Original Article
Pheochromocytomas, Multiple Endocrine Neoplasia Type 2, and von Hippel-Lindau Disease
N Engl J Med 1993; 329:1531-1538November 18, 1993
- 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.
Media in This Article
Figure 1
Pedigrees of the Families Studied.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.Article Activity
- Article
Pheochromocytomas are a feature of two disorders with an autosomal dominant pattern of inheritance -- multiple endocrine neoplasia type 2 (MEN-2) and von Hippel-Lindau disease. Persons carrying the MEN-2 mutation are predisposed to have C-cell hyperplasia or medullary thyroid carcinoma, pheochromocytoma, and hyperparathyroidism (in the MEN-2A subtype) or mucosal neuromas and marfanoid habitus (in the MEN-2B subtype)1,2. The major components of von Hippel-Lindau disease are retinal angioma, hemangioblastoma of the central nervous system, renal cysts and carcinoma, pheochromocytoma, pancreatic cysts, and epididymal cystadenoma3-8. Affected members of families with these disorders (carriers) may have one or several of these lesions.
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 percent4,7,9. 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 1Figure 1
Pedigrees of the Families Studied.) were screened in the prospective part of the study. Forty-two unsuspected tumors were found in 36 of these subjects (Table 1Table 1
Findings in 36 Subjects with Unsuspected Pheochromocytomas.), 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.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 2Figure 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.) 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.The comparison of sporadic with familial pheochromocytomas (Table 2Table 2
Comparison of Sporadic and Familial Pheochromocytomas.) 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 3Figure 3
Age of the Patients at the Time of Diagnosis of Symptomatic Pheochromocytoma., 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).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 4Figure 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.) in 31 subjects, with blindness in 7 (unilateral in 6 and bilateral in 1); hemangioblastoma of the central nervous system in 10 subjects (Figure 5Figure 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.); and renal-cell carcinoma in 2. Pheochromocytoma was the only manifestation of von Hippel-Lindau disease in 23 subjects (38 percent).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 disease3,9. 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 reported7,14,15) 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 percent23,26), whereas the sensitivities of abdominal CT (76 percent vs. 70 to 98 percent22,23,27), MIBG scintigraphy (95 percent vs. 78 to 96 percent22,28) and abdominal MRI (95 percent vs. 86 to 100 percent22,23,27) 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.
- References
References
1
Schimke RN . Multiple endocrine neoplasia: how many syndromes? Am J Med Genet 1990;37:375-383
CrossRef | Web of Science | Medline2
Vasen HFA ,Nieuwenhuijzen Kruseman AC ,Berkel H , et al. Multiple endocrine neoplasia syndrome type 2: the value of screening and central registration: a study of 15 kindreds in The Netherlands. Am J Med 1987;83:847-852
CrossRef | Web of Science | Medline3
Melmon KL ,Rosen SW . Lindau's disease: review of the literature and study of a large kindred. Am J Med 1964;36:595-617
CrossRef | Web of Science | Medline4
Neumann HPH . Basic criteria for clinical diagnosis and genetic counselling in von Hippel-Lindau syndrome. Vasa 1987;16:220-226
Web of Science | Medline5
Horton WA ,Wong V ,Eldridge R . Von Hippel-Lindau disease: clinical and pathological manifestations in nine families with 50 affected members. Arch Intern Med 1976;136:769-777
CrossRef | Web of Science | Medline6
Maher ER ,Yates JRW ,Harries R , et al. Clinical features and natural history of von Hippel-Lindau disease. Q J Med 1990;77:1151-1163
Web of Science | Medline7
Atuk NO ,McDonald T ,Wood T , et al. Familial pheochromocytoma, hypercalcemia and von Hippel-Lindau disease: a ten year study of a large family. Medicine (Baltimore) 1979;58:209-218
Web of Science | Medline8
Green JS ,Bowmer MI ,Johnson GJ . Von Hippel-Lindau disease in a Newfoundland kindred. Can Med Assoc J 1986;134:133-8, 146
Web of Science9
Lamiell JM ,Salazar FG ,Hsia YE . Von Hippel-Lindau disease affecting 43 members of a single kindred. Medicine (Baltimore) 1989;68:1-29
Web of Science | Medline10
O'Connor DT ,Pandian MR ,Carlton E ,Cervenka JH ,Hsiao RJ . Rapid radioimmunoassay of circulating chromogranin A: in vitro stability, exploration of the neuroendocrine character of neoplasia, and assessment of the effects of organ failure. Clin Chem 1989;35:1631-1637
Web of Science | Medline11
Landsberg L, Young JB. Catecholamines and the adrenal medulla. In: Wilson JD, Foster DW, eds. Williams textbook of endocrinology. Philadelphia: W.B. Saunders, 1992:621-705.
