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Previous Volume 329:1531-1538 November 18, 1993 Number 21 Next

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ABSTRACT

Background Pheochromocytoma is a feature of two disorders with an autosomal dominant pattern of inheritance -- multiple endocrine neoplasia type 2 (MEN-2) (with medullary thyroid carcinoma and hyperparathyroidism) and von Hippel-Lindau disease (with angioma of the retina, hemangioblastoma of the central nervous system, renal-cell carcinoma, pancreatic cysts, and epididymal cystadenoma). The frequency of these syndromes in patients with pheochromocytoma is not known.

Methods In an unselected group of patients with pheochromocytoma, we performed pentagastrin tests, parathyroid hormone assays, computed tomography (CT) or magnetic resonance imaging (MRI) of the brain, ophthalmoscopy, CT imaging of the abdomen, and ultrasonography of the testes. We also screened members of families with MEN-2 or von Hippel-Lindau disease for pheochromocytoma by measuring plasma and urine catecholamines and plasma chromogranin A and by performing abdominal ultrasonography, CT and MRI, and metaiodobenzylguanidine scintigraphy.

Results Nineteen of 82 unselected patients with pheochromocytomas (23 percent) were carriers of familial disorders; 19 percent had von Hippel-Lindau disease and 4 percent had MEN-2. Prospectively, in 36 of 79 subjects at risk for pheochromocytoma (46 percent), 42 unsuspected pheochromocytomas were found. Overall, there were 130 patients with 185 pheochromocytomas; 43 had von Hippel-Lindau disease, 24 had MEN-2, and 63 had sporadic tumors. The patients with familial and those with sporadic pheochromocytomas differed in mean age at diagnosis (32 vs. 46 years, P<0.001), multifocal localization (55 vs. 8 percent, P<0.001), and cancer (0 vs. 11 percent, P = 0.005); but not in the frequency of extraadrenal tumors (24 vs. 16 percent). Thirty-eight percent of carriers of von Hippel-Lindau disease and 24 percent of carriers of MEN-2 had pheochromocytoma as the only manifestation of their syndrome.

Conclusions All patients with pheochromocytomas should be screened for MEN-2 and von Hippel-Lindau disease to avert further morbidity and mortality in the patients and their families. All patients in families with MEN-2 or von Hippel-Lindau disease should be screened for pheochromocytoma, even if they are asymptomatic.

Both syndromes are associated with high morbidity and mortality. In MEN-2, approximately 40 percent of carriers have pheochromocytomas,² whereas in families with von Hippel-Lindau disease the frequency of these tumors ranges from 0 to more than 90 percent, with an average of 14 percent^4,7,9. The frequency of these syndromes among unselected patients with pheochromocytoma is not known, because most such patients are not considered to have hereditary cancer syndromes. If this assumption is incorrect, there are many unidentified persons at risk for these syndromes.

We studied a large number of unselected patients with pheochromocytoma to identify carriers of MEN-2 or von Hippel-Lindau disease. In a complementary study, we screened members of families with MEN-2 or von Hippel-Lindau disease for pheochromocytoma. Finally, we compared the characteristics of sporadic pheochromocytomas with those of pheochromocytomas associated with MEN-2 or von Hippel-Lindau disease.

Methods

Study Subjects and Screening

We studied all patients with symptomatic pheochromocytoma at our institutions between January 1, 1971, and July 1, 1993, considering them to be at risk for MEN-2 and von Hippel-Lindau disease. A detailed family history was obtained from each patient, and an attempt was made to review all relevant records for the patients and their affected relatives with MEN-2 or von Hippel-Lindau disease at our institutions or elsewhere. The patients were screened for MEN-2 with a pentagastrin test, a serum parathyroid hormone assay, and extensive pedigree analysis. MEN-2 was diagnosed if the patient or a first-degree relative had medullary thyroid carcinoma or C-cell hyperplasia. Patients were screened for von Hippel-Lindau disease with computed tomography (CT) or magnetic resonance imaging (MRI) of the brain, CT of the abdomen, ultrasonography of the testes, direct ophthalmoscopy after mydriasis, and extensive pedigree analysis. Von Hippel-Lindau disease was diagnosed if the patient or a first-degree relative had retinal angioma or hemangioblastoma of the central nervous system.

