First case of TREX1 mutation-driven retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations coexisting with lupus nephritis: a case report and mechanistic discussion

The TREX1 gene is fundamental for the removal of cytosolic DNA and the preservation of immune tolerance. Mutations within this gene are implicated in a range of disorders, such as Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic Manifestations (RVCL-S), Aicardi-Goutières syndrome (AGS), familial chilblain lupus, and systemic lupus erythematosus (SLE). To the best of our knowledge, this report documents the rare coexistence of TREX1-associated RVCL-S and biopsy-proven lupus nephritis in a single patient.

We report a case involving a middle-aged woman diagnosed with lupus nephritis, confirmed through renal biopsy, who later experienced progressive neurological deficits. Brain imaging demonstrated typical signs of cerebral leukoencephalopathy. Whole-exome sequencing uncovered a pathogenic TREX1 mutation (c.811_812dup, p.Asp272Argfs*6), resulting in a diagnosis of genetically confirmed TREX1-associated RVCL-S with an incomplete phenotype, coexisting with lupus nephritis. This case underscores a significant clinical challenge: the use of immunosuppressive therapy for lupus nephritis is hypothesized to potentially exacerbate the vascular complications associated with RVCL-S.

To the best of our knowledge, this case represents the first documented instance of the TREX1 p.Asp272Argfs*6 mutation contributing to the coexistence of RVCL-S and lupus nephritis. This discovery broadens the recognized phenotypic spectrum associated with TREX1-related disorders and underscores a distinct therapeutic challenge in their management. It is important for clinicians to be aware of this new phenotype to ensure prompt diagnosis and tailored treatment strategies.