REVIEWS IN BASIC AND CLINICAL GASTROENTEROLOGYAND HEPATOLOGY
Robert F. Schwabe and John W. Wiley, Section Editors
The Diagnostic Approach to Monogenic Very Early OnsetInflammatory Bowel Disease
Holm H. Uhlig,1,2 Tobias Schwerd,1 Sibylle Koletzko,3 Neil Shah,4,5 Jochen Kammermeier,4
Abdul Elkadri,6,7 Jodie Ouahed,8,9 David C. Wilson,10,11 Simon P. Travis,1 Dan Turner,12
Christoph Klein,3 Scott B. Snapper,8,9 and Aleixo M. Muise,6,7 for the COLORS in IBDStudy Group and NEOPICS
1Translational Gastroenterology Unit and 2Department of Pediatrics, University of Oxford, Oxford, England; 3Dr von HaunerChildren’s Hospital, Ludwig Maximilians University, Munich, Germany; 4Great Ormond Street Hospital London, London,England; 5Catholic University, Leuven, Belgium; 6SickKids Inflammatory Bowel Disease Center and Cell Biology Program,Research Institute, and 7Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, The Hospital forSick Children, University of Toronto, Toronto, Ontario, Canada; 8Division of Pediatric Gastroenterology, Hepatology, andNutrition, Department of Medicine, Boston Children’s Hospital, Boston, Massachusetts; 9Division of Gastroenterology andHepatology, Brigham & Women’s Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts;10Child Life and Health, University of Edinburgh, Edinburgh, Scotland; 11Department of Pediatric Gastroenterology,Hepatology, and Nutrition, Royal Hospital for Sick Children, Edinburgh, Scotland; and 12Pediatric Gastroenterology Unit,Shaare Zedek Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel
Patients with a diverse spectrum of rare genetic disorderscan present with inflammatory bowel disease (monogenicIBD). Patients with these disorders often develop symptomsduring infancy or early childhood, along with endoscopic orhistological features of Crohn’s disease, ulcerative colitis, orIBD unclassified. Defects in interleukin-10 signaling have aMendelian inheritance patternwith complete penetrance ofintestinal inflammation. Several genetic defects that disturbintestinal epithelial barrier function or affect innate andadaptive immune function have incomplete penetrance ofthe IBD-like phenotype. Several of these monogenic condi-tions do not respond to conventional therapy and are asso-ciated with high morbidity and mortality. Due to the broadspectrum of these extremely rare diseases, a correct diag-nosis is frequently a challenge and often delayed. In manycases, these diseases cannot be categorized based on stan-dard histological and immunologic features of IBD. Geneticanalysis is required to identify the cause of the disorder andoffer the patient appropriate treatment options, whichinclude medical therapy, surgery, or allogeneic hematopoi-etic stem cell transplantation. In addition, diagnosis basedon genetic analysis can lead to genetic counseling for familymembers of patients. We describe key intestinal, extra-intestinal, and laboratory features of 50 genetic variantsassociated with IBD-like intestinal inflammation. In addi-tion,weprovide approaches for identifying patients likely tohave these disorders. We also discuss classic approaches toidentify these variants in patients, starting with phenotypicand functional assessments that lead to analysis of candi-date genes. As a complementary approach, we discuss par-allel genetic screening using next-generation sequencingfollowed by functional confirmation of genetic defects.
nflammatory bowel diseases (IBDs) are a diverse group
Iof complex and multifactorial disorders. The mostcommon subtypes are Crohn’s disease (CD) and ulcerativecolitis (UC).1,2 There is increasing evidence that IBD arises ingenetically susceptible people, who develop a chronic andrelapsing inflammatory intestinal immune response towardthe intestinal microbiota. Disease development and pro-gression are clearly influenced by environmental factors,which have contributed to the rapid global increase in theincidence of IBD in recent decades.3
Developmental, Genetic, and BiologicalDifferences Among Age Groups
IBD location, progression, and response to therapy haveage-dependent characteristics.4–10 The onset of intestinalinflammation in children can affect their development andgrowth. Age of onset can also provide information about the
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type of IBD and its associated genetic features. For example,patients with defects in interleukin (IL)-10 signaling have aparticularly early onset of IBD, within the first few months oflife. Our increasing understanding of age-specific character-istics has led to changes in the classification of pediatric IBD.Based on disease characteristics, several age subgroups havebeen proposed that correspond largely to the generallyaccepted age stages defined by National Institute of ChildHealth and Human Development pediatric terminology.11
Fivemajor subgroups of pediatric IBD can be summarizedaccording to age (Table 1). The Montreal classification12
originally defined patients with age of onset younger than17 years as a distinct group of patients with pediatric-onsetIBD (A1). The Pediatric Paris modification13 of the Mon-treal classification12 later defined the pediatric-onset groupof IBD as A1 but subdivided those with a diagnosis before 10years of age as subgroup A1a and those with a diagnosisbetween 10 and <17 years of age as subgroup A1b.13 Thisreclassification was based on several findings indicating thatchildren with a diagnosis of IBD before 10 years of agedevelop a somewhat different disease phenotype comparedwith adolescents or adults. Particular differences that sup-ported the modification were paucity of ileal inflammationand predominance of pancolonic inflammation as well as alow rate of anti–Saccharomyces cerevisiae antibodies in A1apatients with CD, with an increased risk of surgery (colec-tomy) and biological therapy in A1a patients with UC.13
In this review, we refer to the A1a group as having early-onset IBD (EOIBD). Very early onset IBD (VEOIBD), thesubject of this review, represents children with a diagnosisbefore 6 years of age.14 This age classification includesneonatal, infantile, toddler, and early childhood groups.Proposing an age group between infantile IBD and A1aEOIBD makes sense when taking account that the age ofonset is often older than 2 years in multiple relevant sub-groups of patients with monogenic IBD (such as those withXIAP deficiency, chronic granulomatous disease [CGD], orother neutrophil defects). On the other hand, from the age of7 years, there is a substantial rise in the frequency of pa-tients with a diagnosis of conventional polygenic IBD,particularly CD.6,15 This leads to a relative enrichment ofmonogenic IBD in those with age of onset younger than 6years. Approximately one-fifth of children with IBD youngerthan 6 years of age and one-third of children with IBDyounger than 3 years of age are categorized as having IBDunclassified (or indeterminate colitis),16 reflecting the lackof a refined phenotyping tool to categorize relevant
Table 1.Subgroups of Pediatric IBD According to Age
Group Classification Age range (y)
Pediatric-onset IBD Montreal A1 Younger than 17EOIBD Paris A1a Younger than 10VEOIBD Younger than 6Infantile (and toddler)
onset IBDYounger than 2
Neonatal IBD First 28 days of age
subgroups of patients with VEOIBD and a potential bias dueto incomplete diagnostic workup in very young children.15
The enrichment of monogenic defects in EOIBD andVEOIBD becomes apparent when relating the approximately1% of patients with IBD younger than 6 years of age and<0.2% younger than 1 year of age to reports that the ma-jority of monogenic disorders can present at younger than 6years of age and even younger than 1 year of age (Figure 1).