12
Neumann HPH ,Eggert HR ,Scheremet R , et al. Central nervous system lesions in von Hippel-Lindau syndrome. J Neurol Neurosurg Psychiatry 1992;55:898-901
CrossRef | Web of Science | Medline13
Easton DF ,Ponder MA ,Cummings T , et al. The clinical and screening age-at-onset distribution for the MEN-2 syndrome. Am J Hum Genet 1989;44:208-215
Web of Science | Medline14
Levine E ,Collins DL ,Horton WA ,Schimke RN . CT screening of the abdomen in von Hippel-Lindau disease. AJR Am J Roentgenol 1982;139:505-510
Web of Science | Medline15
Sato Y ,Waziri M ,Smith W , et al. Hippel-Lindau disease: MR imaging. Radiology 1988;166:241-246
Web of Science | Medline16
Wilson RA ,Ibanez ML . A comparative study of 14 cases of familial and nonfamilial pheochromocytomas. Hum Pathol 1978;9:181-188
CrossRef | Web of Science | Medline17
Neumann HPH ,Dinkel E ,Brambs HJ , et al. Pancreatic lesions in the von Hippel-Lindau syndrome. Gastroenterology 1991;101:465-471
Web of Science | Medline18
Griffiths DFR ,Williams GT ,Williams ED . Duodenal carcinoid tumours, phaeochromocytoma and neurofibromatosis: islet cell tumour, phaeochromocytoma and the von Hippel-Lindau complex: two distinctive neuroendocrine syndromes. Q J Med 1987;64:769-782
Web of Science | Medline19
Riccardi VM . Von Recklinghausen neurofibromatosis. N Engl J Med 1981;305:1617-1627
Full Text | Web of Science | Medline20
Carman CT ,Brashaer RE . Pheochromocytoma as an inherited abnormality: report of the tenth affected kindred and review of literature. N Engl J Med 1960;263:419-423
Full Text | Web of Science21
Glowniak JV ,Shapiro B ,Sisson JC , et al. Familial extra-adrenal pheochromocytoma: a new syndrome. Arch Intern Med 1985;145:257-261
CrossRef | Web of Science | Medline22
Bravo EL . Pheochromocytoma: new concepts and future trends. Kidney Int 1991;40:544-556
CrossRef | Web of Science | Medline23
Stein PP ,Black HR . A simplified diagnostic approach to pheochromocytoma: a review of the literature and report of one institution's experience. Medicine (Baltimore) 1991;70:46-66
Web of Science | Medline24
O'Connor DT ,Deftos LJ . Secretion of chromogranin A by peptide-producing endocrine neoplasms. N Engl J Med 1986;314:1145-1151
Full Text | Web of Science | Medline25
Hsiao RJ ,Neumann HPH ,Parmer RJ ,Barbosa JA ,O'Connor DT . Chromogranin A in familial pheochromocytoma: diagnostic screening value, prediction of tumor mass, and post-resection kinetics indicating two-compartment distribution. Am J Med 1990;88:607-613
CrossRef | Web of Science | Medline26
Yeh HC . Sonography of the adrenal glands: normal glands and small masses. AJR Am J Roentgenol 1980;135:1167-1177
Web of Science | Medline27
Quint LE ,Glazer GM ,Francis IR ,Shapiro B ,Chenevert TL . Pheochromocytoma and paraganglioma: comparison of MR imaging with CT and I-131 MIBG scintigraphy. Radiology 1987;165:89-93
Web of Science | Medline28
Chatal JF ,Charbonnel B . Comparison of iodobenzylguanidine imaging with computed tomography in locating pheochromocytoma. J Clin Endocrinol Metab 1985;61:769-772
CrossRef | Web of Science | Medline29
Reinig JW ,Doppman JL ,Dwyer AJ ,Johnson AR ,Knop RH . Adrenal masses differentiated by MR. Radiology 1986;158:81-84
Web of Science | Medline30
Mulligan LM ,Kwok JBJ ,Healey CS , et al. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature 1993;363:458-460
CrossRef | Web of Science | Medline31
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 | Medline32
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
- Citing Articles (114)
Citing Articles
1
Ales Vicha, Milena Holzerova, Anna Krepelova, Zdenek Musil, Pavel Prochazka, David Sumerauer, Roman Kodet, Tomas Eckschlager, Marie Jarosova. (2011) Molecular Cytogenetic Characterization in Four Pediatric Pheochromocytomas and Paragangliomas. Pathology & Oncology Research 17:4, 801-808
CrossRef2
Oliver Gimm, Catherine DeMicco, Aurel Perren, Francesco Giammarile, Martin K. Walz, Laurent Brunaud. (2011) Malignant pheochromocytomas and paragangliomas: a diagnostic challenge. Langenbeck's Archives of Surgery
CrossRef3
