Screening for mutations: in whom, and how?

Thank you again, Foxy, for asking an intriguing question on screening for gene mutations that cause pheochromocytoma. As this is a question of general interest, I put it as a new topic.

The chemicals a tumor produces do not tell much about whether the tumor is likely caused by a known mutation. Pheochromocytomas in MENII usually produce epinephrine, while those in VHL usually make norepinephrine. And in general, most pheochromocytomas tend to make norepinephrine, with or without mutations. Extra-adrenal pheochromocytomas (called paragangliomas) in familial paraganglioma (SDH mutations) and in Carney's triad (unknown gene mutations) may not produce catecholamines. Although these patterns of catecholamine secretion exist, they do not help in determining whether a patient should be screened.

Neither does tumor size or patient sex.

Some other clinical parameters do help. 1) Positive family history certainly suggests familial pheochromocytoma. 2) Age. The younger (<50), the more likely a patient has mutations causing pheochromocytoma. 3) Multifocal pheochromocytomas suggest mutations. 4) Signs of genetic syndromes. For example, a patient may already have meduallary thyroid carcinoma. If a patient has any of these, then genetic testing has higher yield.

Should any patient with pheochromocytoma be screened? At last year's International Symposium on Pheochromocytoma (ISP 2008, Cambridge, UK) which I attended, this topic was lively debated and the arguments were divided at the Atlantic Ocean. The European doctors seem to root for testing everyone as the tests are covered by either insurance or research centers. American doctors are more hesitant. No insurance companies in America I know cover genetic testing of pheochromocytoma in a patient without family history. A few American centers do offer testing in a research setting but the patients have to enter a trial of some sort. It can cost a patient thousands of dollars to do all the commercially available tests.

The other issue is which gene(s) to test first. Six (6) genes are known to cause pheochromocytoma: RET, VHL, NF1, SDHB, SDHD, and SDHC. Clinical history provides some help. Bilateral pheos: RET and VHL first. Extra-adrenal pheos: SDHB, SDHD, and VHL first. The hit rate is not very high even with these clinical history-based strategy. Above all, only 30% of patients without family history really have a mutation known to cause pheochromocytoma.

In my own practice, I highly encourage patients with family history to test for mutations. In those without family history, I explain the above and let them decide. Most patients without family history elect not to do genetic testing. They are followed clinically and by tests and imaging. It is unfortunate that genetic testing even in patients with family history are still not covered by insurance in many instances.