1115. Impact of Pseudo-Hypoxia on Vascular Development in EPAS1 Mutation Syndrome

Authors: Jared Rosenblum; Dominic Maggio; Herui Wang, PhD; Ying Pang, MD, PhD; John Heiss, MD; Karel Pacak, MD, PhD; Zhengping Zhuang, MD, PhD (Bethesda, MD)

Introduction: We previously identified a syndrome of multiple paragangliomas, somatostatinoma, and polycythemia resulting from mosaic gain-of-function EPAS1 mutation, Pacak-Zhuang syndrome. HIF2 a , the product of EPAS1 , is critical to development, particularly at regions of pseudo-hypoxia, such as the endocardial cushion and the dural venous field. Several newly presenting patients also had cardiac anomalies. Further, these patients all developed idiopathic intracranial hypertension. Herein, we aim to characterize the findings in these patients and determine if the cardiac and intracranial findings 1) result from hemodynamic changes of birth-related polycythemia or primary pulmonary arterial hypertension; 2) contribute to the development of paragangliomas/pheochromocytoma via hypoxic state; or 3) are developmental in origin. Methods: Patients presenting from 2012-present were confirmed for all characteristics of the syndrome as above and subsequently evaluated by CT of the chest/abdomen/pelvis, echocardiogram, and CT and MRI of the head for venous anomalies and pulmonary arterial hypertension. Findings were categorized according to anatomic location and related developmental hypoxic state. Results: Cardiac findings in the EPAS1 syndrome patients consistently included right eccentric ventricular and intraventricular septal (IVS) hypertrophy as well as irregular contour of the IVS. One patient with high degree of mosaicism demonstrated a single common atrioventricular valve (AVV). The dural sinuses, cortical veins, basi-vertebral veins, trans-tentorial veins, deep venous system, and subarachnoid spaces were enlarged in all patients, with several patients also demonstrating increased tentorial angle and small posterior fossa. All patients also had sacral dysraphism or segmentation anomalies. Conclusions: Patients with EPAS1 mutation syndrome demonstrated anomalous intracranial and spinal venous and boney architecture and congenital right ventricular and septal heart defects. The defects occur where hypoxia is normally present in early gestation embryos. We hypothesize that constitutive activation of HIF2 a in early development enabled more venous elements than normal to survive through the low-oxygen environment of early gestation, resulting in venous proliferation.