Background: STAT3 deficiency is responsible for autosomal dominant hyper-IgE syndrome characterized by recurrent bacterial and fungal infections, connective tissue abnormalities, hyper-IgE and Th17 lymphopenia. Although vascular abnormalities have been reported in some patients, the prevalence, characteristics and etiology of these features have yet to be described.

Methods We prospectively screened 21 adult STAT3-deficient patients (median age: 26; range 17 - 44) for vascular abnormalities. They were explored with whole-body magnetic resonance imaging angiography, coronary multislice computed tomography and echotracking-based imaging of the carotid arteries. We also assayed for serum biomarkers of inflammation and endothelial dysfunction. Finally, murine models of aortic aneurysm were studied in the presence and absence of inhibitors of STAT3-dependent signaling.

Results: Brain abnormalities (white matter hyperintensities, lacunar lesions suggestive of ischemic infarcts, atrophy) were found in 95% of patients. Peripheral and brain artery abnormalities were reported in 84% of patients, whereas coronary artery abnormalities were detected in 50%. The most frequent vascular abnormalities were ectasia and aneurysm. The carotid intima-media thickness was markedly decreased, with a substantial increase in circumferential wall stress indicating the occurrence of hypotrophic arterial remodeling in this STAT3-deficient population. Systemic inflammatory biomarker levels correlated poorly with the vascular phenotype. In vivo inhibition of STAT3 signaling or blockade of IL-17A resulted in a marked increase in aneurysm severity and fatal rupture in mouse models.

Conclusions Vascular abnormalities are highly prevalent in STAT3-deficient patients. This feature is consistent with the greater susceptibility to vascular aneurysm observed after inhibition of STAT3-dependent signaling in mouse models.