Although it is generally accepted that many patients withVEOIBD have low response rates to conventional anti-inflammatory and immunomodulatory therapy, there is apaucity of well-designed studies to support this hypothesis.Infantile (and toddler) onset of IBD was highlighted in thePediatric Paris classification because of higher rates ofaffected first-degree family relatives, indicating an increasedgenetic component, severe disease course, and high rate ofresistance to immunosuppressive treatment.13 Features ofautoimmunity with dominant lymphoid cell infiltration arefrequently found in infants and toddlers.17 Such patients arelikely to have pancolitis; subgroups of patients developseverely ulcerating perianal disease, and there is a high rateof resistance to conventional therapy, a high rate of first-degree relatives with IBD, and increased lethality.4–8
Recent guidelines and consensus approaches on the diag-nosis and management of IBD18,19 highlight that childrenwith infantile onset of IBD have a particular high risk of anunderlying primary immunodeficiency. An extreme earlysubgroup, neonatal IBD, has been described with manifes-tations during the first 27 days of life.4,5,8
Guidelines on the diagnosis and classification of IBD inpediatric patients13,18–21 have addressed the need torecognize monogenic disorders and immunodeficiencies inparticular, because these require a different treatmentstrategy than conventional IBD. Current guidelines do not,however, cover the spectrum of these rare subgroups ofmonogenic IBD. The identification of an underlying geneticdefect is indeed challenging, owing to the orphan nature ofthese diseases, the wide phenotypic spectrum of disorders,and the limited information available on most genetic de-fects. This review and practice guide provides a compre-hensive summary of the monogenic causes of IBD-likeintestinal inflammation and a conceptual framework for thediagnostic evaluation of patients with suspected monogenicIBD. We categorize known genetic defects into functionalsubgroups and discuss key intestinal and extraintestinalfindings. Based on the enrichment of known causative mu-tations as well as extreme phenotypes in very young chil-dren, we have focused on a practical approach to detectmonogenic disorders in patients with VEOIBD and infantileIBD in particular. Because there is only modest biologicalevidence to support age-specific categorization of IBD aboveinfantile IBD and within the EOIBD subgroup, we alsodiscuss disease- and gene-specific ages of onset of intestinalinflammation (Figure 1).
Epidemiology of Pediatric IBDApproximately 20% to 25% of patients with IBD develop
intestinal inflammation during childhood and adolescence.
Figure 1. Age of onset ofIBD-like symptoms in pa-tients with monogenic dis-eases. Multiple geneticdefects are summarizedin the group of atypicalSCID, Hoyeraal–Hrei-darsson syndrome, CGD,and Hermansky–Pudlaksyndrome. By comparison,an unselected IBD popula-tion is presented (OxfordIBD cohort study; pediatricand adult referral-basedIBD cohort, n ¼ 1605 pa-tients comprising CD,UC, and IBD unclassified[IBDU]). Symbols representindividual patients. Barsrepresent the age range ofcaseseries if individualdatawere not available. The ageranges of infantile IBD,VEOIBD, EOIBD, and Mon-treal/Paris classificationA1a, A1b, A2, and A3 areshown for reference. Age ofonset data refer to refer-ences provided in Table 2.Additional references fordisease subgroups areprovided in SupplementaryInformation for Figure 1.
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IBD in children younger than 1 year of age has been re-ported in approximately 1% and VEOIBD in approximately15% of pediatric patients with IBD.6 VEOIBD has an esti-mated incidence of 4.37 per 100,000 children and a prev-alence of 14 per 100,000 children.22 The incidence ofpediatric IBD is increasing.22,23 Some studies have reportedthat the incidence of IBD is increasing particularly rapidly inyoung children,24,25 although not all studies have confirmedthis observation.9
Polygenic and Monogenic Forms of IBDTwin studies have provided the best evidence for a ge-
netic predisposition to IBD, which is stronger for CD thanUC. Conventional IBD is a group of polygenic disorders inwhich hundred(s) of susceptibility loci contribute to theoverall risk of disease. Meta-analyses of (genome-wide) as-sociation studies of adolescent- and adult-onset IBD iden-tified 163 IBD-associated genetic loci encompassingapproximately 300 potential candidate genes. However, it is
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important to consider that these 163 loci individuallycontribute only a small percentage of the expected herita-bility in IBD.26 This suggests that IBD, including CD and UC,can be regarded as a classic polygenic disorder. Findingsfrom initial genome-wide pediatric association studiesfocused on adolescents and confirm a polygenic model.27,28
There are no well-powered genome-wide associationstudies of patients with EOIBD or VEOIBD.
Although most cases of IBD are caused by a polygeniccontribution toward genetic susceptibility, there is a diversespectrum of rare genetic disorders that produce IBD-likeintestinal inflammation.29 The genetic variants that causethese disorders have a large effect on gene function. How-ever, these variants are so rare in allele frequency (manyprivate mutations) that those genetic signals are notdetected in genome-wide association studies of patientswith IBD. With recent advances in genetic mapping andsequencing techniques and increasing awareness of theimportance of those “orphan” disorders, approximately 50genetic disorders have been identified and associated withIBD-like immunopathology (for a partial summary, seeUhlig29). For simplicity, we refer to these disorders in thefollowing text as monogenic IBD, even if there is a spectrumof penetrance of the IBD phenotype. We will compare thosemonogenic forms of IBD with polygenic conventional IBD.
All data suggest that the fraction of monogenic disorderswith IBD-like presentation among all patients with IBDcorrelates inversely with the age of onset. Despite a growinggenotype spectrum, monogenic disorders still account foronly a fraction of VEOIBD cases. The true fraction is un-known. In a study of 66 patients who developed IBD at agesyounger than 5 years, 5 patients were found to carry mu-tations in IL10RA, 8 in IL10RB, and 3 in IL10.30 All patientsdeveloped symptoms within the first 3 months of life.30 Arecent study detected 4 patients with presumed pathogenicXIAP mutations in a group of 275 patients with pediatricIBD (A1a/A1b Paris classification) and 1047 patients withadult-onset CD (A2 and A3 Montreal classification).31
Because all patients with XIAP variants were infantile toadolescent male patients with CD, this could suggest anapproximate prevalence of 4% among young male patientswith IBD. However, studies like these focus on specific genesand may have strong selection bias toward an expectedclinical subphenotype. They might therefore overestimatethe frequency of specific variants. Analysis of large, multi-center, population-based cohorts is needed to determine theproportion of cases of VEOIBD caused by single gene defectsand to estimate penetrance.
Monogenic defects have been found to alter intestinalimmune homeostasis via several mechanisms (Table 2).These include disruption of the epithelial barrier and theepithelial response as well as reduced clearance of bacteriaby neutrophil granulocytes and other phagocytes. Othersingle-gene defects induce hyperinflammation or auto-inflammation or disrupt T- and B-cell selection and activa-tion. Hyperactivation of the immune response can resultfrom defects in immune inhibitory mechanisms, such asdefects in IL-10 signaling or dysfunctional regulatory T-cellactivity.
Epithelial Barrier and Response DefectsGenetic disorders that affect intestinal epithelial barrier
function include dystrophic epidermolysis bullosa,32 Kindlersyndrome,32 familial diarrhea caused by dominant acti-vating mutations in guanylate cyclase C,33 X-linked ecto-dermal dysplasia and immunodeficiency,34 and ADAM17deficiency.35
X-linked ectodermal dysplasia and immunodeficiency,caused by hypomorphic mutations in IKBKG (encodes nu-clear factor kB essential modulator protein [NEMO])34 andADAM17 deficiency35 cause epithelial and immunedysfunction. Recently, TTC7A deficiency was described inpatients with multiple intestinal atresia, with and withoutsevere combined immunodeficiency (SCID) immunodefi-ciency.36,37 Hypomorphic mutations in TTC7A have beenfound to cause VEOIBD without intestinal stricturing orsevere immunodeficiency, most likely due to a defect inepithelial signaling.38
Dysfunction of Neutrophil GranulocytesVariants in genes that affect neutrophil granulocytes
(and other phagocytes) predispose people to IBD-like in-testinal inflammation. Chronic granulomatous disease ischaracterized by genetic defects in components of thephagocyte reduced nicotinamide adenine dinucleotidephosphate (NADPH) oxidase (phox) complex. Genetic mu-tations in all 5 components of the phagocyte NADPH oxidase(phox)—gp91-phox (CYBB), p22-phox (CYBA), p47-phox(NCF1), p67-phox (NCF2), and p40-phox (NCF4)—areassociated with immunodeficiency and can cause IBD-likeintestinal inflammation.
