Abstract
Here, we report a female (aged 1 year and 8 months) who presented with recurrent skin lesions, hepatosplenomegaly, lymphadenopathy, and fever. She was diagnosed initially with systemic lupus erythematosus and lupus nephritis with mild anemia, thrombocytopenia, hypocomplementemia, massive proteinuria, and hematuria. Antinuclear antibodies and a Coombs test were positive. Leukocytosis and monocytosis in peripheral blood, and hypergammaglobulinemia were also noted, which are consistent with the extremely rare RAS-associated leukoproliferative disease (RALD). Whole-exome sequencing revealed co-existence of a novel de novo heterozygous missense (p.(Asn1024Ser)) mutation in the Y-box domain of phospholipase C gamma 2 (PLCG2) and a p.(Gly13Asp) variant in neuroblastoma RAS viral oncogene homologue (NRAS), which has been repeatedly reported in RALD and is one of the canonical hotspot mutations. In vitro functional experiments revealed that the likely pathogenic PLCG2 mutant had no significant effect on activation of downstream signaling pathways in HEK293T cells. The patient was treated with methylprednisolone, hydroxychloroquine, and mycophenolate mofetil, followed by telitacicept and tacrolimus, resulting in marked symptomatic improvement. This rare case expands our understanding of the clinical phenotypes associated with RALD, and emphasizes the importance of identifying potential inborn errors of immunity in cases with lupus-like symptoms with persistent monocytosis, lymphadenopathy, splenomegaly, and hypergammaglobulinemia, especially during early life. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40348-025-00212-1.