Nonclassic Inflammatory Bowel Disease in Young Infants: Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked Syndrome, and Other Disorders

Pediatric Clinics of North America

Volumn 64, Issue 1, 2017, Pages 139-160

  Chandrakasan, Shanmuganathan ^a   Venkateswaran, Suresh ^a   Kugathasan, Subra ^a  

^a EMORY UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Epithelial barrier defects; IL 10 defects; Inflammasome; IPEX; Neutrophil defects; T cell or B cell defects; Very early onset IBD (VEO IBD)

Indexed keywords

IMMUNOSUPPRESSIVE AGENT; INTERLEUKIN 10;

B LYMPHOCYTE; CHILD; CLINICAL FEATURE; CROHN DISEASE; CYTOTOXIC T LYMPHOCYTE; DIAGNOSTIC TEST; EPITHELIUM; GENETIC DISORDER; GENETIC SCREENING; HEMATOPOIETIC STEM CELL TRANSPLANTATION; HUMAN; IMMUNOLOGICAL TOLERANCE; IMMUNOPATHOLOGY; INCIDENCE; INFANT; INFLAMMATORY BOWEL DISEASE; IPEX SYNDROME; NEUTROPHIL; ONSET AGE; PATHOPHYSIOLOGY; RARE DISEASE; REVIEW; T LYMPHOCYTE; ULCERATIVE COLITIS; DIABETES MELLITUS, TYPE 1; DIARRHEA; DIFFERENTIAL DIAGNOSIS; EARLY DIAGNOSIS; GENETIC DISEASES, X-LINKED; GENETICS; IMMUNE SYSTEM DISEASES; IMMUNOLOGY; INFLAMMATORY BOWEL DISEASES; PRESCHOOL CHILD; RARE DISEASES;

CHILD; CHILD, PRESCHOOL; DIABETES MELLITUS, TYPE 1; DIAGNOSIS, DIFFERENTIAL; DIARRHEA; EARLY DIAGNOSIS; GENETIC DISEASES, X-LINKED; HUMANS; IMMUNE SYSTEM DISEASES; INFANT; INFLAMMATORY BOWEL DISEASES; RARE DISEASES;

EID: 84998636487     PISSN: 00313955     EISSN: 15578240     Source Type: Journal    
DOI: 10.1016/j.pcl.2016.08.010     Document Type: Review

References (95)

