Novel Presentation of a Mosaic STAT5B Gain-of-Function Variant

Abstract

Somatic gain-of-function (GOF) variants in STAT5B have been described in leukemias and lymphomas, and more recently in three patients presenting with nonclonal eosinophilia, atopic dermatitis, diarrhea, and urticaria. Here, we describe a 7-year-old middle-Eastern female presenting with autoimmune adrenal insufficiency and lower extremity weakness. Diagnostic studies revealed CNS demyelination and demyelinating polyneuropathy of the motor nerves. CBC was notable for leukocytosis with eosinophilia, with peak AEC at 3100 cells/cumm. Immunophenotyping demonstrated normal IgG and subclasses and IgA, elevated IgM (233.1 mg/dL), and mildly elevated IgE (135 IU/ml). T cell lymphocytosis was noted on flow cytometry. Extensive infectious and autoantibody testing was unremarkable, and flow cytometry and cytology from CSF, blood, and bone marrow were not concerning for malignancy. She was treated with IV methylprednisolone and steroid taper, followed by rituximab and IVIG. Additional imaging demonstrated an enlarged thymus thought to represent rebound thymic hyperplasia, and splenomegaly. Trio whole exome sequencing performed on a buccal sample was notable for a de novo STAT5B c.1883C>G (p.Thr628Ser) variant present in 13/111 (–12%) of sequencing reads. This STAT5B variant has been reported in T cell prolymphocytic leukemia and studies have shown this variant confers GOF. Clinical evaluation for the STAT5B variant detected mosaicism in buccal swab DNA and near 50% variant allele frequency (VAF) in blood and bone marrow. We then assessed the VAF in various cells on a research basis. The VAF in buccal DNA was 7–9%, 46–48% in whole blood, and 48% in the bone marrow. Cell sorting for CD4+ and CD8+ T cells revealed a VAF of 46–48%. A similar VAF was observed in CD56+ cells (48%) and CD14+ cells (–50%). A fibroblast line was generated from a skin punch biopsy, and the variant allele was absent, suggesting somatic origin. Preliminary data from peripheral blood flow cytometric analysis demonstrated a slight increase in Treg cells, and Th2 skewing of Tregs as implied by cell surface markers. Assessment of pSTAT5 at baseline and after cytokine stimulation suggest increased responsiveness. The patient was started on tofacitinib, a JAK inhibitor primarily targeting JAK1/JAK3. She improved clinically, weaned on steroids, and is being evaluated for HSCT.