A63-06 Pulmonary Arterial Hypertension, Lymphocytic Interstitial Pneumonia, Common Variable Immunodeficiency, and Myopathy in a Patient With a STAT3 Gain of Function Mutation

Abstract Background Signal transducer and activator of transcription (STAT) 3 is a regulator of cellular proliferation, differentiation, and survival. STAT3 gain of function (GOF) disease is a rare disorder of immune dysregulation which is associated with endocrinopathies, lymphoproliferative disease, cytopenias, immunodeficiencies, and interstitial lung disease. STAT3 has also been well described in the pathophysiology of pulmonary arterial hypertension (PAH), where its upregulation leads to downstream upregulation of pro-proliferative and anti-apoptotic mechanisms, including the inhibition of bone morphogenic protein receptor type 2 (BMPR2). Pulmonary artery (PA) biopsies in patients with PAH have demonstrated elevated levels of STAT3 activation. Case A 48-year-old woman with a history of lymphocytic interstitial pneumonia (LIP) diagnosed by surgical lung biopsy, common variable immunodeficiency (CVID), and myopathy of unclear etiology presented to the emergency department with progressive dyspnea and multiple syncopal episodes. Echocardiogram demonstrated a dilated, dysfunctional, and hypertrophic right ventricle (RV) with peak tricuspid regurgitant jet velocity 4.2 meters/second and normal left ventricular function. Right heart catheterization was performed and revealed severe pre-capillary pulmonary hypertension with mean PA pressure 55 mm Hg, cardiac output (CO) 3.7 liters/minute, and pulmonary vascular resistance (PVR) 13.2 Woods units (WU). Vasoreactivity testing with inhaled nitric oxide was performed, and the mPA pressure fell to 31 mm Hg with CO f 3.8 liters/minute and PVR 6.6 WU. CT scan of the chest demonstrated apical predominant nodular opacities, and there was no evidence of chronic thromboembolism on ventilation/perfusion scan. Serologic testing was performed and was negative. The patient was diagnosed with idiopathic, vasoreactive PAH and treatment with calcium channel blockers was attempted but abandoned due to hypotension. The patient was treated with Macitentan and inhaled Treprostinil with significant improvement in exercise capacity and PVR. Due to her multiple immunologic conditions, she was referred for genetic testing and was found to have a gain of function mutation in STAT3. Discussion We present a patient with STAT3 GOF disease with CVID, LIP, myopathy, and PAH. While the immunologic presentations have been well described, PAH has only been described once in the literature in patients with STAT3 GOF disease, and testing for STAT3 mutations is not recommended as part of the genetic evaluation of patients with PAH. Given the physiologic plausibility by which upregulation of STAT3 leads to PAH, it seems likely that this patient’s PAH is secondary to STAT3 GOF disease, which may suggest response to therapies targeted at the JAK/STAT pathway. This abstract is funded by: None