1. 1 Strober, W., The multifaceted influence of the mucosal microflora on mucosal dendritic cell responses. Immunity 31:3 (2009), 377–388.
2. 2 Chu, H., Mazmanian, S.K., Innate immune recognition of the microbiota promotes host-microbial symbiosis. Nat Immunol 14:7 (2013), 668–675.
3. 3 Chistiakov, D.A., Bobryshev, Y.V., Kozarov, E., et al. Intestinal mucosal tolerance and impact of gut microbiota to mucosal tolerance. Front Microbiol, 5, 2014, 781.
4. 4 Tourneur, E., Chassin, C., Neonatal immune adaptation of the gut and its role during infections. Clin Dev Immunol, 2013, 2013, 270301.
5. Kamada, N., Seo, S.U., Chen, G.Y., et al. Role of the gut microbiota in immunity and inflammatory disease. Nat Rev Immunol 13:5 (2013), 321–335.
6. 6 de Souza, H.S., Fiocchi, C., Immunopathogenesis of IBD: current state of the art. Nat Rev Gastroenterol Hepatol 13:1 (2016), 13–27.
7. 7 Uhlig, H.H., Schwerd, T., Koletzko, S., et al. The diagnostic approach to monogenic very early onset inflammatory bowel disease. Gastroenterology 147:5 (2014), 990–1007.e3.
8. 8 Moran, C.J., Klein, C., Muise, A.M., et al. Very early-onset inflammatory bowel disease: gaining insight through focused discovery. Inflamm Bowel Dis 21:5 (2015), 1166–1175.
9. 9 Malmborg, P., Hildebrand, H., The emerging global epidemic of paediatric inflammatory bowel disease - causes and consequences. J Intern Med 279:3 (2016), 241–258.
10. 10 Bendas, A., Rothe, U., Kiess, W., et al. Trends in incidence rates during 1999-2008 and prevalence in 2008 of childhood type 1 diabetes mellitus in Germany–model-based national estimates. PLoS One, 10(7), 2015, e0132716.
11. 11 Benchimol, E.I., Guttmann, A., Griffiths, A.M., et al. Increasing incidence of paediatric inflammatory bowel disease in Ontario, Canada: evidence from health administrative data. Gut 58:11 (2009), 1490–1497.
12. 12 Benchimol, E.I., Mack, D.R., Nguyen, G.C., et al. Incidence, outcomes, and health services burden of very early onset inflammatory bowel disease. Gastroenterology 147:4 (2014), 803–813.e7 [quiz: e814–5].
13. 13 Oliva-Hemker, M., Hutfless, S., Al Kazzi, E.S., et al. Clinical presentation and five-year therapeutic management of very early-onset inflammatory bowel disease in a large North American Cohort. J Pediatr 167:3 (2015), 527–532.e1–3.
14. 14 Kelsen, J.R., Baldassano, R.N., Artis, D., et al. Maintaining intestinal health: the genetics and immunology of very early onset inflammatory bowel disease. Cell Mol Gastroenterol Hepatol 1:5 (2015), 462–476.
15. 15 Kelsen, J.R., Dawany, N., Moran, C.J., et al. Exome sequencing analysis reveals variants in primary immunodeficiency genes in patients with very early onset inflammatory bowel disease. Gastroenterology 149:6 (2015), 1415–1424.
16. 16 Al-Hussaini, A., El Mouzan, M., Hasosah, M., et al. Clinical pattern of early-onset inflammatory bowel disease in Saudi Arabia: a multicenter national study. Inflamm Bowel Dis 22:8 (2016), 1961–1970.
17. 17 Bennett, C.L., Yoshioka, R., Kiyosawa, H., et al. X-Linked syndrome of polyendocrinopathy, immune dysfunction, and diarrhea maps to Xp11.23-Xq13.3. Am J Hum Genet 66:2 (2000), 461–468.
18. 18 Barzaghi, F., Passerini, L., Bacchetta, R., Immune dysregulation, polyendocrinopathy, enteropathy, x-linked syndrome: a paradigm of immunodeficiency with autoimmunity. Front Immunol, 3, 2012, 211.
19. 19 Glocker, E.O., Kotlarz, D., Boztug, K., et al. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N Engl J Med 361:21 (2009), 2033–2045.
20. 20 Kotlarz, D., Beier, R., Murugan, D., et al. Loss of interleukin-10 signaling and infantile inflammatory bowel disease: implications for diagnosis and therapy. Gastroenterology 143:2 (2012), 347–355.
