**Background:** Monogenic intestinal epithelial disorders, also known as congenital diarrheas and enteropathies (CoDEs), are a rare group of life-threatening conditions caused by single-gene variants that directly alter intestinal epithelial function. They present with neonatal or infantile-onset severe diarrhea and malabsorption, often requiring intensive medical support including parenteral nutrition. Historically, these infants were grouped under 'intractable diarrhea of infancy' until the genomic era enabled identification of causative genes. The first descriptions of congenital chloride diarrhea date to 1945, and the causative gene SLC26A3 was identified in 1996. Similarly, microvillus inclusion disease was described in 1978 and its gene MYO5B in 2008. The advent of next-generation sequencing has dramatically accelerated gene discovery. CoDEs are distinguished from very-early-onset inflammatory bowel disease and primary immunodeficiencies by their primary epithelial defect, with minimal or secondary inflammation. Diagnostic evaluation has evolved to include early genetic testing and endoscopic biopsy.
**Methods:** This is a narrative review summarizing the genetics, cell biology, clinical features, and management of CoDE disorders. The authors synthesized literature on archetypal and recently discovered CoDEs, categorizing them into five major functional modules: epithelial transport, epithelial enzymes and metabolism, epithelial structure/trafficking/polarity, enteroendocrine function, and epithelial stem cell function. For each disorder, they describe the gene, inheritance pattern, protein function, pathophysiology, clinical presentation, histology, genotype-phenotype correlations, and treatment. The review also discusses diagnostic approaches, challenges (rarity, diagnostic odyssey, lack of therapies), and future therapeutic outlook including patient-derived enteroids and antisense oligonucleotides.
**Key Results:** The paper details over 30 CoDE-associated genes. Key examples include: SLC26A3 (congenital chloride diarrhea) with founder mutations in Finnish (p.Val317del), Polish (p.Ile675-676ins), and Arab (p.Gly187*) populations; SLC9A3 (congenital sodium diarrhea) with only ~12 confirmed patients; GUCY2C (autosomal dominant secretory diarrhea) with activating mutations; SLC5A1 (glucose-galactose malabsorption) with ~300 reported cases; SI (sucrase-isomaltase deficiency) with prevalence 0.2% in Europeans and 5-10% in Greenland Inuit; DGAT1 deficiency first described in 2012; MTTP and APOB causing abetalipoproteinemia and hypobetalipoproteinemia; SAR1B causing chylomicron retention disease; TMPRSS15 (enterokinase deficiency) with ~20 cases; AGR2 (EAGLES syndrome) with 15 cases; MYO5B (microvillus inclusion disease) with incidence ~1/1,000,000; STX3, UNC45A, STXBP2 also causing MVID-like phenotypes; EPCAM (tufting enteropathy) with incidence 1/50,000-100,000 in Western Europe; SPINT2 causing syndromic sodium diarrhea/tufting enteropathy; TTC7A causing multiple intestinal atresia with combined immunodeficiency; TTC37 and SKIV2L causing trichohepatoenteric syndrome; NEUROG3 (enteric anendocrinosis) with 10 cases; PCSK1 deficiency with ~30 cases; RFX6 (Mitchell-Riley syndrome) with ~20 cases; PERCC1 deficiency discovered via non-coding deletion; WNT2B deficiency with 4 patients; and EGFR deficiency with 23 cases. Many disorders show founder effects in specific populations. Genotype-phenotype correlations are emerging but incomplete for most disorders. Management is primarily supportive with parenteral nutrition, electrolyte supplementation, and dietary modifications. Some disorders (e.g., congenital lactase deficiency, MPI-CDG) have specific treatments (lactose-free diet, mannose supplementation). Prognosis varies widely, with some patients achieving enteral autonomy and others requiring lifelong parenteral nutrition.
**Clinical Implications:** Early diagnosis through genetic testing is critical to reduce the diagnostic odyssey, which can cost approximately $4 million per patient in the U.S. and increase morbidity/mortality. Improved clinical nutrition care has transformed life expectancy from infancy to late childhood and beyond. However, there remains a lack of effective symptomatic and disease-modifying therapies. Patient-derived enteroids offer a powerful model for understanding pathophysiology and testing therapies. Antisense oligonucleotides and other gene-targeted approaches hold promise but face delivery challenges in the GI tract. International consortia like PediCoDE are essential for advancing research and therapy development.