The Diagnostic Approach to Monogenic Very Early Onset Inflammatory Bowel Disease
2014; Elsevier BV; Volume: 147; Issue: 5 Linguagem: Inglês
10.1053/j.gastro.2014.07.023
ISSN1528-0012
AutoresHolm H. Uhlig, Tobias Schwerd, Sibylle Koletzko, Neil Shah, Jochen Kammermeier, Abdul Elkadri, Jodie Ouahed, David C. Wilson, Simon Travis, Dan Turner, Christoph Klein, Scott B. Snapper, Aleixo M. Muise,
Tópico(s)Digestive system and related health
ResumoPatients with a diverse spectrum of rare genetic disorders can present with inflammatory bowel disease (monogenic IBD). Patients with these disorders often develop symptoms during infancy or early childhood, along with endoscopic or histological features of Crohn's disease, ulcerative colitis, or IBD unclassified. Defects in interleukin-10 signaling have a Mendelian inheritance pattern with complete penetrance of intestinal inflammation. Several genetic defects that disturb intestinal epithelial barrier function or affect innate and adaptive immune function have incomplete penetrance of the IBD-like phenotype. Several of these monogenic conditions do not respond to conventional therapy and are associated with high morbidity and mortality. Due to the broad spectrum of these extremely rare diseases, a correct diagnosis is frequently a challenge and often delayed. In many cases, these diseases cannot be categorized based on standard histological and immunologic features of IBD. Genetic analysis is required to identify the cause of the disorder and offer the patient appropriate treatment options, which include medical therapy, surgery, or allogeneic hematopoietic stem cell transplantation. In addition, diagnosis based on genetic analysis can lead to genetic counseling for family members of patients. We describe key intestinal, extraintestinal, and laboratory features of 50 genetic variants associated with IBD-like intestinal inflammation. In addition, we provide approaches for identifying patients likely to have these disorders. We also discuss classic approaches to identify these variants in patients, starting with phenotypic and functional assessments that lead to analysis of candidate genes. As a complementary approach, we discuss parallel genetic screening using next-generation sequencing followed by functional confirmation of genetic defects. Patients with a diverse spectrum of rare genetic disorders can present with inflammatory bowel disease (monogenic IBD). Patients with these disorders often develop symptoms during infancy or early childhood, along with endoscopic or histological features of Crohn's disease, ulcerative colitis, or IBD unclassified. Defects in interleukin-10 signaling have a Mendelian inheritance pattern with complete penetrance of intestinal inflammation. Several genetic defects that disturb intestinal epithelial barrier function or affect innate and adaptive immune function have incomplete penetrance of the IBD-like phenotype. Several of these monogenic conditions do not respond to conventional therapy and are associated with high morbidity and mortality. Due to the broad spectrum of these extremely rare diseases, a correct diagnosis is frequently a challenge and often delayed. In many cases, these diseases cannot be categorized based on standard histological and immunologic features of IBD. Genetic analysis is required to identify the cause of the disorder and offer the patient appropriate treatment options, which include medical therapy, surgery, or allogeneic hematopoietic stem cell transplantation. In addition, diagnosis based on genetic analysis can lead to genetic counseling for family members of patients. We describe key intestinal, extraintestinal, and laboratory features of 50 genetic variants associated with IBD-like intestinal inflammation. In addition, we provide approaches for identifying patients likely to have these disorders. We also discuss classic approaches to identify these variants in patients, starting with phenotypic and functional assessments that lead to analysis of candidate genes. As a complementary approach, we discuss parallel genetic screening using next-generation sequencing followed by functional confirmation of genetic defects. Inflammatory bowel diseases (IBDs) are a diverse group of complex and multifactorial disorders. The most common subtypes are Crohn's disease (CD) and ulcerative colitis (UC).1Maloy K.J. Powrie F. Intestinal homeostasis and its breakdown in inflammatory bowel disease.Nature. 