Table 2:
Genetic causes of VEO-IBD*
| Gene (Inheritance pattern) | Frequency of IBD among those with gene defect | History | Physical examination | Immunologic features |
|---|---|---|---|---|
| High likelihood of presenting with VEO-IBD | ||||
| ADAM17 (AR) | >80% | Staphylococcal infections | Psoriasiform erythroderma, pustules, broken hair, abnormal nails | Slightly low TNF response to LPS in PBMCs and T cells. |
| ARPC1B | >80% | Vasculitis prominent | Vasculitis | Microthrombocytes with aberrant spreading |
| FOXP3 (XL) | >80% enteropathy | Onset near birth | Dermatitis | Low regulatory T cells |
| GUCY2C (AD GOF) | >80% diarrhea, IBD less common | Ileal obstruction, adhesions, esophagitis, electrolyte abnormalities | Dilation of small intestine | Not assessed |
| IL10 (AR) | >80% | IBD onset near birth | Folliculitis, perianal disease | Normal |
| IL10RA (AR) | >80% | IBD onset near birth | Folliculitis, perianal disease | Lack of IL-10 suppression of LPS response |
| IL10RB (AR) | >80% | IBD onset near birth | Folliculitis, perianal disease | Lack of IL-10 suppression of LPS response |
| MALT1 | >80% | Respiratory infections, sepsis, CMV | Dermatitis | Poor response to vaccines, poor antigen-specific proliferation, low switched memory B cells |
| PLA2G4A | >80% stenosing enteritis | Early strictures, Platelet dysfunction |
- | None reported |
| SKIV2L (AR) | >80% enteropathy | IUGR, FTT | Trichorrhexis nodosa, frontal bossing | Villous atrophy, low immunoglobulins, low T cells |
| SLC02A1 (AR) |
>80% ileal ulceration (females) | No response to TNF inhibitors | Digital clubbing in males | Normal |
| SLC9A3 | >80% | Prenatal onset diarrhea | Abdominal distension | Normal or Low IgG, high fecal sodium |
| TTC37 (AR) | >80% enteropathy | IUGR, FTT | Trichorrhexis nodosa, frontal bossing | Villous atrophy, low immunoglobulins, low T cells |
| TTC7A (AR) | >80% | Intestinal atresia | Dermatitis, alopecia | Low T cells |
| Intermediate likelihood of presenting as VEO-IBD | ||||
| COL7A1 (AR) | 16% in childhood | Epidermolysis bullosa | Bullous lesions | Normal or low IgG |
| FERMT1 (AR) | 25% in adults | Infections | Bullous lesions, progressive poikiloderma, gingival fragility |
- |
| IKBKG (XL) | >50% by mid-childhood | Infections | Hypodontia, poor sweat, thin hair, frontal bossing | Poor titers, low NK function, abnormal TLR responses |
| IL2RA (AR) | 30–50% | Infections | - | Poor T cell responses |
| IL2RB (AR) | 30–50% | Infections | - | Poor T cell responses |
| POLA1 | 50% in males | FTT, corneal disease | Reticular pigmentation, photophobia | High interferon signature, amyloid in papillary dermis |
| RTEL (AR) | 30–50% | IUGR, FTT, microcephaly | Fine hair | Low NK cells, apoptosis in biopsy |
| SLC37A4 | 30% | Hypoglycemic episodes | Hepatomegaly | Poor neutrophil funciton |
| STXBP2 (AR) | <50% | HLH | - | Poor NK function, low IgG |
| XIAP (XL) | 30–50% | HLH, IBD does not respond to medications | Splenomegaly | Low IgG |
| Lowest likelihood of presenting with VEO-IBD | ||||
| BTK (XL) | <10% in early life | Infections | Small tonsils | Very low B cells and immunoglobulins |
| CTLA4 (AD) | <10% in early childhood | Infections, interstitial pneumonitis | - | Low immunoglobulins, low switched memory B cells, low CD4 T cells |
| CYBA (AR) P22phox |
<10% in early life | Infections | - | Low DHR, reduced switched memory B cells, low T cells |
| CYBB (XL) Gp91phox |
<10% in early life | Infections, maternal discoid lupus | - | Low DHR, reduced switched memory B cells, low T cells |
| DKC1 (XL) | <10% in early childhood | Microcephalic, IUGR | Small, nail dystrophy | Low B cells. NK cells |
| DOCK8 (AR) | ? | Cutaneous viral infections, other infections | Eczema | Low T cells, high eosinophils |
| G6PC3 (AR) | <10% | Cardiac anomalies, urogenital defects, IUGR | Superficial vessels enlarged | Neutropenia, intermittent thrombocytopenia, lymphopenia in severe forms |
| HPS1 (AR) | <10% in early childhood | Pulmonary fibrosis, founder effect in Puerto Rico and Swiss Alps, bleeding | Oculocutaneous albinism | Pigmented macrophages, lymphoid aggregates on biopsy |
| HPS4 (AR) | <10% in early childhood | Pulmonary fibrosis, bleeding | Oculocutaneous albinism | Pigmented macrophages, lymphoid aggregates on biopsy |
| HSP6 (AR) | <10% early childhood | Bleeding | Oculocutaneous albinism | Pigmented macrophages, lymphoid aggregates on biopsy |