J. Welander, P. Soderkvist, O. Gimm. (2011) Genetics and clinical characteristics of hereditary pheochromocytomas and paragangliomas. Endocrine Related Cancer
CrossRef4
Niraj Naswa, Punit Sharma, Aftab Hasan Nazar, Krishan Kant Agarwal, Rakesh Kumar, Ariachery C. Ammini, Arun Malhotra, Chandrasekhar Bal. (2011) Prospective evaluation of 68Ga-DOTA-NOC PET-CT in phaeochromocytoma and paraganglioma: preliminary results from a single centre study. European Radiology
CrossRef5
Hongyan Yin, Haifei Wu, Yifan Zhang, Weijia Tian, Xufeng Jiang, Xiang Zhou, Chengmo Zhu. (2011) Diagnosis of Multiple Endocrine Neoplasia Type 2A in Patients With Positive Thyroid Imaging by Iodine-131 Metaiodobenzylguanidine Scintigraphy. Clinical Nuclear Medicine 36:9, 772-775
CrossRef6
Nicolette van Duinen, Ido P. Kema, Johannes A. Romijn, Eleonora P.M. Corssmit. (2011) Plasma chromogranin A levels are increased in a small portion of patients with hereditary head and neck paragangliomas. Clinical Endocrinology 74:2, 160-165
CrossRef7
Alberto Pérez-Alvarez, Alicia Hernández-Vivanco, Almudena Albillos. (2010) Past, Present and Future of Human Chromaffin Cells: Role in Physiology and Therapeutics. Cellular and Molecular Neurobiology 30:8, 1407-1415
CrossRef8
Anna Tzontcheva. (2010) Neuroendocrine Tumors — Laboratory Diagnosis. Journal of Medical Biochemistry 29:4, 254-264
CrossRef9
Maciej Otto, Jacek Dzwonkowski, Andrzej Januszewicz, Mariola Pęczkowska, Andrzej Kański, Anna Kasperlik-Załuska, Elżbieta Rosłonowska, Jacek Szmidt. (2010) Hypertension Crisis in Adrenal Surgery and Treatment of Postoperative Hypotension. Polish Journal of Surgery 82:4, 199-211
CrossRef10
MLM Poulsen, E Budtz-Jørgensen, ML Bisgaard. (2010) Surveillance in von Hippel-Lindau disease (vHL). Clinical Genetics 77:1, 49-59
CrossRef11
H K Ganesh, Shrikrishna V Acharya, Joe Goerge, Tushar R Bandgar, Padma S Menon, Nalini S Shah. (2009) Pheochromocytoma in children and adolescents. The Indian Journal of Pediatrics 76:11, 1151-1153
CrossRef12
Cornelis JM Lips, Wendy van Veelen, Thera P Links, Jo WM Höppener. (2009) Multiple endocrine neoplasia type 2. Expert Review of Endocrinology & Metabolism 4:5, 443-465
CrossRef13
Masaki Naito, Takeshi Usui, Tamiko Tamanaha, Sachiko-Tsukamoto Kawashima, Hitomi Iogawa, Hanae Hagiwara, Takashi Kimura, Tetsuya Tagami, Manabu Kurosawa, Akira Shimatsu, Mitsuhide Naruse. (2009) R27X nonsense mutation of the SDHB gene in a patient with sporadic malignant paraganglioma. Endocrine 36:1, 10-15
CrossRef14
M. Dechant, U. Kunzendorf. (2009) Rezidivierende Übelkeit bei einem 47-jährigen Mann. Der Nephrologe 4:4, 348-350
CrossRef15
Monica L. Marvin, Carol R. Bradford, James C. Sisson, Stephen B. Gruber, Russell B. Smith. (2009) Diagnosis and management of hereditary paraganglioma syndrome due to the F933>X67 SDHD mutation. Head & Neck 31:5, 689-694
CrossRef16
N. Reisch, M.K. Walz, Z. Erlic, H.P.H. Neumann. (2009) Das Phäochromozytom – noch immer eine Herausforderung. Der Internist 50:1, 27-35
CrossRef17
Jose M. Rodriguez, Maria Balsalobre, Jose L. Ponce, Antonio Ríos, Nuria M. Torregrosa, Javier Tebar, Pascual Parrilla. (2008) Pheochromocytoma in MEN 2A Syndrome. Study of 54 Patients. World Journal of Surgery 32:11, 2520-2526
CrossRef18
Hideyuki Kano, Ajay Niranjan, Sanjay Mongia, Douglas Kondziolka, John C. Flickinger, L. Dade Lunsford. (2008) THE ROLE OF STEREOTACTIC RADIOSURGERY FOR INTRACRANIAL HEMANGIOBLASTOMAS. Neurosurgery 63:3, 443-451
CrossRef19
Catherine E. Lewis, Michael W. Yeh. (2008) Inherited endocrinopathies: An update. Molecular Genetics and Metabolism 94:3, 271-282
CrossRef20
Zenggang Pan, Susan Repertinger, Caishu Deng, Poonam Sharma. (2008) A Giant Cystic Pheochromocytoma of the Adrenal Gland. Endocrine Pathology 19:2, 133-138
CrossRef21
Seung-Joon Hwang, Mi-kwang Kwon, Suk Chon. (2008) A Case of Retroperitoneal Paraganglioma Manifested as Intractable Constipation with Paralytic Ileus and Aggravated Hyperglycemia. Journal of Korean Endocrine Society 23:6, 450
CrossRef22
STEVEN D. CHERNAUSEK, CHARIS ENG. 2008. Pheochromocytoma and the Multiple Endocrine Neoplasia Syndromes. , 512-529.
