Category: Adrenal Disorders
Paragangliomas ( PGL) are the neuroendocrine tumors of the sympathetic and parasympathetic ganglia. The common mutations for PGL are SDHA, SDHB, SDHD, NF1. We report a case of multifocal paraganglioma with a novel germline mutation in Fumarate Hydratase( FH) gene.
64 y/o male initially admitted to the hospital for rectal bleeding and NSTEMI. He was found to have multi-vessel disease on cardiac cath. He was unable to undergo colonoscopy for GI bleeding due to ongoing cardiac issues. A PET scan obtained showed hypermetabolic enlarged retroperitoneal lymph nodes concerning for malignancy. He underwent an EUS and EGD to biopsy the abdominal lymph node, which showed paraganglioma and stained positive for chromogranin and synaptophysin. The patient did not have any symptoms of palpitation, uncontrolled hypertension. Labs revealed elevated normetanephrine at 2.15nmol/l, metanephrine at 0.39 nmol/l, 24-hour urinary normetanephrine at 87ug/ d. DOTATATE scan showed radiotracer soft tissue mass at left periaortic nodal region consistent with paraganglioma and radiotracer avid lymph nodes in the abdomen.
He was started on alpha blockade with phenoxybenzamine before surgery and was added on beta blocker later. He underwent retroperitoneal mass resection with lymph node dissection. Pathology was consistent with benign multifocal paraganglioma with largest tumor dimension of 3.8 cm. Post resection, plasma normetanephrine levels normalized at 0.83 nmol/l. Genetic testing revealed that the patient has a mutation variant of unknown significance (VUS) in the FH gene while other genetic testing revealed no mutation.
30 % of the PGL is hereditary; hence all the patients should be tested for genetic mutations, especially in patients with multifocal, malignant and recurrent tumor. Diagnosis is usually established by genetic testing which tests for 20 hereditary cancer. In our patient, we have found germline mutation variant in FH gene whose significance is not known. Based on the study by Castro-Vega et al., mutations in the FH gene accounted for 0.83 % of the cases with PGL or pheochromocytoma. Studies have found that the FH gene inactivation causes epigenetic dysregulation similar to SDHB gene deficiency. Since succinate and fumarate are generated by sequential enzymatic reaction in the same metabolic signaling pathway, SDH and FH deficient genes likely will have the same oncogenic mechanism. These results suggest that germline mutation in FH gene can cause multifocal, malignant PGL/PCC.
Mutations in the FH gene can predispose to malignant, multifocal PGL in addition to renal cell cancer and leiomyomatosis, hence close follow up is required in these patients.
Anery Patel– Endocrine Physician, UNMC