21. 21 Moran, C.J., Walters, T.D., Guo, C.H., et al. IL-10R polymorphisms are associated with very-early-onset ulcerative colitis. Inflamm Bowel Dis 19:1 (2013), 115–123.
22. 22 Chen, R., Giliani, S., Lanzi, G., et al. Whole-exome sequencing identifies tetratricopeptide repeat domain 7A (TTC7A) mutations for combined immunodeficiency with intestinal atresias. J Allergy Clin Immunol 132:3 (2013), 656–664.e17.
23. 23 Lemoine, R., Pachlopnik-Schmid, J., Farin, H.F., et al. Immune deficiency-related enteropathy-lymphocytopenia-alopecia syndrome results from tetratricopeptide repeat domain 7A deficiency. J Allergy Clin Immunol 134:6 (2014), 1354–1364.e6.
24. Burroughs, L.M., Torgerson, T.R., Storb, R., et al. Stable hematopoietic cell engraftment after low-intensity nonmyeloablative conditioning in patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. J Allergy Clin Immunol 126:5 (2010), 1000–1005.
25. 25 Rao, A., Kamani, N., Filipovich, A., et al. Successful bone marrow transplantation for IPEX syndrome after reduced-intensity conditioning. Blood 109:1 (2007), 383–385.
26. 26 Engelhardt, K.R., Shah, N., Faizura-Yeop, I., et al. Clinical outcome in IL-10- and IL-10 receptor-deficient patients with or without hematopoietic stem cell transplantation. J Allergy Clin Immunol 131:3 (2013), 825–830.
27. 27 Patey-Mariaud de Serre, N., Canioni, D., Ganousse, S., et al. Digestive histopathological presentation of IPEX syndrome. Mod Pathol 22:1 (2009), 95–102.
28. 28 Worthey, E.A., Mayer, A.N., Syverson, G.D., et al. Making a definitive diagnosis: successful clinical application of whole exome sequencing in a child with intractable inflammatory bowel disease. Genet Med 13:3 (2011), 255–262.
29. 29 Cannioto, Z., Berti, I., Martelossi, S., et al. IBD and IBD mimicking enterocolitis in children younger than 2 years of age. Eur J Pediatr 168:2 (2009), 149–155.
30. 30 Hanson, E.P., Monaco-Shawver, L., Solt, L.A., et al. Hypomorphic nuclear factor-kappaB essential modulator mutation database and reconstitution system identifies phenotypic and immunologic diversity. J Allergy Clin Immunol 122:6 (2008), 1169–1177.e16.
31. 31 Le Bras, S., Geha, R.S., IPEX and the role of Foxp3 in the development and function of human Tregs. J Clin Invest 116:6 (2006), 1473–1475.
32. 32 Bacchetta, R., Barzaghi, F., Roncarolo, M.G., From IPEX syndrome to FOXP3 mutation: a lesson on immune dysregulation. Ann N Y Acad Sci, 2016 [Epub ahead of print].
33. 33 Zama, D., Cocchi, I., Masetti, R., et al. Late-onset of immunodysregulation, polyendocrinopathy, enteropathy, x-linked syndrome (IPEX) with intractable diarrhea. Ital J Pediatr, 40, 2014, 68.
34. 34 Okou, D.T., Mondal, K., Faubion, W.A., et al. Exome sequencing identifies a novel FOXP3 mutation in a 2-generation family with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 58:5 (2014), 561–568.
35. 35 Sharfe, N., Dadi, H.K., Shahar, M., et al. Human immune disorder arising from mutation of the alpha chain of the interleukin-2 receptor. Proc Natl Acad Sci U S A 94:7 (1997), 3168–3171.
36. 36 Bernasconi, A., Marino, R., Ribas, A., et al. Characterization of immunodeficiency in a patient with growth hormone insensitivity secondary to a novel STAT5b gene mutation. Pediatrics 118:5 (2006), e1584–e1592.
37. 37 Uzel, G., Sampaio, E.P., Lawrence, M.G., et al. Dominant gain-of-function STAT1 mutations in FOXP3 wild-type immune dysregulation-polyendocrinopathy-enteropathy-X-linked-like syndrome. J Allergy Clin Immunol 131:6 (2013), 1611–1623.