CrossRef23
Andrew D. Ludwig, Daniel I. Feig, Mary L. Brandt, M. John Hicks, Megan E. Fitch, Darrell L. Cass. (2007) Recent advances in the diagnosis and treatment of pheochromocytoma in children. The American Journal of Surgery 194:6, 792-797
CrossRef24
Benjamin Clarke, Glenn Ryan, John Fraser, Leo Francis. (2007) Uncommon cause of cardiac arrest in the emergency department. Emergency Medicine Australasia 19:2, 169-172
CrossRef25
R. Madani, M. Al-Hashmi, R. Bliss, T.W.J. Lennard. (2007) Ectopic Pheochromocytoma: Does the Rule of Tens Apply?. World Journal of Surgery 31:4, 849-854
CrossRef26
Graeme Eisenhofer, Graham Rivers, Alejandro L Rosas, Zena Quezado, William M Manger, Karel Pacak. (2007) Adverse Drug Reactions in Patients with Phaeochromocytoma. Drug Safety 30:11, 1031-1062
CrossRef27
Amarnath Challapalli, Lisa Howell, Martin Farrier, Anna Kelsey, Jillian Birch, Tim Eden. (2007) Cervical paraganglioma—A case report and review of all cases reported to the Manchester Children's Tumour Registry 1954–2004. Pediatric Blood & Cancer 48:1, 112-116
CrossRef28
Graeme Eisenhofer. (2006) Pheochromocytoma: recent advances and speed bumps in the road to further progress. Journal of Hypertension 24:12, 2341-2343
CrossRef29
Nicole Reisch, Mariola Peczkowska, Andrzej Januszewicz, Hartmut PH Neumann. (2006) Pheochromocytoma: presentation, diagnosis and treatment. Journal of Hypertension 24:12, 2331-2339
CrossRef30
C. Bernal, J.M. Alcázar. (2006) Feocromocitoma: presentación clínica. Diagnóstico y tratamiento. Hipertensión 23:6, 173-183
CrossRef31
Serge A. Jabbour, Batya B. Davidovici, Ronni Wolf. (2006) Rare syndromes. Clinics in Dermatology 24:4, 299-316
CrossRef32
Jessica E. Gosnell, Mark S. Sywak, Stan B. Sidhu, Ian R. Gough, Diana L. Learoyd, Bruce G. Robinson, Leigh W. Delbridge. (2006) NEW ERA: PROPHYLACTIC SURGERY FOR PATIENTS WITH MULTIPLE ENDOCRINE NEOPLASIA-2A. ANZ Journal of Surgery 76:7, 586-590
CrossRef33
Daisuke WATANABE, Akiyo TANABE, Mitsuhide NARUSE, Mika TSUIKI, Nobuyuki TORII, Takao NOSHIRO, Kazue TAKANO. (2006) Transcatheter Arterial Embolization for the Treatment of Liver Metastases in a Patient with Malignant Pheochromocytoma. Endocrine Journal 53:1, 59-66
CrossRef34
J. Fuertes Manuel, E. Mena González, V. Camacho Martí, M.A. Hernández Fructuoso, A. Flotats Giralt, M. Estorch Cabrera, I. Carrió Gasset. (2005) SPECT-TC con 123I-MIBG y sonda gamma portátil en la localización radioguiada de un feocromocitoma. Revista Española de Medicina Nuclear 24:6, 418-421
CrossRef35
Christopher J. Bonar, Albert H. Lewandowski, Baha Arafah, Charles C. Capen. (2005) PHEOCHROMOCYTOMA IN AN AGED FEMALE AFRICAN ELEPHANT (LOXODONTA AFRICANA). Journal of Zoo and Wildlife Medicine 36:4, 719-723
CrossRef36
Jacques WM Lenders, Graeme Eisenhofer, Massimo Mannelli, Karel Pacak. (2005) Phaeochromocytoma. The Lancet 366:9486, 665-675
CrossRef37
Thiagarajan Nambirajan, Karl Leeb, Hartmut P.H. Neumann, Ulrike B. Graubner, Günter Janetschek. (2005) Laparoscopic Adrenal Surgery for Recurrent Tumours in Patients with Hereditary Phaeochromocytoma. European Urology 47:5, 622-626
CrossRef38
I. Brink, S. Hoegerle, J. Klisch, T. A. Bley. (2005) Imaging of pheochromocytoma and paraganglioma. Familial Cancer 4:1, 61-68
CrossRef39
Giuseppe Opocher, Pierantonio Conton, Francesca Schiavi, Beatrice Macino, Franco Mantero. (2005) Pheochromocytoma in von Hippel–Lindau disease and neurofibromatosis type 1. Familial Cancer 4:1, 13-16
CrossRef40
Christian Pawlu, Birke Bausch, Hartmut P. H. Neumann. (2005) Mutations of the SDHB and SDHD genes. Familial Cancer 4:1, 49-54
CrossRef41
Mariola Peczkowska, Andrzej Januszewicz. (2005) Multiple endocrine neoplasia type 2. Familial Cancer 4:1, 25-36
CrossRef42
O Beck, WJ Fassbender, P Beyer, S Kriener, HPH Neumann, T Klingebiel, T Lehrnbecher. (2004) Pheochromocytoma in childhood: implication for further diagnostic procedures. Acta Paediatrica 93:12, 1630-1634
CrossRef43
