Germline gain-of-function STAT3 mutations are identified in early-onset multiorgan autoimmune diseases. Somatic STAT3 mutations are associated with 40% of adult T-cell large granular lymphocytic (LGL) leukemia. The two phenotypes are thought to be distinct.
We describe a child with Evans syndrome who developed in the young adult age a T-cell LGL leukemia.
The patient was born from non-consanguineous healthy parents. From the age of 2, he suffered of pyogenic infections, autoimmune neutropenia, unexplained splenomegaly and hypergammaglobulinemia. At the age of 9, he presented tri-lineage autoimmunity.
At the pediatric age, whole exome sequencing identified a de novo activating p.Y640F STAT3 mutation in blood but not in fibroblasts. He had recurrent mouth ulcers, persistent splenomegaly and severe neutropenia. He received immunoglobulins or steroid pulses and preventive sequential G-CSF. Repeated blood and marrow smears showed no leukemia.
At the age of 21, splenomegaly and neutropenia worsened and a clonal proliferation of large granular lymphocytes CD3+ CD5+ CD7+ CD8+ TiA1+, granzyme B+ perforine+ CD57+ was identified on blood smears, marrow aspirate and biopsy. Ruxolitinib was initiated: 3 months later, the spleen regressed, neutrophil count improved and G-CSF was stopped.
The mutation identified in this patient with early-onset Evans syndrome belongs to the hotspots associated with LGL leukemia. G-CSF use should be limited in this context. The JAK-STAT3 pathway is involved in various germline or somatic diseases. New avenues on pathophysiology, natural history and targeted therapies are opened. Those rare patients require specific care by specialized teams wit a special attention for the transition period.