38. 38 Flanagan, S.E., Haapaniemi, E., Russell, M.A., et al. Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease. Nat Genet 46:8 (2014), 812–814.
39. 39 Milner, J.D., Vogel, T.P., Forbes, L., et al. Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations. Blood 125:4 (2015), 591–599.
40. 40 Lopez-Herrera, G., Tampella, G., Pan-Hammarstrom, Q., et al. Deleterious mutations in LRBA are associated with a syndrome of immune deficiency and autoimmunity. Am J Hum Genet 90:6 (2012), 986–1001.
41. 41 Charbonnier, L.M., Janssen, E., Chou, J., 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 135:1 (2015), 217–227.
42. 42 Kuehn, H.S., Ouyang, W., Lo, B., et al. Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science 345:6204 (2014), 1623–1627.
43. 43 Schubert, D., Bode, C., Kenefeck, R., et al. Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nat Med 20:12 (2014), 1410–1416.
44. 44 Beser, O.F., Conde, C.D., Serwas, N.K., et al. Clinical features of interleukin 10 receptor gene mutations in children with very early-onset inflammatory bowel disease. J Pediatr Gastroenterol Nutr 60:3 (2015), 332–338.
45. 45 Couper, K.N., Blount, D.G., Riley, E.M., IL-10: the master regulator of immunity to infection. J Immunol 180:9 (2008), 5771–5777.
46. 46 Shouval, D.S., Ebens, C.L., Murchie, R., et al. Large B-cell lymphoma in an adolescent patient with interleukin-10 receptor deficiency and history of infantile inflammatory bowel disease. J Pediatr Gastroenterol Nutr 63:1 (2016), e15–e17.
47. 47 Neven, B., Mamessier, E., Bruneau, J., et al. A Mendelian predisposition to B-cell lymphoma caused by IL-10R deficiency. Blood 122:23 (2013), 3713–3722.
48. 48 Yabal, M., Muller, N., Adler, H., et al. XIAP restricts TNF- and RIP3-dependent cell death and inflammasome activation. Cell Rep 7:6 (2014), 1796–1808.
49. 49 Romberg, N., Al Moussawi, K., Nelson-Williams, C., et al. Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation. Nat Genet 46:10 (2014), 1135–1139.
50. 50 Canna, S.W., de Jesus, A.A., Gouni, S., et al. An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome. Nat Genet 46:10 (2014), 1140–1146.
51. 51 Bader-Meunier, B., Florkin, B., Sibilia, J., et al. Mevalonate kinase deficiency: a survey of 50 patients. Pediatrics 128:1 (2011), e152–e159.
52. 52 Pagel, J., Beutel, K., Lehmberg, K., et al. Distinct mutations in STXBP2 are associated with variable clinical presentations in patients with familial hemophagocytic lymphohistiocytosis type 5 (FHL5). Blood 119:25 (2012), 6016–6024.
53. 53 Hazzan, D., Seward, S., Stock, H., et al. Crohn's-like colitis, enterocolitis and perianal disease in Hermansky-Pudlak syndrome. Colorectal Dis 8:7 (2006), 539–543.
54. 54 Yoshiyama, S., Miki, C., Araki, T., et al. Complicated granulomatous colitis in a Japanese patient with Hermansky-Pudlak syndrome, successfully treated with infliximab. Clin J Gastroenterol 2:1 (2009), 51–54.
55. 55 Schappi, M.G., Smith, V.V., Goldblatt, D., et al. Colitis in chronic granulomatous disease. Arch Dis Child 84:2 (2001), 147–151.
56. 56 Kawai, T., Arai, K., Harayama, S., et al. Severe and rapid progression in very early-onset chronic granulomatous disease-associated colitis. J Clin Immunol 35:6 (2015), 583–588.
57. 57 Muise, A.M., Xu, W., Guo, C.H., et al. NADPH oxidase complex and IBD candidate gene studies: identification of a rare variant in NCF2 that results in reduced binding to RAC2. Gut 61:7 (2012), 1028–1035.
58. 58 Dhillon, S.S., Fattouh, R., Elkadri, A., et al. Variants in nicotinamide adenine dinucleotide phosphate oxidase complex components determine susceptibility to very early onset inflammatory bowel disease. Gastroenterology 147:3 (2014), 680–689.e2.
