Genetic defects associated with IBD-like immunopathology
| Group of defects (monogenic disorder) | Gene | Mode of inheritance |
|---|---|---|
| Epithelial barrier and epithelial response defects | ||
| Dystrophic epidermolysis bullosa | COL7A1 | Autosomal recessive |
| CS: moderately severe colitis19 (personal communication A Martinez and N Shah) | ||
| Kindler syndrome | FERMT1 | Autosomal recessive |
| CS: haemorrhagic UC-like colitis99 | ||
| CR: 1 of 4 patients colitis19 (personal communication A Martinez and N Shah) | ||
| X linked ectodermal dysplasia and immunodeficiency | IKBKG | X linked |
| ID: Hyper-IgM syndrome, natural killer cell dysfunction, susceptible to infections100 | ||
| CS: NEMO patients with autoimmune manifestations, including IBD-like.101 Atypical CD-like enterocolitis, villous atrophy and epithelial cell shedding.23 | ||
| CR: anti-TNFα in an 11-year-old boy with severe colitis and high TNFα due to gene reversion mosaicism102 | ||
| ADAM-17 deficiency | ADAM17 | Autosomal recessive |
| CR: skin, hair and gut pathology. First week of life non-bloody later bloody diarrhoea27 | ||
| Familial diarrhoea | GUCY2C | Autosomal dominant |
| CS: 32 members of a family with partially neonatal onset of watery diarrhoea. Seven developed ileal and colonic CD between 22 and 65 years of age20 | ||
| CR: IBD onset at 5 year of age (A Janecke, personal communication). | ||
| Neutropenia and defects in phagocyte bacterial killing | ||
| Chronic granulomatous disease | CYBB | X linked |
| ID: Pneumonia, abscesses, osteomyelitis | CYBA, NCF1, NCF2, NCF4 | Autosomal recessive |
| 37% of patients colitis with granulomas and pigmented macrophages.103 Onset between infancy and 41 years; median age 5 years) | ||
| CS: Patients with IBD-like pathology (CYBB, NCF1, NCF2)32 | ||
| CR: 3-year-old boy with perioral and perianal rash, aphthous ulcers, discontinuous gastrointestinal inflammation with colonic granulomata (NCF4)33 | ||
| CR: bloody diarrhoea since third month of life (CYBA)34 | ||
| Glycogen storage disease type 1b | SLC37A4 | Autosomal recessive |
| ID: Neutropenia and neutrophil dysfunction, including defective chemotaxis | ||
| Perioral and perianal lesions, ileitis and colitis; CD-like36 37 43 | ||
| Congenital neutropenia | G6PC3 | Autosomal recessive |
| ID: Congenital neutropenia | ||
| CS: Four of 11 patients older than 18 years of age developed CD-like disease92 104 | ||
| CR: Child with neutropenia and T cell lymphopenia lacking naive CD4 +CD31+CD45RA+ cells.38 Oral and genital ulcerations started at 6 years of age. Colonic lesions without granuloma or increased cryptic abscesses at the age of 10 years | ||
| Leucocyte adhesion deficiency 1 | ITGB2 | Autosomal recessive |
| ID: Defects in chemotaxis, phagocytosis and bacterial killing | ||
| CR: CD-like with discontinuous ulcerative stomatitis, ileocolitis, perianal abscess, fistulas, adhesions, strictures.39 40 Onset under 2 years of age39 | ||
| Hyper- and autoinflammatory disorders | ||
| Mevalonate kinase deficiency | MVK | Autosomal recessive |
| ID: Febrile attacks, lymphadenopathy, joint pain, skin lesions, splenomegaly, recurrent infections, hypogammaglobulinaemia, polyarthritis, Sjögren's syndrome47 49 | ||
| CS: 27 of 50 patients presented with autoimmunity and IBD47 | ||
| Onset: GI symptoms started during the first 6 months of life in 3 and before the age of 5 years in 46 of 50 patients | ||
| Phospholipase Cγ2 defects | PLCG2 | Autosomal dominant |
| ID: Autoinflammatory disease with mild immunodeficiency, skin lesions and IBD105 | ||
| CR: At the age of 6 months bloody diarrhoea and UC was colonoscopically and histologically diagnosed at the age of 2 years105 | ||
| Familial Mediterranean fever | MEFV | Autosomal recessive |
| ID: Paroxysmal polyserositis, periodic fever, autoimmunity | ||
| CS: UC-like immunopathology.106 107 Three of 7 children with infantile UC MEFV mutations.107 Therapeutic response to colchicine.106 107 In adult IBD patients no consistent associations with common MEFV variants | ||
| Familial haemophagocytic lymphohistiocytosis type 5 | STXBP2 | Autosomal recessive |
| ID: Fever, splenomegaly, haemophagocytosis and cytopenia of two cell types | ||
| CS: Atypical symptoms include diffuse IBD-like colitis and hypogammaglobulinaemia108 | ||
| X linked lymphoproliferative syndrome 2 | XIAP | X linked |
| CS: very early onset and severe fistulising perianal disease in about 20% of patients50–53 | ||
| X linked lymphoproliferative syndrome 1 | SH2D1A | X linked |
| CS: Three patients with large SH2D1A gene deletions with gastrointestinal symptoms of colitis and gastritis109 | ||
| Hermansky–Pudlak syndrome | HPS1, HPS4, HPS6 | Autosomal recessive |
| Oculocutaneous albinism and bleeding diathesis; neutropenia, lung fibrosis and granulomatous colitis110 | ||
| Enterocolitis in 8 of 122 patients.111 Enterocolitis with HPS1 and HPS4 mutations common111–113 with HPS6 mutations rare.114 115 Age of onset IBD in adolescent age but as young as age 3 years.116 CD-like pathology (discontinuous granulomatous partially fistulising inflammation of colon, small intestine or buccal mucosa) and effective response to anti-TNFα treatment111 115 117–119 | ||