2011; 474: 298-306Crossref PubMed Scopus (1149) Google Scholar, 2Khor B. Gardet A. Xavier R.J. Genetics and pathogenesis of inflammatory bowel disease.Nature. 2011; 474: 307-317Crossref PubMed Scopus (1511) Google Scholar There is increasing evidence that IBD arises in genetically susceptible people, who develop a chronic and relapsing inflammatory intestinal immune response toward the intestinal microbiota. Disease development and progression are clearly influenced by environmental factors, which have contributed to the rapid global increase in the incidence of IBD in recent decades.3Cosnes J. Gower-Rousseau C. Seksik P. et al.Epidemiology and natural history of inflammatory bowel diseases.Gastroenterology. 2011; 140: 1785-1794Abstract Full Text Full Text PDF PubMed Scopus (1312) Google Scholar IBD location, progression, and response to therapy have age-dependent characteristics.4Thapar N. Shah N. Ramsay A.D. et al.Long-term outcome of intractable ulcerating enterocolitis of infancy.J Pediatr Gastroenterol Nutr. 2005; 40: 582-588Crossref PubMed Scopus (0) Google Scholar, 5Ruemmele F.M. El Khoury M.G. Talbotec C. et al.Characteristics of inflammatory bowel disease with onset during the first year of life.J Pediatr Gastroenterol Nutr. 2006; 43: 603-609Crossref PubMed Google Scholar, 6Heyman M.B. Kirschner B.S. Gold B.D. et al.Children with early-onset inflammatory bowel disease (IBD): analysis of a pediatric IBD consortium registry.J Pediatr. 2005; 146: 35-40Abstract Full Text Full Text PDF PubMed Scopus (402) Google Scholar, 7Paul T. Birnbaum A. Pal D.K. et al.Distinct phenotype of early childhood inflammatory bowel disease.J Clin Gastroenterol. 2006; 40: 583-586Crossref PubMed Scopus (72) Google Scholar, 8Cannioto Z. Berti I. Martelossi S. et al.IBD and IBD mimicking enterocolitis in children younger than 2 years of age.Eur J Pediatr. 2009; 168: 149-155Crossref PubMed Scopus (86) Google Scholar, 9Ruel J. Ruane D. Mehandru S. et al.IBD across the age spectrum-is it the same disease?.Nat Rev Gastroenterol Hepatol. 2014; 11: 88-98Crossref PubMed Google Scholar, 10Van Limbergen J. Russell R.K. Drummond H.E. et al.Definition of phenotypic characteristics of childhood-onset inflammatory bowel disease.Gastroenterology. 2008; 135: 1114-1122Abstract Full Text Full Text PDF PubMed Scopus (609) Google Scholar The onset of intestinal inflammation in children can affect their development and growth. Age of onset can also provide information about the type of IBD and its associated genetic features. For example, patients with defects in interleukin (IL)-10 signaling have a particularly early onset of IBD, within the first few months of life. Our increasing understanding of age-specific characteristics has led to changes in the classification of pediatric IBD. Based on disease characteristics, several age subgroups have been proposed that correspond largely to the generally accepted age stages defined by National Institute of Child Health and Human Development pediatric terminology.11Williams K. Thomson D. Seto I. et al.Standard 6: age groups for pediatric trials.Pediatrics. 2012; 129: S153-S160Crossref PubMed Scopus (226) Google Scholar Five major subgroups of pediatric IBD can be summarized according to age (Table 1). The Montreal classification12Silverberg M.S. Satsangi J. Ahmad T. et al.Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: report of a Working Party of the 2005 Montreal World Congress of Gastroenterology.Can J Gastroenterol. 2005; 19: 5A-36ACrossref PubMed Google Scholar originally defined patients with age of onset younger than 17 years as a distinct group of patients with pediatric-onset IBD (A1). The Pediatric Paris modification13Levine A. Griffiths A. Markowitz J. et al.Pediatric modification of the Montreal classification for inflammatory bowel disease: the Paris classification.Inflamm Bowel Dis. 2011; 17: 1314-1321Crossref PubMed Scopus (836) Google Scholar of the Montreal classification12Silverberg M.S. Satsangi J. Ahmad T. et al.Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: report of a Working Party of the 2005 Montreal World Congress of Gastroenterology.Can J Gastroenterol. 