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©The Author(s) 2025.
World J Clin Pediatr. Sep 9, 2025; 14(3): 107165
Published online Sep 9, 2025. doi: 10.5409/wjcp.v14.i3.107165
Published online Sep 9, 2025. doi: 10.5409/wjcp.v14.i3.107165
Table 1 Classification of Monogenic inflammatory bowel disease: Etiology, pathogenesis and clinical manifestations
| Group | Genetic condition/ gene (in capital letters)/mode of inheritance (in brackets)1 | Pathogenesis/mechanism | Disease phenotype | Associated manifestations | Ref. |
| Dysfunction of neutrophil granulocytes | 5 components of nicotinamide adenine dinucleotide phosphate hydrogen oxidase (phox) | ||||
| Gp91-phox, CYBB (X-linked), p22-phox, CYBA (AR), p47-phox, NCF1 (AR), p67-phox, NCF2 (AR), p40-phox, NCF4 (AR) | Decreased neutrophil oxidative burst in the intestinal mucosa predisposes to ineffective clearance of bacteria, which provokes a granulomatous reaction, leading to chronic inflammation characteristic of CD, hypergammaglobulinemia | Crohn’s like colitis/IBD-U, recurrent non-bloody diarrhea | Recurrent infections with catalase positive organisms, gastric outlet obstruction epithelioid granulomas in histopathology, pigmented macrophages and multinucleate giant cells | Marks et al[29], Angelino et al[30], Korzenik et al[31] | |
| Defects in glucose-6-phosphate-translocase, SLC37A4 (AR) | Neutropenia, neutrophil dysfunction | Crohn’s like colitis, perianal fistula | Hypoglycemia, hepatomegaly, bleeding manifestations | Melis et al[74] | |
| Glucose-6-phosphatase-catalytic subunit 3, G6PC3 (AR) | Severe congenital neutropenia, insufficient utilization of glycolysis in neutrophils and monocytes in response to lipopolysaccharides hypoglycolytic neutrophils and monocytes release IL-1β and IL-18 (cause pyroptosis) | Crohn’s like colitis, stricturizing disease | Oral ulcers, arthritis, superficial venous patterns, cardiac defects, facial dysmorphism | Mistry et al[32], Boztug et al[33] | |
| Leukocyte adhesion deficiency 1, ITGB2 (AR) | Leukocytosis, defective chemotaxis and bacterial killing, paucity of tissue neutrophils leads to excessive production of IL-23 and IL-17, which are pro-inflammatory | Crohn’s like colitis, stricturizing phenotype | Recurrent skin infections without pus formation, delayed separation of umbilical cord, periodontal infections | Moutsopoulos et al[34] | |
| Hyper- inflammatory and auto-inflammatory disorders | Mevalonate kinase deficiency, mevalonate kinase, MVK (AR) | Defect in mevalonate pathway of cholesterol synthesis, leading to innate immunity activation, and excessive IL-1β, IL-6, TNF secretion | Neonatal onset UC, perianal disease, strictures | Recurrent fever, arthralgia, hyperimmunoglobulinemia D | Favier et al[25] |
| Autoinflammatory phospholipase Cγ2-associated antibody deficiency and immune dysregulation, phospholipase C gamma 2, PLCG2 (AD) | Activation of phospholipase Cγ2 leads to NLRP3 inflammasome activation | Infantile-onset UC | Arthralgia, conjunctivitis, urticaria, pyoderma gangrenosum, vesciculo-pustular rashes, sinopulmonary infections, low Igs (IgM, IgA, IgG, B cells and NK cells) | Wu et al[35] | |
| Familial MEFV, MEFV (AR) | MEFV encodes pyrin, which regulates caspase-1 activation and suppresses IL-1β activation | Crohn’s like colitis, IBD-U, stricturizing disease, infantile UC | Recurrent fevers, erythematous rash, serositis | Yokoyama et al[26] | |
| Hermansky Pudlak Syndrome, HPS1, adaptor related protein complex 3 subunit beta 1, HPS3, HPS4, HSP5, HPS6, DTNBP1, BLOC1S3, PLDN (AR) | Impaired antimicrobial activity due to abnormal lysosomal trafficking | Crohn’s colitis, fistulizing, perianal disease | Partial albinism, bleeding tendency, recurrent infections, macrophage activation syndrome, ceroid lipofuscin in the reticuloendothelial system | Bolton et al[15], O'Brien et al[36] | |
