Incidence and clinical relevance of RET proto-oncogene germline mutations in pheochromocytoma patients

BACKGROUNDAutosomal dominant cancer syndrome – multiple endocrine neoplasia type 2 (MEN 2), may exist more often than expected in patients with pheochromocytoma. Germline mutations identified recently in MEN 2 can be revealed by genetic screening. OBJECTIVETo evaluate the frequency of RET (rearranged during transfection) mutations in patients with pheochromocytoma. DESIGN AND METHODSWe genetically screened germline mutations in the RET protooncogene and clinically reevaluated patients with pheochromocytoma. A pentagastrin test and other biochemical studies were performed in all patients. SETTINGDepartment of Internal Medicine and Hypertension, The Medical University of Warsaw, Warsaw, Poland and the Department of Nephrology and Hypertension, Albert Ludwigs University, Freiburg, Germany. PARTICIPANTSSeventy seven unselected patients with pheochromocytoma (19 men, 58 women, mean age51.55 ± 1.5 years; pheochromocytoma confirmed histopathologically) out of 162 diagnosed and treated in the years 1957–1998 in the Department of Internal Medicine and Hypertension in Warsaw, Poland. The other 85 patients did not respond to the written invitation. MAIN OUTCOME MEASURESThe finding of RET mutations and diagnosis of MEN 2 in patients with pheochromocytoma. RESULTSGenetic testing revealed germline mutations in the RET protooncogene in six patients (7.8%). All carriers had mutation of exon 11, codon 634TGC to CGC. In four patients with this mutation, medullary thyroid carcinoma (MIC) was diagnosed and in three cases, surgically treated.Biochemical parametersparathormone 31.88 ± 2.87 pg/ml, calcitonin0 min 0.23 ± 0.14 ng/ml; 2 min 0.49 ± 0.21 ng/ml; 5 min 0.48 ± 0.21 ng/ml, metoxycatecholamines601.62 ± 42.71 μg/24h, epinephrine1.94 ± 0.17 μg/24h, norepinephrine 13.96 ± 1.3 μg/24h, carcinoembryonic antigen (CEA) 9.94 ± 4.3 ng/ml. Ambulatory blood pressure monitoring (ABPM)systolic blood pressure (SBP)116 ± 1.9 mmHg, diastolic blood pressure (DBP)73.7 ± 0.9 mmHg. Clinical, biochemical and imaging procedures did not reveal any recurrence of pheochromocytoma in the 77 patients studied. CONCLUSIONSPatients with pheochromocytoma should be genetically screened for mutations of the RET protooncogene. These patients should undergo clinical screening for MEN 2. In addition, genetic studies can be useful for the screening of the families of the carriers.