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

Table 1 Inborn errors of immunity associated with immune-mediated cytopenias

Disorders causing cytopenia		Clinical manifestations	Immunological abnormality responsible to cytopenias	Management
Humoral defects	CVID (CD19, CD81, NFkB2, BAFFR, and TACI)	ITP, AIHA, Evans syndrome, pernicious anemia, infection induced bone marrow suppression	Autoreactive T and B cells, increased CD21 low B cells, decreased somatic hypermutations, increased BAFF-R, decreased CD8 T cells, and increased B10 or IL10	Corticosteroids, IVIG, rituximab
Combined immunodeficiency	Leaky SCID, hypomorphic mutations in RAG1, RAG2, Omenn syndrome and WAS	ITP, AIHA, Evans syndrome, infection induced suppression	Autoreactive B and T cells, autoantibody formations	Corticosteroids
Immune dysregulatory disorders	LRBA, CTLA4, APDS, IKAROS, ALPS, STAT3 GOF, IPEX, APECED	ITP, AIHA, Evans syndrome, pernicious anemia, infection induced suppression. Inflammation and lymphoproliferation induced cytopenia	Reduced T regs, reduced B regs, autoreactive T and B cells, increased CD21 low B cells, and autoantibody formation	Abatacept- LRBA, CTLA4, APDS- mTOR inhibitor, leniolisib, ALPS- Sirolimus, STAT3 GOF- JAK inhibitors
	IEIs associated with increased susceptibility to EBV	Due to lymphoproliferation	Due to lymphoproliferation and bone marrow suppression	EBV in B cells- rituximab. EBV in T and NK cells- chemotherapy. Magnesium for MAGT1 deficiency
	HLH- familial HLH 2-5, Griscelli syndrome, Chédiak-Higashi syndrome, and Hermansky-Pudlak syndrome	Pancytopenia	Inflammation due to increased IL-6, IL-18, IL-1 and interferon gamma	HLH protocol. Emapalumab
Bone marrow failure syndromes	GATA2 deficiency/MonoMAC syndrome, dyskeratosis congenita, Schimke syndrome, Shwachman-Diamond syndrome	Aplastic anemia	Bone marrow suppression	HSCT
Autoinflammatory disorders	Interferonopathies, monogenic lupus and complement deficiency	Thrombocytopenia, anemia	Cytokine mediated, chronic inflammation and auto anitbody formation	Steroids, JAK inhibitors, and-FFP transfusion

CVID: Common variable immunodeficiency; CD: Cluster of differentiation; ITP: Immune thrombocytopenia; AIHA: Autoimmune hemolytic anemia; IVIG: Intravenous immunoglobulin; TACI: Transmembrane activator and calcium- modulator and cyclophilin ligand interactor; SCID: Severe combined immunodeficiency; RAG: Recombination-activating gene; WAS: Wiskott Aldrich syndrome; LRBA: Lipopolysaccharide responsive beige like anchor protein; CTLA4: Cytotoxic T lymphocyte associated protein 4; APDs: Activated phosphoinositide 3 kinase delta syndrome; ALPS: Autoimmune lymphoproliferative syndrome; APECED: Autoimmune polyendocrinopathy candidiasis - ectodermal dystrophy; GOF: Gain of function; EBV: Epstein-Barr virus; MAGT1 deficiency: Magnesium transporter 1; HLH: Hemophagocytic lymphohistiocytosis; Monomac: Monocytopenia and mycobacterial infection; HSCT: Hematopoietic stem cell transplantation; FFP: Fresh frozen plasma.

Table 2 Inborn errors of immunity in pediatric systemic lupus erythematosus

Category	Gene(s)	Lupus phenotype	Other clinical features
Complement deficiencies	C1QA, C1QB, C1QC, C1R, C1S, C2, C4A, C4B	Severe cutaneous lupus without major organ involvement (particularly C2 deficiency); CNS disease, glomerulonephritis and severe skin involvement in C1q deficiency; arthritis; ANA positivity; extractable nuclear antigen antibodies, including anti-Ro/SSA (especially in C2 and C4 deficiency)	Recurrent infections, predominantly pneumococcal sinopulmonary infections
Type I interferon pathway disorders	ADAR1, SAMHD1, TREX1, IFIH1, RNASEH2A/B/C	ANA positivity; cutaneous lesions; oral ulcers; anti-dsDNA and ENA antibodies; Jaccoud’s arthropathy	Aicardi–Goutières syndrome; early-onset encephalopathy; basal ganglia calcification; chilblains
	ACP5	ANA positivity; anti-dsDNA and ENA antibodies; lupus nephritis; autoimmune cytopenia	Spondyloenchondrodysplasia (SPENCD); skeletal dysplasia; developmental delay; intracranial calcifications
	DNASE1, DNASE1 L3	ANA positivity; anti-dsDNA antibodies; hypocomplementemia; ANCA positivity	Hypocomplementemic urticarial vasculitis
	ISG15 (loss of function)	Recurrent fever; oral ulcers; facial rash; myositis; ANA and anti-dsDNA positivity	Mendelian susceptibility to mycobacterial disease; intracranial calcifications
	PSMA3, PSMB4, PSMB8	ANA positivity; fever; diffuse rash	Proteasome-associated autoinflammatory syndrome; lipodystrophy; panniculitis; neutrophilic dermatosis; heliotrope peri-orbital rash; myositis; basal ganglia calcifications
Apoptosis pathway defects	FAS (formerly TNFRSF6), FASL	ANA positivity; early autoimmune cytopenias; glomerulonephritis	Lymphoproliferation; hepatosplenomegaly; hypergammaglobulinemia; elevated DNTs
	KRAS, PTPN11, SHOC2	ANA positivity; anti-dsDNA antibodies	Noonan syndrome phenotype; splenomegaly; increased B cells; monocytosis; hypergammaglobulinemia
Loss of immune tolerance	PRKCD	Autoimmune lymphoproliferative syndrome-like presentation; Lupus nephritis; vasculitis; antiphospholipid syndrome; ANA/ENA positivity; hypocomplementemia; hypergammaglobulinemia	CD19 B-cell lymphopenia; low IgG; elevated IgM; recurrent infections
	RAG1, RAG2	Erosive polyarthritis; urticarial rash; class V lupus nephritis; ANA, anti-dsDNA, anti-Smith antibodies	Impaired antibody responses; recurrent sinopulmonary infections; destructive midline granulomatous disease
Other associated disorders	SLC7A7	Lupus nephritis; immune cytopenia; ANA positivity; positive extractable nuclear antigen antibodies; Anti-dsDNA may be indeterminate	Failure to thrive; Lysinuric protein intolerance; hepatosplenomegaly; pulmonary alveolar proteinosis; cognitive delay
	PEPD	ANA positivity; anti-Smith antibodies; arthritis; HLH/MAS	Chronic ulcerations (mostly of the lower limbs); dysmorphic features affecting the eye and nose; developmental delay; recurrent infections; hematological abnormalities; hepatosplenomegaly; chronic pulmonary disease
	CYBB	Affected males: Discoid lupus-like lesions; photosensitivity; carrier states: Raynaud phenomenon; photosensitivity; oral ulcers; arthritis	Recurrent, localized, deep-seated infections (skin, lung, lymph nodes); recurrent pneumonia. Carrier states are usually asymptomatic

ANA: Antinuclear antibody; SSA: Anti-Sjögren’s syndrome antigen A; ENA: Extractable nuclear antigen; SPENCD: Spondyloenchondrodysplasia; dsDNA: Double-stranded DNA.

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.