| X-linked lymphoproliferative syndrome 2, XIAP (X-linked) | XIAP is required for NOD1 and NOD2 signaling, and provides innate immunity against pathogens by activation of the of NF-κB and mitogen-activated protein kinases pathways, provides anti-fungal immunity by Dectin-1 signaling and regulates the activation of NLRP3 inflammasome. XIAP loss causes dysregulation of classical caspase-1/inflammasome activation, overproduction of inflammatory cytokines and cell death | Crohn’s like colitis, perianal disease | Recurrent infections, HLH, splenomegaly, cytopenia, arthritis skin abscesses, EBV and CMV infections, cytopenias, splenomegaly, lymphadenopathy, hypogammaglobulinemia | Mudde et al[22] | |
| TRIM22 defect, TRIM22 (AR) | It is expressed in the intestine and macrophages, TRIM22 variants disrupt both NOD2- dependent NF-κB and IFN-β signaling | Crohn’s like colitis, perianal disease | Granulomatous colitis, fever, oral ulcers | Li et al[37] | |
| Familial HLH type 5, STXBP2 (AR) | Defective vesicle transport in NK cell and cytotoxic T cells lead to impairment of degranulation, STXBP2 can disrupt NHE3 trafficking, this changes the gut microbiota resulting in IBD | Intractable diarrhea | HLH, Crohn’s like colitis, perianal disease, microvillous inclusion disease | Fujikawa et al[38] | |
| Complex defects in T cells and B cells function | LRBA deficiency, LRBA (AR) | LRBA is involved in vesicular trafficking of CTLA-4, its absence leads to rapid degradation of CTLA-4, leading to diminished CTLA-4 in Tregs and activated conventional T cells, (CTLA-4 competes with CD28 and terminates excessive T cell proliferation by binding to CD80/86) Increased double-negative T cells, decreased B cells, hypogammaglobulinemia, low ratio of naïve: Memory T cells, and reduced capacity of T cells to secrete various cytokines following stimulation, lower expression of CD 25 and FOXP3 in Tregs | Crohn’s like enterocolitis (IPEX-like) | Erythema nodosum, AIHA, T1DM, hepatitis, uveitis, psoriasis, thyroiditis, splenomegaly, lymphoproliferation, Burkitt’s lymphoma, exocrine pancreatic insufficiency, interstitial lung disease, repeated sino-pulmonary infections (presents early in pre-school children) | Vardi et al[19], Lo et al[39] |
| CTLA-4 insufficiency, CTLA-4 (AD) | CTLA-4 is constitutively active in Tregs and expressed in conventional T cells upon activation. It inhibits immune responses, by competing with the costimulatory molecule CD28 for the ligands CD80 and CD86 on the antigen-presenting cells. Its insufficiency leads to excess T cell activation, lymphoproliferation, autoimmunity and compromised B cell function (due to chronic B cell stimulation) | CD, UC, IPEX-like | T1DM, autoimmune thyroiditis, interstitial lung disease, AIHA, immune thrombocytopenia, lymphadenopathy, splenomegaly, gastric adenocarcinoma, demyelinating encephalopathy (presents in young adults) | Schwab et al[18], Lo et al[40] | |
| Common variable immunodeficiency type 1, ICOS deficiency, ICOS (AR) | ICOS expression is upregulated upon T cell activation and it delivers a positive co-stimulatory signal to T cells. It is required for T-B cell coactivation, CD40-mediated Ig class switch and Th2, Th17 immune responses. It is also crucial for the development of Tregs | Crohn’s like entero-colitis | Recurrent bacterial and viral (herpes, CMV) infections, lymphoproliferative diseases splenomegaly, autoimmune cytopenia, autoimmune interstitial pneumonitis, psoriasis | Abolhassani et al[41], Schepp et al[42] | |
