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Abstract
Background STING-Associated Vasculopathy with onset in Infancy (SAVI) is an auto-inflammatory monogenic disease. SAVI is caused by an upregulation of type I interferon signaling due to sporadic or inherited gain-of-function mutations in the STimulator of INterferon Gene (STING)/Transmembrane Protein 173 (TMEM173). The first description of this phenotype, and the identification of the mutated gene, was in 2014. SAVI is characterized mainly by cutaneous vasculopathy leading to necrotic lesions, and progressive interstitial lung disease with secondary fibrosis.
Objectives SAVI is a rare disease with unknown prevalence. To the best of our knowledge, 25 cases have been reported so-far. These patients variably manifest cutaneous lesions and inflammatory lung disease. Here we present a case of SAVI with onset of features at the age of 3 years.
Methods A now 8 year old boy born to non-consanguineous parents was described to have experienced recurrent fevers, polyarthralgia and polyarthritis, livedo of the limbs, facial telangiectasia, necrotic lesions of auricles and digits and failure to thrive since the age of 3 years. He has normal cognitive development. His familial history is notable for epilepsy in 2 of his siblings and Behcet disease in a paternal cousin.
Laboratory tests at age 6.5 years revealed increased ESR (60mm/h) while CRP varied from 3 to 14 mg/L. ANA titres were positive (1/640), with normal complement level and negative anti-DNA. c-ANCA and p-ANCA were negative. ECA and lysozymes were in the normal range. Although the child had no respiratory symptoms, chest X-ray revealed diffuse interstitial parenchymal infiltrates. Chest angio-CT showed ground-glass lesions with fibrotic bands and mediastinal and para-hilar adenopathies. FVC and DLCO were reduced on pulmonary functional testing. Lung biopsy was not performed.
Empirical treatment with pulse and oral corticosteroids along with azathioprine was started. Over a period of one year, systemic inflammation and skin involvement regressed dramatically, but his lung disease showed no improvement.
Results Genetic testing identified a previously reported V155M mutation in TMEM173.
Conclusions SAVI is associated with significant morbidity and mortality. The diagnosis should be considered in children with interstitial lung disease after more common causes have been ruled out. Steroids and immunosuppressive therapies apparently show no efficacy in avoiding progression to irreversible lung damage. Promising results with treatment by Janus Kinase inhibitors as a means of blocking signaling downstream of the type I interferon receptor were recently published.
References
Y. Liu, A.A. Jesus, B. Marrero, et al. Activated STING in a vascular and pulmonary syndrome. N Engl J Med, 371 (2014), pp. 507–518.
N. Jeremiah, B. Neven, M. Gentili, et al. Inherited STING-activating mutation underlies a familial inflammatory syndrome with lupus-like manifestations. J Clin Invest, 124 (2014), pp. 5516–5520.
Fremond ML, Rodero MP, et al. Efficacy of the Janus Kinase 1/2 inhibitor ruxolitinib in the treatment of vasculopathy associated with TMEM173-activating mutations in 3 children. J Allergy Clin Immunol. 2016 Dec; 138(6): 1752–1755.
References
Acknowledgements We thank Isabelle Melki for her valuable assistance in this case.
Disclosure of Interest None declared