59. 59 Hayes, P., Dhillon, S., O'Neill, K., et al. Defects in NADPH oxidase genes and in very early onset inflammatory bowel disease. Cell Mol Gastroenterol Hepatol 1:5 (2015), 489–502.
60. 60 Yamaguchi, T., Ihara, K., Matsumoto, T., et al. Inflammatory bowel disease-like colitis in glycogen storage disease type 1b. Inflamm Bowel Dis 7:2 (2001), 128–132.
61. Visser, G., Rake, J.P., Fernandes, J., et al. Neutropenia, neutrophil dysfunction, and inflammatory bowel disease in glycogen storage disease type Ib: results of the European Study on glycogen storage disease type I. J Pediatr 137:2 (2000), 187–191.
62. 62 D'Agata, I.D., Paradis, K., Chad, Z., et al. Leucocyte adhesion deficiency presenting as a chronic ileocolitis. Gut 39:4 (1996), 605–608.
63. 63 Schmidt-Supprian, M., Bloch, W., Courtois, G., et al. NEMO/IKK gamma-deficient mice model incontinentia pigmenti. Mol Cell 5:6 (2000), 981–992.
64. 64 Nenci, A., Becker, C., Wullaert, A., et al. Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature 446:7135 (2007), 557–561.
65. 65 Blaydon, D.C., Biancheri, P., Di, W.L., et al. Inflammatory skin and bowel disease linked to ADAM17 deletion. N Engl J Med 365:16 (2011), 1502–1508.
66. 66 Jyonouchi, S., Forbes, L., Ruchelli, E., et al. Dyskeratosis congenita: a combined immunodeficiency with broad clinical spectrum–a single-center pediatric experience. Pediatr Allergy Immunol 22:3 (2011), 313–319.
67. 67 Ballew, B.J., Joseph, V., De, S., et al. A recessive founder mutation in regulator of telomere elongation helicase 1, RTEL1, underlies severe immunodeficiency and features of Hoyeraal Hreidarsson syndrome. PLoS Genet, 9(8), 2013, e1003695.
68. 68 Villa, A., Notarangelo, L.D., Roifman, C.M., Omenn syndrome: inflammation in leaky severe combined immunodeficiency. J Allergy Clin Immunol 122:6 (2008), 1082–1086.
69. 69 Marrella, V., Maina, V., Villa, A., Omenn syndrome does not live by V(D)J recombination alone. Curr Opin Allergy Clin Immunol 11:6 (2011), 525–531.
70. 70 Washington, K., Stenzel, T.T., Buckley, R.H., et al. Gastrointestinal pathology in patients with common variable immunodeficiency and X-linked agammaglobulinemia. Am J Surg Pathol 20:10 (1996), 1240–1252.
71. 71 Serwas, N.K., Kansu, A., Santos-Valente, E., et al. Atypical manifestation of LRBA deficiency with predominant IBD-like phenotype. Inflamm Bowel Dis 21:1 (2015), 40–47.
72. 72 de Luca, A., Smeekens, S.P., Casagrande, A., et al. IL-1 receptor blockade restores autophagy and reduces inflammation in chronic granulomatous disease in mice and in humans. Proc Natl Acad Sci U S A 111:9 (2014), 3526–3531.
73. 73 Hahn, K.J., Ho, N., Yockey, L., et al. Treatment with anakinra, a recombinant IL-1 receptor antagonist, unlikely to induce lasting remission in patients with CGD colitis. Am J Gastroenterol 110:6 (2015), 938–939.
74. 74 Shouval, D.S., Biswas, A., Goettel, J.A., et al. Interleukin-10 receptor signaling in innate immune cells regulates mucosal immune tolerance and anti-inflammatory macrophage function. Immunity 40:5 (2014), 706–719.
75. 75 Lo, B., Zhang, K., Lu, W., et al. AUTOIMMUNE DISEASE. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy. Science 349:6246 (2015), 436–440.
76. 76 Battaglia, M., Stabilini, A., Tresoldi, E., Expanding human T regulatory cells with the mTOR-inhibitor rapamycin. Methods Mol Biol 821 (2012), 279–293.
77. 77 Ogino, H., Nakamura, K., Iwasa, T., et al. Regulatory T cells expanded by rapamycin in vitro suppress colitis in an experimental mouse model. J Gastroenterol 47:4 (2012), 366–376.
