Endocrine Abstracts

Case history: Hereditary paragangliomas (PGLs) associated with loss of function mutations in SDHx and VHL genes have revealed a remarkable connection between these conditions and the hypoxia signalling pathway: with a ‘pseudohypoxic profile’ driving hypoxia inducible factor (HIF) activity and tissue-limited cellular proliferation. We present a case of sporadic, multiple PGL mediated by HIF activation through true hypoxia. A 32 year old female was referred for assessment. She had been born with cyanotic congenital heart disease (tricuspid atresia with single ventricle physiology), treated in childhood with a Glenn shunt. This produced good symptom control but significant, persisting hypoxaemia (peripheral oxygen saturation 80% at rest). In her 20s, the patient had developed unstable SVT, requiring beta-blockade and an ablation procedure. There was no family history of endocrine or renal disease. CT-pulmonary angiogram (CTPA) and liver MRI were performed to assess the impact of cardiac haemodynamic status on pulmonary and hepatic vascular physiology.

Investigations and Results: Imaging revealed hyper-enhancing, high T2-signal bilateral carotid body and a 5.0×4.9 cm retroperitoneal mass consistent with multiple paragangliomas. Plasma metanephrines measured by LC-tandem MS were as follows.

Subsequent functional imaging with I-123 MIBG confirmed high isotope uptake limited to only the retroperitoneal mass indicating its secretory nature. Multi-gene next generation sequencing did not identify mutations or sequence variants of uncertain significance in any of the paraganglioma predisposition genes: SDHAF2, SDHA, SDHB, SDHC, SDHD, VHL, NF1, RET, MAX, and TMEM127.

Management: Beta-blockers were stopped and incremental alpha blockade was introduced using doxazocin, without development of tachydysrhythmia or hypotension. Further cardiac studies revealed severe functional impairment of the single ventricle, precluding simple excision of the retroperitoneal paraganglioma. Joint congenital heart disease, endocrine and endocrine surgery multidisciplinary team assessments have recommended orthotopic cardiac transplantation, combined with removal of the retroperitoneal paraganglioma.

Conclusion and points for discussion: Data support a diagnosis of multiple paraganglioma driven by chronic hypoxia. Given the role and close association of hypoxia signalling and ‘pseudohypoxia’ in hereditary PGL disease, this case highlights the utility of having a low threshold for assessing patients with chronic systemic hypoxaemia (such as those with cyanotic congenital heart disease) for occult PGL, supporting the view that paragangliomas are a reflection of chronic systemic hypoxaemia.