As high as 40% of patients with CGD develop CD-likeintestinal inflammation.39–41 Multiple granulomas and thepresence of pigmented macrophages can indicate the groupof defects histologically. Missense variants in NCF2 thataffect RAC2 binding sites have recently been reported inpatients with VEOIBD.42 Recently, several heterozygousfunctional hypomorphic variants in multiple components ofthe NOX2 NADPH oxidase complex were detected in pa-tients with VEOIBD that do not cause CGD-like immunode-ficiency but have a moderate effect on reactive oxygenspecies production and confer susceptibility to VEOIBD.43
Tumor necrosis factor a inhibitors can resolve intestinalinflammation in patients with CGD but could increase therisk of severe infections in patients with CGD.44 Allogeneichematopoietic stem cell transplantation (HSCT) can cureCGD and resolve intestinal inflammation.44–46 Monocytesproduce high levels of IL-1 in patients with CGD, and an IL-1receptor antagonist (anakinra) has been used to treatnoninfectious colitis in those patients.47
In addition to CGD, a number of other neutrophildefects are associated with intestinal inflammation. Defectsin glucose-6-phosphate translocase (SLC37A4)48,49 andglucose-6-phosphatase catalytic subunit 3 (G6PC3)50 areassociated with congenital neutropenia (and other distinc-tive features) but also predispose people to IBD. Leukocyteadhesion deficiency type 1 is caused by mutations in thegene encoding CD18 (ITGB2) and is associated with
Table 2.Genetic Defects and Phenotype of Monogenic IBD
21 Hermansky–Pudlak 1 HPS1 AR þ þ 3 þ (þ) þ 60–6322 Hermansky–Pudlak 4 HPS4 AR þ þ 3 þ (þ) þ 60, 62, 15323 Hermansky–Pudlak 6 HPS6 AR 3 þ 6424 T- and B-cell defects CVID 1 ICOS AR 5 p A 8625 CVID 8 LRBA AR þ 3 EN AIHA 87–89
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kinion
h
),
Table 2.Continued
Group Syndrome/disorder Gene Inheritance
Intestinal findings Extraintestinal findings
ReferencesCD-like Granuloma
UC-like
Epithelialdefect
(apoptosis)
Diseaselocation(1–5)
Perianalfistula/abscess
Penetratingfistulas Strictures
Skinlesions
Autoimmunity,inflammation
HLH/MAS Neoplasia
26 IL-21 deficiency (CVID-like) IL21 AR þ þ 9027 Agammaglobulinemia BTK X þ 5 AIHA 75, 7628 Agammaglobulinemia PIK3R1 AR 5 EN þ 7729 Hyper IgM syndrome CD40LG X 1, 5 þ AIHA 7830 Hyper IgM syndrome AICDA AR þ 1, 3 AIHA 7931 WAS WAS X þ 5 e AIHA, A 8032 Omenn syndrome DCLRE1C AR þ 1, 3 8133 SCID ZAP70 AR þ 5 e 15434 SCID/hyper IgM syndrome RAG2 AR 5 þ AIHA 82, 15535 SCID IL2RG X 3 156, 15736 SCID LIG4 AR No further information þ AN 8237 SCID ADA AR No further information þ AIHA 8238 SCID CD3g AR þ 5 þ þ 9539 Hoyeraal–Hreidarsson S. DKC1 X (þ) 1, 3 þ þ, n, h þ 99–10140 Hoyeraal–Hreidarsson S. RTEL1 AR þ 5 þ þ, n, h þ 97, 9841 Hyper IgE syndrome DOCK8 AR þ 1, 5 e PSC 15842 Immunoregulation IPEX FOXP3 X 3 e, p AIHA, HT,
T1D.111, 112
43 IPEX-like IL2RA AR 2 e AIHA, HT,T1D.
114
44 IPEX-like STAT1 AD 2 11645 IL-10 signaling defects IL10RA AR þ (þ) 3 þ þ f, e A þ 30, 102–105, 10746 IL-10 signaling defects IL10RB AR þ (þ) 3 þ þ f A, AIH þ 30, 102–105, 10747 IL-10 signaling defects IL10 AR þ 3 þ þ 30, 102, 104,
105, 10748 Others MASP deficiency MASP2 AR þ þ A 15949 Trichohepatoenteric S. SKIV2L AR 3 h, þ 117, 16050 Trichohepatoenteric S. TTC37 AR 3 h, þ 117
NOTE. Genetic defects are grouped according to functional subgroups. Gene names refer to HUGO gene nomenclature. CD-like and UC-like were marked only whenpatient characteristics in the original reports were described as typical CD or UC pathologies. Unclassified or indeterminate colitis is the not specified default option.Disease location is classified as follows: 1, mouth; 2, enteropathy; 3, enterocolitis; 4, isolated ileitis; 5, colitis; 6, perianal disease. Epithelial defects refer in particular tofinding of epithelial lining nonadherent at the basal membrane or increased epithelial apoptosis and epithelial tufting. Key laboratory findings are provided in SupplementaryTable 1, and examples of additional defects of possible or unclear relevance are listed in the Supplementary Information for Table 1.HLH, hemophagocytic lymphohistiocytosis; AR, autosomal recessive; eb, epidermolysis bullosa; X, X-linked; A, arthritis; vasc, vasculitis; n, nail; h, hair; AD, autosomaldominant; e, eczema; f, folliculitis/pyoderma; SJ, Sjögren syndrome; p, psoriasis; AIHA, autoimmune hemolytic anemia; AN, autoimmune neutropenia; PSC, primarysclerosing cholangitis; HT, Hashimoto thyroiditis; AIH, autoimmune hepatitis; TID, type 1 diabetes mellitus; MAS, macrophage activation syndrome; NSIP, non-specificinterstitial pneumonitis; S, serositis.aPersonal information and communication.
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defective transendothelial migration of neutrophil gran-ulocytes. Patients typically present with high peripheralgranulocyte counts and bacterial infections, and some pre-sent with IBD-like features.51,52
CD-like disease is a typical manifestation of glycogenstorage disease type Ib, characterized by neutropenia andneutrophil granulocyte dysfunction.48,49,53 Granulocytecolony-stimulating factor has been used to treat neutropeniaand colitis in some patients with glycogen storage diseasetype Ib.53
In addition to neutrophil defects, defects in several othergenes, including WAS, LRBA, BTK, CD40LG, and FOXP3, canlead to autoantibody-induced or hemophagocytosis-inducedneutropenia. These multidimensional mechanisms of sec-ondary immune dysregulation indicate the functionalcomplexity of some seemingly unrelated genetic immunedefects and the broad effects they might have on the innateimmune system.
