RAS-associated autoimmune leukoproliferative disease

RAS-associated autoimmune leukoproliferative disease (RALD) is a rare genetic disorder caused by somatic gain-of-function mutations in the KRAS or NRAS genes. These mutations lead to constitutive activation of the RAS signaling pathway in hematopoietic (blood-forming) cells, resulting in a clinical picture that closely resembles autoimmune lymphoproliferative syndrome (ALPS). RALD primarily affects the immune and hematologic systems, causing chronic, non-malignant lymphoproliferation with splenomegaly (enlarged spleen) and lymphadenopathy (enlarged lymph nodes), along with autoimmune cytopenias such as autoimmune hemolytic anemia, thrombocytopenia, and neutropenia. A hallmark feature of RALD is the expansion of double-negative T cells (CD3+TCRαβ+CD4−CD8−) in the peripheral blood, a finding shared with classical ALPS. However, unlike ALPS, RALD is caused by somatic rather than germline mutations, meaning the mutations arise after conception and are present only in a subset of blood cells. Patients may also exhibit elevated immunoglobulin levels, particularly IgG, and have an increased risk of autoimmune manifestations affecting multiple organ systems. Monocytosis and a predisposition to juvenile myelomonocytic leukemia (JMML)-like features have also been described, though most patients follow a benign clinical course. Treatment of RALD is primarily supportive and directed at managing autoimmune complications. Immunosuppressive therapies, including corticosteroids, mycophenolate mofetil, and sirolimus (rapamycin), have been used with variable success to control autoimmune cytopenias and lymphoproliferation. Splenectomy may be considered in refractory cases but carries infection risks. Long-term monitoring is important due to the theoretical risk of malignant transformation, although progression to leukemia appears to be uncommon. There is currently no curative therapy, and management is individualized based on symptom severity.

Common questions about RAS-associated autoimmune leukoproliferative disease