Endocrine Abstracts

JOINT2072

Introduction: Pheochromocytomas and paragangliomas (PPGLs) are rare catecholamine-producing tumours with metastatic potential. Approximately 40% of PPGLs are caused by germline variants. In this report, we present a patient with pheochromocytoma and a MDH2 variant.

Case Presentation: A 66-year-old man was referred to the Endocrinology Department for investigation of a 5.4 cm right adrenal incidentaloma, detected in a chest CT scan performed due to COVID-19 infection, with imaging features not indicative of adenoma (CT density >20 HU, no signal suppression on out-of-phase T1-weighted MRI imaging). During admission, he presented daily episodes of paroxysmic hypertension, tachycardia, headache and pallor lasting approximately 10-20 minutes. Hormonal evaluation revealed markedly elevated 24h urine metanephrine [4149 μg/24h (52-341)] and normetanephrine [6703 μg/24h (88-444)] levels (measured by HPLC) and a diagnosis of pheochromocytoma was made. After two weeks of doxazocin preparation, an uncomplicated laparoscopic right adrenalectomy was performed. Histology revealed a pheochromocytoma (PASS score 7) with Ki-67 of 6%; intense edema and hemorrhagic infiltration in neoplastic cells was also observed. Whole exome sequencing identified the missense MDH2 gene (NM_005918.4) variant, c.478G>A, resulting in replacement of valine by methionine at codon 160, p.Val160Met, of MDH2 protein. At the most recent clinical review, six months after adrenalectomy, the patient is asymptomatic with normal 24h urine metanephrine and normetanephrine levels and no evidence of disease recurrence.

Conclusion: MDH2 encodes the mitochondrial malate dehydrogenase which is essential for the conversion of malate to oxaloacetate as part of the proper functioning of the Krebs cycle and it has been, recently, added to the list of potential PPGL susceptibility genes. To our knowledge, this is the second report of a patient with a MDH2 variant and pheochromocytoma. The p.Val160Met variant of MDH2 is reported in 0.011% of alleles in European (Non-Finnish) individuals in gnomAD database. Although this specific variant is considered to be of uncertain significance according to ACMG criteria, a recent study showed that p.Val160Met variant causes protein 3D structure destabilization and impairment of MDH2 molecular function, classifying it as likely pathogenic. Further genetic studies are needed to determine the role of p.Val160Met MDH2 gene variant in the pathogenesis of PPGLs.