MON-378 Somatic HIF2α Mutation and Pheochromocytoma in a Patient with Cyanotic Congenital Heart Disease

Background: Pheochromocytoma and paraganglioma (PPGL) prevalence is increased in cyanotic congenital heart disease relative to the unaffected population. Chronic hypoxemia promotes stabilization of hypoxia inducible factors (HIFs), which activate downstream hypoxia responsive genes. Somatic mutations in EPAS1 (HIF2α) distort the conformational properties of HIF2α, allowing for avoidance of normally rapid oxygen-dependent enzymatic degradation. EPAS1 mutations have been implicated in PPGL and have recently been proposed to mediate the increased rates of PPGL observed in patients with cyanotic congenital heart disease. Clinical Case: A 48 year old woman with Eisenmenger’s syndrome secondary to congenital ventricular septal defect was admitted to hospital for combined heart and bilateral lung transplantation. Severe pulmonary hypertension with hypoxic respiratory failure had been present for >15 years pre-transplant, and during the 12 months directly preceding admission oxygen saturations routinely measured below 80%. Surgery was complicated by major bleeding and prolonged intraoperative hypotension necessitating initiation of extracorporeal membranous oxygenation to achieve hemodynamic stability. The patient was admitted to the intensive care unit for post-surgical management and within hours of arrival developed paroxysms of pronounced hypertension during which the systolic blood pressure repeatedly exceeded 230 mmHg. On each occasion the hypertensive episode was self-limiting and followed by a period of marked hypotension requiring maximal inotropic support. Plasma metanephrine and normetanephrine concentrations were elevated at 1.00 nmol/L (NR <0.4) and 8.00 nmol/L (NR <0.9) respectively. Computed tomography demonstrated adrenal lesions measuring 18x22x21 mm on the right and 39x38x42 mm on the left. Both adrenal masses were gallium-68 DOTATATE PET-CT avid and pathologic extra-adrenal DOTATATE avidity was not present. The left adrenal tumour was histologically confirmed as PPGL. Histology of the right adrenal gland was unremarkable, but pathologic examination of an extra-adrenal mass identified during surgery was consistent with PPGL. Immunohistochemistry was positive for synaptophysin, chromogranin, CD56 and SDHB in both tumours. Germline mutation screening was negative for pathologic variants in the known PPGL susceptibility genes, but tumour DNA isolated from formalin-fixed paraffin embedded sections identified a pathogenic HIF2α mutation (c.1589C>T, p.Ala530Val) in the left phaeochromocytoma. This variant was not observed in the right PPGL and both PPGL were negative for other known PPGL gene mutations. Conclusions: Chronic hypoxia associated with cyanotic heart conditions may be a risk factor for development of PPGL. Increased risk appears to be mediated, at least in part, through somatic gain of function mutations in the HIF2α gene.