New Insights and Perspectives in Congenital Diarrheal Disorders

Abstract

Purpose of Review

We highlight new entities of congenital diarrheal disorders (CDDs) and progresses in understanding of functionally related genes, opening new diagnostic and therapeutic perspectives.

Recent Findings

The more significant advances have been made in field of pathogenesis, encouraging a better understanding not only of these rare diseases but also of more common pathogenetic mechanisms.

Summary

CDDs represent an evolving group of rare chronic enteropathies with a typical onset early in the life. Usually, severe chronic diarrhea is the main clinical manifestation, but in other cases, diarrhea is only a component of a more complex systemic disease. The number of conditions has gradually increased, and many new genes have been indentified and functionally related to CDDs, opening new diagnostic and therapeutic perspectives. Advances in molecular analysis procedures have modified the diagnostic approach in CDDs, leading to a reduction in invasive and expensive procedures.

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References

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

  1. 1.

    •• Berni Canani R, Castaldo G, Bacchetta R, Martín MG, Goulet O. Congenital diarrhoeal disorders: advances in this evolving web of inherited enteropathies. Nat Rev Gastroenterol Hepatol. 2015;12:293–302. doi:10.1038/nrgastro.2015.44. An interesting review based on a new classification of CDDs.

    Article  Google Scholar 

  2. 2.

    •• Posovszky C. Congenital intestinal diarrhoeal diseases: a diagnostic and therapeutic challenge. Best Pract Res Clin Gastroenterol. 2016;30:187–211. doi:10.1016/j.bpg.2016.03.004.30. An interesting review based on main diagnostic and therapeutic challenge for CDDs.

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Janecke AR, Heinz-Erian P, Müller T. Congenital sodium diarrhea: a form of intractable diarrhea, with a link to inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2016;63:170–6. doi:10.1097/MPG.0000000000001139.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    • Fiskerstrand T, Arshad N, Haukanes BI, Tronstad RR, Pham KD, Johansson S, et al. Familial diarrhea syndrome caused by an activating GUCY2C mutation. N Engl J Med. 2012;366:1586–95. doi:10.1056/NEJMoa1110132. The first study that described this new condition.

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    von Volkmann HL, Nylund K, Tronstad RR, Hovdenak N, Hausken T, Fiskerstrand T, et al. An activating gucy2c mutation causes impaired contractility and fluid stagnation in the small bowel. Scand J Gastroenterol. 2016;51:1308–15. doi:10.1080/00365521.2016.1200139.

    Article  Google Scholar 

  6. 6.

    Haas JT, Winter HS, Lim E, Kirby A, Blumenstiel B, DeFelice M, et al. DGAT1 mutation is linked to a congenital diarrheal disorder. J Clin Invest. 2012;122:4680–4. doi:10.1172/JCI64873. 19.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    • Stephen J, Vilboux T, Haberman Y, Pri-Chen H, Pode-Shakked B, Mazaheri S, et al. Congenital protein losing enteropathy: an inborn error of lipid metabolism due to DGAT1 mutations. Eur J Hum Genet. 2016;24:1268–73. doi:10.1038/ejhg.2016.5. An elegant description of disease pathogenesis.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    • Michaux G, Massey-Harroche D, Nicolle O, Rabant M, Brousse N, Goulet O, et al. The localisation of the apical Par/Cdc42 polarity module is specifically affected in microvillus inclusion disease. Biol Cell. 2016;108:19–28. doi:10.1111/boc.201500034. An elegant description of disease pathogenesis

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    •• Overeem AW, Posovszky C, Rings EH, Giepmans BN, van IJzendoorn SC. The role of enterocyte defects in the pathogenesis of congenital diarrheal disorders. Dis Model Mech. 2016;9:1–12. doi:10.1242/dmm.022269. An useful review on a subgroup of CDDs.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Knowles BC, Roland JT, Krishnan M, Tyska MJ, Lapierre LA, Dickman PS, et al. Myosin Vb uncoupling from RAB8A and RAB11A elicits microvillus inclusion disease. J Clin Invest. 2014;124:2947–62. doi:10.1172/JCI71651.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Kravtsov DV, Ahsan MK, Kumari V, van Ijzendoorn SC, Reyes-Mugica M, Kumar A, et al. Identification of intestinal ion transport defects in microvillus inclusion disease. Am J Physiol Gastrointest Liver Physiol. 2016;311:G142–55. doi:10.1152/ajpgi.00041.2016.

    Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Monies DM, Rahbeeni Z, Abouelhoda M, Naim EA, Al-Younes B, Meyer BF, et al. Expanding phenotypic and allelic heterogeneity of tricho-hepato-enteric syndrome. J Pediatr Gastroenterol Nutr. 2015;60:352–6. doi:10.1097/MPG.0000000000000627.

    Article  PubMed  Google Scholar 

  13. 13.

    Lee WS, Teo KM, Ng RT, Chong SY, Kee BP, Chua KH. Novel mutations in SKIV2L and TTC37 genes in Malaysian children with trichohepatoenteric syndrome. Gene. 2016;586:1–6. doi:10.1016/j.gene.2016.03.049.

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Salomon J, Goulet O, Canioni D, Brousse N, Lemale J, Tounian P, et al. Genetic characterization of congenital tufting enteropathy: EpCAM associated phenotype and involvement of SPINT2 in the syndromic form. Hum Genet. 2014;133:299–310. doi:10.1007/s00439-013-1380-6. 20.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    • Kozan PA, McGeough MD, Peña CA, Mueller JL, Barrett KE, Marchelletta RR, et al. Mutation of EpCAM leads to intestinal barrier and ion transport dysfunction. J Mol Med (Berl). 2015;93:535–45. doi:10.1007/s00109-014-1239-x. An elegant paper on disease pathogenesis.

    CAS  Article  Google Scholar 

  16. 16.

    Ünlüsoy Aksu A, Eğritaş Gürkan Ö, Sarı S, Demirtaş Z, Türkyılmaz C, Poyraz A, et al. Mutant neurogenin-3 in a Turkish boy with congenital malabsorptive diarrhea. Pediatr Int. 2016;58:379–82. doi:10.1111/ped.12783.

    Article  PubMed  Google Scholar 

  17. 17.

    Rubio-Cabezas O, Codner E, Flanagan SE, Gómez JL, Ellard S, Hattersley AT. Neurogenin 3 is important but not essential for pancreatic islet development in humans. Diabetologia. 2014;57:2421–4. doi:10.1007/s00125-014-3349-y.

    Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Rubio-Cabezas O, Jensen JN, Hodgson MI, Codner E, Ellard S, Serup P, et al. Permanent neonatal diabetes and enteric anendocrinosis associated with biallelic mutations in NEUROG3. Diabetes. 2011;60:1349–53. doi:10.2337/db10-1008.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Sayar E, Islek A, Yilmaz A, Akcam M, Flanagan SE, Artan R. Extremely rare cause of congenital diarrhea: enteric anendocrinosis. Pediatr Int. 2013;55:661–3. doi:10.1111/ped.12169.

    Article  PubMed  Google Scholar 

  20. 20.

    Scharfmann R, Didiesheim M, Richards P, Chandra V, Oshima M, Albagli O. Mass production of functional human pancreatic β-cells: why and how? Diabetes Obes Metab. 2016;18:128–36. doi:10.1111/dom.12728.

    Article  PubMed  Google Scholar 

  21. 21.

    • Zhu Z, Li QV, Lee K, Rosen BP, González F, Soh CL, et al. Genome editing of lineage determinants in human pluripotent stem cells reveals mechanisms of pancreatic development and diabetes. Cell Stem Cell. 2016;18:755–68. doi:10.1016/j.stem.2016.03.015. An elegant paper on disease mechanisms.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Suzuki K, Harada N, Yamane S, Nakamura Y, Sasaki K, Nasteska D, et al. Transcriptional regulatory factor X6 (Rfx6) increases gastric inhibitory polypeptide (GIP) expression in enteroendocrine K-cells and is involved in GIP hypersecretion in high fat diet-induced obesity. J Biol Chem. 2013;288:1929–38. doi:10.1074/jbc.M112.42313721.

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Sirisena ND, McElreavey K, Bashamboo A, de Silva KS, Jayasekara RW, Dissanayake VH. A child with a novel de novo mutation in the aristaless domain of the aristaless-related homeobox (ARX) gene presenting with ambiguous genitalia and psychomotor delay. Sex Dev. 2014;8:156–9. doi:10.1159/000365458.

    Article  PubMed  Google Scholar 

  24. 24.

    Ishibashi M, Manning E, Shoubridge C, Krecsmarik M, Hawkins TA, Giacomotto J, et al. Copy number variants in patients with intellectual disability affect the regulation of ARX transcription factor gene. Hum Genet. 2015;134:1163–82. doi:10.1007/s00439-015-1594-x.