| Immune defects that include T and B cell selection and activation defects | ||
| B cell and antibody defects | ||
| Common variable immunodeficiency type 1 | ICOS | Autosomal recessive |
| CR: Autoimmunity (rheumatoid arthritis, interstitial pneumonitis and psoriasis) and IBD.62 Decreased percentage of CD4 central and effector memory T cells, impaired cytokine polarisation and reduced regulatory T cells62 | ||
| Common variable immunodeficiency type 8 | LRBA | Autosomal recessive |
| CS: disturbed B cell development or activation, cytopenias including neutropenia and autoimmunity.63–65 Duodenal villous atrophy, lymphocytic colitis or CD-like63–65 | ||
| Agammaglobulinaemia | BTK | X linked |
| Reduced levels of serum antibodies and peripheral B cells. Autoimmunity (arthritis, haemolytic anaemia, thrombocytopenia or neutropenia) | ||
| CS: CD-like.120 Very early onset of colitis121 | ||
| PIK3R1 | Autosomal recessive | |
| CR: Erythema nodosum, arthritis and colitis, infections, complete absence of B cells in bone marrow and peripheral blood122 | ||
| Hyper-IgM syndrome | CD40LG | X linked |
| ID: Autoimmunity (such as sclerosing cholangitis).123 Oral ulcers, chronic neutropenia124 | ||
| CR: Two of 56 patients IBD-like124 | ||
| AICDA | Autosomal recessive | |
| CS/CR: Six of 29 patients autoimmune pathology, including one patient with CD-like disease68 | ||
| Wiskott–Aldrich syndrome | WAS | X linked |
| ID: eczema, thrombocytopenia and susceptibility to infection. Autoimmune haemolytic anaemia, neutropenia, arthritis and vasculitis57 | ||
| UC-like continuous colonic inflammation with crypt abscesses in early infancy | ||
| Omenn syndrome | DCLRE1C | Autosomal recessive |
| ID: Erythroderma, desquamation, diarrhoea, lymphadenopathy, hepatosplenomegaly, hypereosinophilia and increased IgE. Oligoclonal T-cells and often largely reduced B-cells | ||
| CR: Lymphopenic girl with a hypomorphic mutation in DCLRE1C allowing residual B and T cell development. Chronic ulcerating intestinal inflammation since 9 months of age was steroid dependent over several years until HSCT cured IBD-like pathology58 | ||
| Hyper IgE syndrome | DOCK8 | Autosomal recessive |
| Eczema, elevated serum IgE, multiple allergies, multiple infections. Sclerosing cholangitis, buccal granulomatous disease85 | ||
| CR: age of 2 year; atypical features CD4+ T cell lymphopenia and colitis85 | ||
| Trichohepatoenteric syndrome | SKIV2L, TTC37 | Autosomal recessive |
| Intractable diarrhoea, hepatopathy and trichorrhexis nodosa, low immunoglobulin levels and defect in vaccine response | ||
| Onset of diarrhoea is in the first few weeks of life87 125 | ||
| CS: Colitis in 6 of 18 patients with TTC37 and 3 of 6 patients with SKIV2L defects86 87 | ||
| PTEN hamartoma tumour syndrome | PTEN | Autosomal dominant |
| ID: gastrointestinal lymphoid hyperplasia, inflammatory polyps, autoimmunity (anaemia, thyroiditis)59 | ||
| CR: Indeterminate colitis in two patients59 (manuscript in preparation) | ||
| Regulatory T cells and immune regulation | ||
| X linked immune dysregulation, polyendocrinopathy, enteropathy | FOXP3 | X linked |
| IL2RA | Autosomal recessive | |
| ID: Polyendocrinopathy, enteropathy, eczema, high IgE, autoantibodies and recurrent infections | ||
| CS: First 2 years of life with watery or bloody diarrhoea, subtotal or total villous atrophy and colitis74 75 | ||
| CR: IPEX-like immune dysregulation with enteropathy76 | ||
| IL-10 signalling defects | IL10RA, IL10RB, IL10 | Autosomal recessive |
| Bloody diarrhoea, abscesses, perianal fistula and folliculitis, oral aphthous lesions, arthritis, discontinuous colitis with deep ulcerations reminiscent of CD80–82 126–128 | ||
| Onset gastrointestinal symptoms within the first 3 months of life | ||
| Defects in intestinal innervation | ||
| Hirschsprung's disease | RET | Autosomal dominant |
| Enterocolitis: lymphocyte and neutrophil infiltration (cryptitis, crypt abscesses and ulceration of mucosal epithelium), intestinal perforation | ||
| Germline RET mutation in 3 of 7 patients with preoperative enterocolitis22 | ||
Gene names were used according to HUGO gene nomenclature.
Example publications related to this table are provided partially as online supplemental information.
Note: A patient with Chediak–Higashi syndrome and CD was described before genetic diagnosis became available.129
The role of complement defects such as C2- and C1-esterase deficiency for causing IBD-like inflammation is currently not clear (reviewed by Marks and colleagues130). Although there are descriptions of patients with selective IgA deficiency and CD or UC, the estimated association can be explained by the high incidence of IgA deficiency (reviewed by Marks6).
CD, Crohn's disease; CR, case report; CS, case series; HSCT, haematopoietic stem cell transplantation; IBD, inflammatory bowel disease; ID, immune defect; IL, interleukin; NEMO, nuclear factor kB essential modulator protein; TNFα, tumour necrosis factor α; UC, ulcerative colitis.