Congenital Sodium Diarrhoea

Congenital sodium diarrhoea is a rare congenital secretory diarrhoea in which defective intestinal sodium absorption or increased secretion causes severe watery diarrhoea with high stool sodium, hyponatraemia and metabolic acidosis from birth.

Syndromic forms are caused by variants in SPINT2 (with choanal atresia, anal atresia, corneal erosions, hypertelorism and tufting enteropathy), and non-syndromic forms by variants in SLC9A3 (encoding the sodium hydrogen exchanger 3) or activating variants of GUCY2C (guanylate cyclase C). Inheritance is autosomal recessive for SLC9A3 and SPINT2, and autosomal dominant for GUCY2C.

Only a small number of cases are reported. Maternal polyhydramnios and dilated bowel loops are seen antenatally. Outcome depends on the cause: GUCY2C disease can improve with age, while SPINT2 disease is often dependent on parenteral nutrition.

Pathophysiology.

Loss of the epithelial sodium hydrogen exchanger, or increased cyclic GMP signalling with activation of the cystic fibrosis transmembrane conductance regulator, causes failure of sodium absorption and secretion of fluid and bicarbonate into the lumen.

Stool sodium is high, with loss of bicarbonate leading to metabolic acidosis, and secondary hyperaldosteronism worsens potassium loss.

• Severe watery diarrhoea from the first days, abdominal distension and dehydration.
• Hyponatraemia, hypokalaemia and metabolic acidosis, low urinary sodium from total body sodium depletion, and failure to thrive.
• Syndromic features in SPINT2 disease: choanal atresia, corneal erosions, hypertelorism and anal anomalies.
• Associated: nephrocalcinosis, poor growth and, with GUCY2C variants, inflammatory bowel disease in some.

Red flags.

• Severe dehydration with hyponatraemia and acidosis in a neonate.
• Choanal atresia or corneal disease with diarrhoea.
• Persistent diarrhoea despite fasting (secretory pattern).

• Stool sodium over 70 mmol/L (and often over 100 mmol/L) with a stool pH over 7, and persistent diarrhoea when feeds are stopped (secretory pattern).
• Blood gas and electrolytes: hyponatraemia, hypokalaemia, metabolic acidosis, and low urinary sodium.
• Genetic testing (SLC9A3, SPINT2, GUCY2C, and the panel for congenital diarrhoea).
• Intestinal biopsy to exclude microvillus inclusion disease and tufting enteropathy (tufts in SPINT2 disease).
• Exclude infection, cystic fibrosis, congenital chloride diarrhoea, bile acid malabsorption, and allergic or autoimmune enteropathy.

Differential diagnosis. Congenital chloride diarrhoea (alkalosis), microvillus inclusion disease, tufting enteropathy, glucose galactose malabsorption, congenital lactase deficiency, enteropeptidase deficiency, autoimmune enteropathy and infection.

• Rehydration with IV fluids containing sodium and potassium, with correction of acidosis.
• Sodium replacement, mostly as bicarbonate or citrate (to correct acidosis), in the range of 5 to 15 mmol/kg/day orally in divided doses, adjusted to blood gas, serum sodium and urinary sodium over 20 mmol/L. Potassium 2 to 4 mmol/kg/day.
• Parenteral nutrition for infants who cannot absorb enteral nutrition, with an amino-acid-based or hydrolysed formula when feeding is attempted.
• Central venous catheter care, with strategies to protect against catheter sepsis and liver disease.
• Intestinal transplantation is considered for dependence on parenteral nutrition with complications.
• Treat syndromic features (choanal atresia surgery, eye care).

Monitoring. Electrolytes, blood gas, creatinine, growth, weight, stool sodium and nutritional status. Renal ultrasound for nephrocalcinosis.

Referral and escalation. Refer to an intestinal failure unit and paediatric genetics for all affected infants.