Beginning in 1984, in a complementary study, we studied subjects considered at risk for pheochromocytoma. These persons were affected members of families with MEN-2 or von Hippel-Lindau disease and their first-degree relatives, patients with retinal angiomas as their only symptom, and first-degree relatives of patients with multifocal pheochromocytoma. The program included abdominal ultrasonography, CT and MRI of the abdomen, metaiodobenzylguanidine (MIBG) scintigraphy, and measurement of plasma and urine catecholamines and plasma chromogranin A. All the patients and subjects gave informed consent.

Analytic Methods

Serum calcitonin concentrations were measured at the time of the intravenous administration of 0.5 µg of pentagastrin per kilogram of body weight and two and five minutes thereafter by radioimmunoassay (RIA-mat Calcitonin I, Byk Sangtec, Dietzenbach, Germany). Serum parathyroid hormone was measured by immunoradiometric assay (IRMA PTH intact, Diagnostic Systems Laboratories, Webster, Tex.). Urinary norepinephrine, epinephrine, and vanilmandelic acid were measured by spectrofluorometry. Plasma norepinephrine and epinephrine were determined radioenzymatically. Plasma chromogranin A was measured by radioimmunoassay¹⁰. Blood samples for the last three of these measurements were obtained after the subjects had been supine for 30 minutes. The mean (±2 SD) values for these measurements in 43 subjects (26 women and 17 men with a mean [±SD] age of 34 ±16 years, none of whom had symptoms, one of whom had hypertension, and all of whom had negative MIBG scintigraphy, MRI of the retroperitoneum, or both) were as follows: urinary norepinephrine, 43 ±38 µg per day (256 ±221 nmol per day); urinary epinephrine, 6.2 ±8.2 µg per day (34 ±46 nmol per day); urinary vanilmandelic acid, 2.4 ±4.8 mg per day (12 ±24 µmol per day); plasma norepinephrine, 0.4 ±0.3 ng per milliliter (2.4 ±1.9 nmol per liter); plasma epinephrine, 0.08 ±0.05 ng per milliliter (0.43 ±0.28 nmol per liter); and chromogranin A, 18 ±37 ng per milliliter. Blood pressure was measured for 24 hours in patients with newly detected pheochromocytomas with use of an automatic blot-pressure monitor (SpaceLabs, Kaarst, Germany), with measurements obtained every 20 minutes from 8 a.m. to 8 p.m. and every 30 minutes from 8 p.m. to 8 a.m.

Imaging Procedures

Radiologic imaging was performed by persons aware that the patients and subjects were at risk for MEN-2 or von Hippel-Lindau disease or for pheochromocytoma. Abdominal ultrasonography, CT, MRI, and MIBG scintigraphy were performed with standard techniques. Several generations of CT scanners were used; the slice thickness was 4 to 8 mm. For MRI (Tomikon R23 with 0.23 T, Bruker, Karlsruhe, Germany), both T₁- and strongly T₂-weighted axial and T₂-weighted coronal spin-echo sequences with a slice thickness of 8 mm were obtained. Scintigraphy was performed 48 hours after the intravenous administration of MIBG labeled with iodine-131 or iodine-123 (Dual Head Bodyscan, Siemens, Erlangen, Germany).

Statistical Analysis

All results were entered into a specifically designed data base. Statistical analysis was performed with software from the Statistical Package for Social Sciences (SPSS, Chicago). Groups of patients with distinct types of pheochromocytomas (familial vs. sporadic tumors, those associated with von Hippel-Lindau disease and those associated with MEN-2) were compared by parametric and nonparametric tests (two-tailed t-tests, chi-square tests, or Wilcoxon rank-sum tests), as applicable. P values less than 0.05 were considered to indicate statistical significance.

