Pseudohypoaldosteronism Type 1

Pseudohypoaldosteronism type 1 is a rare inherited salt wasting disorder with target organ resistance to aldosterone. It has two forms: renal (autosomal dominant, NR3C2) and systemic (autosomal recessive, SCNN1A, SCNN1B or SCNN1G).

The renal form is mild, limited to the kidney, and usually improves with age. The systemic form affects kidney, colon, sweat and salivary glands and lung, and is lifelong and severe.

Neonates present in the first weeks of life with failure to thrive, vomiting, dehydration, hyponatraemia, hyperkalaemia and metabolic acidosis, with a markedly raised renin and aldosterone.

Pathophysiology.

In the renal form, reduced mineralocorticoid receptor function lowers sodium reabsorption in the collecting duct. In the systemic form, loss of function of the epithelial sodium channel affects every tissue that uses it.

Lung fluid clearance fails, causing respiratory distress and recurrent chest infection.

• Neonate and infant: poor weight gain, vomiting, dehydration, hypotension, arrhythmia and growth failure.
• Systemic form: respiratory distress or recurrent wheeze, miliaria like skin rash and high sweat sodium, and failure to thrive.
• Dominant renal form: milder symptoms, with improvement from about 2 to 3 years of age.

Red flags.

• Potassium over 7 mmol/L or arrhythmia.
• Severe dehydration or shock in a neonate with normal genitalia and cortisol.

• Sodium low, potassium high, bicarbonate low. Plasma renin and aldosterone very high (usually over 10 times the upper limit), urinary sodium raised, normal cortisol and 17-hydroxyprogesterone.
• Sweat chloride raised in the systemic form. Chest radiograph for lung fluid.
• NR3C2 testing for the dominant form; SCNN1A, SCNN1B and SCNN1G for the recessive form. Parents of recessive patients are carriers.

Differential diagnosis.

• Congenital adrenal hyperplasia (21-hydroxylase deficiency) and primary adrenal insufficiency.
• Secondary pseudohypoaldosteronism with urinary infection or obstructive uropathy.
• Cystic fibrosis (differs in electrolytes and genes) and Gordon syndrome.

• Emergency treatment of hyperkalaemia: calcium gluconate 10% 10 mL intravenously over 10 minutes (0.5 mL/kg in infants), soluble insulin 10 units with glucose 25 g (insulin 0.1 units/kg with glucose 0.5 g/kg in infants), nebulised salbutamol, and rehydration with 0.9% sodium chloride 10 to 20 mL/kg.
• Long term sodium chloride supplements: 10 to 20 mmol/kg daily (up to 40 mmol/kg in the systemic form), spread over feeds, with rises as sodium requires.
• Potassium binders, a low potassium diet and bicarbonate for acidosis. Indomethacin has been used to reduce urinary salt loss and hyperkalaemia in the systemic form.
• Chest physiotherapy and early treatment of chest infection in systemic disease.
• Fludrocortisone and hydrocortisone do not help.
• Genetic counselling for families.

Special groups. Dominant renal form: supplements are often stopped by 2 to 3 years of age with continued monitoring. Systemic form: lifelong treatment, with pulmonary follow up.

Monitoring. Sodium, potassium, bicarbonate and weight monthly in infancy, then every 3 to 6 months, and growth and lung function in systemic disease.

Referral and escalation. Paediatric endocrinology and nephrology; respiratory team for systemic disease; emergency admission for severe hyperkalaemia.