Thomas B. Repas, DO, FACP, FACE, CDE, is an endocrinologist, lipidologist and physician nutrition specialist in clinical practice at the Regional Medical Clinic Endocrinology and Diabetes Education Center in Rapid City, SD. Dr. Repas is the former chairman of the professional diabetes advisory committees of the Wyoming and the Wisconsin Diabetes Prevention and Control Programs. He is board certified in the areas of endocrinology, diabetes and metabolism, clinical lipidology, internal medicine and nutrition, and is also a certified diabetes educator.

Genetic testing in pheochromocytoma

Recently a colleague asked me about a patient she had with recurrent pheochromocytoma. I wondered about his family history and whether genetic testing would be appropriate.

Most solitary adrenal pheochromocytomas are sporadic. However, up to 24% may have mutation on genetic testing, even without family history. In familial disorders, pheochromocytoma is more likely to be bilateral and often presents at younger ages.

There are several disorders associated with familial pheochromocytoma and paraganglioma. These include: multiple endocrine neoplasia type 2, von Hippel-Lindau syndrome, neurofibromatosis type 1 and familial paraganglioma.

MEN2 is due to mutations of the RET proto-oncogene. In addition to medullary thyroid cancer and primary hyperparathyroidism, MEN2 can also be associated with pheochromocytoma, often bilateral. Pheochromocytoma occurs in about 50% of cases with MEN2. Patients with pheochromocytoma due to MEN2 often present at younger ages and with less hypertension than those with sporadic disease.

Von Hippel-Lindau syndrome is due to a mutation in the VHL tumor suppressor gene. In addition to pheochromocytoma (often bilateral) and rarely paragangliomas, von Hippel-Lindau syndrome is also associated with retinal angiomas, cerebellar hemangioblastoma, renal cell carcinoma and other tumors/cysts. The pheochromocytomas associated with von Hippel-Lindau syndrome tend to present at younger ages and are often clinically silent.

Neurofibromatosis type 1 is an autosomal disorder associated with neurofibromas, axillary freckling, café au lait spots and iris hamartomas. Only 2% to 5% of patients with neurofibromatosis type 1 will have pheochromocytoma. Most are solitary. Bilateral adrenal pheochromocytoma and extra-adrenal paragangliomas can occur but are rare.

Familial paraganglioma is an autosomal disorder due to mutations in the succinate dehydrogenase subunit genes (SDHB, SDHC, SDHD). The SDHC and SDHD mutations are associated with clinically silent head and neck paragangliomas. The SDHB mutation is associated with thoracic, abdominal and pelvic paragangliomas, often functioning. Those with the SDHB mutation tend to present at younger ages and are more likely to develop malignant disease.

Which individuals with pheochromocytoma/paraganglioma should be tested for genetic mutation? The patient must always be involved in this discussion. Identifying a mutation in a family can have implications, all of which must be discussed fully before testing is performed. Although most pheochromocytoma are sporadic, missing a genetic syndrome could have serious, even fatal, consequences for that patient and family member. Genetic testing is expensive, however, and not often covered by insurance.

Testing should be considered in bilateral, multifocal, recurrent or malignant disease, family history of catecholamine secreting tumor, extra-adrenal paragangliomas, early age of onset or history suggesting one of the syndromes discussed above. Family members at risk should not be tested until a mutation is confirmed in the person afflicted.

An excellent review is available at http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=paragangliomas.