Recent Progress in Congenital Diarrheal Disorders


Congenital diarrheal disorders (CDD) are a group of rare enteropathies related to specific genetic defects. Infants with these disorders have chronic diarrhea, frequently requiring parenteral nutrition support. Etiologies and prognoses are variable. We propose a new classification of CDD into four groups, taking into account the specific etiology and genetic defect: 1) defects in digestion, absorption, and transport of nutrients and electrolytes; 2) disorders of enterocyte differentiation and polarization; 3) defects of enteroendocrine cell differentiation; and 4) dysregulation of the intestinal immune response. The present review focuses on the recent advances made in understanding the pathophysiology of CDD that could potentially improve the clinical approach to these conditions.

This is a preview of subscription content, access via your institution.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.

    Berni Canani R, Cirillo P, Terrin G. Chronic and intractable diarrhea. In: Guandalini S Ed. Essential Pediatric Gastroenterology Hepatology, and Nutrition. McGraw-Hill Mediacla Publishing Division Chicago 2005; 25–47.

  2. 2.

    •• Ruemmele FM. Chronic enteropathy: molecular basis. In Gastrointestinal Disorders. Nestlè Nutr Workshop Ser Pediatr Program. 2007; 59:73–88. This article provides an excellent review of molecular mechanisms of chronic enteropathy.

  3. 3.

    •• Berni Canani R, Terrin G, Cardillo G, et al. Congenital diarrheal disorders: improved understanding of gene defects is leading to advances in intestinal physiology and clinical management. J Pediatr Gastroenterol Nutr. 2010; 50:360–6. This article is an interesting review based on a new classification of congenital diarrhea.

    Google Scholar 

  4. 4.

    Sherman PM, Mitchell DJ, Cutz E. Neonatal enteropathies: defining the causes of protracted diarrhea of infancy. J Pediatr Gastroenterol Nutr. 2004;38:16–26.

    PubMed  Article  Google Scholar 

  5. 5.

    Guarino A, Spagnuolo MI, Russo S, et al. Etiology and risk factors of severe and protracted diarrea. J Pediatr Gastroenterol Nutr. 1995;20:173–8.

    PubMed  Article  CAS  Google Scholar 

  6. 6.

    Passariello A, Terrin G, Baldassarre ME, et al. Diarrhea in neonatal intensive care unit. World J Gastroenterol. 2010;16:2664–8.

    PubMed  Article  Google Scholar 

  7. 7.

    Heyman MB. Lactose intolerance in infants, children, and adolescents. Committee on Nutrition. Pediatrics. 2006;118:1279–86.

    PubMed  Article  Google Scholar 

  8. 8.

    Järvelä I, Torniainen S, Kolho KL. Molecular genetics of human lactase deficiencies. Ann Med. 2009;41:568–75.

    PubMed  Article  Google Scholar 

  9. 9.

    Torniainen S, Freddara R, Routi T, et al. Four novel mutations in the lactase gene (LCT) underlying congenital lactase deficiency (CLD). BMC Gastroenterol. 2009;9:8.

    PubMed  Article  Google Scholar 

  10. 10.

    Robayo-Torres CC, Quezada-Calvillo R, Nichols BL. Disaccharide digestion: clinical and molecular aspects. Clin Gastroenterol Hepatol. 2006;4:276–87.

    PubMed  Article  CAS  Google Scholar 

  11. 11.

    Nichols BL, Quezada-Calvillo R, Robayo-Torres CC, et al. Mucosal maltase-glucoamylase plays a crucial role in starch digestion and prandial glucose homeostasis of mice. J Nutr. 2009;139:684–90.

    PubMed  Article  CAS  Google Scholar 

  12. 12.

    •• Venkatasubramanian J, Ao M, Rao MC. Ion transport in the small intestine. Curr Opinion Gatroenterol. 2010; 26:123–8. Interesting review focusing on ions transport mechanisms.

  13. 13.

    • Xin B, Wang H. Multiple sequence variations in SLC5A1 gene are associated with glucose-galactose malabsorption in a large cohort of Old Order Amish. Clin Genet. 2011;79(1):86–91. doi:10.1111/j.1399-0004.2010.01440.x. The authors of this interesting study report new clinical and molecular insights from a large population of affected subjects.

  14. 14.

    Gibson PR, Newnham E, Barrett JS, et al. Review article: fructose malabsorption and the bigger picture. Aliment Pharmacol Ther. 2007;25:349–63.

    PubMed  Article  CAS  Google Scholar 

  15. 15.

    Leturque A, Brot-Laroche E, Le Gall M. GLUT2 mutations, translocation, and receptor function in diet sugar managing. Am J Physiol Endocrinol Metab. 2009;296:E985–92.

    PubMed  Article  CAS  Google Scholar 

  16. 16.

    •• Dorwart MR, Shcheynikov N, Baker JM, et al. Congenital chloride-losing diarrhea causing mutations in the STAS domain result in misfolding and mistrafficking of SLC26A3. J Biol Chem. 2008;283:8711–22. An important study that sheds light on the role of the STAS domain in the function of the SLC26A3 gene.