Hyperinflammatory andAutoinflammatory Disorders
VEOIBD has been described in a number of hyper-inflammatory and autoinflammatory disorders such asmevalonate kinase deficiency,54,55 phospholipase C-g2 de-fects,56 familial Mediterranean fever,57–59 Herman-sky–Pudlak syndrome (type 1, 4, and 6),60–64 X-linkedlymphoproliferative syndrome type 165 and type 2,66–68 orfamilial hemophagocytic lymphohistiocytosis type 5.69
Among these, mevalonate kinase deficiency is a prototypicautoinflammatory disorder, characterized by increasedactivation of caspase-1 and subsequent activation of IL-1b.70 Inhibiting IL-1b signaling with antibodies that blockIL-1b or IL-1 receptor antagonists can induce complete orpartial remission in patients, including those withVEOIBD.54,55,71
X-linked lymphoproliferative syndrome 2 is caused bydefects in the XIAP gene. At least 20% of patients with XIAPdefects develop a CD-like immunopathology with severefistulizing perianal phenotype.66–68,72,73 In these patients,Epstein–Barr virus infections can lead to life-threateninghemophagocytic lymphohistiocytosis. Originally associatedwith a poor outcome after HSCT,74 less toxic inductionregimens could improve the prognosis and cure this form ofIBD.67,73
Complex Defects in T- and B-CellFunction
IBD-like immunopathology is a common finding in pa-tients with defects in the adaptive immune system. Multiplegenetic defects that disturb T- and/or B-cell selection andactivation can cause complex immune dysfunction,including immunodeficiency and autoimmunity as well asintestinal inflammation. Disorders associated with IBD-likeimmunopathology include B-cell defects such as commonvariable immunodeficiency (CVID), hyper-immunoglobulin(Ig) M syndrome, and agammaglobulinemia.75–79 Severalother primary immune deficiencies, such as Wiskott–
Aldrich syndrome80 (WAS) and atypical SCID or Omennsyndrome81,82 can also cause IBD-like intestinalinflammation.
CVID, Agammaglobulinemia, and HyperIgM Syndrome
Patients with CVID have clinical features of differenttypes of IBD, spanning CD, UC, and ulcerative proctitis–likefindings.83,84 Although CVID is largely polygenic, a smallproportion of cases of CVID have been associated withspecific genetic defects. CVID type 1 is caused by variants inthe gene encoding the inducible T-cell costimulator(ICOS),85,86 whereas CVID type 8 is caused by variants inLRBA.87–89 Patients with these mutations can present withIBD-like pathology. Recently, IBD and CVID-like disease wasdescribed in a family with IL-21 deficiency.90
Patients with agammaglobulinemia, caused by defects inBTK or PIK3R1, as well as patients with subtypes of hyperIgM syndrome caused by defects in CD40LG, AICDA, orIKBKG can develop IBD-like immunopathology.75–79 It isworth considering that several other immunodeficiencies,not regarded as primary B-cell defects, are similarly asso-ciated with low numbers of B cells and/or Igs (such as thosecaused by variants in SKIV2L and TTC37; see Table 2 andSupplementary Table 1).
WASWAS is a primary immunodeficiency. Many patients with
WAS present with UC-like noninfectious colitis during earlyinfancy.80 The syndrome is caused by the absence orabnormal expression of the cytoskeletal regulator WASPand is associated with defects in most immune subsets(effector and regulatory T cells, natural killer [NK] T cells, Bcells, dendritic cells, macrophages, NK cells, and neutro-phils).91 In addition to features of UC, patients developmany other autoimmune complications. Allogeneic bonemarrow transplantation is the standard of care for thosepatients.80 Patients who are not candidates for bonemarrow transplantation have been successfully treated withexperimental gene therapy approaches.92,93
Atypical SCID DefectsPatients with atypical SCID defects have residual B- and
T-cell development and oligoclonal T-cell expansion.94
VEOIBD is commonly observed in patients with atypicalSCID due to hypomorphic defects in multiple genes such asDCLRE1C, ZAP70, RAG2, IL2RG, LIG4, ADA, and CD3G.81,82,95
This list of genes is likely not complete, and it seemsreasonable to assume that most genetic defects that cause T-cell atypical SCID also cause IBD.
A subset of patients with SCID present with severeeczematous rash (Omenn syndrome).81 It is not clearwhether residual lymphocyte function in patients withhypomorphic TTC7A mutations is a precondition for IBD orcontributes to VEOIBD.38 Intestinal and skin lesions alsodevelop in patients with SCID due to graft-versus-host dis-ease in response to maternal cells.96
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Hoyeraal–Hreidarsson SyndromeHoyeraal–Hreidarsson syndrome is a severe form of
dyskeratosis congenita characterized by dysplastic nails,lacy reticular skin pigmentation, and oral leukoplakia. It isa multiorgan disorder. Patients with mutations inRTEL197,98 or DKC199–101 can develop SCID and intestinalinflammation.
Regulatory T Cells and IL-10 SignalingLoss-of-function defects in IL-10 and its receptor
(encoded by IL10RA and IL10RB)102–106 cause VEOIBD withperianal disease and folliculitis within the first months oflife. All patients with loss-of-function mutations that preventIL-10 signaling develop IBD-like immunopathology, indi-cating that these defects are a monogenic form of IBD with100% penetrance.106,107 The anti-inflammatory cytokine IL-10 is secreted by natural and induced regulatory T cells (inparticular, intestinal CD4þFOXP3þ and Tr1 cells), macro-phages, and B cells. Many intestinal and extraintestinal celltypes express the IL-10 receptor and respond to IL-10.Defects in IL-10 receptor signaling affect the differentia-tion of macrophage M1/M2, shifting them toward an in-flammatory phenotype.108 Defects in IL-10 signaling areassociated with extraintestinal inflammation such as follic-ulitis or arthritis and predispose to B-cell lym-phoma.102,103,109 Conventional therapy options are largelynot effective in patients with IL-10 signaling defects, butallogeneic matched or mismatched HSCT can induce sus-tained remission of intestinal inflammation.30,102,103,107,110
X-linked immune dysregulation, polyendocrinopathy,enteropathy syndrome (IPEX) is caused by mutations in thetranscription factor FOXP3. Those mutations affect naturaland induced regulatory T cells, causing autoimmunity andimmunodeficiency but also enteropathy in a large percent-age of patients with colitis.111,112 The intestinal lesions thatdevelop in patients with IPEX can be classified as graft-versus-host disease–like changes with small bowelinvolvement and colitis, celiac disease–like lesions, or en-teropathy with goblet cell depletion.113
Antibodies against enterocytes and/or antibodiesagainst goblet cells can be detected in the serum of patientswith IPEX.113 IPEX-like immune dysregulation with enter-opathy can also be caused by defects in IL-2 signaling inpatients with defects in the IL-2 receptor a chain (IL2RA,encoding CD25)114,115 or a dominant gain of function inSTAT1 signaling.116
Other Disorders and GenesIBD or IBD-like disorders have been described in pa-
tients with several other disorders. In some disorders, thereis no well-defined plausible functional mechanism. Forexample, patients with trichohepatoenteric syndrome havepresumed defects in epithelial cells that lead to intractablediarrhea.117,118 However, an adaptive immune defect mightalso cause this disorder, because the patients have Ig de-ficiencies that require Ig substitution.
Several genes, described in the SupplementaryInformation for Table 1, are associated with a single or
less well-defined case report of patients who developedIBD-like features. Some of these patients might happen tohave intestinal inflammation by coincidence, and evenseveral case reports cannot exclude a publication bias.
Heterozygous defects in the PTEN phosphatase are associ-ated not only with multiple tumors but also immune dysregu-lation and autoimmunity.119 Inflammatory polyps are commonamong patients with PTEN hamartoma tumor syndrome andindeterminate colitis, and ileitis is a rare complication.119 Thefunctional mechanism involved in intestinal inflammatorypolyps and intestinal inflammation is not clear because het-erozygous mutations in PTEN are not associated with conven-tional immunodeficiency and affect multiple cell types.
Very early onset enteropathies and intestinal infectionsare described in several monogenic immunodeficiency and/or autoinflammation disorders, including defects in the itchyE3 ubiquitin protein ligase activity encoded by the ITCHgene, defects in E3 ubiquitin ligase HOIL-1 encoded byHOIL1, and gain of function defects in IKBA encoded byNFKBIA (see Supplementary Information for Table 1). It isnot clear what activates the inflammatory events in thosepatients; it could be pathogenic microbes in the intestine,food, or IBD-like intestinal inflammation induced by thecommensal microbiota.
