Endocrine Abstracts

Introduction: Phaeochromocytomas and paragangliomas (PPGLs) are neoplasms which arise from chromaffin cells of neural crest origin. Up to 40% patients with PPGLs harbour germline pathogenic variants (PVs), with somatic PVs identified in 30–45% cases. EPAS1 gain-of-function mutations drive aberrant activation of hypoxia signalling pathways and have been reported in both sporadic and syndromic PPGLs, such as in the Pacak–Zhuang syndrome, and in patients with chronic hypoxic conditions such as cyanotic congenital heart disease. Sickle cell disease (SCD), characterised by recurrent hypoxic episodes, may similarly predispose to these mutations. This case describes a novel EPAS1 variant identified in a patient with sickle cell disease and a paraganglioma.

Case: A 33-year-old Afro-Caribbean woman with SCD presented with left flank pain. She had a history of frequent SCD-associated hospital admission since childhood, with episodes of vaso-occlusive crises and acute chest syndromes, and chronic anaemia (Hb 73 g/l). She had been on hydroxycarbamide, which she took inconsistently. Routine imaging incidentally revealed a right-sided retrocaval soft tissue mass. Functional imaging with ¹⁸F-FDG PET showed intense uptake, but a ⁶⁸Ga-DOTATATE PET scan was negative. Histology demonstrated a paraganglioma (chromogranin, synaptophysin, S100, GATA3 and SDHB-positive; Ki-67 <1%). Somatic mutation analysis identified a novel likely-pathogenic EPAS1 variant (Exon 12, c.1594T>G, p.Tyr532Asp; VAF 39.9%). She was referred for surgical removal of the mass, but declined, and opted for surveillance as she was asymptomatic. She also opted against further diagnostic workup with plasma metanephrines and germline mutation studies

Discussion: Endothelial PAS domain-containing protein 1 (EPAS1), encoded by the EPAS1 gene, is also known as Hypoxia-Inducible Factor 2-α (HIF-2α), a HIF subunit of transcription complex HIF-2. At normal oxygen concentrations, HIF-α are subject to proteasomal degradation by prolyl hydroxylation. In hypoxic conditions, stable HIF- α subunits form dimer complexes promoting angiogenesis and cell proliferative activity. This case illustrates a clinically relevant association between SCD and an EPAS1-driven paraganglioma, and supports an emerging hypothesis that chronic hypoxia creates a selective environment favouring gain-of-function mutations in the clonal expansion of EPAS1-mutated cells. The identified p.Tyr532Asp variant lies within the hydroxylation domain and likely mediates constitutive HIF pathway activation, driving tumorigenesis. Prior series have shown a high prevalence of EPAS1 mutations in PPGLs associated with chronic hypoxaemia, including patients with haemoglobinopathies. Awareness of this link is essential for early recognition and genetic characterisation in younger patients presenting with PPGLs.