Mosaic KRAS Mutation Leading to RAS-Associated Autoimmune Leukoproliferative Disorder

BackgroundRAS-associated autoimmune leukoproliferative disorder (RALD) is a rare immune-dysregulation syndrome caused by pathogenic mutations in RAS–MAPK pathway genes, most commonly KRAS. It is characterized by autoimmune cytopenias, monocytosis, hepatosplenomegaly, and chronic lymphoproliferation without malignant transformation.Case PresentationWe report a case of a 3-year-old Saudi girl with a mosaic pathogenic variant in the KRAS gene. She was born at term with an unremarkable neonatal period and remained well until 1 year and 9 months of age, when she presented with fever, respiratory symptoms, skin rash, and epistaxis. Evaluation revealed splenomegaly, pancytopenia, and lobar pneumonia, for which she was treated with antibiotics and oral prednisolone 2 mg/kg/day for 4 weeks, followed by a gradual taper over 2 months targeting autoimmune cytopenias.Following the initial episode, she experienced recurrent admissions every 2–3 months for respiratory or gastrointestinal infections. Her weight remained below the 3rd percentile; however, no dysmorphic features or lymphadenopathy were noted. Immunologic evaluation revealed B cell lymphocytosis (CD19: 3,127 cells/μL), persistent monocytosis (>1,500 cells/μL), and a positive Coombs test. Bone marrow analysis demonstrated left-shifted granulopoiesis with normal blast percentage. Serial abdominal ultrasounds showed progressive splenomegaly (10 → 11.3 → 13 cm within one year) and mild hepatomegaly.Whole-exome sequencing identified a mosaic KRAS c.37G>T (p.Gly13Cys) pathological variant with a 14% allelic ratio. This variant has been previously reported to cause a gain-of-function KRAS, confirming the diagnosis of RALD. She also developed hypothyroidism, treated with levothyroxine.Sirolimus was later initiated to control cytopenias and lymphoproliferation, with partial clinical response. She is currently undergoing evaluation for hematopoietic stem cell transplantation (HSCT) pending matched donor availability.ConclusionThis case emphasizes the importance of considering molecular testing in children with early-onset autoimmune cytopenias and splenomegaly. Evaluation for mosaicism is critical in suspected RALD to ensure an accurate diagnosis and guide appropriate targeted management.