Fascinating article describing a vasculopathic cutaneous and pulmonary syndrome associated with autosomal dominant mutations in TMEM173, the gene encoding stimulator of interferon genes (STING). An incredible body of work presented with numerous clinical pictures and photomicrographs in the supplementary appendix that nicely illustrate the pathologic changes. This work sheds light on an important inflammatory pathway through the description of this "experiment of nature."
Liu Y, Jesus AA, Marrero B, et al. Activated STING in a Vascular and Pulmonary Syndrome. New England Journal of Medicine published online July 16, 2014.
Studies involving children with monogenic autoinflammatory disease have provided insights into the regulation of key proinflammatory cytokine pathways and their role in causing systemic and organ-specific inflammation.1,2 We studied six patients who presented in early infancy with systemic inflammation and violaceous, scaling lesions of fingers, toes, nose, cheeks, and ears that progressed to acral necrosis in most of the patients and did not respond to therapy. A mixed histologic pattern was observed, consisting of a prominent dermal inflammatory infiltrate with features of leukocytoclastic vasculitis and microthrombotic angiopathy of small dermal vessels. Three of the patients had severe interstitial lung disease.
Although many of the genetically defined autoinflammatory diseases are associated with increased interleukin-1 signaling and have a clinical response to interleukin-1 inhibition,2 interleukin-1–inhibiting therapy was ineffective in one of the patients. A prominent interferon-response-gene signature in the peripheral blood of this participant suggested interferon dysregulation similar to that seen in other genetically defined inflammatory syndromes, including the Aicardi–Goutières syndrome,3,4 an early-onset inflammatory encephalopathy, and chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE),5,6 a proteasome-associated autoinflammatory syndrome with proposed interferon-mediated pathologic features.7,8 We detected autosomal dominant mutations in TMEM173, the gene encoding the stimulator of interferon genes (STING), in the six children we assessed, who presented with a clinical syndrome we have called STING-associated vasculopathy with onset in infancy (SAVI).