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• W4220797674 abstract "Systemic lupus erythematosus (SLE) is a rare autoimmune disorder characterized by multiple organ involvement with various clinical features. Monogenic SLE due to single gene mutations generally occurs in children younger than 5 years old. Various environmental, genetic and immunological factors play a major role in the pathogenesis, such as the loss of self-tolerance of immunological antigens, formation of immune complexes, complement consumption, dysregulation of apoptosis, degradation of nucleic acids and excessive production of type I interferons (IFNs) relate in tissue damage. In recent years, genome wide association studies (GWAS) stated more than 100 risk loci associated with SLE, whereas only more than 30 genes, such as TREX1, SAMHD1, DNASE1, DNASE1L3, TMEM173, etc, were robustly associated with monogenic SLE DNase 1 encoded by the DNASE1L3 gene is the primary enzyme, which splits both single-stranded and double-stranded DNA, and removes both the exogenous DNA and self-DNA from pathogens and apoptotic cells. Circulating microparticles from apoptotic cells activate the plasmacytoid and myeloid dendritic cells that cause the production of excessive IFN-α. Deficiency of DNase 1 enzyme causes early disease onset, nephritis, hypocomplementaemia, positive anti-nuclear antibody (ANA) and anti-dsDNA antibody with familial SLE.1 Herein, we report a paediatric patient diagnosed as monogenic lupus due to DNASE1L3 deficiency. A 2-year-old female patient was referred to our hospital with fever and urticarial skin lesions unresponsive to antibiotic and antihistamine therapies for a duration of 1 month. Her parents were first-degree cousins. There were no rheumatological or immunological diseases in her past medical history. Physical examination revealed paleness, diffuse maculopapular rash on her trunk and extremities. Laboratory work-up showed microscopic haematuria, nephrotic level proteinuria (960 mg/d, 80 mg/m2/h), decreased serum complement levels (C3; 54 mg/dL, C4; 5.6 mg/dL), anaemia (Hb; 5.6 g/dL), low albumin (3 g/dL), ANA positivity (1/320 titre), anti-dsDNA antibody positivity (360 IU/mL), anti-neutrophil cytoplasmic antibodies (ANCA) positivity and anti-phosphatidylserine IgG positivity (360 IU/mL). Renal and liver function tests were normal. Acute phase reactants were slightly elevated (C-reactive protein; 11 mg/dL, erythrocyte sedimentation rate; 42 mm/h). Direct Coombs test was negative. Chest X-ray was normal. Renal biopsy was compatible with the class III lupus nephritis with mesangial staining for C3, C4, IgG, IgA and C1q. The patient was diagnosed as SLE. Corticosteroid, hydroxychloroquine, aspirin and 6 doses of monthly cyclophosphamide were prescribed as induction therapy, and mycophenolate mofetil as maintenance therapy. The proteinuria and urticarial rash regressed. Corticosteroid therapy was tapered gradually after the first month of therapy and continued as a low dose. At the 7-year follow-up, chilblain skin lesions developed in her fingers. Whole-exome sequencing (WES) showed a homozygous T97Ifs*2 mutation in DNASE1L3 in our patient, whereas a heterozygous T97Ifs*2 mutation in DNASE1L3 in her sister and mother. A written informed consent obtained from the patient's parents. DNASE1L3 deficiency is an extremely rare disease causing monogenic SLE, and to date only a few case presentations have been reported in the current literature (Table I).2-6 The clinical and laboratory presentations of these patients include a very young age of onset of SLE, severe disease activity, chronic urticarial rash, glomerulonephritis, hypocomplementaemia, positive anti-dsDNA antibody and positive ANCA.¹ Al-Mayouf et al3 described DNASE1L3 mutation with an autosomal recessive inheritance in 17 SLE patients from 6 consanguineous families who were paediatric onset disease with a high frequency of lupus nephritis, positive ANA, positive anti-dsDNA antibody, positive ANCA and hypocomplementaemia. Ozcakar et al5 reported DNASE1L3 mutation in 5 paediatric patients (within 2 families) with hypocomplementemic urticarial vasculitis disease. Three patients developed SLE during the follow-up period, and they suggested an association between hypocomplementaemic urticarial vasculitis and SLE.5 Afterward, the third family in the world described by Carbonella et al,7 and they reported an adult patient who had paediatric onset SLE disease, urticarial rash, hypocomplementaemia and positive ANA, anti-dsDNA antibody and ANCA. There was no clinical improvement with immunosuppressive therapies. His mother had undergone kidney transplantation for unknown aetiology and his sister had a history of low complement level. GWAS of the family showed DNASE1L3 deficiency in the index case and his sister and mother.7 Kisla Ekinci et al2 described a paediatric monogenic lupus patient due to DNASE1L3 deficiency with urticarial rash, hypocomplementaemia, pulmonary haemorrhage and immune complex glomerulonephritis. In another study, WES was performed in 7 early-onset paediatric SLE patients. They found DNASE1L3 deficiency in 1 patient who had scleritis, pulmonary involvement, nephritis, maculopapular rash, hypocomplementaemia, ANA and anti-dsDNA antibody positivity with a severe disease course.4 DOCK8 variant, responsible for the hyper-IgE recurrent infection syndrome, was detected in a child with DNASE1L3 mutation presented by severe autoimmune haemolytic anaemia. This patient died due to unresponsiveness to the immunosuppressive therapies.6 Our case had urticarial and chilblain rashes, immune-complex nephritis, hypocomplementaemia and ANA, anti-dsDNA antibody and ANCA positivities. However, she had significantly benefited from immunosuppressive therapies. We did not observe neither scleritis nor pulmonary involvement during the follow-up period. In conclusion, monogenic SLE disease, particularly DNASE1L3 deficiency, should be kept in mind in paediatric patients who presented with early-onset symptoms for SLE, hypocomplementaemia, glomerulonephritis, recurrent chronic urticarial rash and positive autoantibodies. The authors are grateful to Professor Carola G Vinuesa and her laboratory team in Australian National University for the genetic analysis of the patient and her family. The authors declare no conflict of interest. DGY and SAB developed the concept and designed research; DGY and SAB performed research and acquired data; DGY and SAB analysed data; DGY and SAB interpreted data; DGY and SAB wrote and reviewed the manuscript. Data sharing not applicable – no new data generated, or the article describes entirely case report." @default.
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• W4220797674 date "2022-03-29" @default.
• W4220797674 modified "2023-10-16" @default.
• W4220797674 title "Monogenic lupus caused by mutations in DNASE1L3: A rare cause of systemic lupus erythematosus in children" @default.
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• W4220797674 doi "https://doi.org/10.1111/sji.13162" @default.
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