JAK inhibition in early-onset somatic, nonclonal STAT5B gain-of-function disease

Early-onset somatic signal transducer and activator of transcription 5B(STAT5B) gain-of-function is a newly recognized monogenic atopic disorder, now with demonstrable sustained response to targeted therapy. Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathways mediate the signaling of multiple cytokines for a myriad of leukocyte functions.1 Somatic gain-of-function (GOF) mutations in STAT5B, especially N642H, are described in multiple neoplasms, in particular leukemia and lymphoma, and can be associated with significant eosinophilia.2-5 A different phenotype for somatic STAT5B N642H mutations has recently been observed whereby a nonmalignant process affects multiple hematopoietic lineages and presents with early-onset, extreme hypereosinophilia with urticaria, dermatitis, and diarrhea.6 We describe the responses of 2 patients to targeted JAK inhibition. Patient A's presentation complements the phenotype of the previously published cases of early-onset somatic STAT5B GOF, with marked peripheral and gastrointestinal eosinophilia, elevated IgE, atopy, recurrent viral respiratory infections, and failure to thrive.6 In addition, we report for the first time the response to targeted therapy with ruxolitinib in this disease.