IL6ST encodes the GP130 protein which transduces the proinflammatory signaling of the IL6 cytokine family through JAK/STAT activation. Biallelic loss-of-function IL6ST variants cause autosomal recessive hyper-IgE syndrome or a variant of Stuve-Wiedemann syndrome. Somatic gain-of-function IL6ST mutations, in particular small monoallelic in-frame deletions of which the most prevalent is IL6ST Ser187_Tyr190del, are an established cause of inflammatory hepatocellular tumors (IHCA) but so far, no disease caused by such mutations present constitutively has been described. Herein, we report a pediatric proband with a novel syndrome of neonatal onset immunodeficiency with autoinflammation and dysmorphy associated with the IL6ST Tyr186_Tyr190del variant present constitutively. Tyr186_Tyr190del was found by exome sequencing and shown to be de novo (absent in proband's parents and siblings) and mosaic (present in approx. 15-40% of cells depending on the tissue studied-blood, urine sediment, hair bulbs, buccal swab). Functional studies were performed in EBV-immortalized patient's B-cell lymphoblastoid cell line, which carried the variant in approximately 95% of cells. Western blot showed that the patient's cells exhibited constitutive hyperphosphorylation of Tyr705 in STAT3 indicative of IL6 independent activation of GP130. Interestingly, the STAT3 phosphorylation could be inhibited with ruxolitinib as well as tofacitinib, which are clinically approved JAK1 and JAK3 (to lesser extent JAK2 and JAK1) inhibitors, respectively. Given our results and the recent reports of ruxolitinib and tofacitinib use for the treatment of diseases caused by direct activation of STAT3 or STAT1 we speculate that these drugs may be effective in the treatment of our patient's condition.