Results

We studied all 82 patients with symptomatic pheochromocytomas who were admitted to our institutions between January 1, 1971, and July 1, 1993. Patients were excluded if they already had a confirmed diagnosis of MEN-2 or von Hippel-Lindau disease. All the screening studies for MEN-2 and von Hippel-Lindau disease were performed in 63 patients, and some studies were performed in 10 patients; 9 patients died before screening and were studied at autopsy. Three patients were found to be carriers of MEN-2, and 16 to be carriers of von Hippel-Lindau disease. Thus, 19 patients (23 percent) had evidence of one of the two familial tumor syndromes. In the three patients with MEN-2, pheochromocytoma was detected first and C-cell disease afterward. In the 16 patients with von Hippel-Lindau disease, pheochromocytoma was the first symptomatic lesion. In nine patients retinal angiomatosis was detected by screening, whereas six patients had a positive family history of von Hippel-Lindau disease as the only indication of the disease. Two patients with von Hippel-Lindau disease who presented with recurrent multifocal pheochromocytomas were identified only by family screening. In 12 families with von Hippel-Lindau disease, only pheochromocytoma, retinal angioma, and hemangioblastoma of the central nervous system were found, whereas renal-cell carcinoma occurred in two families with this disease.

An atypical coincidence of endocrine tumors was found in a 34-year-old woman who had had two operations for adrenal and thoracic pheochromocytomas -- the only extraretroperitoneal tumor found in this study -- and at autopsy was found to have a contralateral adrenal pheochromocytoma, a pancreatic islet-cell tumor 15 cm in diameter, and a basophilic anterior pituitary adenoma. The results of screening for both syndromes in the woman's relatives were normal, and the tumor was classified as a sporadic pheochromocytoma. No other patients with atypical tumors were found in this series, and no patient had evidence of neurofibromatosis type 1.

Seventy-nine subjects at risk for pheochromocytoma (Figure 1) were screened in the prospective part of the study. Forty-two unsuspected tumors were found in 36 of these subjects (Table 1), 27 of whom had von Hippel-Lindau disease and 9 of whom had MEN-2. Five of these subjects had symptoms -- e.g., palpitation, headache, or sweating attacks. Twenty-eight were normotensive, and eight had hypertension. Nineteen of the 28 normotensive subjects had 24-hour blood-pressure measurements; only 4 had episodes of hypertension. The sensitivity of the tests used to detect pheochromocytoma was as follows: urinary norepinephrine, 86 percent; urinary epinephrine, 53 percent; urinary vanilmandelic acid, 64 percent; plasma norepinephrine, 58 percent; plasma epinephrine, 33 percent; plasma chromogranin A, 52 percent; abdominal ultrasonography, 40 percent; abdominal CT, 76 percent; abdominal MRI, 95 percent; and MIBG scintigraphy, 95 percent.

View larger version (59K): [in this window] [in a new window]   Figure 1. Pedigrees of the Families Studied. Fourteen families had von Hippel-Lindau disease (VHL), 10 had MEN-2, and 1 had neither syndrome. Circles denote females, squares males, slashes dead subjects, solid areas the presence of a finding, and open areas the absence of a finding. In the families with von Hippel-Lindau disease, the symbols for the subjects are subdivided to indicate the clinical findings as follows: upper left, hemangioblastoma of the central nervous system; upper middle, renal-cell carcinoma; upper right, retinal angiomatosis; lower left, right adrenal pheochromocytoma; lower middle, extraadrenal pheochromocytoma; and lower right, left adrenal pheochromocytoma. In the symbols for members of families with MEN-2, the area at upper left denotes medullary thyroid carcinoma or C-cell hyperplasia; the area at right, hyperparathyroidism; the other areas are as described above. Small open circles indicate subjects in the unselected series who were found to be carriers of one of the familial syndromes. Small numbered solid circles indicate the subjects and their relatives in whom pheochromocytoma was detected by screening during the study. The 36 subjects numbered were found to have unsuspected pheochromocytomas. The figure does not show which of multiple tumors in a subject were detected by screening and which were detected because of symptoms; nor does it show the number of tumors at the same location.