| IL-21 deficiency, IL-21 (AR) | IL-21 receptor mediates CD8+ T cell activation and proliferation, NK cell maturation, and differentiation of CD4+ T cells, including Tregs, most potent action on B cells; isotype switching, hypogammaglobulinemia | Crohn’s like entero- colitis | Recurrent sino-pulmonary and gastrointestinal bacterial and fungal infections, cryptosporidiosis-related cholangitis, neutropenia, asthma, urticaria | Cagdas et al[43] | |
| Hyper-Ig, IgM syndrome, CD40L (X-linked), activation-induced cytidine deaminase, AICDA (AR) | Defective isotype switching, elevated/normal IgM; low IgA and IgG, CD40 is expressed on antigen presenting cells, B cells and macrophages; and CD40 Ligand is expressed on T cell. Peripheral B cell tolerance development requires CD40-CD40 L and major histocompatibility complex-II T cells receptor interaction, its absence leads to autoimmunity. Additionally, there are decreased Tregs in hyper IgM syndrome | Crohn’s like colitis | Sinopulmonary infections, susceptibility to intracellular organisms, Pneumocystis pneumonia, cryptosporidium infections, sclerosing cholangitis, neutropenia, AIHA, aphthous stomatitis | Jesus et al[44], Hervé et al[45] | |
| Agammaglobulinemia, BTK (X-linked) | Absent B cells, hypogammaglobulinemia. BTK inhibits NLRP3 inflammasome activity. Disinhibited NLRP3-meditates proinflammatory IL-1β and IL-18 signaling leading to CD like colitis | Crohn’s like colitis, stricturizing, fistulizing disease | Recurrent gastrointestinal infections, sino-pulmonary infections, AIHA | Khan et al[46], Mao et al[47] | |
| WAS, WASP (X-linked) | WAS protein is involved in T cell dependent activation, cytotoxic function of CD8+ T cells, Tregs and NK cells. Motility and migration of B cells is defective microbial dysbiosis, ineffective suppression of effector T cells and B cells by Tregs leads to autoimmunity | UC-like colitis, CD, IBD-U | Microthrombocytopenia, eczema, atopic dermatitis, skin vasculitis, AIHA, neutropenia, lymphoreticular malignancy, B cells lymphoma | Suri et al[28], Catucci et al[48] | |
| ARPC1B deficiency, ARPC1B (AR) | Arp2/3 complex is involved in actin polymerization and cell migration of neutrophils, T cells and platelets | UC | Recurrent infections, microthrombocytopenia, eosinophilia, elevated IgE, leukocytoclastic vasculitis, bleeding manifestations, food allergies (resembles WAS) | Kahr et al[49] | |
| Omenn syndrome, DOCK8 (AD/AR) | DOCK8 has a role in regulating actin cytoskeleton, thereby implicated in causing immunodeficiency, atopy, autoimmunity and malignancies | Crohn’s like colitis | Atopy, staphylococcal infection, cutaneous viral infections, candidiasis, food allergy, autoimmunity, vasculitis, autoimmune hepatitis, hyper IgE, hematopoietic stem cell transplantation curative | Engelhardt et al[50], Sanal et al[51] | |
| Phosphatidylinositol-3-kinase activation syndrome 1 and 2, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta, PIK3CD (AD), phosphoinositide-3-kinase regulatory subunit 1, PIK3R1 (AR) | Hyperactivation of the mammalian target of rapamycin pathway leads to senescent T cells, impaired B cell maturation, elevated/normal IgM, absent class switched memory B cells | Colitis | Recurrent sino-pulmonary infections, cytopenia, hepatosplenomegaly, lymphoproliferation, increased risk of lymphoma, viral infections | Tessarin et al[52] | |
| X-linked severe combined immunodeficiency disease, IL-2RG (X-linked) | Mutation in the gene encoding IL-2 receptor | Colitis | Most common sub-type, recurrent fungal/viral opportunistic infections, lymphopenia, Reduced circulating T cells and NK cells | Ouahed et al[24], Justiz-Vaillant et al[53], Felgentreff et al[54] | |