| ICOS (AR) | <10% | Infectious enteritis, founder effect along the Danube river | Splenomegaly | Absent class switched memory B cells, low TFH, poor germinal centers in lymph nodes, low IgG, nodular lymphoid hyperplasia of GI tract |
| ITGB2 (AR) | <10% in early childhood | Severe infections, delayed separation of umbilical cord | Gingivitis, scarring (poor wound healing) | High WBC/ANC, low CD18 expression, reduction of factor XIIIa+ DC in lymph node |
| LRBA (AR) | <10% in early childhood | Infections, interstitial pneumonitis | - | Low immunoglobulins, low switched memory B cells, low CD4 T cells |
| MEFV (AR) | <10% | Serositis, founder effect in Mediterranean | - | - |
| MVK | <10% in early life | Nausea and fever episodically, abdominal pain | Adenopathy, oral ulcers, arthritis | - |
| NCF1 (AR) P47phox |
<10% in early life | Infections | - | Low DHR, reduced switched memory B cells, low T cells |
| NCF2 (AR) P67phox |
<10% in early life | Infections | - | Low DHR, reduced switched memory B cells, low T cells |
| NPC1 | <10% in early life | Airway infections, developmental delay | Splenomegaly, ataxia | Foam cell macrophages on biopsy |
| PIK3CD (AD GOF) P100 |
<10% in early life | Infections, PSC, herpes, lymphoma | Bronchiectasis, adenopathy, HSM | High IgM, low IgG, low CD4/CD45RA, nodular lymphoid hyperplasia, EBV viremia |
| PIK3R1 (AD LOF) P85 |
<10% in early life | Insulin resistance | Short stature | High IgM, low IgG, low CD4/CD45RA, nodular lymphoid hyperplasia, |
| PLCG2 (AD) | <10% in early childhood | Pleomorphic inflammation, may be cold induced | Dermatitis, evaporative cooling may induce urticaria | Low immunoglobulins, low switched memory B cells |
| PTEN (AD) | <10% in early life | Thyroiditis, autoimmune hemolytic anemia, hamartomas | Adenopathy, large tonsils, macrocephaly, developmental delay | Nodular lymphoid hyperplasia, low IgG |
| SLC26A3 (AR) | <10% in early life, but all have diarrhea | Onset of secretary diarrhea at birth | - | Inflammation occurs later in life |
| SLC37A4 (AR) | <10% in early life | Hypoglycemic episodes | Hepatomegaly | Neutropenia |
| STAT1 (AD GOF) | <10% in early life but enteropathy common | Pleomorphic autoimmunity, candida, other infections | Poor growth | Low NK cells, low IgA |
| STAT3 (AD GOF) | <10% in early life but enteropathy common | Pleomorphic autoimmunity: diabetes, thyroid | Poor growth, eczema | Low regulatory T cells, low IgG |
| TGFBR1 (AD) | <10% early in life | Aneurysms, | Cleft palate/uvula, hypertelorism, arachnodactyly, pectus, joint laxity | Eosinophilic colitis, high IgE, high eosinophils |
| TGFBR2 (AD) | <10% early in life | Aneurysms, | Cleft palate/uvula, hypertelorism, arachnodactyly, pectus, joint laxity | Eosinophilic colitis, high IgE, high eosinophils |
| WAS (XL) | <10% early in life | Thrombocytopenia | Eczema | Poor T/B/NK function |
| ZBTB24 (AR) | <10% | Developmental delay | Frontal bossing, short stature | Progressive decline in antibodies and T cells |
| Unknown frequency of IBD | ||||
| ALPI (AR) | ? | None noted | - | - |
| ANKZF1 (AR) | ? | Infantile onset IBD | Perioral and oral inflammation | Lymphocytic colon infiltrates, T/B/NK lymphopenia (some) |
| CD55 | ? | Protein losing enteropathy, thrombosis | Complement deposition on biopsy | |
| DUOX2 | ? | Hypothyroidism | - | High lymphocyte count |
| IL21R (AR) | ? | Cryptosporidia, cholangitis | - | Low switched memory B cells |
| IL21 (AR) | ? | Infections | - | Low B cells, low switched memory B cells, low IgG |
| NCF4 (AR) P40phox |
? | Infections | - | DHR slightly low |
| NLRC4 (AD) | ? | HLH, episodic inflammation | - | - |
| TGFB1 | ? | Encephalopathy, eosinophilic esophagitis | Posterior leukoencephalopathy | High IgG and IgE, poor proliferative responses |
| TRIM22 | ? | Early infancy onset, infections | Severe perianal disease | - |
*
Excluding leaky severe combined immunodeficiency genes- all of which could theoretically be associated with VEO-IBD.
Abbreviations: DHR= dihydrorhodamine, HLH= hemophagocytic lymphohistiocytosis, IUGR= intrauterine growth retardation, FTT= failure to thrive, HSM= hepatosplenomegaly, and PSC= primary sclerosing cholangitis. Inheritance is given as AR= autosomal recessive, AD= autosomal dominant, XL= X-linked, GOF= gain of function mutation.