A Systematic Review of Monogenic Inflammatory Bowel Disease

Abstract

Background & aims: Advances in genomic technologies have led to increasing reports of monogenic inflammatory bowel disease (IBD). Here, we systematically review the literature to determine the clinical features, genetic profile, and previously used treatment strategies in monogenic IBD.

Methods: A systematic review of MEDLINE articles published between January 2000 and December 2020 was conducted. A total of 750 individual monogenic IBD cases were identified from 303 eligible articles.

Results: The most frequently reported monogenic IBD genes were IL10RA/B, XIAP, CYBB, LRBA, and TTC7A. In total, 63.4% of patients developed IBD before 6 years of age, 17.4% developed IBD between ages 10 and 17.9 years, and 10.9% developed IBD after age 18. There was a substantial difference between these age groups and the underlying monogenic disorders. Only 31.7% had any history of extraintestinal comorbidity (EIC) before IBD onset, but 76.0% developed at least 1 EIC during their clinical course. The most common EICs were atypical infection (44.7%), dermatologic abnormality (38.4%), and autoimmunity (21.9%). Bowel surgery, biologic therapy, and hematopoietic stem cell transplantation were performed in 27.1%, 32.9%, and 23.1% of patients, respectively.

Conclusions: Monogenic IBD cases, although rare, have varied extraintestinal comorbidities and limited treatment options including surgery and transplant. Early identification and improved understanding of the characteristics of the genes and underlying disease processes in monogenic IBD is important for effective management.

Keywords: IBD; Monogenic Disorder; Pediatric; VEOIBD; Whole-Exome Sequence.

Figure 1.. Common genes and age of onset of monogenic IBD.

(A) Number of reported monogenic IBD cases and articles stratified by gene. Only genes that have ten or more cases are listed. Dark blue; number of cases, Light blue; number of articles. (B) Distribution of IBD onset age. Orange bar (left Y axis) is the number of cases in each age group. The line graph (right Y axis) is the proportion of patients with extraintestinal manifestations before onset of IBD.

Figure 2.. Distribution of age of IBD onset stratified by underlying monogenic disorder.

The blue shaded region; 0–1.9 years, the red shaded region; 2–5.9 years. Each blue dot is a separate patient, and the vertical red lines indicates the mean with the horizontal line showing the standard error. GUCY2C, Familial GUCY2C diarrhea syndrome (GUCY2C); HPS, Hermansky-Pudlak syndrome (HPS1, HPS4, HPS6,); CEAS, Chronic enteropathy associated with SLCO2A1 gene (SLCO2A1); Agammaglobulinemia, (BTK, PIK3CD, PIK3R1); GSD1b, Glycogen storage disease type 1B (SLC37A4); NP-C, Niemann-Pick disease type C (NPC1); G6PC3, G6PC3 deficiency (G6PC3); XIAP, XIAP deficiency (XIAP); Loeys-Dietz, Loeys-Dietz syndrome (TGFBR1, TGFBR2); CGD, Chronic granulomatous disease (CYBA, CYBB, NCF1, NCF2, NCF4); HA20, haploinsufficiency of A20 (TNFAIP3); WAS/WAS-like, Wiskott-Aldrich syndrome/Wiskott-Aldrich -like syndrome (WAS, ARPC1B); IPEX-like immunodysregulation polyendocrinopathy enteropathy X-linked -like syndrome (STAT1, STAT3, CTLA4, LRBA, IL21, MALT1); Kindler, Kindler syndrome (FERMT1); IPEX, immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (FOXP3); NEMO, Nuclear factor-kappa B Essential MOdulator deficiency (IKBKG); H-HS, Hoyeraal-Hreidarsson Syndrome (DKC1, RTEL1); THE-S, Trichohepatoenteric syndrome (SKIV2L, TTC37); RIPK1, RIPK1 deficiency (RIPK1); SCID, severe combined immunodeficiency (CD3G, DCLRE1C, IL2RG, LIG4, RAG1); IL10/R, IL-10 and IL-10-receptor associated colitis (IL10, IL10RA, IL10RB); TTC7A, TTC7A deficiency (TTC7A).

Figure 3.. Number of extraintestinal comorbidities across monogenic IBD cases.

(A) Number of EICs in all monogenic IBD cases, where reported (red highlights show GI complications of perianal disease and oral ulcers). Autoimmunity includes autoimmune hepatitis, arthritis, arthralgia, type 1 diabetes mellitus, hypothyroiditis, psoriasis, autoimmune hemolytic anemia, autoimmune neutropenia, immune thrombocytopenic purpura, uveitis, primary sclerosing cholangitis, vasculitis, autoimmune pancreatitis, autoimmune growth hormone deficiency, glomerular nephropathy, nephrotic syndrome and autoimmune lymphoproliferative syndrome. Chronic lung disease includes interstitial lung disease, bronchiectasis, and pulmonary fibrosis. Perianal disease includes fistula, abscess, rectovaginal fistula and ulcer (not including fissure or skin tags). (B) Number of monogenic IBD cases with HLH/MAS by causative genes. HLH, hemophagocytic lymphohistiocytosis; MAS, macrophage activation syndrome. (C) Number of monogenic IBD cases associated with malignancy by causative genes. LCH, Langerhans cell histiocytosis; AC, adenocarcinoma.

Figure 4.. Therapeutic management across monogenic IBD cases.

(A) Proportion of monogenic IBD cases shown requiring bowel surgery and for those cases requiring surgery, proportions of the types of surgery. (B) Proportion of monogenic IBD cases receiving biologic therapies (including infliximab, adalimumab, golimumab, ustekinumab and vedolizumab, abatacept, anakinra, basiliximab, canakinumab, cerotilizumab, etanercept, natalizumab, rituximab, tocilizumab, tofacitinib* and Ruxolitinib*), and efficacy. *a small molecule drug (C) Proportion of monogenic IBD cases that underwent hematopoietic stem cell transplant (HSCT) and, of those, the response rate. The rightmost image illustrates the details of the cases that HSCT that did not improve.

Figure 5.

Executive flowchart for the management of monogenic IBD. HLH, hemophagocytic lymphohistiocytosis; MAS, macrophage activation syndrome; CBC, complete blood count; TRECs, T-cell receptor excision circles; DHR-123, dihydrorhodamine 123; HSCT, hematopoietic stem cell transplantation.