Congenital chloride diarrhoea

Affected individuals typically present in utero with polyhydramnios, dilated fetal bowel loops and preterm labour. From birth, chloride-rich watery diarrhoea, often initially mistaken for urine in the neonate, causes rapid weight loss, dehydration and disturbed electrolytes, with hyponatraemia, hypochloraemia, hypokalaemia and hypochloraemic metabolic alkalosis. Untreated disease is fatal within the first weeks of life. Failure to thrive and nephropathy may develop, mimicking but without the abnormal calcium handling characteristic of that condition. With lifelong oral salt substitution, affected individuals can reach adulthood, although long-term renal complications, including chronic kidney disease have been reported.

The estimated prevalence is 1/30,000 to 1/40,000 in Finland, with the highest worldwide rates reported in Kuwait and Saudi Arabia at 1/3,200 to 1/5,000, attributed to founder variants and consanguinity.

Congenital chloride diarrhoea is caused by biallelic germline pathogenic variants in SLC26A3, which encodes the apical chloride/bicarbonate exchanger of intestinal epithelial cells. Loss-of-function variants inactivate the exchanger so that chloride absorption fails and faecal chloride concentrations rise, while impaired bicarbonate secretion acidifies the intestinal lumen and disrupts electroneutral sodium absorption coupled through NHE3; the combined defect produces high-volume watery diarrhoea with systemic hypochloraemic metabolic alkalosis.

Congenital chloride diarrhoea is inherited in an autosomal recessive manner. Both parents of an affected individual are typically heterozygous carriers, and the recurrence risk for each pregnancy of a carrier couple is 25%. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

The diagnosis is established by a faecal chloride concentration greater than 90 mmol/l in stool collected after correction of serum electrolyte and acid-base disturbances by salt substitution, confirmed by molecular genetic testing of SLC26A3. Prenatal ultrasound typically shows polyhydramnios and dilated foetal bowel loops, which may be misinterpreted as intrauterine bowel obstruction.

• Establishing the molecular diagnosis confirms the clinical suspicion, ends the diagnostic process and provides a definitive aetiological basis for individualised management.
• Knowing the underlying genetic cause informs individualised clinical management decisions and is a prerequisite for any targeted medical care; specific measures are determined by the treating physicians in consultation with the affected individual.
• Once the familial pathogenic variants have been identified, predictive and carrier testing of at-risk relatives can clarify their genetic status and inform reproductive and personal decisions.

• Babcock SJ, Flores-Marin D, Thiagarajah JR. The genetics of monogenic intestinal epithelial disorders. Human Genetics. 2023;142(5):613-654. doi: 10.1007/s00439-022-02501-5.SLC26A3. PMID: . PMCID: PMC10182130.
• Cendal I, Szafrańska A, Fuchs T, Patkowski D, Smigiel R, Królak-Olejnik B. Prenatal and Postnatal Manifestations of Congenital Chloride Diarrhea Due to a Heterozygote Variant of the SLC26A3 Gene: A Case Report. Frontiers in Pediatrics. 2021;9:758006. doi: 10.3389/fped.2021.758006. PMID: . PMCID: PMC8721094.
• Kamal NM, Khan HY, El-Shabrawi MHF, Sherief LM. Congenital chloride losing diarrhea: A single center experience in a highly consanguineous population. Medicine. 2019;98(22):e15928. doi: 10.1097/MD.0000000000015928. PMID: . PMCID: PMC6709049.
• Sadagah LF, Makeen AZ, Kotbi ET. Diagnostic Challenge of Congenital Chloride Diarrhea and Ulcerative Colitis Overlap in an Adult Misdiagnosed with Bartter Syndrome: Case Report and Literature Review. The American Journal of Case Reports. 2022;23:e936715. doi: 10.12659/AJCR.936715. PMID: . PMCID: PMC9272577.