Crohn's Disease Phenotype in a Patient With Severe Congenital Neutropenia Caused by CSF3R Variants: Exploring the Pathogenesis and Effects of Thalidomide Treatment.

This study describes a case of severe congenital neutropenia (SCN) harboring biallelic CSF3R variants and presenting with a novel inflammatory bowel disease (IBD) phenotype that responded remarkably to thalidomide. We performed functional studies to reveal the pathogenicity of the CSF3R and to elucidate the potential mechanisms underlying the therapeutic effects of thalidomide. A comprehensive review of the literature identified 18 reported cases of SCN associated with CSF3R variants. We subsequently validated the pathogenicity of the variants in the patient's peripheral blood by flow cytometry, which demonstrated reduced granulocyte colony-stimulating factor (G-CSF) receptor (G-CSFR) expression and markedly decreased phosphorylation of signal transducer and activator of transcription (STAT)3 (p-STAT3) following stimulation with recombinant human G-CSF (rhG-CSF). Thalidomide augmented rhG-CSF-induced STAT3 phosphorylation in HEK293T cells harboring the CSF3R Q257  ∗ or R308G/Q257  ∗ variants, and this effect was suppressed by a Janus kinase (JAK)1 inhibitor. Thus, IBD might represent a novel phenotype of SCN caused by CSF3R variants, and thalidomide could potentially alleviate the symptoms by modulating the JAK1/STAT3 signaling pathway.