Autoimmune lymphoproliferative syndrome (ALPS) is characterized by defective lymphocyte apoptosis caused by abnormalities in the FAS signaling pathway and presents with lymphadenopathy, splenomegaly, and autoimmune manifestations. RAS-associated autoimmune lymphoproliferative disorder (RALD) is classified as an ALPS-related disorder and is caused by somatic mutations in NRAS or KRAS, resulting in constitutive activation of the RAS signaling pathway. This leads to impaired apoptosis, abnormal lymphocyte proliferation, and autoimmune manifestations. Compared with classic ALPS, RALD may exhibit distinct clinical features such as mild monocytosis or juvenile myelomonocytic leukemia (JMML)-like findings, making accurate differential diagnosis essential. Although glucocorticoids are generally considered first-line therapy, optimal management strategies for glucocorticoid-refractory cases remain to be established.
A two-year-old boy who had been diagnosed with autoimmune hemolytic anemia at eight months of age developed transient thrombocytopenia and nephrotic syndrome. His cytopenia was unresponsive to glucocorticoid therapy, and he became transfusion dependent. Genetic testing later identified a mosaic KRAS variant (p.Gly13Asp), leading to the diagnosis of RALD. Based on recent reports suggesting the possibility of efficacy for mTOR inhibitors in monogenic disorders characterized by immune dysregulation and lymphoproliferation, an investigator-initiated clinical trial using sirolimus was proposed and initiated after obtaining consent. After the introduction of sirolimus, the patient achieved transfusion independence. However, his clinical course was complicated by secondary hypogammaglobulinemia, which currently requires ongoing immunoglobulin replacement therapy.
Sirolimus suppresses the activation and proliferation of T and B lymphocytes, thereby controlling pathological lymphoproliferation and autoimmune manifestations in RALD. This case highlights the clinical utility of sirolimus as a promising therapeutic option for glucocorticoid-refractory RALD.
