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.