Congenital diarrheal disorders (CDDs) are a group of inherited enteropathies with a typical onset early in the life. Infants with these disorders have frequently chronic diarrhea of sufficient severity to require parenteral nutrition. For most CDDs the disease-gene is known and molecular analysis may contribute to an unequivocal diagnosis. We review CDDs on the basis of the genetic defect, focusing on the significant contribution of molecular analysis in the complex, multistep diagnostic work-up.
References
[1]
Guarino, A.; Spagnuolo, M.I.; Russo, S.; Albano, F.; Guandalini, S.; Capano, G.; Cucchiara, S.; Vairano, P.; Liguori, R.; Casola, A.; et al. Etiology and risk factors of severe and protracted diarrhea. J. Pediatr. Gastroenterol. Nutr 1995, 20, 173–178.
[2]
Berni Canani, R.; Cirillo, P.; Terrin, G. Chronic and Intractabile Diarrhea. In Essential Pediatric Gastroenterology Hepatology and Nutrition; Guandalini, S., Ed.; McGraw-Hill: Chicago, IL, USA, 2005; pp. 25–47.
[3]
Berni Canani, R.; Terrin, G.; Cardillo, G.; Tomaiuolo, R.; Castaldo, G. Congenital diarrheal disorders: Improved understanding of gene defects is leading to advances in intestinal physiology and clinical management. J. Pediatr. Gastroenterol. Nutr 2010, 50, 360–366.
Tomaiuolo, R.; Spina, M.; Castaldo, G. Molecular diagnosis of Cystic Fibrosis: Comparison of four analytical procedures. Clin. Chem. Lab. Med 2003, 41, 26–32.
[6]
Passariello, A.; Terrin, G.; Baldassarre, M.E.; de Curtis, M.; Paludetto, R.; Berni Canani, R. Diarrhea in neonatal intensive care unit. World J. Gastroenterol 2010, 16, 2664–2668.
[7]
Sebastio, G.; Sperandeo, M.P.; Andria, G. Lysinuric protein intolerance: Reviewing concepts on a multisystem disease. Am. J. Med. Genet. C 2011, 157, 54–62.
[8]
Swallow, D.M.; Poulter, M.; Hollox, E.J. Intolerance to lactose and other dietary sugars. Drug Metab. Dispos 2001, 29, 513–516.
[9]
Wedenoja, S.; Pekansaari, E.; H？glund, P.; M？kel？, S.; Holmberg, C.; Kere, J. Update on SLC26A3 mutations in congenital chloride diarrhea. Hum. Mutat 2011, 32, 715–722.
[10]
Berni Canani, R.; Terrin, G.; Cirillo, P.; Castaldo, G.; Salvatore, F.; Cardillo, G.; Coruzzo, A.; Troncone, R. Butyrate as an effective treatment of congenital chloride diarrhea. Gastroenterology 2004, 127, 630–634.
[11]
Berni Canani, R.; Terrin, G. Recent progress in congenital diarrheal disorders. Curr. Gastroenterol. Rep 2011, 13, 257–264.
Holzinger, A.; Maier, E.M.; Buck, C.; Mayerhofer, P.U.; Kappler, M.; Haworth, J.C.; Moroz, S.P.; Hadorn, H.B.; Sadler, J.E.; Roscher, A.A. Mutations in the proenteropeptidase gene are the molecular cause of congenital enteropeptidase deficiency. Am. J. Hum. Genet 2002, 70, 20–25.
[19]
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–E992.
[20]
Schmitt, S.; Kury, S.; Giraud, M.; Dréno, B.; Kharfi, M.; Bézieau, S. An update on mutations of the SLC39A4 gene in acrodermatitis enteropathica. Hum. Mutat 2009, 30, 926–933.
[21]
Wang, J.; Cortina, G.; Wu, S.V.; Tran, R.; Cho, J.H.; Tsai, M.J.; Bailey, T.J.; Jamrich, M.; Ament, M.E.; Treem, W.R.; et al. Mutant neurogenin-3 in congenital malabsorptive diarrhea. N. Engl. J. Med 2006, 355, 270–280.
[22]
Ruemmele, F.M.; Müller, T.; Schiefermeier, N.; Ebner, H.L.; Lechner, S.; Pfaller, K.; Th？ni, C.E.; Goulet, O.; Lacaille, F.; Schmitz, J.; et al. Loss-of-function of MYO5B is the main cause of microvillus inclusion disease: 15 novel mutations and a CaCo-2 RNAi cell model. Hum. Mutat 2010, 31, 544–551.
[23]
Bennett, C.L.; Christie, J.; Ramsdell, F.; Brunkow, M.E.; Ferguson, P.J.; Whitesell, L.; Kelly, T.E.; Saulsbury, F.T.; Chance, P.F.; Ochs, H.D. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat. Genet 2001, 27, 20–21.
[24]
Sharma, R.; Ju, S.T. Genetic control of the inflammatory T-cell response in regulatory T-cell deficient scurfy mice. Clin. Immunol 2010, 136, 162–169.