KAISA SALMENKIVI, PAIVI HEIKKILA, CAJ HAGLUND, JOHANNA AROLA. (2004) Malignancy in pheochromocytomas. Review article. APMIS 112:9, 551-9
CrossRef44
D. Taieb, F. Sebag, J. G. Hubbard, O. Mundler, J. F. Henry, B. Conte-Devolx. (2004) Does iodine-131 meta-iodobenzylguanidine (MIBG) scintigraphy have an impact on the management of sporadic and familial phaeochromocytoma?. Clinical Endocrinology 61:1, 102-108
CrossRef45
Randy L. Jensen, David Gillespie, Paul House, Lester Layfield, Clough Shelton. (2004) Endolymphatic sac tumors in patients with and without von Hippel—Lindau disease: the role of genetic mutation, von Hippel—Lindau protein, and hypoxia inducible factor-1α expression. Journal of Neurosurgery 100:3, 488-497
CrossRef46
Hao Ling, Markus Cybulla, Oliver Schaefer, Christian Arnold, Marcus Schories, Hartmut P.H. Neumann. (2004) When to Look for Von Hippel-Lindau Disease in Gastroenteropancreatic Neuroendocrine Tumors?. Neuroendocrinology 80:Suppl. 1, 39-46
CrossRef47
Usha Gurunathan, Grace Korula. (2004) Unsuspected Pheochromocytoma: Von Hippel-Lindau Disease. Journal of Neurosurgical Anesthesiology 16:1, 26-28
CrossRef48
Masatoshi Iihara, Rumi Suzuki, Akiko Kawamata, Yoko Omi, Hitomi Kodama, Yuka Igari, Kiyomi Yamazaki, Takao Obara. (2003) Adrenal-preserving laparoscopic surgery in selected patients with bilateral adrenal tumors. Surgery 134:6, 1066-1072
CrossRef49
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
CrossRef50
Lee C. Pederson, Jeffrey E. Lee. (2003) Pheochromocytoma. Current Treatment Options in Oncology 4:4, 329-337
CrossRef51
Birke Bausch, Robin Munk, Jörg Schipper, Stefan Hoegerle, Dietmar P. Berger, Nikolaus Böhm, Hartmut P.H. Neumann. (2003) SDHD mutations in carotid body tumors and pheochromocytomas: paraganglioma syndrome type 1. Current Opinion in Endocrinology and Diabetes 10:3, 197-204
CrossRef52
Taupenot, Laurent, Harper, Kimberly L., O'Connor, Daniel T., . (2003) The Chromogranin–Secretogranin Family. New England Journal of Medicine 348:12, 1134-1149
Full Text53
Toshiaki Sano, Hidehisa Horiguchi. (2003) Von Hippel-Lindau disease. Microscopy Research and Technique 60:2, 159-164
CrossRef54
Danny Gauthier, Donald J. D’Amico, Shizuo Mukai. (2002) von Hippel-Lindau Disease. International Ophthalmology Clinics 41:4, 173-187
CrossRef55
Robert G. Dluhy. (2002) Screening for genetic causes of hypertension. Current Hypertension Reports 4:6, 439-444
CrossRef56
T. Matsuda, T. Murota, N. Oguchi, G. Kawa, K. Muguruma. (2002) Section 3. Adrenal. Biomedicine & Pharmacotherapy 56, 132-138
CrossRef57
CHRISTIAN A. KOCH, ALEXANDER O. VORTMEYER, ZHENGPING ZHUANG, FREDERIEKE M. BROUWERS, KAREL PACAK. (2002) New Insights into the Genetics of Familial Chromaffin Cell Tumors. Annals of the New York Academy of Sciences 970:1, 11-28
CrossRef58
JACQUES W.M. LENDERS, KAREL PACAK, GRAEME EISENHOFER. (2002) New Advances in the Biochemical Diagnosis of Pheochromocytoma. Annals of the New York Academy of Sciences 970:1, 29-40
CrossRef59
McCLELLAN M. WALTHER. (2002) New Therapeutic and Surgical Approaches for Sporadic and Hereditary Pheochromocytoma. Annals of the New York Academy of Sciences 970:1, 41-53
CrossRef60
Neumann, Hartmut P.H., Bausch, BirkeMcWhinney, Sarah R., Bender, Bernhard U., Gimm, Oliver, Franke, Gerlind, Schipper, Joerg, Klisch, Joachim, Altehoefer, Carsten, Zerres, Klaus, Januszewicz, Andrzej, Smith, Wendy M., Munk, Robin, Manz, Tanja, Glaesker, Sven, Apel, Thomas W., Treier, Markus, Reineke, Martin, Walz, Martin K., Hoang-Vu, Cuong, Brauckhoff, Michael, Klein-Franke, Andreas, Klose, Peter, Schmidt, Heinrich, Maier-Woelfle, Margarete, Peçzkowska, Mariola, Szmigielski, Cesary, Eng, Charis, . (2002) Germ-Line Mutations in Nonsyndromic Pheochromocytoma. New England Journal of Medicine 346:19, 1459-1466
Full Text61
Dluhy, Robert G., . (2002) Pheochromocytoma — Death of an Axiom. New England Journal of Medicine 346:19, 1486-1488
Full Text62