Additional disorders are associated with intestinalinflammation without immunodeficiency or without knownepithelial mechanisms. For example, some patients withHirschsprung disease, an intestinal innervation and dys-motility disorder, develop enterocolitis associated withdominant germline mutations in RET.120,121 One possiblepathomechanism could be increased bacterial translocationdue to bacterial stasis leading to subsequent inflammation.
Despite multiple reports of complement system de-ficiencies and IBD, this group of disorders is not clearlydefined. MASP2 deficiency has been reported in a patientwith pediatric-onset IBD. However, reports of intestinalinflammation in several other complement defects are muchharder to interpret because those patients present withinconsistent disease phenotypes; some are less well docu-mented and could be simple chance findings (seeSupplementary Information for Table 1).
Why Should We Care AboutMonogenic Defects?
It is a challenge to diagnose the rare patients withmonogenic IBD, but differences in the prognosis and medi-cal management argue that a genetic diagnosis should notbe missed. As a group, these diseases have high morbidityand subgroups have high mortality if untreated. Based ontheir causes, some require different treatment strategiesthan most cases of IBD.
Allogeneic HSCT has been used to treat several mono-genic disorders. It is the standard treatment for patientswith disorders that do not respond to conventional treat-ment, those with high mortality, or those that increasesusceptibility to hematopoietic cancers (eg IL-10 signalingdefects, IPEX, WAS, or increasingly XIAP deficiency). Intro-duction of HSCT as a potentially curative treatment option
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for intestinal and extraintestinal manifestations of thesedisorders has changed clinical practice.30,73,74,107,111
However, there is evidence from mouse models andclinical studies that patients with epithelial barrier defectsare less amenable to HSCT, because this does not correct thedefect that causes the disease (eg, NEMO deficiency orpossibly TTC7A deficiency). For example, severe recurrenceof multiple intestinal atresia after HSCT in patients withTTC7A deficiency36,37 indicates a contribution of theenterocyte defect to pathogenesis. Due to the significant riskassociated with HSCT, including graft-versus-host diseaseand severe infections, it is important to determine the ge-netic basis of each patient’s VEOIBD before selecting HSCTas a treatment approach.
Understanding the pathophysiology of a disorder causedby a genetic defect can identify unconventional biologicaltreatment options that interfere with specific pathogenicpathways. Patients with mevalonate kinase deficiency orCGD produce excess amounts of IL-1b, so treatment withIL-1b receptor antagonists has been successful.54,55 Thistreatment is not part of the standard therapeutic repertoirefor patients with conventional IBD. Access to individualizedgenotype-specific therapies is particularly important,because it might avoid both surgery (including colectomy)and the adverse effects of medical therapy in patients whoare unlikely to benefit from conventional IBD therapies inthe long term.
A further incentive to establish a specific genetic diag-nosis is the ability to anticipate complications. Some pa-tients should be screened for infections (such as forEpstein–Barr virus infection status in XIAP defects) or can-cer (including B-cell lymphomas in patients with IL-10 re-ceptor deficiency109 or skin and hematopoietic malignanciesin Hoyeraal–Hreidarsson syndrome). Genetic informationcan also identify patients who should be screened forextraintestinal manifestations such as idiopathic thrombo-cytopenic purpura, autoimmune hemolytic anemia, autoim-mune neutropenia, or autoimmune hepatitis (Table 2).
Table 3.Pivotal Prompts for Suspecting Monogenic IBD
Key points
Very early age of onset of IBD-likeimmunopathology
Likelihood increof age at dia
Family history In particular confamily memb
Atypical endoscopic or histological findings For example, exResistance to conventional therapies Such as exclusSkin lesions, nail dystrophy, or hair abnormalities For example, ep
woolen hair,Severe or very early onset perianal disease Fistulas and abLymphoid organ abnormalities For example, lyRecurrent or atypical infections Intestinal and nHemophagocytic lymphohistiocytosis Induced by vira
macrophageAssociated autoimmunity For example, ar
dysfunctionEarly development of tumors For example, no
Knowledge of the genetic predisposition can reduce the timeto detect associated complications.
Families who are aware of the genetic basis of theirdisease can receive genetic counseling.
When Should We SuspectMonogenic IBD?
The timely diagnosis of monogenic IBD requires as-sessments of intestinal and extraintestinal disease pheno-types in conjunction with the histopathology andappropriate laboratory tests to exclude allergies or in-fections.18,19 Classification of clinical, endoscopic, histologi-cal, and imaging findings into CD-like and UC-likephenotypes can be helpful but is not sufficient to differen-tiate patients with a monogenic disorder from conventionalidiopathic CD (such as discontinuous, transmural inflam-mation affecting the entire gastrointestinal tract, fistulizingdisease, or granuloma formation) or UC (a continuous,colonic disorder with crypt abscess formation and increasesin chronic inflammatory cells, typically restricted to thelamina propria). Histopathologists use nonspecific termssuch as IBD unclassified in a relevant proportion of patientswith VEOIBD, including monogenic forms of IBD. In theabsence of highly specific and sensitive intestinal histologi-cal markers of monogenic forms of IBD, extraintestinalfindings and laboratory test results are important factors tofocus the search for monogenic forms of IBD (Table 3 andFigure 2). A phenotypic aide-mémoire summarizing the keyfindings to ensure that a careful clinical history for VEOIBDand examination to narrow the search for an underlyingmonogenetic defect is YOUNG AGE MATTERS MOST (YOUNGAGE onset, Multiple family members and consanguinity,Autoimmunity, Thriving failure, Treatment with conven-tional medication fails, Endocrine concerns, Recurrent in-fections or unexplained fever, Severe perianal disease,Macrophage activation syndrome and hemophagocyticlymphohistiocytosis, Obstruction and atresia of intestine,
Comments
ases with very early onset, particularly in those younger than 2 yearsgnosissanguinity, predominance of affected males in families, or multipleers affectedtreme epithelial apoptosis or loss of germinal centersive enteral nutrition, corticosteroids, and/or biological therapyidermolysis bullosa, eczema, folliculitis, pyoderma or abscesses,or trichorrhexis nodosascessesmph node abscesses, splenomegalyonintestinall infections such as Epstein–Barr virus or cytomegalovirus oractivation syndromethritis, serositis, sclerosing cholangitis, anemia, and endocrinesuch as thyroiditis, type 1 diabetes mellitusn-Hodgkin lymphoma, skin tumors, hamartoma, thyroid tumors
Figure 2. Diagnosis of VEOIBD. Patient and family history, physical examination, endoscopic investigations, imaging, andlimited biochemistry and microbiology/virology tests are required to establish the diagnosis of IBD, assess disease localizationand behavior, and determine inflammatory activity. If there is doubt, those tests can contribute to exclude the much morefrequent gastrointestinal infections and non-IBD immune responses toward dietary antigens. Cow’s milk protein allergy canpresent with enteropathy and colitis, and celiac disease can mimic autoimmune enteropathies. Fecal calprotectin can behelpful but may be increased even in healthy infants. The current diagnostic strategy to investigate a monogenic cause of IBD-like intestinal inflammation is largely based on restricted functional screening followed by genetic confirmation. A restricted setof laboratory tests is needed to propose candidate genes of the most common genetic defects for subsequent limitedsequencing. As a complementary approach, genetic screening for IBD-causative rare variants using next-generationsequencing might be followed by limited functional confirmatory studies. The complexity of problems in these children re-quires interdisciplinary support, including pediatric gastroenterologists, immunologists, geneticists, and infectious diseasespecialists. CBC, complete blood count; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; CMV, cytomegalo-virus; TB, tuberculosis; HIV, human immunodeficiency virus; CMPA, cow’s milk protein allergy.
