Clinical features of patients carrying TLR7 GOF variations
| Reference . | TLR7 variant . | Inheritance . | Sex, age at onset . | Phenotype . | Auto-Ab IFN signature . | Evolution under treatment . |
|---|---|---|---|---|---|---|
| (7) Family C | R28G | Het. Unknown | F, 18 yo | SLE with malar rash, arthralgia, Raynaud’s phenomenon, alopecia, fever, and oral ulcers, lymphopenia, thrombocytopenia | ANA+, anti-dsDNA+, anti-U1RNP+, SSA Ro52+, and Ro60+ | Active episode (recurrent fever, headache, leucopenia) treated with corticosteroid and GM-CSF |
| (7) Family A | Y264H | Het. De novo | F, 7 yo | SLE with thrombocytopenia, arthralgia, and renal involvement (hypertensive crisis), mild mitral insufficiency and hemichorea | ANA+, +IFN signature | Severe thrombocytopenia (8G/L) that required corticosteroid, azathioprine, MMF, rituximab, IVIg, etanercept. Intermittent episode of chorea treated with haloperidol |
| (7) Family B (mother) | F507L | Het. Unknown | F, 25 yo | SLE and hemiplegic cerebral palsy of unclear etiology | NA | NA |
| (7) Family B (proband) | F507L | Het. Maternal | F, 9 yo | Relapsing NMO and transverse myelitis | ANA+, AQP4+ | NMO exacerbations treated with IVIg and MMF. Received rituximab, then inebilizumab-cdon |
| (9) | P267L | Het. De novo | F, 13 mo | Anti-NMDAR encephalitis, SLE with pericardial effusion and profound hemolytic anemia, severe neuroinflammatory vasculitis with sudden-onset status epilepticus | ANA+, anti-dsDNA+ IFN signature+ (high) | Neurovasculitis treated initially with corticosteroid pulse IVIg, ofatumumab, cyclophosphamide, then baricitinib 2 months before HSCT. Currently only experiencing occasional hemolysis |
| (8) AGS571 (proband) | F507S | Het. Maternal | F, 4 yo | SLE with malar rash, anemia, lymphopenia, lupus nephritis class III/IV, intestinal ischemia, myocardial infarction, cerebral vasculitis, cerebral calcifications | ANA+, anti-dsDNA, aCL+, anti-β2GPI+, lupus anticoagulant IFN signature+(high, 14) | Died of acute myocardial infarction at the age of 17 |
| (8) AGS571 (brother) | F507S | Hemizygous Maternal | M, 3 mo | Neonatal refractory epilepsy, dystonia, severe developmental delay, cerebral calcifications, leucopenia, and malar rash | ANA– IFN signature+(high) | Received corticosteroids, MMF, ruxolitinib. Currently, persistence of severe developmental delay and dystonia |
| (8) AGS571 (mother) | F507S | Unknown | F, 12 yo | Malar rash, thrombocytopenia, anemia | ANA+ IFN signature+(high) | NA |
| (8) AGS3740 | L528I | Het. De novo | F, 1 yo | Refractory Evans-like syndrome, panniculitis, mild motor developmental delay, stereotypic movement disorder, leukoencephalopathy with brain atrophy and calcifications | ANA+, anti-SSA+ | HSCT complicated by a chronic cutaneous GvHD treated with ruxolitinib. Currently, persistence of a slight motor deficit and hypokinesia |
| (11) | G818V | Het. De novo | F, 8 mo | Thrombocytopenia, anemia | ANA− | Relapse under rituximab, eltrombopag and baricitinib. HSCT. Currently no sign of disease activity |
| (10) | F506S | Somatic | M, 15 days | SLE with anemia, thrombocytopenia, rash, proteinuria, intestinal vasculitis, myocardial damage, thyroid dysfunction, intracranial calcification | ANA+ | Bioclinical improvement under ruxolitinib 15 mg |
| This report | P435S | Het. De novo | F, 2 yo | SLE with lupus nephritis, thrombocytopenia, anemia, chilblains, and pyramidal syndrome | ANA+ Anti IFN+ IFN signature+ (high) | Clinically stable under belimumab with mild proteinuria and pyramidal syndrome |
| Reference . | TLR7 variant . | Inheritance . | Sex, age at onset . | Phenotype . | Auto-Ab IFN signature . | Evolution under treatment . |
|---|---|---|---|---|---|---|