[25]
Montalto, M.; D’Onofrio, F.; Santoro, L.; Gallo, A.; Gasbarrini, A.; Gasbarrini, G. Autoimmune enteropathy in children and adults. Scand. J. Gastroenterol 2009, 44, 1029–1036.
[26]
Kuokkanen, M.; Kokkonen, J.; Enattah, N.S.; Ylisaukko-Oja, T.; Komu, H.; Varilo, T.; Peltonen, L.; Savilahti, E.; Jarvela, I. Mutations in the translated region of the lactase gene (LCT) underlie congenital lactase deficiency. Am. J. Hum. Genet 2006, 78, 339–344.
[27]
Nichols, B.L.; Avery, S.E.; Karnsakul, W.; Jahoor, F.; Sen, P.; Swallow, D.M.; Luginbuehl, U.; Hahn, D.; Sterchi, E.E. Congenital maltase-glucoamylase deficiency associated with lactase and sucrase deficiencies. J. Pediatr. Gastroenterol. Nutr 2002, 35, 573–579.
[28]
Jones, H.F.; Butler, R.N.; Brooks, D.A. Intestinal fructose transport and malabsorption in humans. Am. J. Physiol. Gastrointest. Liver Physiol 2011, 300, G202–G206.
[29]
Heinz-Erian, P.; Muller, T.; Krabichler, B.; Schranz, M.; Becker, C.; Rüschendorf, F.; Nürnberg, P.; Rossier, B.; Vujic, M.; Booth, I.W.; et al. Mutations in SPINT2 cause a syndromic form of congenital sodium diarrhea. Am. J. Hum. Genet 2009, 84, 188–196.
[30]
Muller, T.; Wijmenga, C.; Phillips, A.D.; Janecke, A.; Houwen, R.H.; Fischer, H.; Ellemunter, H.; Frühwirth, M.; Offner, F.; Hofer, S.; et al. Congenital sodium diarrhea is an autosomal recessive disorder of sodium/proton exchange but unrelated to known candidate genes. Gastroenterology 2000, 119, 1506–1513.
[31]
Figarella, C.; de Caro, A.; Leupold, D.; Poley, J.R. Congenital pancreatic lipase deficiency. J. Pediatr 1980, 96, 412–416.
[32]
Rebours, V.; Levy, P.; Ruszniewski, P. An overview of hereditary pancreatitis. Dig. Liver Dis 2011, 44, 8–15.
[33]
Amato, F.; Bellia, C.; Cardillo, G.; Castaldo, G.; Ciaccio, M.; Elce, A.; Lembo, F.; Tomaiuolo, R. Extensive molecular analysis of patients bearing CFTR-related disorders. J. Mol. Diagn 2012, 14, 81–89.
[34]
Narcisi, T.M.; Shoulders, C.C.; Chester, S.A.; Read, J.; Brett, D.J.; Harrison, G.B.; Grantham, T.T.; Fox, M.F.; Povey, S.; de Bruin, T.W.; et al. Mutations of the microsomal triglyceride-transfer-protein gene in abetalipoproteinemia. Am. J. Hum. Genet 1995, 57, 1293–1310.
[35]
Benayoun, L.; Granot, E.; Rizel, L.; Allon-Shalev, S.; Behar, D.M.; Ben-Yosef, T. Abetalipoproteinemia in Israel: Evidence for a founder mutation in the Ashkenazi Jewish population and a contiguous gene deletion in an Arab patient. Mol. Genet. Metab 2007, 90, 453–457.
[36]
Schonfeld, G. Familial hypobetalipoproteinemia: A review. J. Lipid Res 2003, 44, 878–883.
[37]
Zhong, S.; Magnolo, A.L.; Sundaram, M.; Zhou, H.; Yao, E.F.; di Leo, E.; Loria, P.; Wang, S.; Bamji-Mirza, M.; Wang, L.; et al. Nonsynonymous mutations within APOB in human familial hypobetalipoproteinemia: Evidence for feedback inhibition of lipogenesis and postendoplasmic reticulum degradation of apolipoprotein B. J. Biol. Chem 2010, 285, 6453–6464.
[38]
Boocock, G.R.; Morrison, J.A.; Popovic, M.; Richards, N.; Ellis, L.; Durie, P.R.; Rommens, J.M. Mutations in SBDS are associated with Shwachman-Diamond syndrome. Nat. Genet 2003, 33, 97–101.
[39]
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, 233–248.
Ko, J.S.; Seo, J.K.; Shim, J.O.; Hwang, S.H.; Park, H.S.; Kang, G.H. Tufting enteropathy with EpCAM mutations in two siblings. Gut Liver 2010, 4, 407–410.
[42]
Fabre, A.; Martinez-Vinson, C.; Roquelaure, B.; Missirian, C.; André, N.; Breton, A.; Lachaux, A.; Odul, E.; Colomb, V.; Lemale, J.; et al. Novel mutations in TTC37 associated with Tricho-Hepato-Enteric syndrome. Hum. Mutat 2011, 32, 277–281.
[43]
Goulet, O.; Vinson, C.; Roquelaure, B.; Brousse, N.; Bodemer, C.; Cézard, J.P. Syndromic (phenotypic) diarrhea in early infancy. Orphanet. J. Rare. Dis 2008, 28, 3–6.