 

View this table: [in this window] [in a new window]   Table 1. Findings in 36 Subjects with Unsuspected Pheochromocytomas.

 
Thirty-two tumors in 27 subjects were confirmed by surgery. Ten tumors in nine subjects were diagnosed by both MRI and MIBG scintigraphy; of these subjects, three rejected surgery, and the six who had normotension even when their blood pressure was measured for 24 hours decided to have regular follow-up. Three tumors were nonfunctional -- e.g., the subjects had normal 24-hour blood-pressure values, and all their biochemical values were normal. Eleven percent of the subjects found to have pheochromocytomas had normal catecholamine values in urine and 36 percent had normal values in plasma. The majority of false negative results were found in the subjects who had small or extraadrenal tumors (Table 1). Eleven extraadrenal pheochromocytomas were found in 10 subjects, and six of these tumors were not detected by either ultrasonography or CT. Three adrenal tumors not detected by CT measured 1.0 to 2.3 cm in diameter. Seventeen of 31 adrenal tumors with a mean diameter of 2.5 cm were not detected by ultrasonography, whereas 14 adrenal tumors with a mean diameter of 4.4 cm were detected. By MRI, all tumors showed high signal intensity in T₂-weighted images (Figure 2) and intermediate intensity in T₁-weighted images. The specificity of the tests was as follows: abdominal ultrasonography, 100 percent; abdominal CT, 100 percent; abdominal MRI, 97 percent; MIBG scintigraphy, 97 percent; urinary norepinephrine, 95 percent; urinary epinephrine, 98 percent; urinary vanilmandelic acid, 91 percent; plasma norepinephrine, 97 percent; plasma epinephrine, 94 percent; and plasma chromogranin A, 95 percent.

View larger version (55K): [in this window] [in a new window]   Figure 2. Imaging Studies Showing One Left Adrenal Pheochromocytoma and Two Extraadrenal Pheochromocytomas in a 16-Year-Old Asymptomatic Boy with von Hippel-Lindau Disease, Subject 5 in Figure 1. The left adrenal tumor is labeled 1, and the extraadrenal tumors 2 and 3. Panel A shows an [123I] metaiodobenzylguanidine scintigram in the anterior view. U indicates activity in the urinary bladder, and L activity in the liver. Panel B shows one MRI slice of a T2-weighted multislice, multi-echo sequence showing only the left adrenal tumor (1 and arrows). K denotes kidney (part of the anterior cortex), and the star shows the L4 vertebral body. Panel C shows an angiogram of the left kidney with three pheochromocytomas; there is a pigtail catheter in the aorta.

 
The comparison of sporadic with familial pheochromocytomas (Table 2) is based on 130 cases (involving 63 patients with sporadic tumors, 24 carriers of MEN-2, and 43 carriers of von Hippel-Lindau disease) in which 185 pheochromocytomas were found. The familial pheochromocytomas were found in patients identified as carriers in the unselected series, subjects identified during screening for pheochromocytoma, and affected relatives of the carriers. Among the patients with symptomatic pheochromocytomas, those with sporadic as compared with familial tumors at the time of diagnosis were significantly younger (P<0.001) (Figure 3, Table 2). Multifocal tumors were more common in patients with familial tumors than in those with sporadic tumors (P<0.001), and they were more common in families with MEN-2 than in families with von Hippel-Lindau disease (P = 0.02). Age at the time of diagnosis was similar in the families with MEN-2 and those with von Hippel-Lindau disease. The frequency of extraadrenal tumors was similar in the various groups. Thirty-one patients had bilateral adrenal tumors, 19 of them detected metachronously and 12 detected synchronously. The interval before the detection of the contralateral tumor was as long as 31 years (mean, 10). The pheochromocytoma was malignant in only 7 of 63 patients with sporadic tumors and in none of the 67 patients with von Hippel-Lindau disease or MEN-2. Metastases were found in the lung (five patients), liver (five patients), skeletal system (three patients), lymph nodes (two patients), and central nervous system (two patients).

