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

Background Autosomal dominant cancer syndrome multiple endocrine neoplasia type 2 (MEN 2), may exist more often than expected in patients with pheochr omocytoma. Germline mutations identified recently in MEN 2 can be revealed by genetic screening, Objective To evaluate the frequency of RET (rearranged during transfection) mutations in patients with pheochromocytoma. Design and methods We genetically screened germline mutations in the RET pr oto-oncogene and clinically reevaluated patients with pheochromocytoma. A p entagastrin test and other biochemical studies were performed in all patien ts. Setting Department of Internal Medicine and Hypertension, The Medical Unive rsity of Warsaw, Warsaw, Poland and the Department of Nephrology and Hypert ension, Albert Ludwigs University, Freiburg, Germany. Participants Seventy seven unselected patients with pheochromocytoma (19 me n, 58 women, mean age: 51.55 +/- 1.5 years; pheochromocytoma confirmed hist opathologically) out of 162 diagnosed and treated in the years 1957-1998 in the Department of Internal Medicine and Hypertension in Warsaw, Poland. Th e other 85 patients did not respond to the written invitation. Main outcome measures The finding of RET mutations and diagnosis of MEN 2 i n patients with pheochromocytoma. Results Genetic testing revealed germline mutations in the RET proto-oncoge ne in six patients (7.8%). All carriers had mutation of exon 11, codon 634: TGC to CGC. In four patients with this mutation, medullary thyroid carcino ma (MIC) was diagnosed and in three cases, surgically treated. Biochemical parameters: parathormone 31.88 +/- 2.87 pg/ mi, calcitonin: 0 m in 0.23 +/- 0.14 ng/ml; 2 min 0.49 +/- 0.21 ng/ml; 5 min 0.48 +/- 0.21 ng/m l, metoxycatecholamines: 601.62 +/- 42.71 mu g/24h, epinephrine: 1.94 +/- 0 .17 mu g/24h, norepinephrine 13.96 +/- 1.3 mu g/24h, carcinoembryonic antig en (CEA) 9.94 +/- 4.3 ng/ml. Ambulatory blood pressure monitoring (ABPM): s ystolic blood pressure (SBP): 116 +/- 1.9 mmHg, diastolic blood pressure (D BP): 73.7 +/- 0.9 mmHg. Clinical, biochemical and imaging procedures did no t reveal any recurrence of pheochromocytoma in the 77 patients studied. Conclusions Patients with pheochromocytoma should be genetically screened f or mutations of the RET proto-oncogene. These patients should undergo clini cal screening for MEN 2. In addition, genetic studies can be useful for the screening of the families of the carriers. J Hypertens 2000, 18:1019-1023 (C) Lippincott Williams & Wilkins.