Peter Reichardt, Thomas W. Apel, Manfred Domula, Ralf-Bodo Tröbs, Ingrid Krause, Uta Bierbach, Hartmut P. H. Neumann, Wieland Kiess. (2002) Recurrent Polytopic Chromaffin Paragangliomas in a 9-Year-Old Boy Resulting From a Novel Germline Mutation in the von Hippel–Lindau Gene. Journal of Pediatric Hematology/Oncology 24:2, 145-148
CrossRef63
Steven A. Narod. (2002) MODIFIERS OF RISK OF HEREDITARY BREAST AND OVARIAN CANCER. Nature Reviews Cancer 2:2, 113-123
CrossRef64
H Vierhapper. (2002) Adrenocortical tumors: clinical symptoms and biochemical diagnosis. European Journal of Radiology 41:2, 88-94
CrossRef65
Diana E. Benn, Deborah J. Marsh, Bruce G. Robinson. (2002) Genetics of pheochromocytoma and paraganglioma. Current Opinion in Endocrinology & Diabetes 9:1, 79-86
CrossRef66
William M. Manger, Ray W. Gifford. (2002) Pheochromocytoma. The Journal of Clinical Hypertension 4:1, 62-72
CrossRef67
Arun D Singh, Carol L Shields, Jerry A Shields. (2001) von Hippel–Lindau Disease. Survey of Ophthalmology 46:2, 117-142
CrossRef68
(2001) Case 13-2001: Genetic Testing in Pheochromocytoma. New England Journal of Medicine 345:7, 547-548
Full Text69
H.Christoph Klingler, Paul J. Klingler, J.Kirk Martin, Robert C. Smallridge, Stephen L. Smith, Ronald A. Hinder. (2001) Pheochromocytoma. Urology 57:6, 1025-1032
CrossRef70
Günter Janetschek, Hartmut P.H. Neumánn. (2001) Laparoscopic surgery for pheochromocytoma. Urologic Clinics of North America 28:1, 97-105
CrossRef71
E. Mirallié, M. D. Leclair, P. Lagausie, D. Weil, V. Plattner, C. Duverne, A. Wint, G. Podevin, Y. Héloury. (2001) Laparoscopic adrenalectomy in children. Surgical Endoscopy 15:2, 156-160
CrossRef72
P.F Plouin, A.P Gimenez-Roqueplo, A La Batide Alanore, S Salenave, J.M Duclos. (2000) Progrès récents dans le diagnostic, l’évaluation pronostique et le traitement des phéochromocytomes. La Revue de Médecine Interne 21:12, 1075-1085
CrossRef73
Salvador J. Diaz-Cano, Manuel de Miguel, Alfredo Blanes, Robert Tashjian, Hugo Galera, Hubert J. Wolfe. (2000) Clonal patterns in phaeochromocytomas and MEN-2A adrenal medullary hyperplasias: histological and kinetic correlates. The Journal of Pathology 192:2, 221-228
CrossRef74
Andrzej Januszewicz, Hartmut P.H. Neumann, Izabella Łoń, Cezary Szmigielski, Bartosz Symonides, Marek Kabat, Thomas W. Apel, Bożenna Wocial, Mariusz Łapiński, Włodzimierz Januszewicz. (2000) Incidence and clinical relevance of RET proto-oncogene germline mutations in pheochromocytoma patients. Journal of Hypertension 18:8, 1019-1023
CrossRef75
Jonathan H. Ross. (2000) PHEOCHROMOCYTOMA. Urologic Clinics of North America 27:3, 393-402
CrossRef76
R. Mössner, M. Keidel. (2000) Malignant pheochromocytoma with progressive paraparesis in �von Hippel-Lindau disease. European Journal of Neurology 7:4, 439-442
CrossRef77
Koper, J. Lamberts. (2000) Sporadic endocrine tumours and their relationship to the hereditary endocrine neoplasia syndromes. European Journal of Clinical Investigation 30:6, 493-500
CrossRef78
Job Kievit, Harm R. Haak. (2000) DIAGNOSIS AND TREATMENT OF ADRENAL INCIDENTALOMA. Endocrinology & Metabolism Clinics of North America 29:1, 69-90
CrossRef79
Vicki Couch, Noralane M. Lindor, Pamela S. Karnes, Virginia V. Michels. (2000) von Hippel-Lindau Disease. Mayo Clinic Proceedings 75:3, 265-272
CrossRef80
V Couch, N M Lindor, P S Karnes, V V Michels. (2000) von Hippel-Lindau disease.. Mayo Clinic Proceedings 75:3, 265-272
CrossRef81
McCLELLAN M. WALTHER, ROBERT REITER, HARRY R. KEISER, PETER L. CHOYKE, DAVID VENZON, KATHY HURLEY, JAMES R. GNARRA, JAMES C. REYNOLDS, GLADYS M. GLENN, BERTON ZBAR, W. MARSTON LINEHAN. (1999) CLINICAL AND GENETIC CHARACTERIZATION OF PHEOCHROMOCYTOMA IN VON HIPPEL-LINDAU FAMILIES: COMPARISON WITH SPORADIC PHEOCHROMOCYTOMA GIVES INSIGHT INTO NATURAL HISTORY OF PHEOCHROMOCYTOMA. The Journal of Urology 162:3, 659-664
CrossRef82