78. 78 Bindl, L., Torgerson, T., Perroni, L., et al. Successful use of the new immune-suppressor sirolimus in IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome). J Pediatr 147:2 (2005), 256–259.
79. 79 Yong, P.L., Russo, P., Sullivan, K.E., Use of sirolimus in IPEX and IPEX-like children. J Clin Immunol 28:5 (2008), 581–587.
80. Kucuk, Z.Y., Bleesing, J.J., Marsh, R., et al. A challenging undertaking: stem cell transplantation for immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. J Allergy Clin Immunol 137:3 (2016), 953–955.e4.
81. 81 Klemann, C., Pannicke, U., Morris-Rosendahl, D.J., et al. Transplantation from a symptomatic carrier sister restores host defenses but does not prevent colitis in NEMO deficiency. Clin Immunol 164 (2016), 52–56.
82. 82 Fish, J.D., Duerst, R.E., Gelfand, E.W., et al. Challenges in the use of allogeneic hematopoietic SCT for ectodermal dysplasia with immune deficiency. Bone Marrow Transplant 43:3 (2009), 217–221.
83. 83 Samuels, M.E., Majewski, J., Alirezaie, N., et al. Exome sequencing identifies mutations in the gene TTC7A in French-Canadian cases with hereditary multiple intestinal atresia. J Med Genet 50:5 (2013), 324–329.
84. 84 Marsh, R.A., Rao, K., Satwani, P., et al. Allogeneic hematopoietic cell transplantation for XIAP deficiency: an international survey reveals poor outcomes. Blood 121:6 (2013), 877–883.
85. 85 Morillo-Gutierrez, B., Beier, R., Rao, K., et al. Treosulfan based conditioning for allogeneic HSCT in children with chronic granulomatous disease: a multicentre experience. Blood 128:3 (2016), 440–448.
86. 86 Gungor, T., Teira, P., Slatter, M., et al. Reduced-intensity conditioning and HLA-matched haemopoietic stem-cell transplantation in patients with chronic granulomatous disease: a prospective multicentre study. Lancet 383:9915 (2014), 436–448.
87. 87 Pai, S.Y., Cowan, M.J., Stem cell transplantation for primary immunodeficiency diseases: the North American experience. Curr Opin Allergy Clin Immunol 14:6 (2014), 521–526.
88. 88 Moratto, D., Giliani, S., Bonfim, C., et al. Long-term outcome and lineage-specific chimerism in 194 patients with Wiskott-Aldrich syndrome treated by hematopoietic cell transplantation in the period 1980-2009: an international collaborative study. Blood 118:6 (2011), 1675–1684.
89. 89 Pai, S.Y., Logan, B.R., Griffith, L.M., et al. Transplantation outcomes for severe combined immunodeficiency, 2000-2009. N Engl J Med 371:5 (2014), 434–446.
90. 90 Tesi, B., Priftakis, P., Lindgren, F., et al. Successful hematopoietic stem cell transplantation in a patient with LPS-Responsive Beige-Like Anchor (LRBA) gene mutation. J Clin Immunol 36:5 (2016), 480–489.
91. 91 Seidel, M.G., Hirschmugl, T., Gamez-Diaz, L., et al. Long-term remission after allogeneic hematopoietic stem cell transplantation in LPS-responsive beige-like anchor (LRBA) deficiency. J Allergy Clin Immunol 135:5 (2015), 1384–1390.e1–8.
92. 92 Aldave, J.C., Cachay, E., Nunez, L., et al. A 1-year-old girl with a gain-of-function STAT1 mutation treated with hematopoietic stem cell transplantation. J Clin Immunol 33:8 (2013), 1273–1275.
93. 93 Passerini, L., Rossi Mel, E., Sartirana, C., et al. CD4(+) T cells from IPEX patients convert into functional and stable regulatory T cells by FOXP3 gene transfer. Sci Transl Med, 5(215), 2013, 215ra174.
94. 94 Hacein-Bey-Abina, S., Pai, S.Y., Gaspar, H.B., et al. A modified gamma-retrovirus vector for X-linked severe combined immunodeficiency. N Engl J Med 371:15 (2014), 1407–1417.
95. 95 Hacein-Bey Abina, S., Gaspar, H.B., Blondeau, J., et al. Outcomes following gene therapy in patients with severe Wiskott-Aldrich syndrome. JAMA 313:15 (2015), 1550–1563.