Delayed Diagnosis in a Male With Congenital Chloride Losing Diarrhea

**Background:** Congenital chloride diarrhea (CLD) is a rare autosomal recessive disorder caused by mutations in the SLC26A3 gene, which encodes an apical chloride/bicarbonate exchanger in the ileum and colon. Loss of function leads to chloride malabsorption, bicarbonate loss, and secondary disruption of sodium/hydrogen exchange, resulting in hypokalemia, hypochloremia, and metabolic alkalosis. Diagnosis is confirmed by stool chloride >90 mmol/L and genetic testing. Only approximately 250 children with CLD have been reported in the literature.

**Methods:** This is a single case report of a male infant born at 35 weeks gestational age with prenatal ultrasound showing polyhydramnios and dilated bowel loops. The authors describe his clinical course from birth through 28 months of age, including laboratory values, imaging, endoscopic findings, genetic testing, and treatment response.

**Key Results:** On day of life 3, the patient had hyponatremic, hypochloremic metabolic alkalosis (sodium 126 mmol/L, chloride 86 mmol/L, bicarbonate 29 mmol/L). Symptoms initially resolved on an elemental formula, and he was discharged on day 24. He grew appropriately on hydrolyzed formula until 10 months, when diarrhea developed after transition to cow's milk protein formula. At 12 months, he was hospitalized with severe electrolyte derangements: sodium 133 mmol/L, potassium 2.0 mmol/L, chloride 67 mmol/L, bicarbonate 47 mmol/L. Stool electrolytes showed chloride 145 mmol/L, sodium 55 mmol/L, and potassium 38 mmol/L, establishing the diagnosis of CLD. Genetic testing revealed a heterozygous 4.3-kb deletion encompassing exons 15-17 of SLC26A3 and a sequence variant c.610T>G; pTyr204Asp initially classified as a variant of unknown significance. Parental testing confirmed the deletion (maternal) and sequence variant (paternal) were on opposite alleles, reclassifying the variant as pathogenic. The patient was treated with oral NaCl and KCl supplementation and an elemental formula. At 28 months, he is growing at the 25th percentile for weight with stable serum electrolytes.

**Clinical Implications:** This case highlights that CLD can present atypically with delayed onset of diarrhea, potentially masked by elemental or hydrolyzed formulas. The novel combination of a large 4.3-kb deletion (the second largest reported in CLD) and a sequence variant previously seen in only one patient expands the known genotypic spectrum of CLD. The reclassification of the c.610T>G; pTyr204Asp variant from 'variant of unknown significance' to pathogenic based on parental testing and clinical phenotype is a valuable contribution to the literature. Clinicians should maintain a high index of suspicion for CLD in infants with prenatal polyhydramnios, dilated bowel loops, and electrolyte abnormalities consistent with hypokalemic metabolic alkalosis, even in the absence of early diarrhea.