2005; 19: 5A-36ACrossref PubMed Google Scholar later defined the pediatric-onset group of IBD as A1 but subdivided those with a diagnosis before 10 years of age as subgroup A1a and those with a diagnosis between 10 and <17 years of age as subgroup A1b.13Levine A. Griffiths A. Markowitz J. et al.Pediatric modification of the Montreal classification for inflammatory bowel disease: the Paris classification.Inflamm Bowel Dis. 2011; 17: 1314-1321Crossref PubMed Scopus (836) Google Scholar This reclassification was based on several findings indicating that children with a diagnosis of IBD before 10 years of age develop a somewhat different disease phenotype compared with adolescents or adults. Particular differences that supported the modification were paucity of ileal inflammation and predominance of pancolonic inflammation as well as a low rate of anti–Saccharomyces cerevisiae antibodies in A1a patients with CD, with an increased risk of surgery (colectomy) and biological therapy in A1a patients with UC.13Levine A. Griffiths A. Markowitz J. et al.Pediatric modification of the Montreal classification for inflammatory bowel disease: the Paris classification.Inflamm Bowel Dis. 2011; 17: 1314-1321Crossref PubMed Scopus (836) Google ScholarTable 1Subgroups of Pediatric IBD According to AgeGroupClassificationAge range (y)Pediatric-onset IBDMontreal A1Younger than 17EOIBDParis A1aYounger than 10VEOIBDYounger than 6Infantile (and toddler) onset IBDYounger than 2Neonatal IBDFirst 28 days of age Open table in a new tab In this review, we refer to the A1a group as having early-onset IBD (EOIBD). Very early onset IBD (VEOIBD), the subject of this review, represents children with a diagnosis before 6 years of age.14Muise A.M. Snapper S.B. Kugathasan S. The age of gene discovery in very early onset inflammatory bowel disease.Gastroenterology. 2012; 143: 285-288Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar This age classification includes neonatal, infantile, toddler, and early childhood groups. Proposing an age group between infantile IBD and A1a EOIBD makes sense when taking account that the age of onset is often older than 2 years in multiple relevant subgroups of patients with monogenic IBD (such as those with XIAP deficiency, chronic granulomatous disease [CGD], or other neutrophil defects). On the other hand, from the age of 7 years, there is a substantial rise in the frequency of patients with a diagnosis of conventional polygenic IBD, particularly CD.6Heyman M.B. Kirschner B.S. Gold B.D. et al.Children with early-onset inflammatory bowel disease (IBD): analysis of a pediatric IBD consortium registry.J Pediatr. 2005; 146: 35-40Abstract Full Text Full Text PDF PubMed Scopus (402) Google Scholar, 15de Bie C.I. Buderus S. Sandhu B.K. et al.Diagnostic workup of paediatric patients with inflammatory bowel disease in Europe: results of a 5-year audit of the EUROKIDS registry.J Pediatr Gastroenterol Nutr. 2012; 54: 374-380Crossref PubMed Scopus (82) Google Scholar This leads to a relative enrichment of monogenic IBD in those with age of onset younger than 6 years. Approximately one-fifth of children with IBD younger than 6 years of age and one-third of children with IBD younger than 3 years of age are categorized as having IBD unclassified (or indeterminate colitis),16Prenzel F. Uhlig H.H. Frequency of indeterminate colitis in children and adults with IBD - a metaanalysis.J Crohns Colitis. 2009; 3: 277-281Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar reflecting the lack of a refined phenotyping tool to categorize relevant subgroups of patients with VEOIBD and a potential bias due to incomplete diagnostic workup in very young children.15de Bie C.I. Buderus S. Sandhu B.K. et al.Diagnostic workup of paediatric patients with inflammatory bowel disease in Europe: results of a 5-year audit of the EUROKIDS registry.J Pediatr Gastroenterol Nutr. 2012; 54: 374-380Crossref PubMed Scopus (82) Google Scholar The enrichment of monogenic defects in EOIBD and VEOIBD becomes apparent when relating the approximately 1% of patients with IBD younger than 6 years of age and <0.2% younger than 1 year of age to reports that the majority of monogenic disorders can present at younger than 