| ADA deficiency, ADA (AR) | Deficiency of ADA leads to accumulation of deoxyadenosine, which is toxic to lymphoid precursors | Colitis | Recurrent infections, hearing and visual impairment, skeletal abnormalities | Justiz-Vaillant et al[53], Felgentreff et al[54] | |
| RAG-1 and RAG-2 mutations (AR) | Defect in T cells receptor development leading to abnormal T cells | Colitis | Recurrent infections, reduced T and B cells | Justiz-Vaillant et al[53], Felgentreff et al[54] | |
| DNA Ligase IV deficiency, Ligase IV, LIG4 (AR) | DNA ligase IV is involved in DNA double-strand breaks repair and class switching | Enterocolitis, colitis | Recurrent infections, growth retardation, facial dysmorphism, myelodysplastic syndrome, Reduced T and B cells, vitiligo, pancytopenia, thrombocytopenia | Sun et al[55] | |
| CD3G mutations (AR) | Arrest of T cell differentiation, impaired T cell activation, loss of Treg functions lead to autoimmunity | Colitis, autoimmune enteropathy | Recurrent bacterial/ viral infections, AIHA, chronic interstitial lung disease | Rowe et al[56] | |
| ZAP70-related combined immunodeficiency, ZAP-70 (AR) | Abnormal T cell differentiation, peripheral CD4+ T cells are refractory to T cells receptor-mediated activation | Colitis | Recurrent viral and fungal infections, reduced CD4+ T cells, and CD8+ T cells, autoimmune cytopenia | Shirkani et al[57] | |
| Artemis-deficiency combined immunodeficiency DCLRE1C (AR) | DCLRE1C codes for artemis, which is a component of V(D)J recombination and the non-homologous end-joining pathway, for degeneration of antigen diversity and early T and B cell maturation | Crohn’s like colitis | Recurrent sinopulmonary infections, fungal and viral infections, bacillus calmette-guerin adenitis, reduced T cells and B cells, normal NK cells | Ghadimi et al[58] | |
| Defects in TGF-β signaling TGF-β1 deficiency, TGF-β1(AR) | TGF-β regulates the survival and differentiation of various immunological (T cells, B cells, NK cells and dendritic cells) and non-immunological cells | Infantile-onset IBD, perianal disease | Recurrent infections, skeletal muscle atrophy, neurological symptoms epilepsy, leukoencephlopathy | Kotlarz et al[59] | |
| Loeys-Dietz syndrome TGF-βR1/TGF-βR2 (AR) | UC | Cranio-facial dysmorphism, hypertelorism, cleft palate, bifid uvula, hyperextensible joints, cardiovascular anomalies like dilatation of aortic root | Naviglio et al[60] | ||
| RIPK1 deficiency, RIPK1 (AR) | RIPK1 is a central regulator of apoptosis and inflammation. Inflammasome is activated in RIPK1 deficient macrophages leading to secretion of inflammatory cytokines | Infantile-onset IBD, perianal disease | Severe bacterial, viral infections, arthritis, recurrent fever | Sultan et al[61] | |
| Tregs and IL-10 signaling | IL-10 signaling defect, IL-10 RA and IL-10RB (AR), IL-10 (AR) | IL-10 is released by type 2 helper T cells, it inhibits Th1 pathway and limits the release of pro-inflammatory cytokines like IL-2 IFN-γ, TNF-α and IL-12 | Severe early onset enterocolitis, Perianal disease, fistulizing disease | Folliculitis, pneumonia, arthritis | Glocker et al[62] |
| Immune dysregulation polyendocrinopathy, enteropathy, X linked (IPEX), FOXP3 (X-linked) | FOXP3 is a regulator of Treg development and competitiveness. Treg downregulate activated B cells | Early onset small bowel type, intractable diarrhea in infancy, graft-versus-host disease like changes (apoptotic bodies) | Classic triad: Intractable diarrhea, T1DM and eczema. Atopic eczema, hypoparathyroidism, hashimoto thyroiditis, AIHA, antibody-mediated cytopenia, lymphadenopathy, CMV/EBV infection, food allergies | Gambineri et al[17], Consonni et al[63] | |
