Somatic Mosaicism for a NRAS Mutation Associates with Disparate Clinical Features in RAS-associated Leukoproliferative Disease: a Report of Two Cases

RAS-associated leukoproliferative disease (RALD) is a newly classified disease; thus its clinical features and management are not fully understood. The cases of two patients with characteristic features of RALD are described herein. Patient 1 was a 5-month-old female with clinical features typical of autoimmune lymphoproliferative syndrome (ALPS) and markedly elevated TCRαβ⁺CD4⁻CD8⁻ T cell numbers. Genetic analyses failed to detect an ALPS-related gene mutation; however, whole exome sequencing and other genetic analyses revealed somatic mosaicism for the G13D NRAS mutation. These data were indivative of NRAS-associated RALD with highly elevated αβ-double-negative T cells. Patient 2 was a 12-month-old girl with recurrent fever who clearly met the diagnostic criteria for juvenile myelomonocytic leukemia (JMML). Genetic analyses revealed somatic mosaicism, again for the G13D NRAS mutation, suggesting RALD associated with somatic NRAS mosaicism. Notably, unlike most JMML cases, Patient 2 did not require steroids or hematopoietic stem cell transplantation. Genetic analysis of RAS should be performed in patients fulfilling the diagnostic criteria for ALPS in the absence of ALPS-related gene mutations if the patients have elevated αβ-double-negative-T cells and in JMML patients if autoimmunity is detected. These clinical and experimental data increase our understanding of RALD, ALPS, and JMML.