| (7) Family C | R28G | Het. Unknown | F, 18 yo | SLE with malar rash, arthralgia, Raynaud’s phenomenon, alopecia, fever, and oral ulcers, lymphopenia, thrombocytopenia | ANA+, anti-dsDNA+, anti-U1RNP+, SSA Ro52+, and Ro60+ | Active episode (recurrent fever, headache, leucopenia) treated with corticosteroid and GM-CSF |
| (7) Family A | Y264H | Het. De novo | F, 7 yo | SLE with thrombocytopenia, arthralgia, and renal involvement (hypertensive crisis), mild mitral insufficiency and hemichorea | ANA+, +IFN signature | Severe thrombocytopenia (8G/L) that required corticosteroid, azathioprine, MMF, rituximab, IVIg, etanercept. Intermittent episode of chorea treated with haloperidol |
| (7) Family B (mother) | F507L | Het. Unknown | F, 25 yo | SLE and hemiplegic cerebral palsy of unclear etiology | NA | NA |
| (7) Family B (proband) | F507L | Het. Maternal | F, 9 yo | Relapsing NMO and transverse myelitis | ANA+, AQP4+ | NMO exacerbations treated with IVIg and MMF. Received rituximab, then inebilizumab-cdon |
| (9) | P267L | Het. De novo | F, 13 mo | Anti-NMDAR encephalitis, SLE with pericardial effusion and profound hemolytic anemia, severe neuroinflammatory vasculitis with sudden-onset status epilepticus | ANA+, anti-dsDNA+ IFN signature+ (high) | Neurovasculitis treated initially with corticosteroid pulse IVIg, ofatumumab, cyclophosphamide, then baricitinib 2 months before HSCT. Currently only experiencing occasional hemolysis |
| (8) AGS571 (proband) | F507S | Het. Maternal | F, 4 yo | SLE with malar rash, anemia, lymphopenia, lupus nephritis class III/IV, intestinal ischemia, myocardial infarction, cerebral vasculitis, cerebral calcifications | ANA+, anti-dsDNA, aCL+, anti-β2GPI+, lupus anticoagulant IFN signature+(high, 14) | Died of acute myocardial infarction at the age of 17 |
| (8) AGS571 (brother) | F507S | Hemizygous Maternal | M, 3 mo | Neonatal refractory epilepsy, dystonia, severe developmental delay, cerebral calcifications, leucopenia, and malar rash | ANA– IFN signature+(high) | Received corticosteroids, MMF, ruxolitinib. Currently, persistence of severe developmental delay and dystonia |
| (8) AGS571 (mother) | F507S | Unknown | F, 12 yo | Malar rash, thrombocytopenia, anemia | ANA+ IFN signature+(high) | NA |
| (8) AGS3740 | L528I | Het. De novo | F, 1 yo | Refractory Evans-like syndrome, panniculitis, mild motor developmental delay, stereotypic movement disorder, leukoencephalopathy with brain atrophy and calcifications | ANA+, anti-SSA+ | HSCT complicated by a chronic cutaneous GvHD treated with ruxolitinib. Currently, persistence of a slight motor deficit and hypokinesia |
| (11) | G818V | Het. De novo | F, 8 mo | Thrombocytopenia, anemia | ANA− | Relapse under rituximab, eltrombopag and baricitinib. HSCT. Currently no sign of disease activity |
| (10) | F506S | Somatic | M, 15 days | SLE with anemia, thrombocytopenia, rash, proteinuria, intestinal vasculitis, myocardial damage, thyroid dysfunction, intracranial calcification | ANA+ | Bioclinical improvement under ruxolitinib 15 mg |
| This report | P435S | Het. De novo | F, 2 yo | SLE with lupus nephritis, thrombocytopenia, anemia, chilblains, and pyramidal syndrome | ANA+ Anti IFN+ IFN signature+ (high) | Clinically stable under belimumab with mild proteinuria and pyramidal syndrome |
ANA, antinuclear antibodies; F, female; GM-CSF, granulocyte–macrophage colony-stimulating factor; GvHD, graft-versus-host disease; Het., heterozygous; HSCT, hematopoietic stem cell transplantation; IFN, interferon; IVIG: Intravenous Immunoglobulin; M, male; MMF, mycophenolate mofetil; NA, not available; NMDAR, N-methyl-D-aspartate receptor; NMO, neuromyelitis optica; SLE, systemic lupus erythematosus; SSA: Sjögren's Syndrome Antigen A; yo, years old.