PULMONARY HYPERTENSION IN A CHILD WITH STAT3 GAIN OF FUNCTION MUTATION-ASSOCIATED INTERSITIAL LUNG DISEASE

Abstract

SESSION TITLE: Fellows Pediatrics Posters SESSION TYPE: Fellow Case Report Posters PRESENTED ON: October 18-21, 2020 INTRODUCTION: STAT3 gain of function mutations are a recently described cause of autoimmunity that affect multiple organ systems, including the lungs. CASE PRESENTATION: The patient was first diagnosed with autoimmune lymphoproliferative syndrome (ALPS) at age 2 in the setting of lymphadenopathy, hepatosplenomegaly, & autoimmune cytopenias. Treatment was initially steroids & IVIG; he later started sirolimus as a steroid-sparing agent. No genetic defect consistent with ALPS was identified though he was found to have short telomeres, of unclear significance as he did not fit a dyskeratosis congenita phenotype. Further evaluation revealed a gain of function (GOF) mutation in STAT3. At age 9, he developed dyspnea & syncope; evaluation revealed mild pulmonary hypertension (PH) with positive vasoreactivity testing and CT chest with upper-lobe predominant subpleural cystic lung disease & scattered pulmonary nodules. Immunosuppression was switched from sirolimus to mycophenolate. For the PH, he was prescribed dual oral therapy, with symptomatic improvement. He developed hypoxemia at age 11. VQ scan was notable for markedly heterogeneous perfusion despite homogenous ventilation & PFTs revealed a reduced DLCO with mild restriction. Given concern for worsening pulmonary disease in the setting of the STAT3 mutation, he was started on tocilizumab (in place of mycophenolate) with partial improvement in hypoxemia. At age 12, given persistent oxygen requirement & CT showing new upper lobe predominant mosaic attenuation with groundglass (& overall stable cystic lung disease), he started ruloxitinib with some improvement in his dyspnea & hypoxemia. Since tocilizumab & ruloxitinib were initiated, his TLC & DLCO have normalized. DISCUSSION: In the largest series of patients with STAT3 GOF autoimmunity, 36% were reported to have interstitial lung disease (ILD), though none had cystic lung disease1. Upper-lobe predominant subpleural cystic disease, as seen in our patient, is most reminiscent of that often incidentally found in Trisomy 21, and has not been described in other pediatric populations2. In addition to autoimmunity related to STAT3 GOF involving the lungs, there is evidence that inappropriate activation of STAT3 is involved in the development of fibrosis in patients with UIP/IPF, suggestive of a potential alternative pathway to ILD in these patients3. Pulmonary hypertension has not previously been described as a consequence of STAT3 GOF mutations. Our patient developed PH years before he became hypoxemic, suggestive that his PH is not simply due to chronic hypoxemia. CONCLUSIONS: In this patient, STAT3 GOF mutation was associated with cystic lung disease and pulmonary hypertension, manifestations that have not previously been described. Reference #1: Fabre A, Marchal S, Barlogis V, et al. Clinical aspects of STAT3 gain-of-function germline mutations: a systematic review. J Allergy Clin Immunol Pract. 2019;7(6):1958-69. Reference #2: George M, Amodio J, Lee H. Cystic lung disease in Down syndrome: a case report and literature review. Case Rep Pediatr. 2016;2016:4048501. Reference #3: Pechkovsky DV, Prele CM, Wong J, et al. STAT3-mediated signaling dysregulates lung fibroblast-myofibroblast activation and differentiation in UIP/IPF. AJP. 2012;180(4):1398-1412. DISCLOSURES: No relevant relationships by Sarah Cohen, source=Web Response No relevant relationships by Stephen Kirkby, source=Web Response