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Sporadic Pheochromocytomas Are Rarely Associated with Germline Mutations in the vhl Tumor Suppressor Gene or the ret Protooncogene¹

Laboratory of Oncology, Womens Hospital Eppendorf (H.B., T.W.), and Institute for Hormone and Fertility Research (W.H.), University of Hamburg, Hamburg; and the Laboratory of Molecular Pathology, Institute of Pathology and Pathological Anatomy, Technical University (H.J.), and the Endocrinology Unit, Department of Medicine II, Ludwig Maximilian University (D.E., M.M. R.), and the Department of Surgery, Hospital Maria-Martha (F.S.), Munich, Germany

Address all correspondence and requests for reprints: to Dr. Hiltrud Brauch, Laboratory of Oncology, Womens Hospital Eppendorf, University of Hamburg, Martinistrasse 52, 20246 Hamburg, Germany.

Pheochromocytoma is a tumor that may occur sporadically or may be a manifestation of a hereditary disease, such as von Hippel-Lindau disease (VHL) and multiple endocrine neoplasia (MEN) type 2. As patients with VHL or MEN type 2 are at risk to develop multiple tumors, they must be distinguished from sporadic cases. We determined the incidence of VHL and MEN type 2 among 62 German patients diagnosed with pheochromocytoma without a history of a hereditary disease. Germline analyses of the vhl gene and exons 10, 11, and 13 of the ret protooncogene were performed by PCR, single strand conformation polymorphism, enzyme digestion, or sequencing. Two patients (3%) showed vhl mutations (95% confidence interval, 1–11%). One patient showed loss of the MspI restriction site at nucleotides 712/713. Another patient had a C/T change at an intronic site that was also detected in 2 of his offspring. No mutations were detected in the ret protooncogene (97.5% confidence interval, 0–6%).

In Germany, most sporadic pheochromocytomas are not due to VHL or MEN type 2. Therefore, clinical work-up in patients with pheochromocytoma without signs of hereditary disease is not recommended. However, because the costs of genetic screening are relatively low, and each index case allows optimal care for family members, molecular testing might be cost-effective.

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