Correspondence

Pheochromocytoma, Multiple Endocrine Neoplasia Type 2, and von Hippel-Lindau Disease

N Engl J Med 1994; 330:1090-1091April 14, 1994

Article

To the Editor:

The report by Neumann et al. (Nov. 18 issue)1 underscores the importance of screening for hereditary disorders in patients with pheochromocytoma. The authors' determination, however, that 23 percent of unselected patients with pheochromocytoma had hereditary disease is a higher figure than that in any prior report, including one series not listed by the authors in which the figure was approximately 7 percent2. The authors may be correct, but there could be an ascertainment bias, a possibility they suggested in a previous article in which they reported a high incidence of von Hippel-Lindau syndrome in the Freiburg region3. What percentage of the kindreds with multiple endocrine neoplasia type 2 (MEN-2) or von Hippel-Lindau disease came from each institution included in this analysis?

Whatever the true incidence of hereditary pheochromocytoma, it is difficult to screen subjects at potential risk for MEN-2 or von Hippel-Lindau disease with any degree of adequacy. Even for physicians attuned to the potential of hereditary disease, soliciting the cooperation of the family is difficult. The cost of long-term screening, complex social interactions within families, and the potential stigma of hereditary tumors lead family members to eschew testing4. The results of recent studies in kindreds with MEN-2 indicate that 95 percent of affected subjects have a mutation of one of five cysteine residues within the ret proto-oncogene5. It seems likely that similar mutational analysis will become available for von Hippel-Lindau disease in the near future. Rather than screen all family members at risk, it seems more appropriate to develop strategies to examine patients with pheochromocytomas for the presence of mutations associated with MEN-2 or von Hippel-Lindau disease and to reserve costly and repetitive biochemical and radiologic screening procedures -- need they be as complex as those described by the authors, anyway? -- for pheochromocytoma and the other components of these disorders for use in known gene carriers only. This approach may fail to detect a carrier state caused by a previously unidentified mutation, but it is becoming increasingly evident that such examples are likely to be rare.

Robert F. Gagel, M.D.
University of Texas M.D. Anderson Cancer Center, Houston, TX 77030

5 References

1. 1

   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
   Full Text | Web of Science | Medline

2. 2

   Sizemore GW, Carney JA, Heath H III. Epidemiology of medullary carcinoma of the thyroid gland: a 5-year experience (1971-1976). Surg Clin North Am 1977;57:633-645
   Web of Science | Medline

3. 3

   Neumann HPH, Wiestler OD. Clustering of features of von Hippel-Lindau syndrome: evidence for a complex genetic locus. Lancet 1991;337:1052-1054
   CrossRef | Web of Science | Medline

4. 4

   Gagel RF. The role of genetic screening in the management of hereditary malignancy. Horm Metab Res 1993;25:481-483
   CrossRef | Web of Science | Medline

5. 5

   Mulligan LM, Kwok JB, Healey CS, et al. Germline mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature 1993;363:458-460
   CrossRef | Web of Science | Medline

Author/Editor Response

Dr. Neumann replies:

To the Editor: Ninety-five percent of the 82 patients with pheochromocytoma whom we studied came from the Freiburg area, which has a population of about 2 million people. Twelve of the 14 families with von Hippel-Lindau disease, with 53 of the 60 gene carriers, and 5 of the 10 families with MEN-2, with 7 of the 29 gene carriers, lived in the area. Epidemiologic studies of von Hippel-Lindau disease have so far been presented only for the Freiburg area1 and for East Anglia2; the prevalences were similar (1:39,000 and 1:53,000, respectively), but the incidence of pheochromocytoma differed. At the time of our report, the prevalence of von Hippel-Lindau disease, including families both with and without pheochromocytoma, had increased to 1:31,000. Forty-four of the carriers (65 percent) are descendants of the 12 families mentioned above, but only 21 had symptomatic lesions. These results support the hypothesis that there is a distinct disease -- i.e., a subtype of von Hippel-Lindau disease -- among the majority of gene carriers in the Freiburg region. Discussion of possible bias in the figure of 23 percent for the inheritance of pheochromocytoma in our area should, however, be postponed until studies are presented that include a similar number of patients with pheochromocytoma screened elsewhere in a comparable fashion.

Undoubtedly, testing for inherited mutations causing MEN-2 or von Hippel-Lindau disease will facilitate the care of such families. The mutations known at present are those of the subtype MEN-2A, which is diagnostic in 97 percent of cases,3 and recently the subtype MEN-2B,4 whereas in the identified gene for von Hippel-Lindau disease there seem to be a large number of mutations,5 which consequently make genetic testing time-consuming and costly, if the exclusion of carrier status is to be definite.

In patients presenting with pheochromocytoma, regardless of expected genetic discoveries, clinical screening for inheritance is indispensable, since the results of family history taking, calcitonin and parathyroid hormone assays, direct ophthalmoscopy after mydriasis, and magnetic resonance imaging of the brain are available immediately and, if positive, are diagnostic for inheritance. It remains to be shown whether clinical screening performed only once is less sensitive in identifying gene carriers than genetic testing.

Hartmut P.H. Neumann, M.D.
Albert-Ludwigs-Universitat, 79106 Freiburg, Germany

5 References

1. 1

   Neumann HPH, Wiestler OD. Clustering of features of von Hippel-Lindau syndrome: evidence for a complex genetic locus. Lancet 1991;337:1052-1054
   CrossRef | Web of Science | Medline

2. 2

   Maher ER, Iselius L, Yates JR, et al. Von Hippel-Lindau disease: a genetic study. J Med Genet 1991;28:443-447
   CrossRef | Web of Science | Medline

3. 3

   Mulligan LM, Eng C, Healey CS, et al. Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN 2A and FMTC. Nat Genet 1994;6:70-74
   CrossRef | Web of Science | Medline

4. 4

   Eng C, Smith DP, Mulligan LM, et al. Point mutation within the tyrosine kinase domain of the RET proto-oncogene in multiple endocrine neoplasia type 2B and related sporadic tumors. Hum Mol Genet (in press).
   

5. 5

   Latif F, Tory K, Gnarra J, et al. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 1993;260:1317-1320
   CrossRef | Web of Science | Medline