Interface between inborn errors of immunity and rheumatological disorders in children: A pediatrician’s conundrum

Table 3 Disorders with clinical features suggestive of inflammatory bowel disease and inborn errors of immunity

Category	Disease/gene	IBD phenotype	Immunodeficiency phenotype
Neutrophil disorders	Chronic granulomatous disease (CYBB, CYBA, NCF1/2/4)	Crohn’s disease–like intestinal inflammation with granulomas and strictures	Recurrent deep-seated infections, including liver abscess and pneumonia
	Congenital neutropenia (G6PC3)	Non-specific IBD phenotype	Gingivitis; aphthous ulcers; pneumonia; deep tissue abscess; colitis
	Leukocyte adhesion deficiency (ITGB2)	Non-specific IBD phenotype	Neutrophilic leukocytosis; chronic skin ulcers; delayed umbilical cord separation
	Glycogen storage disorder type 1b (SLC37A4)	Crohn's disease–like intestinal inflammation	Gingivitis; fever; hepatomegaly; growth retardation
T cell/B cell	Agammaglobulinemia; hyper-IgM syndrome; CVID	Crohn’s disease-like or ulcerative colitis-like inflammation	Recurrent sinopulmonary infections; chronic infectious diarrhea
	Wiskott-Aldrich syndrome	Ulcerative colitis-like inflammation	Eczema; thrombocytopenia; recurrent viral infections
	Atypical SCID (DCLRE1C, ZAP70, RAG2, LIG4, ADA, CD3G)	Non-specific IBD phenotype	Recurrent infections, including chronic diarrhea and pneumonia
	TTC7A deficiency	Early-onset severe enterocolitis	Multiple intestinal atresia; severe T-cell lymphopenia
Regulatory T-cell/IL-10 signalling defects	IL10, IL10RA, IL10RB	Early-onset IBD; perianal disease; Folliculitis	Extra-intestinal inflammation; arthritis; lymphoma predisposition
	IPEX syndrome	Autoimmune enteropathy with chronic diarrhea	Multiple autoimmune diseases, including type 1 diabetes and autoimmune cytopenias
	CD25 (IL2RA) deficiency	IPEX-like autoimmune enteropathy	Recurrent CMV infection and bacterial infections
	LRBA deficiency; CTLA4 haploinsufficiency	Chronic diarrhea; IBD-like phenotype	Hypogammaglobulinemia; otitis media and recurrent pneumonia; lymphoproliferation (EBV induced); autoimmunity; reduced T-cell proliferation response
Autoinflammatory disorders	MVK deficiency	Very early onset IBD; peritoneal adhesions; small bowel occlusion/perforation/necrosis	Hyper-IgD syndrome; recurrent fever; tender lymphadenopathy; aphthous ulcers
	RIPK1 deficiency	Very early onset IBD	Combined immunodeficiency; inflammatory arthropathy
HLH-associated disorders	XIAP, SH2D1A	Crohn’s disease-like enterocolitis	X-linked lymphoproliferative disease; EBV-associated HLH
	STXBP2	Chronic diarrhea; colitis	Familial hemophagocytic lymphohistiocytosis
	HPS1, HPS4, HPS6	Crohn’s disease-like granulomatous colitis	Hermansky-Pudlak syndrome with albinism and bleeding diathesis

IBD: Inflammatory bowel disease; G6PC3: Glucose-6-phosphatase catalytic subunit 3; SLC37A4: Solute carrier family 37 member 4; ITGB2: Integrin subunit beta 2; MVK: Mevalonate kinase; STXBP2: Syntaxin-binding protein 2; XIAP: X-linked inhibitor of apoptosis protein; SH2D1A: SH2 domain containing 1A; ZAP70: Zeta-chain associated protein kinase 70 kDa; LIG4: DNA ligase 4; DCLRE1C: DNA cross-link repair 1C; IL: Interleukin.