6 years of age and even younger than 1 year of age (Figure 1). Although it is generally accepted that many patients with VEOIBD have low response rates to conventional anti-inflammatory and immunomodulatory therapy, there is a paucity of well-designed studies to support this hypothesis. Infantile (and toddler) onset of IBD was highlighted in the Pediatric Paris classification because of higher rates of affected first-degree family relatives, indicating an increased genetic component, severe disease course, and high rate of resistance to immunosuppressive treatment.13Levine A. Griffiths A. Markowitz J. et al.Pediatric modification of the Montreal classification for inflammatory bowel disease: the Paris classification.Inflamm Bowel Dis. 2011; 17: 1314-1321Crossref PubMed Scopus (836) Google Scholar Features of autoimmunity with dominant lymphoid cell infiltration are frequently found in infants and toddlers.17Ojuawo A. St Louis D. Lindley K.J. et al.Non-infective colitis in infancy: evidence in favour of minor immunodeficiency in its pathogenesis.Arch Dis Child. 1997; 76: 345-348Crossref PubMed Google Scholar Such patients are likely to have pancolitis; subgroups of patients develop severely ulcerating perianal disease, and there is a high rate of resistance to conventional therapy, a high rate of first-degree relatives with IBD, and increased lethality.4Thapar N. Shah N. Ramsay A.D. et al.Long-term outcome of intractable ulcerating enterocolitis of infancy.J Pediatr Gastroenterol Nutr. 2005; 40: 582-588Crossref PubMed Scopus (0) Google Scholar, 5Ruemmele F.M. El Khoury M.G. Talbotec C. et al.Characteristics of inflammatory bowel disease with onset during the first year of life.J Pediatr Gastroenterol Nutr. 2006; 43: 603-609Crossref PubMed Google Scholar, 6Heyman M.B. Kirschner B.S. Gold B.D. et al.Children with early-onset inflammatory bowel disease (IBD): analysis of a pediatric IBD consortium registry.J Pediatr. 2005; 146: 35-40Abstract Full Text Full Text PDF PubMed Scopus (402) Google Scholar, 7Paul T. Birnbaum A. Pal D.K. et al.Distinct phenotype of early childhood inflammatory bowel disease.J Clin Gastroenterol. 2006; 40: 583-586Crossref PubMed Scopus (72) Google Scholar, 8Cannioto Z. Berti I. Martelossi S. et al.IBD and IBD mimicking enterocolitis in children younger than 2 years of age.Eur J Pediatr. 2009; 168: 149-155Crossref PubMed Scopus (86) Google Scholar Recent guidelines and consensus approaches on the diagnosis and management of IBD18Levine A. Koletzko S. Turner D. et al.ESPGHAN revised porto criteria for the diagnosis of inflammatory bowel disease in children and adolescents.J Pediatr Gastroenterol Nutr. 2014; 58: 795-806Crossref PubMed Scopus (653) Google Scholar, 19Turner D. Levine A. Escher J.C. et al.Management of pediatric ulcerative colitis: joint ECCO and ESPGHAN evidence-based consensus guidelines.J Pediatr Gastroenterol Nutr. 2012; 55: 340-361Crossref PubMed Scopus (279) Google Scholar highlight that children with infantile onset of IBD have a particular high risk of an underlying primary immunodeficiency. An extreme early subgroup, neonatal IBD, has been described with manifestations during the first 27 days of life.4Thapar N. Shah N. Ramsay A.D. et al.Long-term outcome of intractable ulcerating enterocolitis of infancy.J Pediatr Gastroenterol Nutr. 2005; 40: 582-588Crossref PubMed Scopus (0) Google Scholar, 5Ruemmele F.M. El Khoury M.G. Talbotec C. et al.Characteristics of inflammatory bowel disease with onset during the first year of life.J Pediatr Gastroenterol Nutr. 2006; 43: 603-609Crossref PubMed Google Scholar, 8Cannioto Z. Berti I. Martelossi S. et al.IBD and IBD mimicking enterocolitis in children younger than 2 years of age.Eur J Pediatr. 2009; 168: 149-155Crossref PubMed Scopus (86) Google Scholar Guidelines on the diagnosis and classification of IBD in pediatric patients13Levine A. Griffiths A. Markowitz J. et al.Pediatric modification of the Montreal classification for inflammatory bowel disease: the Paris classification.Inflamm Bowel Dis. 2011; 17: 1314-1321Crossref PubMed Scopus (836) Google Scholar, 18Levine A. Koletzko S. Turner D. et al.ESPGHAN revised porto criteria for the diagnosis of inflammatory bowel disease in children and adolescents.J Pediatr Gastroenterol Nutr. 2014; 58: 795-806Crossref PubMed Scopus (653) Google Scholar, 19Turner D. Levine A. Escher J.C. et al.Management of pediatric ulcerative colitis: joint ECCO and ESPGHAN evidence-based consensus guidelines.J Pediatr Gastroenterol Nutr. 2012; 55: 340-361Crossref PubMed Scopus (279) Google Scholar, 20Turner D. Travis S.P. Griffiths A.M. et al.Consensus for managing acute severe ulcerative colitis in children: a systematic review and joint statement from ECCO, ESPGHAN, and the Porto IBD Working Group of ESPGHAN.Am J Gastroenterol. 