View this table: [in this window] [in a new window]   Table 2. Comparison of Sporadic and Familial Pheochromocytomas.

 

View larger version (16K): [in this window] [in a new window]   Figure 3. Age of the Patients at the Time of Diagnosis of Symptomatic Pheochromocytoma. The cumulative age distributions of 43 patients with von Hippel-Lindau disease (VHL), 24 patients with MEN-2, and 63 patients with sporadic pheochromocytoma are shown.

 
The spectrum of manifestations was studied in affected members of 10 families with MEN-2 and 14 families with von Hippel-Lindau disease (Figure 1). Eighty-three percent of the 29 carriers of MEN-2 had pheochromocytomas. The tumor was the only manifestation of MEN-2 in seven subjects (24 percent), all of whom had normal pentagastrin tests and normal concentrations of serum parathyroid hormone. Seventy-two percent of 60 carriers of von Hippel-Lindau disease had pheochromocytoma. The associated lesions were retinal angiomas (Figure 4) in 31 subjects, with blindness in 7 (unilateral in 6 and bilateral in 1); hemangioblastoma of the central nervous system in 10 subjects (Figure 5); and renal-cell carcinoma in 2. Pheochromocytoma was the only manifestation of von Hippel-Lindau disease in 23 subjects (38 percent).

View larger version (106K): [in this window] [in a new window]   Figure 4. Angioma of the Retina of the Left Eye (Arrowheads), Detected by Screening in the Brother of Subject 9 in Figure 1, Who Had Symptomatic Pheochromocytoma but No Visual Symptoms.

 

View larger version (148K): [in this window] [in a new window]   Figure 5. Two Hemangioblastomas of the Central Nervous System and a Tumor-Induced Cervical Syrinx (Arrowheads) in a 54-Year-Old Woman, Subject 8 in Figure 1. The hemangioblastomas were in the posterior fossa (1) and spinal cord (2). Sagittal MRI with gadolinium-diethylenetriamine pentaacetic acid was used. This woman underwent resection of cerebellar hemangioblastomas 18 and 14 years before this writing. Pheochromocytoma was detected by screening family members.

 
Discussion

Two pheochromocytoma-associated cancer syndromes are disorders with an autosomal dominant pattern of inheritance -- MEN-2 and von Hippel-Lindau disease. Establishing either of these diagnoses is important for the patient and the family, because the risk of other tumors involves not only the index patient but also the whole family, and early detection of the components of the two syndromes is important for successful management. In particular, hemangioblastoma of the central nervous system and metastatic renal cancer in von Hippel-Lindau disease, medullary thyroid cancer in MEN-2, and pheochromocytoma in both syndromes are life-threatening conditions; in addition, retinal angiomas can cause loss of vision in von Hippel-Lindau disease^3,9. Therefore, we studied unselected patients with pheochromocytoma who were seen over a period of 22.5 years in order to identify their tumors as manifestations of MEN-2 or von Hippel-Lindau disease.

Twenty-three percent of the 82 patients with pheochromocytomas were found to be gene carriers of MEN-2 or von Hippel-Lindau disease -- more than four times the percentage usually considered to be carriers among such patients¹¹. Our figure may represent the lower limit of incidence, since 12 percent of the patients underwent incomplete screening and another 11 percent had autopsies in which the eyes were not examined for retinal angiomas or the thyroid gland for C-cell hyperplasia. Most (nearly 20 percent) were carriers of von Hippel-Lindau disease -- an unexpected but plausible result, since 53 percent of patients with this disease who had pheochromocytomas had no other lesion, whereas retinal angiomas, the most frequent finding in the remaining 47 percent, were mostly asymptomatic and were found by screening. This previously unsuspected high risk for von Hippel-Lindau disease is understandable, since no biochemical test to identify carriers is available. Complete screening presupposes well-equipped and well-staffed centers and is costly and time-consuming for both patient and physician. Screening for von Hippel-Lindau disease is warranted, however, because of the risk of hemangioblastoma of the central nervous system; this tumor, which has an excellent prognosis if it is recognized and removed promptly,¹² developed in 17 percent of the carriers.

