The Essential Role of Genetic Evaluation in Prepubertal Systemic Lupus Erythematosus

Introduction Systemic lupus erythematosus (SLE) in prepubertal children is rare and can indicate a monogenic cause. Although outcomes are variable, monogenic lupus is often difficult to treat with long-term complications related to the disease and treatment. Over thirty immune regulatory genes have been reported as a cause, including defects in the protein kinase C delta (PRKCD) gene. Promising preclinical studies suggest that mTOR inhibition can serve as a targeted therapy in SLE due to the PRKCD G510S mutation. Case presentation We describe a case of monogenic lupus in a two-year-old female who initially presented with photosensitive rashes, epistaxis, and thrombocytopenia. Evaluation revealed diffuse alopecia, hemolytic anemia (direct Coombs 3+ anti-C3d), severe thrombocytopenia (platelets 9K/µL), high-titer antinuclear antibody (>1:2,560), positive anti-double-stranded DNA (36 IU/mL) and anti-Smith antibodies (>8 AI), and hypocomplementemia (complement C4 6mg/dL, complement C3 71 mg/dL). Findings fulfilled the 1997 American College of Rheumatology revised classification criteria. Whole-genome sequencing showed a heterozygous, likely pathogenic variant of the PRKCD gene: c.1840C>T, p.Arg614Trp. The patient did not have evidence of lymphoproliferation. The patient was treated with conventional lupus therapy, including mycophenolate mofetil and high-dose corticosteroids. The patient had an incomplete response to this regimen with subsequent evolution of lupus nephritis, necessitating 6 months of cyclophosphamide therapy. Additionally, she was not able to wean systemic steroids and developed multiple sequelae of long-term steroid use. One year after initial presentation, the patient’s genome was reanalyzed, given significant suspicion for PRCKD-related immune dysregulation disorder. On reanalysis, an additional variant of uncertain significance was found on the PRCKD gene, c.-20.285delA p.? with paternal inheritance. Given the clinical presentation and the two inherited gene variants, a diagnosis of PRKCD deficiency was strongly suspected. The patient started on sirolimus as primary immunosuppressive therapy with remarkable improvement of symptoms and ability to wean steroids. Discussion Our report highlights the importance of genetic evaluation and interval reanalysis in prepubertal SLE. Furthermore, our case suggests use of sirolimus can be pivotal in PRKCD deficiency with monogenic lupus, including non-G510S variants. We propose considering genetic testing in all children with a prepubertal SLE diagnosis.