[44]
Rubio-Cabezas, O.; Jensen, J.N.; Hodgson, M.I.; Codner, E.; Ellard, S.; Serup, P.; Hattersley, A.T. Permanent neonatal diabetes and enteric anendocrinosis associated with biallelic mutations in NEUROG3. Diabetes 2011, 60, 1349–1353.
[45]
Pinney, S.E.; Oliver-Krasinski, J.; Ernst, L.; Hughes, N.; Patel, P.; Stoffers, D.A.; Russo, P.; de León, D.D. Neonatal diabetes and congenital malabsorptive diarrhea attributable to a novel mutation in the human neurogenin-3 gene coding sequence. J. Clin. Endocrinol. Metab 2011, 96, 1960–1965.
[46]
Jackson, R.S.; Creemers, J.W.; Farooqi, I.S.; Raffin-Sanson, M.L.; Varro, A.; Dockray, G.J.; Holst, J.J.; Brubaker, P.L.; Corvol, P.; Polonsky, K.S.; et al. Small-intestinal dysfunction accompanies the complex endocrinopathy of human proprotein convertase 1 deficiency. J. Clin. Invest 2003, 112, 1550–1560.
Blanco Quirós, A.; Arranz Sanz, E.; Bernardo Ordiz, D.; Garrote Adrados, J.A. From autoimmune enteropathy to the IPEX (immune dysfunction, polyendocrinopathy, enteropathy, X-linked) syndrome. Allergol. Immunopathol 2009, 37, 208–215.
[49]
Harbuz, R.; Lespinasse, J.; Boulet, S.; Francannet, C.; Creveaux, I.; Benkhelifa, M.; Jouk, P.S.; Lunardi, J.; Ray, P.F. Identification of new FOXP3 mutations and prenatal diagnosis of IPEX syndrome. Prenat. Diagn 2010, 30, 1072–1078.
[50]
Heino, M.; Peterson, P.; Kudoh, J.; Shimizu, N.; Antonarakis, S.E.; Scott, H.S.; Krohn, K. APECED mutations in the autoimmune regulator (AIRE) gene. Hum. Mutat 2001, 18, 205–211.
[51]
Faiyaz-Ul-Haque, M.; Bin-Abbas, B.; Al-Abdullatif, A.; Abdullah Abalkhail, H.; Toulimat, M.; Al-Gazlan, S.; Almutawa, A.M.; Al-Sagheir, A.; Peltekova, I.; Al-Dayel, F.; et al. Novel and recurrent mutations in the AIRE gene of autoimmune polyendocrinopathy syndrome type 1 (APS1) patients. Clin. Genet 2009, 76, 431–440.
[52]
Caudy, A.A.; Reddy, S.T.; Chatila, T.; Atkinson, J.P.; Verbsky, J.W. CD25 deficiency causes an immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome, and defective IL-10 expression from CD4 lymphocytes. J. Allergy Clin. Immunol 2007, 119, 482–487.
[53]
Castaldo, G.; Martinelli, P.; Massa, C.; Fuccio, A.; Grosso, M.; Rippa, E.; Paladini, D.; Salvatore, F. Prenatal diagnosis of cystic fibrosis: A case of twin pregnancy diagnosis and a review of 5 years’ experience. Clin. Chim. Acta 2000, 298, 121–133.
[54]
Rantanen, E.; Hietala, M.; Kristoffersson, U.; Nippert, I.; Schmidtke, J.; Sequeiros, J.; Kaariainen, H. Regulations and practices of genetic counselling in 38 European countries: The perspective of national representatives. Eur. J. Hum. Genet 2008, 16, 1208–1216.
[55]
Castaldo, G.; Lembo, F.; Tomaiuolo, R. Review: Molecular diagnostics: Between chips and customized medicine. Clin. Chem. Lab. Med 2010, 48, 973–982.
[56]
Tomaiuolo, R.; Sangiuolo, F.; Bombieri, C.; Bonizzato, A.; Cardillo, G.; Raia, V.; D’Apice, M.R.; Bettin, M.D.; Pignatti, P.F.; Castaldo, G.; et al. Epidemiology and a novel procedure for large scale analysis of CFTR rearrangements in classic and atypical CF patients: A multicentric Italian study. J. Cyst. Fibros 2008, 7, 347–351.
[57]
Taruscio, D.; Falbo, V.; Floridia, G.; Salvatore, M.; Pescucci, C.; Cantafora, A.; Marongiu, C.; Baroncini, A.; Calzolari, E.; Cao, A.; et al. Quality assessment in cytogenetic and molecular genetic testing: The experience of the Italian project on standardization and quality assurance. Clin. Chem. Lab. Med 2004, 42, 915–922.
[58]
Elce, A.; Boccia, A.; Cardillo, G.; Giordano, S.; Tomaiuolo, R.; Paolella, G.; Castaldo, G. Three novel CFTR polymorphic repeats improve segregation analysis for cystic fibrosis. Clin. Chem 2009, 55, 1372–1379.