2011; 106: 574-588Crossref PubMed Scopus (132) Google Scholar, 21Van Assche G. Dignass A. Reinisch W. et al.The second European evidence-based Consensus on the diagnosis and management of Crohn's disease: special situations.J Crohns Colitis. 2010; 4: 63-101Abstract Full Text Full Text PDF PubMed Scopus (639) Google Scholar have addressed the need to recognize monogenic disorders and immunodeficiencies in particular, because these require a different treatment strategy than conventional IBD. Current guidelines do not, however, cover the spectrum of these rare subgroups of monogenic IBD. The identification of an underlying genetic defect is indeed challenging, owing to the orphan nature of these diseases, the wide phenotypic spectrum of disorders, and the limited information available on most genetic defects. This review and practice guide provides a comprehensive summary of the monogenic causes of IBD-like intestinal inflammation and a conceptual framework for the diagnostic evaluation of patients with suspected monogenic IBD. We categorize known genetic defects into functional subgroups and discuss key intestinal and extraintestinal findings. Based on the enrichment of known causative mutations as well as extreme phenotypes in very young children, we have focused on a practical approach to detect monogenic disorders in patients with VEOIBD and infantile IBD in particular. Because there is only modest biological evidence to support age-specific categorization of IBD above infantile IBD and within the EOIBD subgroup, we also discuss disease- and gene-specific ages of onset of intestinal inflammation (Figure 1). Approximately 20% to 25% of patients with IBD develop intestinal inflammation during childhood and adolescence. IBD in children younger than 1 year of age has been reported in approximately 1% and VEOIBD in approximately 15% of pediatric patients with IBD.6Heyman M.B. Kirschner B.S. Gold B.D. et al.Children with early-onset inflammatory bowel disease (IBD): analysis of a pediatric IBD consortium registry.J Pediatr. 2005; 146: 35-40Abstract Full Text Full Text PDF PubMed Scopus (402) Google Scholar VEOIBD has an estimated incidence of 4.37 per 100,000 children and a prevalence of 14 per 100,000 children.22Benchimol E.I. Fortinsky K.J. Gozdyra P. et al.Epidemiology of pediatric inflammatory bowel disease: a systematic review of international trends.Inflamm Bowel Dis. 2011; 17: 423-439Crossref PubMed Scopus (615) Google Scholar The incidence of pediatric IBD is increasing.22Benchimol E.I. Fortinsky K.J. Gozdyra P. et al.Epidemiology of pediatric inflammatory bowel disease: a systematic review of international trends.Inflamm Bowel Dis. 2011; 17: 423-439Crossref PubMed Scopus (615) Google Scholar, 23Henderson P. Hansen R. Cameron F.L. et al.Rising incidence of pediatric inflammatory bowel disease in Scotland.Inflamm Bowel Dis. 2012; 18: 999-1005Crossref PubMed Scopus (135) Google Scholar Some studies have reported that the incidence of IBD is increasing particularly rapidly in young children,24Benchimol 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. 2009; 58: 1490-1497Crossref PubMed Scopus (268) Google Scholar, 25Benchimol E.I. Mack D.R. Nguyen G.C. et al.Incidence, outcomes, and health services burden of children with very early onset inflammatory bowel disease.Gastroenterology. 2014 Jun 18; ([Epub ahead of print])Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar although not all studies have confirmed this observation.9Ruel J. Ruane D. Mehandru S. et al.IBD across the age spectrum-is it the same disease?.Nat Rev Gastroenterol Hepatol. 