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Skin lesions and dental and hair abnormalities, and Tu-mors). An important component of management is to solicitadvice from a specialist in VEOIBD.
Very early age of onset of intestinal symptoms and IBD-like endoscopic and histological changes are strong in-dicators of monogenic IBD as a group (Figure 1). However,there are clear gene-specific differences in the age of onset.The reported time of onset of IBD-like immunopathology insubgroups with, for example, IL-10 signaling defects, WAS, orIPEX, is infancy and early childhood. However, atypical lateonset of IBD has been reported in patients withWAS122,123 aswell as IPEX.124–126 The age is variable in neutrophil defects,B-cell defects, and XIAP deficiency. Indeed, XIAP deficiencycaused by identical genetic defects within families can beassociated with VEOIBD or adult-onset IBD.68,73,127 Otherdiseases, such as GUCY2C deficiency, typically develop duringadulthood (Figure 1). Phenotypes of many monogenic formsof IBD change over time; gastrointestinal problems can pre-sent as an initial or a later finding.
Some candidate disorders will be recognized by theirpathognomonic symptom combinations. Because there areno specific and fully reliable endoscopic and histologicalfeatures of monogenic VEOIBD, patients with VEOIBD andmultiple other features (listed in Table 3) should be
considered to have increased likelihood to carry disease-causing mutations. The degree of suspicion should dictatethe extent of functional and genetic exploration for an un-derlying cause. It is important to emphasize that in the ma-jority of patients with infantile IBD or VEOIBD, no geneticdefect has currently been discovered that would explain theimmunopathology. This fraction of causative defects will in-crease as our knowledge expands and with a growing num-ber of patients undergoing whole-exome sequencing (WES).Although young age of IBD onset is a strong indicator, astrong suspicion for amonogenic cause should lead to limitedfunctional or genetics screening irrespective of age.
Laboratory Tests and FunctionalScreens
Laboratory tests, upper and lower gastrointestinalendoscopy with histological analysis of multiple biopsyspecimens, and imaging should be performed for everypatient with VEOIBD according to guidelines.13,18–21,128
Histological investigation is paramount not only to differ-entiate IBD-like features but also to exclude other estab-lished pathologies such as eosinophilic or allergicgastrointestinal disease and infection.
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Cow’s milk protein allergy is common and can cause se-vere colitis that resembles UC and even requires hospitali-zation. It manifests typically within the first 2 to 3 months ofexposure to cow’s milk protein. This may be apparent withbreast-feeding or only after introducing formula feeding.Colitis resolves after cow’smilk is removed from the diet, so atrial of exclusive feeding with an amino acid–based infantformula is a customary treatment strategy for all VEOIBDdiagnosed when the patient is younger than 1 year of age.However, improvement of symptoms or inflammation doesnot exclude the possibility that a patient could have amonogenetic IBD disorder, because food intolerance and al-lergy can be secondary to the disorder and allergen avoid-ance by exclusive enteral nutrition with elemental formulacould also alleviate the inflammation of classic IBD.
High levels of IgE and/or eosinophilia are also found inpatients with monogenic disorders caused by defects inFOXP3, IL2RA, IKBKG, WAS, or DOCK8 (Table 2 andSupplementary Table 1). It should also be standard practiceto exclude infectious causes such as bacteria (Yersinia spp,Salmonella spp, Shigella spp, Campylobacter spp, Mycobac-terium tuberculosis, Clostridium difficile), parasites(Entamoeba histolytica, Giardia lamblia), and viral infections(cytomegalovirus or human immunodeficiency virus),remembering that some infections can mimic IBD. However,most of these pathogens do not cause bloody diarrhea formore than 2 to 3 weeks. In addition, monogenic disorders(such as B- or T-cell defect immunodeficiencies or familialHLH type 5, caused by STXBP2 deficiency) predispose pa-tients to intestinal infections.69 Celiac disease should beconsidered as a differential diagnosis for patients withsuspected autoimmune enteropathy presenting with villousatrophy (such as IPEX or IPEX-like patients).
To detect possible causes of monogenic IBD-like immu-nopathology, we propose additional laboratory screeningfor all children diagnosed before 6 years of age. The limitedset of laboratory tests includes measurements of IgA, IgE,IgG, and IgM; flow cytometry analysis of lymphocyte subsets(CD3, CD4, CD8, CD19/CD20, NK cells); and analysis ofoxidative burst by neutrophils (using the nitro blue tetra-zolium test or flow cytometry–based assays such as thedihydrorhodamine fluorescence assay).
When placed in the context of clinical, histopathologic,and radiological data, these tests can guide the diagnosistoward the more prevalent defects of neutrophil, B-cell, orT-cell dysfunction. Further tests are necessary to charac-terize particular subgroups, such as those who develop thedisease when they are younger than 2 years of age, thosewith excessive autoimmunity, or those with severe perianaldisease. Those tests include flow cytometry analysis of XIAPexpression by lymphocytes and NK cells129,130 or FOXP3expression in CD4þ T cells, which can diagnose a significantproportion of patients with XLP2 and IPEX. Flow cytometrycan detect functional defects in MDP signaling in patientswith XIAP deficiency.131 IL10RA and IL10RB defects can bedetected by assays that determine whether exogenous IL-10will suppress lipopolysaccharide-induced peripheral bloodmononuclear cell cytokine secretion or IL-10–inducedSTAT3 phosphorylation.30,103,107 Increased levels of
antibodies against enterocytes can indicate autoimmuneenteropathy, in particular in patients with IPEX.
In contrast to measurements of Igs, flow cytometry, andoxidative burst assays (which are largely standardized),other tests such as IL-10–mediated suppression of LPS-induced peripheral blood mononuclear cell activation anddetection of antibodies against enterocytes are nonroutineassays. Similarly, additional tests for extremely rare geneticdefects might be appropriate but are only available atspecialized laboratories, often as part of research projects.The clinical utility of the algorithm to use a limited set oflaboratory tests to differentiate between conventional andmonogenic VEOIBD, as suggested in Figure 2, is based onexperience, case reports, and case series of individual dis-orders. It has not been validated in prospective studies ofpatients with all forms of VEOIBD.
Diagnosis via Sequencing of Candidate GenesVersus Parallel Next-Generation Sequencing
The classic approach to detect monogenic forms of IBD,as described in the preceding text and summarized inFigure 2, is based on careful phenotypic analysis andcandidate sequencing to confirm a suspected genetic diag-nosis. Due to the increasing number of candidate genes,sequential candidate sequencing can be costly and timeconsuming. It is therefore not surprising to propose that thisstrategy of functional screening followed by genetic confir-mation will increasingly be complemented by early parallelgenetic screening using next-generation sequencing fol-lowed by functional confirmation. The US Food and DrugAdministration has recently granted marketing authoriza-tion for the first next-generation genomic sequencer, whichwill further pave the way for genome, exome, or other tar-geted parallel genetic tests in routine practice.132,133 WES oreven whole-genome sequencing will increasingly becomepart of the routine analysis of patients with suspected ge-netic disorders including subtypes of IBD.59,134,135 This hasseveral important implications for selecting candidate genelists, identification of disease-causing variants, and dealingwith a large number of genetic variants of unknown rele-vance. In research and clinical settings, WES has beenshown to reliably detect genetic variants that cause VEOIBDin genes such as XIAP,67 IL10RA,136,137 G6PC3,138 MEFV,59
LRBA,88 FOXP3,126 and TTC7A.38
There are several reasons to propose extended parallelcandidate sequencing for patients with suspected mono-genic IBD. Immune and gastrointestinal phenotypes of pa-tients evolve over time, whereas the diagnosis needs to bemade at the initial presentation to avoid unnecessary testsand treatment. IBD-like immunopathology can be linked tononclassic phenotypes of known immunodeficiencies, suchas hypomorphic genetic defects in SCID patients (in genessuch as ZAP70, RAG2, IL2RG, LIG4, ADA, DCLRE1C, CD3G, orTTC7A; see Table 2) with residual B- and T-cell develop-ment,38,81,82 glucose-6-phosphatase 3 deficiency with lym-phopenia,50 or FOXP3 defects without the classic IPEXphenotype.126 WES has revealed unexpected known causa-tive variants67 even after workup in centers with specialized
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immunologic and genetic clinical and research facilities. Thisall demonstrates that current knowledge about the diseasephenotype spectrum is incomplete, which means that a purecandidate approach is not reliable and genetic screeningmay have advantages. The 50 monogenic defects associatedwith IBD provide an initial filter to identify patients withmonogenic disorders.
