Presentation of a missense MDH2 variant in a Greek patient with pheochromocytoma

Approximately 40% of pheochromocytomas and paragangliomas (PPGLs) are caused by germline mutations. MDH2 encodes the mitochondrial malate dehydrogenase, a Krebs cycle enzyme, which is essential for the conversion of malate to oxaloacetate and which has recently been added to the list of potential PPGL susceptibility genes. In this report, we present a MDH2 germline variant in a Greek patient with pheochromocytoma.

A 66-year-old male patient presented for investigation of a 5.4 cm right adrenal incidentaloma, with imaging features not indicative of adenoma. During hospitalization, he experienced daily episodes of paroxysmal hypertension, tachycardia, headache, and pallor lasting approximately 10-20 min. Hormonal evaluation revealed significantly increased 24-h urine metanephrine and normetanephrine levels, leading to a diagnosis of pheochromocytoma. After alpha-blockers preparation, an uncomplicated laparoscopic right adrenalectomy was performed. Histology revealed a pheochromocytoma (PASS score 7) with a Ki-67 index of 6%. Εxome sequencing identified the missense MDH2 variant, c.478G > A, resulting in replacement of valine by methionine at codon 160, p.Val160Met, of the MDH2 protein. Although this variant is considered to be of uncertain significance, recent in silico analysis showed that it results in protein three-dimensional structure destabilization and impairment of MDH2 molecular function, classifying it as likely pathogenic. Twelve months after adrenalectomy, the patient is asymptomatic with no evidence of disease recurrence.

To our knowledge, this is the second reported case with the germline c.478G > A MDH2 variant and a pheochromocytoma. Further genetic studies are needed to determine the role of this variant in the PPGLs pathogenesis.