RAS-ASSOCIATED AUTOIMMUNE LEUKOPROLIFERATIVE DISORDER IS ASSOCIATED WITH ACTIVATION OF MYELOID AND LYMPHOID CELLS IN 2-YEAR OLD BOY
- Nina F. Øbro, Denmark
Abstract
Background and Aims
RAS-associated autoimmune leukoproliferative disorder (RALD) is a very rare and sparsely characterized non-malignant condition occurring in patients with somatic, gain-of-function mutations in NRAS or KRAS. We here present a 2-year old boy with somatic NRAS mutation followed due to delayed development, recurrent respiratory tract infections and liver dysfunction, who was acutely admitted with severe edemas, dyspnea, fatigue, and minor bleedings.
Methods
Flow cytometric analyses of BM, PB and lymph node.
Results
Laboratory test revealed persistent thrombocytopenia, leukocytosis with monocytosis and hypergammaglobulinemia with multiple autoantibodies, which all had been present from 8 months of age. Repeated BM assessments showed JMML-like phenotype without blast cells. CT scan showed hepatomegaly and systemic lymphoid tissue expansion. A sigmoid biopsy displayed mononuclear cell infiltrates. Flow cytometry revealed many CD14+CD16+ non-classical monocytes (63% of monocytes in lymph nodes, 30% in PB) and B-cell lymphocytosis but only 2.4% CD3+TCRαβ+CD4-CD8- DNT cells, suggesting the diagnosis of RALD.
Additional phenotyping showed activation of neutrophils and B cells, maturation, activation and exhaustion of the T cell compartment and numerous FOXP3+ regulatory T cells (Figure), indicating an immune dysregulation of both myeloid and lymphoid lineages. Furthermore, two small populations of immature mCD3-cyCD3+ T cells were found in PB and lymph node.
Conclusions
We show increased activation of myeloid and lymphoid cell subsets, and a marked increase in regulatory T cells in addition to clinical and laboratory characteristics of RALD. Treatment with steroids and sirolimus was initiated, but inhibition of the Ras pathway (e.g. with selumetinib) could be another potential target.