SAT631 EPAS1 Mutations In Three Adjacent Nucleotides Resulting In Different Phenotypes
Authors: Alswailem Meshael , Alghamdi Balgees , Alobaid Lulu Abdulaziz , Al-Hindi Hindi , Aldawish Mohammed , Alsagheir Osamah , Alzahrani Ali Saeed 
Published: October 2023

Disclosure: M. Alswailem: None. B. Alghamdi: None. L.A. Alobaid: None. H. Al-Hindi: None. M. Aldawish: None. O. Alsagheir: None. A.S. Alzahrani: None.

EPAS1 (HIF2a) mutations have been described in patients (pts) with paragangliomas (PGL) in association with cyanotic congenital heart disease (CHD), polycythemia and some additional tumors. Here, we present 3 cases of PGL with closely located EPAS1 mutations. Despite the common gene location, their manifestations are different. 1. A 14-year-old girl found at age 9 years (yrs) to have polycythemia (Hb 177-195 g/l) and hypertension. At age 14 years, she was diagnosed to have multiple mid abdomenal and the urinary bladder PGLs. U. noremetanephrine was 35.8 umol/day (0-3.43). No evidence of somatostatinoma so far. Family hx is negative for PGL and WES revealed no germline mutations in PGL-associated genes. Tumor testing revealed a novel heterozygous EPAS1 variant (c.1589C&gt;T, p.A530V). 2. A 32-yr-old woman has a complex cyanotic CHD diagnosed since birth. She underwent five cardiac surgeries between 1993 and 2015. In 2011, she was diagnosed with two abdominal PGLs. She underwent surgery and remained free of disease until 2019 when she developed recurrence with metastases (mets) to the liver and spine. She received external beam radiotherapy to the spine. Currently PGL mets remained stable. WES was negative for any germline mutation but tumor testing revealed a heterozygous EPAS1 mutation (c.1591C&gt;T, p.P531S). 3. A 55-yr-old man diagnosed to have an upper abdominal PGL with lung and bone metastases at the age of 9 yrs. Biopsy from a right femoral met confirmed the diagnosis of bone mets. He underwent four abdominal surgeries between 1978-2008 and received MIBG Tx 6 times with a cumulative dose is 586 mCi. His last surgery in 2008 revealed PGLs but also a non-functioning Pancreatic neuroendocrine tumor (pNET). PGL mets remained stable over the last 15 yrs. WES revealed no germline mutation in any of the known PGL genes but tumor testing revealed an EPAS1 mutation (c.1592C&gt;A, p.P531H). Discussion:EPAS1 mutations are very rare. In this series, we present 3 pts with EPAS1 mutations in 3 adjacent nucleotides (c.1589, 1591, 1592) in 2 adjacent codons (p.530-531). These mutations are located in a domain that is important for recognition by propyl hydroxylases that normally lead to inactivation and proteasomal degradation of HIF2a (EPAS1). Despite the common location, the manifestations are quite different. Although all of them developed PGL at a young age, Pt # 1 had severe polycythemia, Pt#2 had complex CHD, and pt#3 had pNET. The first two patients had extensive mets but these mets have a smoldering course, especially in pt#3 who has been living with these mets for 44 yrs! Since EPAS1 mutations are usually postzygotic, as suggested by its involvement of more than one organ, it is possible that the variable presentations of these same domain adjacently located mutations is related to the timing of their post zygotic development. Another possibility is that the variable expression of the mutated EPAS1 in different tissues

Presentation: Saturday, June 17, 2023