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Du A, McCracken KW, Walp ER, Terry NA, Klein TJ, Han A, et al. Arx is required for normal enteroendocrine cell development in mice and humans. Dev Biol. 2012;365:175–88. doi:10.1016/j.ydbio.2012.02.024.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Lee K, Mattiske T, Kitamura K, Gecz J, Shoubridge C. Reduced polyalanine-expanded Arx mutant protein in developing mouse subpallium alters Lmo1 transcriptional regulation. Hum Mol Genet. 2014;23:1084–94. doi:10.1093/hmg/ddt503.

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Martín MG, Lindberg I, Solorzano-Vargas RS, Wang J, Avitzur Y, Bandsma R, et al. Congenital proprotein convertase 1/3 deficiency causes malabsorptive diarrhea and other endocrinopathies in a pediatric cohort. Gastroenterology. 2013;145:138–48. doi:10.1053/j.gastro.2013.03.048.

    Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Bandsma RH, Sokollik C, Chami R, Cutz E, Brubaker PL, Hamilton JK, et al. From diarrhea to obesity in prohormone convertase 1/3 deficiency: age-dependent clinical, pathologic, and enteroendocrine characteristics. J Clin Gastroenterol. 2013;47:834–43. doi:10.1097/MCG.0b013e3182a89fc8.

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Yourshaw M, Solorzano-Vargas RS, Pickett LA, Lindberg I, Wang J, Cortina G, et al. Exome sequencing finds a novel PCSK1 mutation in a child with generalized malabsorptive diarrhea and diabetes insipidus. J Pediatr Gastroenterol Nutr. 2013;57:759–67. doi:10.1097/MPG.0b013e3182a8ae6c.

    Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Barzaghi F, Passerini L, Bacchetta R. Immune dysregulation, polyendocrinopathy, enteropathy, x-linked syndrome: a paradigm of immunodeficiency with autoimmunity. Front Immunol. 2012;3:211. doi:10.3389/fimmu.2012.00211.

    Article  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Colobran R, Álvarez de la Campa E, Soler-Palacín P, Martín-Nalda A, Pujol-Borrell R, de la Cruz X, et al. Clinical and structural impact of mutations affecting the residue Phe367 of 22 FOXP3 in patients with IPEX syndrome. Clin Immunol. 2016;163:60–5. doi:10.1016/j.clim.2015.12.014.

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Reichert SL, McKay EM, Moldenhauer JS. Identification of a novel nonsense mutation in the FOXP3 gene in a fetus with hydrops—expanding the phenotype of IPEX syndrome. Am J med Genet a. 2016;170A:226–32. doi:10.1002/ajmg.a.37401.

    Article  PubMed  Google Scholar 

  33. 33.

    Lampasona V, Passerini L, Barzaghi F, Lombardoni C, Bazzigaluppi E, Brigatti C, et al. Autoantibodies to harmonin and villin are diagnostic markers in children with IPEX syndrome. PLoS One. 2013;8:e78664. doi:10.1371/journal.pone.0078664.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Chida N, Kobayashi I, Takezaki S, Ueki M, Yamazaki Y, Garelli S, et al. Disease specificity of anti-tryptophan hydroxylase-1 and anti-AIE-75 autoantibodies in APECED and IPEX syndrome. Clin Immunol. 2015;156:36–42. doi:10.1016/j.clim.2014.10.010.

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    •• Bacchetta R, Barzaghi F, Roncarolo MG. From IPEX syndrome to FOXP3 mutation: a lesson on immune dysregulation. N Y Acad Sci. 2016; doi:10.1111/nyas.13011. Useful review on this subgroup of CDDs.

  36. 36.

    Passerini L, Santoni de Sio FR, Porteus MH, Bacchetta R. Gene/cell therapy approaches for immune dysregulation polyendocrinopathy enteropathy X-linked syndrome. Curr Gene Ther. 2014;14:422–8.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Kinnunen T, Chamberlain N, Morbach H, Choi J, Kim S, Craft J, et al. Accumulation of peripheral autoreactive B cells in the absence of functional human regulatory T cells. Blood. 2013;121:1595–603. doi:10.1182/blood-2012-09-457465.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Goudy K, Aydin D, Barzaghi F, Gambineri E, Vignoli M, Ciullini Mannurita S, et al. Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity. Clin Immunol. 2013;146:248–61. doi:10.1016/j.clim.2013.01.004.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Charbonnier LM, Janssen E, Chou J, Ohsumi TK, Keles S, Hsu JT, et al. Regulatory T-cell deficiency and immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like disorder caused by loss-of-function mutations in LRBA. J Allergy Clin Immunol. 2015;135:217–27. doi:10.1016/j.jaci.2014.10.01923.