Because of the greatly reduced costs of next-generationsequencing, it is probably cost effective in many cases toperform multiplex gene sequencing, WES, or whole-genomesequencing rather than sequential Sanger sequencing ofmultiple genes. A big advantage of WES is the potential toidentify novel causal genetic variants once the initialcandidate filter list of known disease-causing candidates hasbeen analyzed. The number of gene variants associated withVEOIBD is indeed constantly increasing, largely due to thenew sequencing technologies, so data sets derived fromWES allow updated analysis of candidates as well as novelgenes. Because multiple genetic defects can lead to spon-taneous or induced colitis in mice,1,139 assuming homology,it is likely that many additional human gene variants will beassociated with IBD.
Targeted sequencing of genes of interest is an alternativeapproach to exome-targeted sequencing. Initial studies toperform targeted next-generation parallel sequencingshowed the potential power of this approach.140 Targetednext-generation sequencing of the 170 primary immuno-deficiency (PID)-related genes accurately detected pointmutations and exonic deletions.140 Only 9 of 170 PID-related genes analyzed showed inadequate coverage. Fourof 26 patients with PID without an established prescreeninggenetic diagnosis, despite routine functional and genetictesting, were diagnosed, indicating the advantage of parallelgenetic screening. Because a major group of VEOIBD-causing variants is associated with PID-related genes, it isobvious how this approach can be adapted and extended tomonogenic IBD genes.
Genetic approaches also offer practical advantages.Specialized functional immune assays are often only avail-able in research laboratories and are not necessarily vali-dated; functional tests often require rapid processing ofperipheral blood mononuclear cells or biopsy specimens inspecialized laboratories. This means that handling of DNAand sequencing seems far less prone to error or variation.
However, relying solely on genetic screening can bemisleading, because computational mutation prediction canfail to detect functional damaging variants. For example,variants in the protein-coding region of the IL10RA geneweremisclassified as “tolerated” by certain prediction tools,whereas other prediction tools and functional analysis re-ported defects in IL-10 signaling.30 Although most studiesreport variants in protein-coding regions in monogenic dis-eases, there could be selection bias. It is indeed far moredifficult to establish thebiological effects of variants that affectprocesses such as splicing, gene expression, or messengerRNA stability. It should go without saying that novel geneticvariants require appropriate functional validation.
The increased availability of sequencing data sets high-lights the role of mutation-specific IBD-causing variants that
illustrate the functional balance of gene products affected bygain or loss of function variants as well as gene dosage ef-fects. Inherited gain-of-function mutations in guanylylcyclase cause diarrhea and increase susceptibility to IBD,whereas loss-of-function mutations lead to intestinalobstruction and meconium ileus.141 Gain-of-function muta-tions in STAT1 cause an IPEX-like syndrome with enterop-athy,116 whereas loss-of-function mutations are found inpatients with autosomal dominant chronic mucocutaneouscandidiasis.142 Loss of TTC7A activity results in multipleintestinal atresia and SCID,36,37,143 whereas hypomorphicmutations cause VEOIBD.38 Similarly, loss-of-function vari-ants cause classic SCID defects, whereas hypomorphicvariants in the same genes allow residual oligoclonalT-cell activation and are associated with immunopathology,including colitis.
Performing next-generation sequencing exome-wide orgenome-wide will identify (in each patient) genetic variantsof unknown relevance and, in some patients, known vari-ants that are associated with incomplete penetrance orvariable phenotype severity. Increasing use of DNAsequencing technologies will lead to detection of hypo-morphic variants that cause milder phenotypes and/or lateronset of IBD. The increased availability of genotype-phenotype data sets in databases such as ClinVar (http://www.ncbi.nlm.nih.gov/clinvar)144 or commercial databaseswill increase our ability to differentiate variants that causeIBD from those without biological effects. WES analysis ofpatients with pediatric onset of IBD, including VEOIBD, hasrevealed multiple rare genetic variants in those IBD sus-ceptibility genes that were discovered by associationstudies.145 Similarly, WES analysis of patients with geneti-cally confirmed mevalonate kinase deficiency identifiedmultiple variants in IBD-related genes outside of the MVKgene.146 It is currently not clear how strongly these rarevariants influence the genetic susceptibility to IBD as addi-tive or synergistic factors. In particular, in patients withnonconventional forms of IBD, the identification of variantsof unknown relevance can lead to the therapeutic dilemmaof whether to wait for the disease to progress or start earlytreatment. Because some of the disease-specific treatmentoptions have potentially severe adverse effects, carefulevaluation of genetic variants is required not only to vali-date sequence data147 and statistical association but toprovide functional evidence that those variants causedisease.133,148
ConclusionRare monogenic disorders that affect intestinal immune
and epithelial function can lead to VEOIBD and severephenotypes. These disorders are diagnosed based on clin-ical and genetic information. Accurate genetic diagnosis isrequired for assessing prognosis and proper treatment ofpatients. We summarized phenotypes and laboratory find-ings for more than 50 monogenic disorders and suggest adiagnostic strategy to identify these extremely rare dis-eases, which have large effects on patients and theirfamilies.
Supplementary MaterialNote: To access the supplementary material accompanyingthis article, visit the online version of Gastroenterology atwww.gastrojournal.org and at http://dx.doi.org/10.1053/j.gastro.2014.07.023.
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Author names in bold designate shared co-first authorship.
Received March 5, 2014. Accepted July 15, 2014.
Reprint requestsAddress requests for reprints to: Dr Holm H. Uhlig, TranslationalGastroenterology Unit, Experimental Medicine Division and Department ofPaediatrics, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU,England. e-mail: [email protected].