Eisenhofer, Graeme, Lenders, Jacques W.M., Linehan, W. Marston, Walther, McClellan M., Goldstein, David S., Keiser, Harry R., . (1999) Plasma Normetanephrine and Metanephrine for Detecting Pheochromocytoma in von Hippel–Lindau Disease and Multiple Endocrine Neoplasia Type 2. New England Journal of Medicine 340:24, 1872-1879
Full Text83
Richard E. Goldstein, James A. O’Neill, George W. Holcomb, Walter M. Morgan, Wallace W. Neblett, John A. Oates, Nancy Brown, John Nadeau, Bradley Smith, David L. Page, Naji N. Abumrad, H. William Scott. (1999) Clinical Experience Over 48 Years With Pheochromocytoma. Annals of Surgery 229:6, 755
CrossRef84
Salvador J. Diaz-Cano. (1998) Clonality studies in the analysis of adrenal medullary proliferations: Application principles and limitations. Endocrine Pathology 9:4, 301-316
CrossRef85
Erwin van der Harst, Ronald R. de Krijger, Hajo A. Bruining, Steven W. J. Lamberts, H. Jaap Bonjer, Winand N. M. Dinjes, Charles Proye, Jan W. Koper, Fré T. Bosman, Jürgen Roth, Philipp U. Heitz, Paul Komminoth. (1998) Prognostic value ofRET proto-oncogene point mutations in malignant and benign, sporadic phaeochromocytomas. International Journal of Cancer 79:5, 537-540
CrossRef86
GUNTER JANETSCHEK, GERD FINKENSTEDT, RUDOLPH GASSER, URSULA G. WAIBEL, REINHARD PESCHEL, GEORG BARTSCH, HARTMUT P. H. NEUMANN. (1998) LAPAROSCOPIC SURGERY FOR PHEOCHROMOCYTOMA. The Journal of Urology330-334
CrossRef87
GUNTER JANETSCHEK, GERD FINKENSTEDT, RUDOLPH GASSER, URSULA G. WAIBEL, REINHARD PESCHEL, GEORG BARTSCH, HARTMUT P.H. NEUMANN. (1998) LAPAROSCOPIC SURGERY FOR PHEOCHROMOCYTOMA: ADRENALECTOMY, PARTIAL RESECTION, EXCISION OF PARAGANGLIOMAS. The Journal of Urology 160:2, 330-334
CrossRef88
E. van der Harst, R. R. de Krijger, W. N. M. Dinjens, L. E. Weeks, H. J. Bonjer, H. A. Bruining, S. W. J. Lamberts, J. W. Koper. (1998) Germline mutations in thevhl gene in patients presenting with phaeochromocytomas. International Journal of Cancer 77:3, 337-340
CrossRef89
Steven A. Curley, Steven T. Lott, James W. Luca, Marsha L. Frazier, Ann M. Killary. (1998) Surgical Decision-Making Affected By Clinical and Genetic Screening of a Novel Kindred With Von Hippel-Lindau Disease and Pancreatic Islet Cell Tumors. Annals of Surgery 227:2, 229-235
CrossRef90
Skoldberg, Grimelius, Woodward, Rorsman, Van Schothorst, Winqvist, Karlsson, Akerstrom, Kampe, Husebye. (1998) A family with hereditary extra-adrenal paragangliomas without evidence for mutations in the von Hippel-Lindau disease or ret genes. Clinical Endocrinology 48:1, 11-16
CrossRef91
ALTHEADA LAVERNE JOHNSON. (1997) The von Hippel-Lindau Family Alliance. Annals of the New York Academy of Sciences 833:1 Cancer, 195-197
CrossRef92
Gabriel M. Mulcahy, Michael Goggins, Dawn Willis, Ruth A. Decker, Michael C. Luce, Ramon Parsons, Sanford Markowitz, Steven A. Narod, Jeffrey T. Holt, David L. Page, Alvin M. Mauer, Ann Thor. (1997) Pathology and genetic testing. Cancer 80:S3, 636-648
CrossRef93
Hartmut P H Neumann, Berton Zbar. (1997) Renal cysts, renal cancer and von Hippel-Lindau disease. Kidney International 51:1, 16-26
CrossRef94
T. Manger, S. Piatek, S. Klose, D. Kopf, D. Kunz, H. Lehnert, H. Lippert. (1997) Bilaterale laparoskopische transperitoneale Adrenalektomie beim Phäochromozytom. Langenbecks Archiv für Chirurgie 382:1, 37-42
CrossRef95
Jeffrey E. Lee, Steven A. Curley, Robert F. Gagel, Douglas B. Evans, Robert C. Hickey. (1996) Cortical-sparing adrenalectomy for patients with bilateral pheochromocytoma. Surgery 120:6, 1064-1071
CrossRef96
François N. Pattou, Frederic P. Combemale, Jean-François Poirette, Bruno Carnaille, Jean-Louis Wemeau, Damien Huglo, Olivier Ernst, Charles A.G. Proye. (1996) Questionability of the benefits of routine laparotomy as the surgical approach for pheochromocytomas and abdominal paragangliomas. Surgery 120:6, 1006-1012
CrossRef97
Hartmut P.H. Neumann, Bernhard Bender, Ingeborg Zäuner, Dietmar P. Berger, Charis Eng, Hiltrud Brauch, Berton Zbar. (1996) Monogenetic hypertension and pheochromocytoma. American Journal of Kidney Diseases 28:3, 329-333
