A rare cause of congenital diarrhea: a homozygous AGR2 frameshift variant in an infant.

Abstract

Background: Congenital diarrheal disorders and enteropathies (CODE) are rare genetic conditions presenting with severe diarrhea and growth failure beginning in infancy. Biallelic variants in the anterior gradient 2 (AGR2) gene have recently been associated with a cystic fibrosis-like disorder characterized by multisystem involvement, including gastrointestinal and respiratory manifestations.

Case presentation: We report a male infant born to consanguineous parents, who presented with severe congenital secretory diarrhea starting in the neonatal period, failure to thrive, dehydration, and metabolic acidosis. The diarrhea was refractory to bowel rest, suggesting a secretory mechanism. Stool studies, fecal elastase, sweat chloride testing, and CFTR gene analysis were normal. Endoscopic evaluation revealed antral gastritis, bulbitis, and duodenitis, with duodenal biopsies showing villous flattening. The patient developed recurrent hyponatremia requiring prolonged oral sodium supplementation and experienced a single episode of bronchiolitis, which may represent either a possible early respiratory manifestation or a coincidental common infantile infection. Whole exome sequencing identified a homozygous frameshift variant in the AGR2 gene (c.247_250del; p.His83ValfsTer4), and parental testing confirmed autosomal recessive inheritance.

Conclusion: This case expands the clinical spectrum of AGR2-related disease by highlighting a predominantly gastrointestinal presentation with severe congenital secretory diarrhea, failure to thrive, electrolyte imbalance, and a possible early respiratory manifestation. Given the rarity of this condition, AGR2 deficiency may be considered in selected infants presenting with severe congenital diarrhea and failure to thrive, particularly in the setting of consanguinity, even in the absence of definite pulmonary involvement.