  17. 17.

    Al Makadma AS, Al-Akash SI, Al Dalaan I, et al. Congenital sodium diarrhea in a neonate presenting as acute renal failure. Pediatr Nephrol. 2004;19:905–7.

    Google Scholar 

  18. 18.

    Leturque A, Brot-Laroche E, Le Gall M. GLUT2 mutations, translocation, and receptor function in diet sugar managing. Am J Physiol Endocrinol Metab. 2009;296:E985–92.

    PubMed  Article  CAS  Google Scholar 

  19. 19.

    Schmitt S, Küry S, Giraud M, et al. An update on mutations of the SLC39A4 gene in acrodermatitis enteropathica. Hum Mutat. 2009;30:926–33.

    PubMed  Article  CAS  Google Scholar 

  20. 20.

    Sperandeo MP, Andria G, Sebastio G. Lysinuric protein intolerance: update and extended mutation analysis of the SLC7A7 gene. Hum Mutat. 2008;29:14–21.

    PubMed  Article  CAS  Google Scholar 

  21. 21.

    Burroughs L, Woolfrey A, Shimamura A. Shwachman-Diamond syndrome: a review of the clinical presentation, molecular pathogenesis, diagnosis, and treatment. Hematol Oncol Clin North Am. 2009;23:233–48.

    PubMed  Article  Google Scholar 

  22. 22.

    Cutting GR. Modifier genes in Mendelian disorders: the example of cystic fibrosis. Ann N Y Acad Sci. 2010;1214:57–69. doi:10.1111/j.1749-6632.2010.05879.x.

    PubMed  Article  CAS  Google Scholar 

  23. 23.

    Holzinger A, Maier EM, Bück C, et al. Mutations in the proenteropeptidase gene are the molecular cause of congenital enteropeptidase deficiency. Am J Hum Genet. 2002;70:20–5.

    PubMed  Article  CAS  Google Scholar 

  24. 24.

    Zamel R, Khan R, Pollex RL, Hegele RA. Abetalipoproteinemia: two case reports and literature review. Orphanet J Rare Dis. 2008;3:19.

    PubMed  Article  Google Scholar 

  25. 25.

    Marcil V, Peretti N, Delvin E, Levy E. Digestive and absorptive processes of lipids. Gastroenterol Clin Biol. 2004;28:1257–66.

    PubMed  Article  CAS  Google Scholar 

  26. 26.

    Shneider BL. Intestinal bile acid transport: biology, physiology, and pathophysiology. J Pediatr Gastroenterol Nutr. 2001;32:407–17.

    PubMed  Article  CAS  Google Scholar 

  27. 27.

    • Müller T, Hess MW, Schiefermeier N, et al. MYO5B mutations cause microvillus inclusion disease and disrupt epithelial cell polarity. Nat Genet. 2008; 40:1163–5. This well-designed study suggests a defect in MYO5B as a cause of disease.

  28. 28.

    Iancu TC, Mahajnah M, Manov I, Shaoul R. Microvillous inclusion disease: ultrastructural variability. Ultrastruct Pathol. 2007;31:173–88.

    PubMed  Article  Google Scholar 

  29. 29.

    • Sivagnanam M, Mueller JL, Lee H, et al. Identification of EpCAM as the gene for congenital tufting enteropathy. Gastroenterology. 2008;135:429–37. This is the first article describing the gene responsible for the disease.

  30. 30.

    Wang J, Cortina G, Wu SV, et al. Mutant neurogenin-3 in congenital malabsorptive diarrhea. N Engl J Med. 2006;355:270–80.

    PubMed  Article  CAS  Google Scholar 

  31. 31.

    Bjerknes M, Cheng H. Neurogenin 3 and the enteroendocrine cell lineage in the adult mouse small intestinal epithelium. Dev Biol. 2006;300:722–35.

    PubMed  Article  CAS  Google Scholar 

  32. 32.

    Blanco Quirós A, Arranz Sanz E, Bernardo Ordiz D, Garrote Adrados JA. From autoimmune enteropathy to the IPEX (immune dysfunction, polyendocrinopathy, enteropathy, X-linked) syndrome. Allergol Immunopathol. 2009;37:208–15.

  33. 33.

    •• Sharma R, Ju ST. Genetic control of the inflammatory T-cell response in regulatory T-cell deficient scurfy mice. Clin Immunol 2010;136:162–9. The authors provide a well-written review on the role of regulatory T cells.

Download references


Conflicts of interest: R.B. Canani—none; G. Terrin—none.

Author information



Corresponding author

Correspondence to Roberto Berni Canani.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Canani, R.B., Terrin, G. Recent Progress in Congenital Diarrheal Disorders. Curr Gastroenterol Rep 13, 257–264 (2011).

Download citation


  • Congenital chloride-losing diarrhea
  • Congenital sodium diarrhea
  • Microvillous inclusion disease
  • Tufting enteropathy
  • Enteric anendocrinosis
  • Immune dysregulation
  • Polyendocrinopathy
  • Enteropathy
  • X-linked syndrome