| IPEX-like syndromes: Defects in the IL-2 receptor α chain, IL-2RA/CD25 (AR) | Normal FOXP3 expression with CD25 deficiency. CD25 deficiency leads to Treg dysfunction | Autoimmune enteropathy, villous atrophy | Multisystem autoimmunity, lymphoproliferation, polyendocrinopathy, eczema, hemolytic anemia | Gambineri et al[17], Caudy et al[64] | |
| STAT1 GOF disease (AD) | STAT1 is a cytoplasmic transcription factor which binds to JAK in response to IFNs and IL-27. In STAT1 GOF mutation, there is enhanced STAT1-dependent response to type I and II IFNs | Severe autoimmune enteropathy, CD, UC | Recurrent viral infections, EBV, CMV, candidiasis, hypothyroidism, early onset diabetes, recurrent sinopulmonary infections, hypogammaglobulinemia | Okada et al[20] | |
| STAT3 GOF disease (AD) | STAT3 GOF leads to prolonged activation of STAT3 and its downstream effects, which include lymphoproliferation, autoimmunity | Severe autoimmune enteropathy | Diffuse lymphadenopathy, splenomegaly, cytopenias, interstitial lung disease, early onset type 1 diabetes, vasculitis, arthritis, recurrent viral, fungal and bacterial infections | Vogel et al[21] | |
| JAK1 GOF disease (AD) | JAK1 GOF leads to downstream activation of JAK/STAT pathway and associated inflammatory disease | IBD-U | Pruritus, atopic dermatitis, ichthyosis, arthralgia, calcifying fibrous tumors | Fayand et al[23] | |
| Epithelial barriers | TTC7A deficiency, TTC7A (AR) | TTC7A dysfunction leads to loss of polarity of intestinal epithelium and poor barrier function | Severe enterocolitis from birth | Multiple intestinal atresia from pylorus, small bowel, ileocaecal valve to colon, combined immunodeficiency, lymphocytopenia | Jardine et al[65] |
| NEMO deficiency, inhibitor of NF-κB kinase regulatory subunit gamma, IKBKG (X-linked) | NEMO deficiency leads to impairment in toll-like receptor signaling, B cell response, impaired T cell response | Crohn’s colitis | Anhidrotic ectodermal dysplasia involving skin, teeth, viral and fungal infections | Miot et al[27] | |
| ADAM-17 deficiency, ADAM-17 (AR) | ADAM-17 sheds cytokine and cytokine receptors including TNF-α and TNF receptors, and IL-6 receptors | Neonatal IBD | Alopecia, erythroderma, recurrent sepsis, eosinophilia, lymphadenopathy | Imoto et al[66] | |
| Dystrophic epidermolysis bullosa, COL7A (AR) | Defective barrier function triggers inflammation | UC | Blistering skin condition, photosensitivity, esophageal strictures | Zimmer et al[67] | |
| Kindler syndrome, fermitin family member 1, FERMT1 (AR) | Altered kindlin-1 leads to epithelial barrier disruption in colonic epithelium, leads to penetration of antigens and IBD | UC, CD | Neonatal onset inflammatory skin disease, poikiloderma, strictures, esophagitis | Roda et al[68] | |
| Familial diarrhea, guanylyl cyclase 2C, GUCY2 (AD) | GOF mutation in the guanylate cyclase-coupled receptors leads to signaling to cystic fibrosis transmembrane conductance regulator and increases chloride secretion | Secretory diarrhea | Secretory diarrhea, failure to thrive, antenatal polyhydramnios | Fiskerstrand et al[69] | |
| Congenital sodium diarrhea, solute carrier family 9 isoform 3, SLC9A3 (AR) | Defective the Na+/H+ exchanger NHE3 leads to impaired sodium absorption and alters microbiome | Congenital sodium diarrhea (early and adolescent onset UC) | Secretory diarrhea, failure to thrive, antenatal polyhydramnios | Janecke et al[70] | |
