Druggable monogenic immune defects hidden in diverse medical specialties: Focus on overlap syndromes

Table 1 Characteristics of pathologies

	Gene	Meccanism	Immune assessment	Clinicsautoimmunity	Lymphoproliferation	Infections	Therapy
APDS	PIK3CDPIK3R1	PI3K delta hyperactivation	Hypogammaglobulinemia IgA and IgG lowSenescent CD8 T cellsDNT	IBD; diabetes; arthritis	Lymphadenopathy, splenomegaly	Recurrent respiratory infections; herpes virus infections	HSCT; antibioticsrituximab and rapamycin; PI3Kδ inhibitors
STAT3 GOF	STAT3	STAT3 hyperactivation	Hypogammaglobulinemia; decrease NK cells; decrease memory B cells; decrease regulatory T cells	Autoimmune cytopenia; diabetes; thyroiditis; arthritis	Adenopathy, hepatosplenomegaly	Herpes virus infections; fungal infections; bacterial infections; respiratory infections	JACK inhibitors
APECED	AIRE	Decrease of negative selection of autoreactive T cells in thymus	Autoantibodies;CD8+ effector T cells;FOXP3+ regulatory T cells	Autoimmune hypoparathyroidism;Addison’s disease		Chronic Candida infection	Hormone replacement therapy according to affected organs; immunosuppressive therapies; rituximab
CTLA4 deficiency	CTLA4	Defective switch off of lymphocyte activation	Hypogammaglobulinemia; DNT;increase of regulatory T cells with reduced expression of FOXP3;CD19+ B cells and switched memory B	Autoimmunecytopenia; hemolytic anemia and thrombocytopenia	Splenomegaly;chronic lymphadenopathy;hepatomegaly	Respiratory tract infections	Sirolimus; abatacept; HSCT
LRBA deficiency	LRBA	Defective switch off of lymphocyte activation	Hypogammaglobulinemia; DNT; FOXP3+regulatory T cells;CD19+ B cells;Natural Killer cells; increase of CD4+ and CD8+ memory T cells	Autoimmune gastritis;autoimmunecytopenia; hemolytic anemia; IBD;Autoimmune enteropathy	Splenomegaly;hepatomegaly	Respiratory infections	sirolimus; abatacept; HSCT
IPEX	FOXP3	Failure of immune tolerance	Loss of FOXP3+ T cells;increased of Th2 and Th17 cells;autoantibodiesHypergammaglobulinemia IgA, IgE	Autoimmune enteropathy; autoimmune hemolytic anemia; autoimmune thrombocytopenia; autoimmune neutropenia; autoimmune thyroiditis; nephropathy; hepatitis		Skin infections	Glucocorticoids;Msirolimus;Mtacrolimus; abatacept; HSCT
STAT1 GOF	STAT1	STAT1 hyperactivation due to increase STAT1 phosphorylation	Low Th17 cells; low switched memory B cells;Hypergammaglobulinemia IgG	Chronic mucocutaneous candidiasis; hypothyroidism; autoimmune cytopenia, hepatopathy; psoriasis	Hepatomegaly; splenomegaly	Fungal, viral and mycobacterial infections; skin infections; Respiratory infections	Antifungal treatment; antibiotic prophylaxis; JACK inhibitors
DADA2	ADA2	Reduced activity level of the adenosine deaminase 2	Hypogammaglobulinemia; increases macrophage release of TNF-α; upregulation of neutrophil activity; upregulation of pro-inflammatory cytokines; upregulation of type 1 interferon stimulated genes; aberrant B cell development and differentiation; decrease in NK	Vasculitis, immunodeficiency; autoimmune neutropenia; autoimmune cytopenia	Splenomegaly; lymphadenopathy; hepatomegaly	Verrucosis; herpes virus infections; increased susceptibility to infection with dsDNA viruses	Anti-TNF treatment (etanercept, infliximab,adalimumab); high-dose of glucocorticoids; HSCT; immunosuppressive drugs in isolated cases (mycophenolate, azathioprine, cyclosporine, rituximab, sirolimus, tacrolimus)
TNFAIP3 deficiency	TNFAIP3	Excessive activation of NF-kB signalling	Antinuclear and anti-DNA antibodies; increased production of interferons and proinflammatory cytokines	Autoimmune cytopenias			Anti-TNF treatment; anti-IL1 treatment; glucocorticoid; colchicine

Characteristics of pathologies[10,20,28,31,37,44,49,52,53]. HSCT: Hematopoietic stem cell transplantation; IBD: Inflammatory bowel disease.

Table 2 Clinical and laboratory red flags

Clinical red flags

Early onset in childhood: The development of complex inflammatory disorders before puberty and particularly before early childhood rises suspicion of a congenital immune dysregulation

Overlap of symptoms in distinct specialties: A clinical history of distinct rheumatologic and non-rheumatologic conditions is not common in pediatrics, addressing a monogenic disorder

Lymphoproliferative manifestations: The presence of splenomegaly and/or lymphadenopathy in association with inflammatory or autoimmune diseases suggests an underlying inborn error of immunity.

Recurrent infections: The recurrence of severe or atypical infections (especially candidiasis) in association with inflammatory or autoimmune diseases is rarely a consequence of immunomodulatory therapies in children, but it does suggest an immunological defect

Familiarity with autoimmunity: The clustering of autoimmune disorders in families acknowledges a likely monogenic cause

Laboratory red flags

Hypogammaglobulinemia

Hypergammaglobulinemia

Leukopenia

Hypereosinophilia

Wide positivity of autoantibodies

Positive interferon signature