Table 1

Genetic defects associated with IBD-like immunopathology

Group of defects (monogenic disorder)GeneMode of inheritance
Epithelial barrier and epithelial response defects
Dystrophic epidermolysis bullosaCOL7A1Autosomal recessive
  CS: moderately severe colitis19 (personal communication A Martinez and N Shah)
Kindler syndromeFERMT1Autosomal recessive
  CS: haemorrhagic UC-like colitis99
  CR: 1 of 4 patients colitis19 (personal communication A Martinez and N Shah)
X linked ectodermal dysplasia and immunodeficiencyIKBKGX 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 deficiencyADAM17Autosomal recessive
  CR: skin, hair and gut pathology. First week of life non-bloody later bloody diarrhoea27
Familial diarrhoeaGUCY2CAutosomal 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 diseaseCYBBX linked
  ID: Pneumonia, abscesses, osteomyelitisCYBA, NCF1, NCF2, NCF4Autosomal 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 1bSLC37A4Autosomal recessive
  ID: Neutropenia and neutrophil dysfunction, including defective chemotaxis
  Perioral and perianal lesions, ileitis and colitis; CD-like36 37 43
Congenital neutropeniaG6PC3Autosomal 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 1ITGB2Autosomal 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 deficiencyMVKAutosomal 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 defectsPLCG2Autosomal 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 feverMEFVAutosomal 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 5STXBP2Autosomal 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 2XIAPX linked
  CS: very early onset and severe fistulising perianal disease in about 20% of patients50–53
X linked lymphoproliferative syndrome 1SH2D1AX linked
  CS: Three patients with large SH2D1A gene deletions with gastrointestinal symptoms of colitis and gastritis109
Hermansky–Pudlak syndromeHPS1, HPS4, HPS6Autosomal 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 1ICOSAutosomal 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 8LRBAAutosomal recessive
  CS: disturbed B cell development or activation, cytopenias including neutropenia and autoimmunity.63–65 Duodenal villous atrophy, lymphocytic colitis or CD-like63–65
AgammaglobulinaemiaBTKX 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
PIK3R1Autosomal recessive
  CR: Erythema nodosum, arthritis and colitis, infections, complete absence of B cells in bone marrow and peripheral blood122
Hyper-IgM syndromeCD40LGX linked
  ID: Autoimmunity (such as sclerosing cholangitis).123 Oral ulcers, chronic neutropenia124
  CR: Two of 56 patients IBD-like124
AICDAAutosomal recessive
  CS/CR: Six of 29 patients autoimmune pathology, including one patient with CD-like disease68
Wiskott–Aldrich syndromeWASX 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 syndromeDCLRE1CAutosomal 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 syndromeDOCK8Autosomal 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 syndromeSKIV2L, TTC37Autosomal 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 syndromePTENAutosomal 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, enteropathyFOXP3X linked
IL2RAAutosomal 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 defectsIL10RA, IL10RB, IL10Autosomal 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 diseaseRETAutosomal 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.