2014; 11: 88-98Crossref PubMed Google Scholar Twin studies have provided the best evidence for a genetic predisposition to IBD, which is stronger for CD than UC. Conventional IBD is a group of polygenic disorders in which hundred(s) of susceptibility loci contribute to the overall risk of disease. Meta-analyses of (genome-wide) association studies of adolescent- and adult-onset IBD identified 163 IBD-associated genetic loci encompassing approximately 300 potential candidate genes. However, it is important to consider that these 163 loci individually contribute only a small percentage of the expected heritability in IBD.26Jostins L. Ripke S. Weersma R.K. et al.Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.Nature. 2012; 491: 119-124Crossref PubMed Scopus (2943) Google Scholar This suggests that IBD, including CD and UC, can be regarded as a classic polygenic disorder. Findings from initial genome-wide pediatric association studies focused on adolescents and confirm a polygenic model.27Kugathasan S. Baldassano R.N. Bradfield J.P. et al.Loci on 20q13 and 21q22 are associated with pediatric-onset inflammatory bowel disease.Nat Genet. 2008; 40: 1211-1215Crossref PubMed Scopus (250) Google Scholar, 28Imielinski M. Baldassano R.N. Griffiths A. et al.Common variants at five new loci associated with early-onset inflammatory bowel disease.Nat Genet. 2009; 41: 1335-1340Crossref PubMed Scopus (0) Google Scholar There are no well-powered genome-wide association studies of patients with EOIBD or VEOIBD. Although most cases of IBD are caused by a polygenic contribution toward genetic susceptibility, there is a diverse spectrum of rare genetic disorders that produce IBD-like intestinal inflammation.29Uhlig H.H. Monogenic diseases associated with intestinal inflammation: implications for the understanding of inflammatory bowel disease.Gut. 2013; 62: 1795-1805Crossref PubMed Scopus (201) Google Scholar The genetic variants that cause these disorders have a large effect on gene function. However, these variants are so rare in allele frequency (many private mutations) that those genetic signals are not detected in genome-wide association studies of patients with IBD. With recent advances in genetic mapping and sequencing techniques and increasing awareness of the importance of those "orphan" disorders, approximately 50 genetic disorders have been identified and associated with IBD-like immunopathology (for a partial summary, see Uhlig29Uhlig H.H. Monogenic diseases associated with intestinal inflammation: implications for the understanding of inflammatory bowel disease.Gut. 2013; 62: 1795-1805Crossref PubMed Scopus (201) Google Scholar). For simplicity, we refer to these disorders in the following text as monogenic IBD, even if there is a spectrum of penetrance of the IBD phenotype. We will compare those monogenic forms of IBD with polygenic conventional IBD. All data suggest that the fraction of monogenic disorders with IBD-like presentation among all patients with IBD correlates inversely with the age of onset. Despite a growing genotype spectrum, monogenic disorders still account for only a fraction of VEOIBD cases. The true fraction is unknown. In a study of 66 patients who developed IBD at ages younger than 5 years, 5 patients were found to carry mutations in IL10RA, 8 in IL10RB, and 3 in IL10.30Kotlarz D. Beier R. Murugan D. et al.Loss of interleukin-10 signaling and infantile inflammatory bowel disease: implications for diagnosis and therapy.Gastroenterology. 2012; 143: 347-355Abstract Full Text Full Text PDF PubMed Scopus (304) Google Scholar All patients developed symptoms within the first 3 months of life.30Kotlarz D. Beier R. Murugan D. et al.Loss of interleukin-10 signaling and infantile inflammatory bowel disease: implications for diagnosis and therapy.Gastroenterology. 