Correspondence

Case 13-2001: Genetic Testing in Pheochromocytoma

N Engl J Med 2001; 345:547-548August 16, 2001

Article

To the Editor:

The Case Record in the April 26 issue1 describes a thoracic pheochromocytoma (paraganglioma) in a 19-year-old man and notes that his father received a diagnosis of hypertension in his 50s and that his mother had migraines. Although a partial differential diagnosis of pheochromocytoma and paraganglioma on the basis of genetics has been discussed, this presentation is quickly dismissed as sporadic, with the note that the father's age at diagnosis points to essential hypertension.

Unless there were other facts not evident in the published Case Record, we are concerned. Although it is partly true that multiple endocrine neoplasia type 2 rarely, if ever, presents as isolated pheochromocytoma, germ-line mutations in the VHL gene, causing von Hippel–Lindau disease, and mutations in the SDHD gene, causing a pheochromocytoma–paraganglioma syndrome, together have been shown to account for 15 to 20 percent of all nonfamilial presentations of pheochromocytoma.2-4 The patient described in Case 13-2001 therefore has a high risk of harboring a germ-line SDHD mutation. If the father indeed had a pheochromocytoma–paraganglioma syndrome as well, then the likelihood of finding a germ-line mutation in SDHD or VHL rises above 20 percent. A population-based registry of cases of pheochromocytoma based in Freiburg, Germany, shows presentations at all ages, even the 70s, in hereditary pheochromocytoma (unpublished data). The American Society of Clinical Oncology recommends genetic testing when a person or family carries the minimal threshold of a 10 percent likelihood of a mutation in a cancer-susceptibility gene.5 Such a threshold also is consistent with the guidelines of cancer-genetics professionals.

Hartmut P.H. Neumann, M.D.
Martin Reincke, M.D.
Albert-Ludwigs University, D-79106 Freiburg, Germany
neumann@med1.ukl.uni-freiburg.de

Charis Eng, M.D., Ph.D.
Ohio State University, Columbus, OH 43210

5 References

1. 1

   Case Records of the Massachusetts General Hospital (Case 13-2001). N Engl J Med 2001;344:1314-1320
   Full Text | Web of Science | Medline

2. 2

   Neumann HPH, Berger DP, Sigmund G, et al. Pheochromocytomas, multiple endocrine neoplasia type 2, and von Hippel-Lindau disease. N Engl J Med 1993;329:1531-1538[Erratum, N Engl J Med 1994;331:1535.]
   Full Text | Web of Science | Medline

3. 3

   Eng C. The RET proto-oncogene in multiple endocrine neoplasia type 2 and Hirschsprung's disease. N Engl J Med 1996;335:943-951
   Full Text | Web of Science | Medline

4. 4

   Gimm O, Armanios M, Dziema H, Neumann HPH, Eng C. Somatic and occult germ-line mutations in SDHD, a mitochondrial complex II gene, in non-familial pheochromocytoma. Cancer Res 2000;60:6822-6825
   Web of Science | Medline

5. 5

   Statement of the American Society of Clinical Oncology: genetic testing for cancer susceptibility adopted on February 20, 1996. J Clin Oncol 1996;14:1730-1736
   Web of Science | Medline

Author/Editor Response

The discussant replies:

To the Editor: Neumann and colleagues are concerned that my discussion of a patient with extraadrenal pheochromocytoma does not sufficiently address the possibility that the patient had an occult genetic syndrome and thus did not have a sporadic tumor. Minimal information was provided about the patient's family history. That his father was given a diagnosis of hypertension in his 50s could be interpreted by some as evidence of his having occult pheochromocytoma. I interpreted this information as consistent with a far more common diagnosis, essential hypertension. However, I later discussed the genetic syndromes associated with pheochromocytoma but found no firm evidence to link them to this patient.

With regard to genetic testing for mutations in the VHL and SDHD genes in patients with sporadic pheochromocytoma, Neumann, Eng, and colleagues have published data that suggest a sufficiently high prevalence to support routine testing. In contrast, a report by Aguiar et al.1 found no mutations in the SDHD gene in sporadic pheochromocytomas, and Brauch et al.2 reported that only 3 percent of sporadic pheochromocytomas were associated with mutations in the VHL gene and that none were associated with mutations in the RET proto-oncogene. Thus, the latter findings are at variance with those of Neumann, Eng, and colleagues and do not support routine genetic testing in patients with sporadic pheochromocytoma.

It is clearly important to obtain a careful family history in these patients, and in some, genetic testing of the proband may be appropriate. It is also likely that further research will identify mutations with a sufficiently high prevalence to warrant routine genetic testing. At present, it does not appear that the field is sufficiently mature to make this a general recommendation.

Paul R. Conlin, M.D.
Harvard Medical School, Boston, MA 02115

2 References

1. 1

   Aguiar RCT, Cox G, Pomeroy SL, Dahia PLM. Analysis of the SDHD gene, the susceptibility gene for familial paraganglioma syndrome (PGL1), in pheochromocytomas. J Clin Endocrinol Metab 2001;86:2890-2894
   CrossRef | Web of Science | Medline

2. 2

   Brauch H, Hoeppner W, Jahnig H, et al. Sporadic pheochromocytomas are rarely associated with germline mutations in the vhl tumor suppressor gene or the ret protooncogene. J Clin Endocrinol Metab 1997;82:4101-4104
   CrossRef | Web of Science | Medline

Citing Articles (1)

Citing Articles

1. 1

   J. Bryant, J. Farmer, L. J. Kessler, R. R. Townsend, K. L. Nathanson. (2003) Pheochromocytoma: The Expanding Genetic Differential Diagnosis. JNCI Journal of the National Cancer Institute 95:16, 1196-1204
   CrossRef