CrossRef98
R. Z. Słapa, W. Jakubowski, E. Dibrowska, A. Januszewicz, B. Tymińska, T. Feltynowski, M. słapiński, J. Fijuth. (1996) Magnetic resonance imaging differentiation of adrenal masses at 1.5 t: t2-weighted images, chemical shift imaging, and gd-dtpa dynamic studies. Magma: Magnetic Resonance Materials in Physics, Biology, and Medicine 4:3-4, 163-179
CrossRef99
Dominique Chauveau, Christian Duvic, Yves Chrétien, François Paraf, Dominique Droz, Philippe Melki, Olivier Hélénon, Stéphane Richard, Jean-Pierre Grünfeld. (1996) Renal involvement in von Hippel-Lindau disease. Kidney International 50:3, 944-951
CrossRef100
Ann W. Hsing, Jun-Mo Nam, Harvey T. Co Chien, Joseph K. McLaughlin, Joseph F. Fraumeni. (1996) Risk factors for adrenal cancer: An exploratory study. International Journal of Cancer 65:4, 432-436
CrossRef101
Giulio J. D'Angio, Audrey E. Evans, Luana Padovan, Giorgio Perilongo, Antonio Battistella, Marina Gardiman, Luisa Pinello, Carla Carollo, Mario Pellone. (1996) Multiple central nervous system haemangioblastomas. Medical and Pediatric Oncology 26:2, 116-124
CrossRef102
M. Ercan, S. Kahraman, E. Başgül, Ü. Aypar. (1996) Anaesthetic management of a patient with von Hippel-Lindau disease: a combination of bilateral phaeochromocytoma and spinal cord haemangioblastoma. European Journal of Anaesthesiology 13:1, 81-83
CrossRef103
Berton Zbar, Takeshi Kishida, Fan Chen, Laura Schmidt, Eamonn R. Maher, Frances M. Richards, Paul A. Crossey, Andrew R. Webster, Nabeel A. Affara, Malcolm A. Ferguson-Smith, Hiltrud Brauch, Damjan Glavac, Hartmut P.H. Neumann, Sam Tisherman, John J. Mulvihill, David J. Gross, Taro Shuin, Jean Whaley, Berndt Seizinger, Nickolai Kley, Sylviane Olschwang, Cecile Boisson, Stephane Richard, C.H.M. Lips, W. Marston Linehan, Michael Lerman. (1996) Germline mutations in the Von Hippel-Lindau disease (VHL) gene in families from North America, Europe, and Japan. Human Mutation 8:4, 348-357
CrossRef104
Nikolai Kley, Jean Whaley, Bernd R. Seizinger. (1995) Neurofibromatosis type 2 and von Hippel-Lindau disease: From gene cloning to function. Glia 15:3, 297-307
CrossRef105
Paul Komminoth, Seraina Muletta-Feurer, Parvin Saremaslani, Eva K. Kunz, Xavier Matias-Guiu, Olaf Hiort, Sören Schröder, Walter K. F. Seelentag, Jürgen Roth, Philipp U. Heitz. (1995) Molecular diagnosis of multiple endocrine neoplasia (MEN) in paraffin-embedded specimens. Endocrine Pathology 6:4, 267-278
CrossRef106
Steven A. Narod. (1995) Screening for cancer in high risk families. Clinical Biochemistry 28:4, 367-372
CrossRef107
Xavier Matias-Guiu, Anna Colomer, Eugenia Mato, Miriam Cuatrecasas, Paul Komminoth, Jaime Prat, Hubert Wolfe. (1995) Expression of theret proto-oncogene in phaeochromocytoma. Anin situ hybridization and northern blot study. The Journal of Pathology 176:1, 63-68
CrossRef108
W. P. Tormey, R. J. FitzGerald. (1995) Lack of uniformity in the clinical approach to the interpretation of urinary catecholamines and their metabolites. Irish Journal of Medical Science 164:2, 146-150
CrossRef109
Hartmut P.H. Neumann, Cornells J.M. Lips, Y. Edward Hsia, Berton Zbar. (1995) Von Hippel-Lindau Syndrome. Brain Pathology 5:2, 181-193
CrossRef110
W. P. Tormey, R. J. FitzGerald. (1995) Phaeochromocytoma — A laboratory experience. Irish Journal of Medical Science 164:2, 142-145
CrossRef111
Godela M Fick, Patricia A Gabow. (1994) Hereditary and acquired cystic disease of the kidney. Kidney International 46:4, 951-964
CrossRef112
H. P. H. Neumann. (1994) Genetics of hypertension: the pheochromocytoma model. The Clinical Investigator 72:9, 729-730
CrossRef113
S. L. Chew. (1994) Phaeochromocytoma and familial tumour syndromes. Clinical Endocrinology 40:6, 715-716
CrossRef114
(1994) Pheochromocytoma, Multiple Endocrine Neoplasia Type 2, and von Hippel-Lindau Disease. New England Journal of Medicine 330:15, 1090-1091
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