| Trichohepatoenteric syndrome, TTC37 or SKIV2 L (AR) | Abnormalities of the expression and localization of transporter proteins in the enterocytes and hepatocytes | Diarrhea (both secretory and osmotic) | Facial dysmorphism, trichorrhexis nodosa, low Igs, congenital cardiac anomalies, enlarged platelets, liver disease, rarely liver failure, intra uterine growth retardation | Hartley et al[71] | |
| Others | Endothelial cell defects | Azabdaftari et al[14] | |||
| Chronic enteropathy associated with SLCO2A1 gene, SLCO2A1 (AR) | SLCO2A1 encodes prostaglandin transporter, which mediates PGE2 uptake and inactivation in gastrointestinal tract. Its absence leads to elevated serum PGE2, has pro-inflammatory effects and disrupts mechanical barrier | Multiple strictures of the small intestines | Protein-losing enteropathy, iron deficiency anemia, intestinal obstruction, primary hypertrophic osteoarthropathy | Xie et al[72] | |
| CHAPLE, CHAPLE syndrome (AR) | CD55 is expressed in capillary endothelium, brush-border and lymphocytes, and is a complement regulatory protein. Its absence leads to decreased IL-10 secretion, excessive complement activation, TNF secretion and intestinal inflammation | Protein-losing enteropathy | Hypogammaglobulinemia, recurrent respiratory infections, deep vein thromboses, polyarthritis | Ozen et al[73] |
Table 2 Clinical clues towards specific etiologies of monogenic inflammatory bowel disease
| Clinical clues | Underlying condition/affected genes |
| Epidermolysis bullosa, nail dystrophy | Epithelial barrier defect (IKBKG, a disintegrin and metalloproteinase 17, COL7A1) |
| Woolly hair, trichorrhexis nodosa | Tricho-entero-hepatic syndrome |
| Severe perianal disease (rectovaginal fistula), folliculitis, and/or arthritis | IL-10 signaling pathway defects |
| Abscess without pus | Leukocyte adhesion defect |
| Eczema | Wisckot-Aldrich syndrome, hyper immunoglobulin E syndrome, IPEX syndrome, IKBKG defect |
| Hepatosplenomegaly | Chronic granulomatous disease |
| Autoimmune anemia, type 1 diabetes mellitus, autoimmune thrombocytopenia, autoimmune thyroiditis, interstitial pneumonia | IPEX, IPEX-like syndromes |
| No bacillus calmette-guerin scar | T cell defect |
| Oral ulcer, leukoplakia | Dyskeratosis congenita 1, regulator of telomere elongation 1 |
| Dysmorphic features | IKBKG, mucosa-associated lymphoid tissue lymphoma translocation protein 1, glucose-6-phosphatase-catalytic subunit 3, SKIV2 L |
| Hemophagocytic lymphohistiocytosis, macrophage activation syndrome | X-linked inhibitors of apoptosis, mevalonate kinase, syntaxin-binding protein-2 |
| Periostosis | Solute carrier organic anion transporter family member 2A1 |
| Albinism | Hermansky-Pudlak syndrome 1/4/6 |
| Malignancy (lymphoma, gastric adenocarcinoma) | IL-10/IL-10RA/B, lipopolysaccharide-responsive and beige-like anchor protein, cytotoxic T lymphocyte antigen-4 |
| Absent tonsils | Agammaglobulinemia |
Table 3 Clinical scenarios to suspect monogenic inflammatory bowel disease
| Conditions to suspect monogenic IBD |
| Young age matters most |
| Young age (onset < 2 years/< 6 years with red flags) |
| Multiple family members with IBD with suspected monogenic disorder and consanguinity |
| Autoimmunity |
| Thriving failure |
| Treatment with conventional medication fails |
| Endocrine concerns |
| Recurrent infections or unexplained fever |
| Severe perianal disease |
| Macrophage activation syndrome and hemophagocytic lymphohistiocytosis |
| Obstruction and atresia of the intestine |
| Skin lesions, dental and hair abnormalities |
| Tumors |
- Citation: Ghosh U, Samanta A. Monogenic inflammatory bowel disease: An unfolding enigma. World J Clin Pediatr 2025; 14(3): 107165
- URL: https://www.wjgnet.com/2219-2808/full/v14/i3/107165.htm
- DOI: https://dx.doi.org/10.5409/wjcp.v14.i3.107165