In MEN-2, measurement of serum calcitonin after the administration of pentagastrin is the standard screening test¹³. Twenty-four percent of carriers of MEN-2 had only pheochromocytoma, and three of the tumors were extraadrenal, representing so-far-unknown phenotypes. Although rare in MEN-2, extraadrenal tumors were frequent in von Hippel-Lindau disease (Table 2).

When we compared sporadic pheochromocytomas with familial ones (those associated with MEN-2 and von Hippel-Lindau disease), the striking findings were the younger age of the patients when the familial tumors were detected and the higher frequency of multifocal tumors in patients with familial tumors. There seems to be a very low incidence of malignant pheochromocytoma in patients with familial syndromes; none of the 67 carriers of MEN-2 and von Hippel-Lindau disease who had pheochromocytomas had distant metastases, as compared with 7 of the 63 patients with sporadic pheochromocytomas. These results confirm other reports that malignant pheochromocytoma is rare in von Hippel-Lindau disease (with four cases reported^7,14,15) and in MEN-2 (with one case¹⁶).

Pancreatic islet-cell tumors, although rare in von Hippel-Lindau disease,^9,17 have been reported in association with pheochromocytoma as a separate entity¹⁸. Only one patient in this study had this phenotype, and that patient had a pituitary adenoma in addition. We found no association between pheochromocytoma and neurofibromatosis; the reported incidence of the combined conditions is less than 1 percent¹⁹. A few kindreds with pheochromocytoma alone have been reported,^20,21 but they may ultimately be reclassified as having von Hippel-Lindau disease or MEN-2.

In the prospective part of our study we screened affected members of families with MEN-2 and von Hippel-Lindau disease and their first-degree relatives, patients who had only retinal angiomas, and patients with multifocal pheochromocytomas and found an unexpectedly high number of pheochromocytomas. Thirty-six of the 79 subjects at risk (46 percent) had a total of 42 tumors. Some subjects reported contacts with physicians who had found intermittent or persistent hypertension but did not consider pheochromocytoma. On the other hand, 24-hour blood-pressure measurements were normal in 15 of these subjects. No biochemical test was completely diagnostic for pheochromocytoma in this study. However, in contrast to other studies,²² this study found that plasma catecholamine measurements did not have a high sensitivity, and urinary norepinephrine values more than twice as high as the upper limit of normal, which was regarded as very suggestive of pheochromocytoma,²³ were found in only 64 percent. The best test was the measurement of urinary norepinephrine excretion, with a sensitivity of 86 percent. Remarkably, urinary norepinephrine, epinephrine, and vanilmandelic acid excretion and plasma norepinephrine and epinephrine concentrations were normal in 11 percent and 36 percent of the 36 subjects, respectively. Plasma chromogranin A, a new marker for pheochromocytoma,²⁴ had a sensitivity of only 52 percent. Tumor size and chromogranin A were correlated (23 subjects, r = 0.70, with 4 subjects omitted who had extensive regressive alterations of tumor tissue), confirming an earlier study,²⁵ and most of the normal values were found in subjects with small tumors. Therefore, both radiologic imaging and biochemical tests are essential for the detection of pheochromocytoma.

The screening part of the study tests the methods used to detect pheochromocytoma, because it was carried out prospectively and in a high-risk population. As compared with other studies, the most obvious discrepancy was the lower sensitivity of ultrasonography (40 percent vs. 90 to 95 percent^23,26), whereas the sensitivities of abdominal CT (76 percent vs. 70 to 98 percent^22,23,27), MIBG scintigraphy (95 percent vs. 78 to 96 percent^22,28) and abdominal MRI (95 percent vs. 86 to 100 percent^22,23,27) were similar to the values in those reports. The report that high signal intensity in T₂-weighted MRI is diagnostic for pheochromocytoma²⁹ was confirmed in this series. Excellent documentation was obtained in both the transverse and the coronal planes; the latter seems even more suitable for the detection of extraadrenal lesions.

