Expanding the clinical spectrum of DNASE1L3-associated monogenic lupus

RATIONALE: DNASE1L3 deficiency is a rare autosomal-recessive monogenic form of systemic lupus erythematosus, characterized by defective clearance of extracellular DNA, leading to immune-complex formation, autoantibody production, and systemic inflammation. While early-onset lupus nephritis and hypocomplementemic urticarial vasculitis are hallmark features, the full clinical spectrum remains incompletely understood, particularly in pediatric populations. PATIENT CONCERNS AND DIAGNOSES: We report 4 cases from 2 unrelated consanguineous Syrian families, including 1 genetically confirmed case with a pathogenic DNASEI L3 variant, 1 case harboring a homozygous DNASEI L3 variant of uncertain significance, and 2 phenotypically concordant siblings without genetic testing. Clinical, laboratory, and histopathologic data were reviewed to characterize disease manifestations, organ involvement, serologic profiles, and therapeutic outcomes. INTERVENTIONS AND OUTCOMES: All patients presented with recurrent fever, cutaneous rash, and musculoskeletal involvement, with notable variability in autoantibody profiles, renal pathology, and disease severity. Genetic analysis identified a homozygous pathogenic DNASEI L3 variant in case 3 and a homozygous DNASEI L3 variant of uncertain significance in case 1, supporting a clinically suspected DNASEI L3-associated monogenic lupus-spectrum disease. Renal involvement ranged from IgA glomerulonephritis to class IV lupus nephritis. Ocular manifestations, including conjunctival congestion and papilledema, were observed in 3 patients, highlighting an underrecognized feature. Therapeutic responses varied: 1 patient remained stable on baricitinib, while 2 patients succumbed to severe neurologic or renal complications. This series underscores the heterogeneous phenotypic spectrum of DNASEI L3-associated disease, including atypical seronegative presentations and diverse renal pathology. LESSONS: DNASEI L3-associated disease should be considered in children with early-onset vasculitic rash, hypocomplementemia, and nephritis, regardless of classical autoantibody status. Our cases expand the known clinical spectrum, emphasize the potential for ocular involvement, and suggest a role for targeted therapies such as JAK inhibitors in interferon-driven disease. Early genetic testing is essential for timely diagnosis and management of this potentially life-threatening condition.