Expanding the clinical spectrum of DNASE1L3-associated monogenic lupus: A case series of 4 syrian pediatric cases.

Authors

Alyamama Kousa, Ahmad Alhamwi, Mohammad Khaled Alsayed, Sara Jabaly, Basheer Khalil

Published in

Medicine. Volume 105. Issue 33. Pages e50283. Aug 14, 2026.

Abstract

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.
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.
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.
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.

PMID:
42601766
Bibliographic data and abstract were imported from PubMed on 15 Aug 2026.

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