Conflicts of interestThe authors disclose the following: H.H.U. has participated in industrial projectcollaboration with Eli Lilly, UCB Pharma, and Vertex Pharmaceuticals andreceived travel support from GlaxoSmithKline Foundation, Essex Pharma,Actelion, and MSD. T.S. has received speaker’s fees from MSD and travelsupport from Nestlé Nutrition. S.K. has received consulting or speaker’s feesfrom AbbVie, Danone, Janssen Pharmaceutical Research & Development,Merck, MSD, Nestlé Nutrition, Vifor, and Wyeth and has participated inindustrial project collaboration with Euroimmun, Eurospital, Inova, MeadJohnson, Phadia/Thermo Fisher Scientific, and Nestlé Nutrition. N.S. hasserved as an advisory board member for Mead Johnson and received aunrestricted educational grant from MSD. D.C.W. has received consultingfees, speaker’s fees, meeting attendance support, or research support fromMSD, Ferring Pharmaceuticals, Falk, Pfizer, and Nestlé. S.P.T. has receivedconsulting fees from AbbVie, Cosmo Technologies, Ferring Pharmaceuticals,GlaxoSmithKline, Janssen Pharmaceutical Research & Development, Merck,Novartis, Novo Nordisk, Pfizer, Santarus, Schering-Plough, Shire
Pharmaceuticals, Sigmoid Pharma, Tillotts Pharma AG, UCB Pharma, Vifor,and Warner Chilcott UK; research grants from AbbVie, JanssenPharmaceutical Research & Development, Novartis, Pfizer, and UCB Pharma;and payments for lectures from AbbVie, Ferring Pharmaceuticals, Merck,Sanofi, and Tillotts Pharma AG. D.T. has received consulting fees, researchgrants, royalties, or honorarium from MSD, Janssen, Shire, Bristol-MyersSquibb, Hospital for Sick Children, and Abbott. S.B.S. has receivedconsulting fees from AbbVie, Janssen Pharmaceutical Research &Development, Talecris, Cubist, Ironwoods, and Pfizer; speaking fees fromUCB; and research grants from Pfizer. The remaining authors disclose noconflicts.
FundingH.H.U. is supported by the Crohn’s & Colitis Foundation of America. T.S. issupported by the Deutsche Forschungsgemeinschaft (SCHW1730/1-1). C.K.is supported by DFG SFB1054, BaySysNet, and DZIF. S.B.S is supported byNational Institutes of Health grants HL59561, DK034854, and AI50950 andthe Wolpow Family Chair in IBD Treatment and Research. A.M.M. issupported by an Early Researcher Award from the Ontario Ministry ofResearch and Innovation and a Canadian Institute of Health Researchoperating grant (MOP119457). This work was supported in part by a grantfrom The Leona M. and Harry B. Helmsley Charitable Trust (to A.M.M., C.K.,and S.B.S.). The COLORS in IBD Study Group is supported by a grant fromWellcome Trust Sanger Institute, a Crohn’s and Colitis UK grant to the UKand Irish Paediatric IBD Genetics Group, and in part by an Medical ResearchCouncil grant for the Paediatric-Onset Inflammatory Bowel Disease Cohortand Treatment Study (PICTS) study.
Supplementary Information for Table 1Examples of genetic variants with potential association
with IBD and syndromes associated with IBD are shown. Asystematic review of the literature was performed, focusingon IBD-like immunopathology in monogenic disorderslargely through PubMed and OMIM databases. In addition toan iterated literature search focused on pediatric onset ormonogenic IBD, an extensive list of primary immunodefi-ciencies1,2 was searched for occurrence of the PID-associated gene symbols (partially gene or protein name)with reports of “colitis” or “Crohn” or “IBD” or “inflamma-tory bowel disease.” A list of likely causative gene defectswith association with IBD-like immunopathology wascreated. We selected intestinal and extraintestinal clinicalfeatures as well as laboratory findings that define key sub-groups of patients with prototypic monogenic defects.
For each genetic defect, relevant reports were retrievedand selected clinical features and laboratory parameterswere recorded. Data extraction was performed indepen-dently by 4 clinicians using a structured approach. Dis-agreements in data interpretation were resolved by severalrounds of discussion until consensus was reached. All au-thors discussed key phenotype criteria that suggest mono-genic IBD-like immunopathology as well as the corediagnostic approach to VEOIBD.
Because there are a number of hypomorphic variantswith nonconventional phenotype, the key findings wereextracted from the patients with IBD-like immunopathologyand are therefore often but not necessarily representative ofthe classic disease phenotype. Activation mutations (gain offunction) in IKBA are associated with diarrhea due to en-teropathy, early intestinal infections, and possibly colitis.3–6
ITCH deficiency can lead to autoimmune enteropathy withlymphocytic inflammation of the small bowel lamina prop-ria, associated with antienterocyte antibodies, perinuclearantineutrophil cytoplasmic antibodies, or anti–smoothmuscle antibodies.7
A very early onset of colitis was reported in a girl withsevere congenital hypertriglyceridemia. WES identifiedcompound heterozygous mutations in the GPIHBP1 gene.8
Patients who developed IBD have been reported in otherdisorders. These include SIRT1 defects,9 Wolfram syndrome(WFS1),10 Niemann–Pick type C disease (NPC1),11–13 Char-cot–Marie–Tooth disease (CMT4C),14 Gorlin syndrome(PTCH1),15 and Brooke–Spiegler syndrome (CYLD).16
No genetic diagnosis was provided in a patient with Che-diak–Higashi syndrome17 and patients with autoimmunelymphoproliferative syndrome18 (personal communication,David Teachey, October 2013). Clear syndromal featureswithout genetic diagnosis are seen in other patients, such as inpigmentary disorder, reticulate, with systemic manifestation(PDR syndrome)19 or leukoencephalopathy, arthritis, colitis,and hypogammaglobulinemia (LACH syndrome).20 Inflam-mation of the small and large bowel was found in patientswith tufting enteropathy confirmed by negative epithelial celladhesion molecule immunohistochemical staining.21 Inter-estingly, the inflammatory infiltrates in those patients withtufting enteropathy resolved spontaneously over time.
A group of complement defects can present with intes-tinal inflammation. Despite a range of possible candidategenes, for the majority there is either no genetic diagnosisprovided, no histological proof of IBD-like intestinalinflammation, or single patient adult-onset IBD that couldpresent a chance finding or publication bias (reviewed byMarks et al22,23). This includes C2 deficiency and C1-esterase deficiency (reviewed by Marks et al22,23), C6 defi-ciency,24 or H-ficolin deficiency (FCN3).25
Supplementary Information for Figure 1Additional information is provided regarding age of in-
testinal inflammation in patients with CGD,26,27 IPEX,28–47
WAS,48–51 ITGB2,52 IL10RA,53 and LRBA defects.
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3. Dupuis-Girod S, Cancrini C, Le Deist F, et al. Successfulallogeneic hemopoietic stem cell transplantation in achild who had anhidrotic ectodermal dysplasia with im-munodeficiency. Pediatrics 2006;118:e205–e211.
4. Ohnishi H, Miyata R, Suzuki T, et al. A rapid screeningmethod to detect autosomal-dominant ectodermaldysplasia with immune deficiency syndrome. J AllergyClin Immunol 2012;129:578–580.
5. Janssen R, van Wengen A, Hoeve MA, et al. The sameIkappaBalpha mutation in two related individuals leads tocompletely different clinical syndromes. J Exp Med 2004;200:559–568.
6. Lopez-Granados E, Keenan JE, Kinney MC, et al. A novelmutation in NFKBIA/IKBA results in a degradation-resistant N-truncated protein and is associated withectodermal dysplasia with immunodeficiency. HumMutat 2008;29:861–868.
7. Lohr NJ, Molleston JP, Strauss KA, et al. Human ITCH E3ubiquitin ligase deficiency causes syndromic multi-system autoimmune disease. Am J Hum Genet 2010;86:447–453.
8. Gonzaga-Jauregui C, Mir S, Penney S, et al. Whole-exome sequencing reveals GPIHBP1 mutations in a caseof infantile colitis with severe hypertriglyceridemia.J Pediatr Gastroenterol Nutr 2014;59:17–21.
9. Biason-Lauber A, Boni-Schnetzler M, Hubbard BP, et al.Identification of a SIRT1 mutation in a family with type 1diabetes. Cell Metab 2013;17:448–455.
10. Hildebrand MS, Sorensen JL, Jensen M, et al. Autoim-mune disease in a DFNA6/14/38 family carrying a novelmissense mutation in WFS1. Am J Med Genet A 2008;146A:2258–2265.
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