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Alkhairy OK, Abolhassani H, Rezaei N, Fang M, Andersen KK, Chavoshzadeh Z, et al. Spectrum of phenotypes associated with mutations in LRBA. J Clin Immunol. 2016;36:33–45. doi:10.1007/s10875-015-0224-7.

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Shah N, Kammermeier J, Elawad M, Glocker EO. Interleukin-10 and interleukin-10-receptor defects in inflammatory bowel disease. Curr Allergy Asthma rep. 2012;12:373–9. doi:10.1007/s11882-012-0286-z.

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    Charbit-Henrion F, Jeverica AK, Bègue B, Markelj G, Parlato M, Avčin SL, et al. Deficiency in mucosa associated lymphoid tissue lymphoma translocation 1 (MALT1): a novel cause of IPEX-like syndrome. J Pediatr Gastroenterol Nutr. 2016; doi:10.1097/MPG.0000000000001262.

  43. 43.

    Horino S, Sasahara Y, Sato M, Niizuma H, Kumaki S, Abukawa D, et al. Selective expansion of donor-derived regulatory T cells after allogeneic bone marrow transplantation in a patient with IPEX syndrome. Pediatr Transplant. 2014;18:E25–30. doi:10.1111/petr.12184.

    CAS  Article  PubMed  Google Scholar 

  44. 44.

    Agne M, Blank I, Emhardt AJ, Gäbelein CG, Gawlas F, Gillich N, et al. Modularized CRISPR/dCas9 effector toolkit for target-specific gene regulation. ACS Synth Biol. 2014;3:986–9. doi:10.1021/sb500035y.

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Duclaux-Loras R, Collardeau-Frachon S, Nancey S, Fabien N, Kaiserlian D, Lachaux A. Long-term disease course in a patient with severe neonatal IPEX syndrome. Clin Res Hepatol Gastroenterol. 2015;39:e43–7. doi:10.1016/j.clinre.2015.03.006.

    Article  PubMed  Google Scholar 

  46. 46.

    Kucuk ZY, Bleesing JJ, Marsh R, Zhang K, Davies S, Filipovich AH. A challenging undertaking: stem cell transplantation for immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. J Allergy Clin Immunol. 2016;137:953–5.e4. doi:10.1016/j.jaci.2015.09.030.

    Article  PubMed  Google Scholar 

  47. 47.

    Sheikine Y, Woda CB, Lee PY, Chatila TA, Keles S, Charbonnier LM, et al. Renal involvement in the immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) disorder. Pediatr Nephrol. 2015;30:1197–202. doi:10.1007/s00467-015-3102-x.

    Article  PubMed  Google Scholar 

  48. 48.

    Passariello A, Terrin G, Baldassarre ME, De Curtis M, Paludetto R, Berni Canani R. Diarrhea in neonatal intensive care unit. World J Gastroenterol. 2010;16:2664–2668.24.

    Article  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Maruotti GM, Frisso G, Calcagno G, Fortunato G, Castaldo G, Martinelli P, et al. Prenatal diagnosis of inherited diseases: 20 years’ experience of an Italian Regional Reference Centre. Clin Chem Lab Med. 2013;51:2211–7. doi:10.1515/cclm-2013-0194.

    CAS  Article  PubMed  Google Scholar 

  50. 50.

    Berni Canani R, Terrin G, Elce A, Pezzella V, Heinz-Erian P, Pedrolli A, et al. Genotype-dependency of butyrate efficacy in children with congenital chloride diarrhea. Orphanet J Rare Dis. 2013;8:194. doi:10.1186/1750-1172-8-194.

    Article  Google Scholar 

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Correspondence to Roberto Berni Canani.

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Conflict of Interest

Vincenza Pezzella, Giusi Grimaldi, Mariateresa Russo, Serena Mazza, Domenica Francesca Mariniello, Lorella Paparo, Ausilia Elce, Giuseppe Castaldo, and Roberto Berni Canani each declare no potential conflicts of interest.

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Pezzella, V., Grimaldi, G., Russo, M. et al. New Insights and Perspectives in Congenital Diarrheal Disorders. Curr Pediatr Rep 5, 156–166 (2017). https://doi.org/10.1007/s40124-017-0136-5

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Keywords

  • Chronic diarrhea
  • Genes
  • Molecular analysis
  • Mutations
  • Children