On the basis of this study, we recommend that every patient with a pheochromocytoma be screened for both MEN-2 and von Hippel-Lindau disease by the pentagastrin test, the measurement of serum parathyroid hormone, ophthalmoscopy, MRI of the brain, CT of the kidneys and pancreas, and ultrasonography of the testes. Careful pedigree evaluation is essential, since pheochromocytoma may be the only abnormality in gene carriers of MEN-2 or von Hippel-Lindau disease. Since the presence of multiple pheochromocytomas is a striking sign of the familial syndromes, screening should be extended to first-degree relatives of such patients, even if they are asymptomatic. If MEN-2 or von Hippel-Lindau disease is diagnosed, screening of the patient's family should include investigations for pheochromocytoma. For that purpose, a combined biochemical and radiologic approach using measurement of 24-hour urine norepinephrine excretion and MRI is most effective.

In June 1993, missense mutations of the RET proto-oncogene were identified in 20 of 23 families with MEN-2A,³⁰ and three different restriction-fragment rearrangements encompassing the identified gene for von Hippel-Lindau disease in 28 of 221 families with von Hippel-Lindau disease have been reported³¹. These important discoveries must, however, be confirmed by studies of additional families, and the introduction of genetic tests in place of clinical screening cannot be recommended as long as such markers are not completely diagnostic. Furthermore, for MEN-2 the subtype MEN-2B remains to be characterized. The finding of pheochromocytoma, retinal angiomatosis, and hemangioblastoma of the central nervous system in the absence of renal, pancreatic, and epididymal lesions in 12 of the 14 families with von Hippel-Lindau disease, confirming our previously reported clustering of manifestations,³² suggests the existence of a distinct subtype of von Hippel-Lindau disease that may have unique molecular-genetic characteristics.

We are indebted to our colleagues at the University of Freiburg: Peter Schollmeyer, M.D., Ingeborg Zauner, M.D., and Manfred Lehmann, M.D., of the Department of Medicine; Mathias Langer, M.D., Berthold Wimmer, M.D., Jorg Laubenberger, M.D., Ernst Moser, M.D., Ph.D., and Carl Schumichen, M.D., of the Department of Radiology; Eduard Farthmann, M.D., of the Department of Surgery; Georg Hertting, M.D., of the Department of Pharmacology; and Hans-Eckart Schaefer, M.D., and Norbert Bohm, M.D., of the Department of Pathology; to Gunter Mangold, M.D. (Community Hospital, Lahr), and Volker Hofmann, M.D. (St. Barbara Hospital, Halle an der Saale), for their support and cooperation in the Freiburg study of von Hippel-Lindau disease; to Dieter Engelhardt, M.D. (Department of Endocrinology, University of Munich), and Soren Schroder, M.D. (Department of Pathology, University of Hamburg), for contributing data on Family 3 with MEN-2; to Otto A. Muller, M.D. (Hospital Rotes Kreuz, Munich), for data on Family 7 with MEN-2; to Lothar Heuser, M.D. (Department of Radiology, Ruhr University, Bochum-Langendreer), for permission to use Figure 5; and to Ms. Christiane Stick, Ms. Anita Mamier, Martin Andre, M.D., Mr. Achim Elert, and Mr. Hans Hetzel for assistance in the preparation of the manuscript.

Source Information

From the Departments of Medicine (H.P.H.N., D.P.B., B.V.), Radiology (G.S., U.B.), Ophthalmology (D.S.), and Surgery (G.K.), Albert-Ludwigs-Universitat, Freiburg, Germany; and the Department of Medicine, University of California, San Diego (R.J.P.).

Address reprint requests to Dr. Neumann at the Division of Nephrology and Hypertension, University of Freiburg, Hugstetterstr. 55, D-79106 Freiburg im Breisgau, Germany.

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Pheochromocytoma, Multiple Endocrine Neoplasia Type 2, and von Hippel-Lindau Disease
Gagel R. F., Neumann H. P.H.
Extract | Full Text  
N Engl J Med 1994; 330:1090-1091, Apr 14, 1994. Correspondence

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