A sting in the tale

Abstract

This report describes a 2.5 year-old girl of Chinese-Malay heritage who presented at 6 months of age with a chronic dry cough, tachypnoea, recurrent fevers, and poor growth. She was hypoxic and had elevated inflammatory markers with no evidence of infection. Chest computed tomography revealed bilateral intralobular and interstitial thickening with volume loss consistent with interstitial lung disease. Genetic screening for surfactant protein mutations was negative. Clinical and radiological progression continued despite monthly pulses of intravenous methylprednisolone (three days of 30mg/kg/day) for 6 months and daily hydroxychloroquine. Immunoglobulin levels, vaccine responses, absolute lymphocyte count and subsets, regulatory T and recent thymic emigrants populations, and lymphocyte response to mitogens performed at 1-year-of-age were largely normal. She had a mildly reduced CD4 (1.29 × 109/L) and CD8 count (0.55 × 109/L). An anti-nuclear antibody titre of 1:160 (speckled) was identified but extractable nuclear antigens, anti-double stranded DNA antigens, and anti-MDA-5 antibodies were not detected. Histology of a lung biopsy sample demonstrated diffuse follicular lymphoid hyperplasia, interstitial lymphoplasmacytic infiltrates, and tubular reticular inclusions. With this suggestion of innate immune dysregulation, targeted suppression of the Janus Associated Kinase (JAK) pathway using Ruxolitinib 2.5 mg twice daily was initiated. Treatment was tolerated, enabling up-titration to 5 mg twice daily (1mg/kg/day). The patient's fevers and cough have abated and respiratory rate reduced. Genetic testing has identified a gain-offunction mutation in TMEM173 known to be causative of autosomal dominant infantile-onset STING-associated vasculopathy (SAVI). Published cases describe chronic, inappropriate activation of type-1 interferon signalling, with typical presentations characterized by early-onset vasculitis, failure to thrive and lung disease. This patient is now enrolled in an international cohort study. This case highlights the importance of multi-modal investigation to obtain a definitive diagnosis for a patient who presents atypically. It emphasises the emerging role for rapid gene sequencing leading to targeted treatments in monogenic immune-mediated disease.L6251340192018-11-28 <br />