2012; 143: 347-355Abstract Full Text Full Text PDF PubMed Scopus (304) Google Scholar A recent study detected 4 patients with presumed pathogenic XIAP mutations in a group of 275 patients with pediatric IBD (A1a/A1b Paris classification) and 1047 patients with adult-onset CD (A2 and A3 Montreal classification).31Zeissig Y. Petersen B.S. Milutinovic S. et al.XIAP variants in male Crohn's disease.Gut. 2014 Feb 26; ([Epub ahead of print])Google Scholar Because all patients with XIAP variants were infantile to adolescent male patients with CD, this could suggest an approximate prevalence of 4% among young male patients with IBD. However, studies like these focus on specific genes and may have strong selection bias toward an expected clinical subphenotype. They might therefore overestimate the frequency of specific variants. Analysis of large, multicenter, population-based cohorts is needed to determine the proportion of cases of VEOIBD caused by single gene defects and to estimate penetrance. Monogenic defects have been found to alter intestinal immune homeostasis via several mechanisms (Table 2). These include disruption of the epithelial barrier and the epithelial response as well as reduced clearance of bacteria by neutrophil granulocytes and other phagocytes. Other single-gene defects induce hyperinflammation or autoinflammation or disrupt T- and B-cell selection and activation. Hyperactivation of the immune response can result from defects in immune inhibitory mechanisms, such as defects in IL-10 signaling or dysfunctional regulatory T-cell activity.Table 2Genetic Defects and Phenotype of Monogenic IBDGroupSyndrome/disorderGeneInheritanceIntestinal findingsExtraintestinal findingsReferencesCD-likeGranulomaUC-likeEpithelial defect (apoptosis)Disease location (1–5)Perianal fistula/abscessPenetrating fistulasStricturesSkin lesionsAutoimmunity, inflammationHLH/MASNeoplasia1Epithelial barrierDystrophic bullosaCOL7A1AR+3+eb32Freeman E.B. Koglmeier J. Martinez A.E. et al.Gastrointestinal complications of epidermolysis bullosa in children.Br J Dermatol. 2008; 158: 1308-1314Crossref PubMed Scopus (0) Google Scholar (A. MartinezaPersonal information and communication.)2Kindler syndromeFERMT1AR++5+eb32Freeman E.B. Koglmeier J. Martinez A.E. et al.Gastrointestinal complications of epidermolysis bullosa in children.Br J Dermatol. 2008; 158: 1308-1314Crossref PubMed Scopus (0) Google Scholar, 149Kern J.S. Herz C. Haan E. et al.Chronic colitis due to an epithelial barrier defect: the role of kindlin-1 isoforms.J Pathol. 2007; 213: 462-470Crossref PubMed Scopus (0) Google Scholar (A. MartinezaPersonal information and communication.)3X-linked ectodermal immunodeficiencyIKBKGX++3+A, Vasc34Cheng L.E. Kanwar B. Tcheurekdjian H. et al.Persistent systemic inflammation and atypical enterocolitis in patients with NEMO syndrome.Clin Immunol. 2009; 132: 124-131Crossref PubMed Scopus (57) Google Scholar, 150Mizukami T. Obara M. Nishikomori R. et al.Successful treatment with infliximab for inflammatory colitis in a patient with X-linked anhidrotic ectodermal dysplasia with immunodeficiency.J Clin Immunol. 2012; 32: 39-49Crossref PubMed Scopus (33) Google Scholar, 151Orange J.S. Jain A. Ballas Z.K. et al.The presentation and natural history of immunodeficiency caused by nuclear factor kappaB essential modulator mutation.J Allergy Clin Immunol. 2004; 113: 725-733Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar4TTC7A deficiencyTTC7AAR+3+38Avitzur Y. Guo C. Mastropaolo L.A. et al.Mutations in tetratricopeptide repeat domain 7A result in a severe form of very early onset inflammatory bowel disease.Gastroenterology. 2014; 146: 1028-1039Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar5ADAM17 deficiencyADAM17AR(+)+3n, h35Blaydon D.C. Biancheri P. Di W.L. et al.Inflammatory skin and bowel disease linked to ADAM17 deletion.N Engl J Med. 2011; 365: 1502-1508Crossref PubMed Scopus (225) Google Scholar6Familial diarrheaGUCY2CAD+3+33Fiskerstrand T. Arshad N. Haukanes B.I. et al.Familial diarrhea syndrome caused by an activating GUCY2C mutation.N Engl J Med. 2012; 366: 1586-1595Crossref PubMed Scopus (130) Google Scholar (A. JaneckeaPersonal information and communication.)7Phagocyte defectsCGDCYBBX++1, 3+e39Schappi M.G. Smith V.V. Goldblatt D. et al.Colitis in chronic granulomatous disease.Arch Dis Child. 2001; 84: 147-151Crossref PubMed Scopus (104) Google Scholar8CGDCYBAAR++3+e41Al-Bousafy A. Al-Tubuly A. Dawi E. et al.Libyan boy with autosomal recessive trait (P22-phox defect) of chronic granulomatous disease.Libyan J Med. 2006; 1: 162-171Crossref PubMed Google Scholar9CGDNCF1AR++1, 3+e39Schappi M.G. Smith V.V. Goldblatt D. et al.Colitis in chronic granulomatous disease.Arch Dis Child. 2001; 84: 147-151Crossref PubMed Scopus (104) Google Scholar10CGDNCF2AR++1, 3+e39Schappi M.G. Smith V.V. Goldblatt D. et al.Colitis in c
Referência(s)