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

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.