kg) in divided feeds, up to 20 to 40 mmol/kg daily in the systemic form. Monitor for hypernatraemia and diarrhoea. Adjust doses to sodium 135 to 145 mmol/L, weight gain and plasma renin.
• Potassium lowering: dietary potassium restriction, and calcium polystyrene sulphonate 0.5 to 1 g/kg daily in divided doses (rectal or oral; separate from other drugs). Sodium zirconium cyclosilicate is not licensed under 18 years.
• Use loop diuretic furosemide 1 to 2 mg/kg daily in 2 doses where volume allows. Give sodium bicarbonate 1 to 2 mmol/kg daily in divided doses for acidosis.
• Fludrocortisone is ineffective in the systemic form. In the renal form 0.1 to 0.3 mg daily is rarely helpful.
• Systemic form: chest physiotherapy, early antibiotics for respiratory infections, maintain hydration. Salt supplements and potassium binders continue life long. Indomethacin 1 to 2 mg/kg daily has been used for hyperkalaemia.
• Renal form: supplements can often be stopped by 18 months to 3 years once growth is normal and sodium and potassium are stable.

Monitoring. Check sodium, potassium, bicarbonate and creatinine weekly at start, then every 1 to 3 months in infancy. Check weight, length and head circumference at each visit. Use a sick day plan with increased salt and urgent review for vomiting.

Referral and escalation. Paediatric nephrology and endocrinology from diagnosis; genetics for family counselling. Escalate urgently for potassium over 6.5 mmol/L, ECG changes or shock.

Special groups

• Families: recessive form carries a 25% recurrence risk in each pregnancy; prenatal testing is possible.
• Pregnancy in affected women (renal form): maintain salt intake and monitor potassium monthly.
• Adults with renal form: usually asymptomatic. Check potassium during illness and with drugs that raise potassium.