Background Pheochromocytoma is a feature of two disorders withan autosomal dominant pattern of inheritance -- multiple endocrineneoplasia type 2 (MEN-2) (with medullary thyroid carcinoma andhyperparathyroidism) and von Hippel-Lindau disease (with angiomaof the retina, hemangioblastoma of the central nervous system,renal-cell carcinoma, pancreatic cysts, and epididymal cystadenoma).The frequency of these syndromes in patients with pheochromocytomais 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, andultrasonography of the testes. We also screened members of familieswith MEN-2 or von Hippel-Lindau disease for pheochromocytomaby measuring plasma and urine catecholamines and plasma chromograninA and by performing abdominal ultrasonography, CT and MRI, andmetaiodobenzylguanidine scintigraphy.
Results Nineteen of 82 unselected patients with pheochromocytomas(23 percent) were carriers of familial disorders; 19 percenthad 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, therewere 130 patients with 185 pheochromocytomas; 43 had von Hippel-Lindaudisease, 24 had MEN-2, and 63 had sporadic tumors. The patientswith familial and those with sporadic pheochromocytomas differedin mean age at diagnosis (32 vs. 46 years, P<0.001), multifocallocalization (55 vs. 8 percent, P<0.001), and cancer (0 vs.11 percent, P = 0.005); but not in the frequency of extraadrenaltumors (24 vs. 16 percent). Thirty-eight percent of carriersof von Hippel-Lindau disease and 24 percent of carriers of MEN-2had pheochromocytoma as the only manifestation of their syndrome.
Conclusions All patients with pheochromocytomas should be screenedfor MEN-2 and von Hippel-Lindau disease to avert further morbidityand mortality in the patients and their families. All patientsin families with MEN-2 or von Hippel-Lindau disease should bescreened for pheochromocytoma, even if they are asymptomatic.
Pheochromocytomas are a feature of two disorders with an autosomaldominant pattern of inheritance -- multiple endocrine neoplasiatype 2 (MEN-2) and von Hippel-Lindau disease. Persons carryingthe MEN-2 mutation are predisposed to have C-cell hyperplasiaor 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-Lindaudisease are retinal angioma, hemangioblastoma of the centralnervous system, renal cysts and carcinoma, pheochromocytoma,pancreatic cysts, and epididymal cystadenoma3,4,5,6,7,8. Affectedmembers of families with these disorders (carriers) may haveone or several of these lesions.
Both syndromes are associated with high morbidity and mortality.In MEN-2, approximately 40 percent of carriers have pheochromocytomas,2whereas in families with von Hippel-Lindau disease the frequencyof these tumors ranges from 0 to more than 90 percent, withan average of 14 percent4,7,9. The frequency of these syndromesamong unselected patients with pheochromocytoma is not known,because most such patients are not considered to have hereditarycancer syndromes. If this assumption is incorrect, there aremany unidentified persons at risk for these syndromes.
We studied a large number of unselected patients with pheochromocytomato identify carriers of MEN-2 or von Hippel-Lindau disease.In a complementary study, we screened members of families withMEN-2 or von Hippel-Lindau disease for pheochromocytoma. Finally,we compared the characteristics of sporadic pheochromocytomaswith those of pheochromocytomas associated with MEN-2 or vonHippel-Lindau disease.
Methods
Study Subjects and Screening
We studied all patients with symptomatic pheochromocytoma atour institutions between January 1, 1971, and July 1, 1993,considering them to be at risk for MEN-2 and von Hippel-Lindaudisease. A detailed family history was obtained from each patient,and an attempt was made to review all relevant records for thepatients and their affected relatives with MEN-2 or von Hippel-Lindaudisease at our institutions or elsewhere. The patients werescreened for MEN-2 with a pentagastrin test, a serum parathyroidhormone assay, and extensive pedigree analysis. MEN-2 was diagnosedif the patient or a first-degree relative had medullary thyroidcarcinoma or C-cell hyperplasia. Patients were screened forvon Hippel-Lindau disease with computed tomography (CT) or magneticresonance imaging (MRI) of the brain, CT of the abdomen, ultrasonographyof the testes, direct ophthalmoscopy after mydriasis, and extensivepedigree analysis. Von Hippel-Lindau disease was diagnosed ifthe patient or a first-degree relative had retinal angioma orhemangioblastoma of the central nervous system.
Beginning in 1984, in a complementary study, we studied subjectsconsidered at risk for pheochromocytoma. These persons wereaffected members of families with MEN-2 or von Hippel-Lindaudisease and their first-degree relatives, patients with retinalangiomas as their only symptom, and first-degree relatives ofpatients with multifocal pheochromocytoma. The program includedabdominal ultrasonography, CT and MRI of the abdomen, metaiodobenzylguanidine(MIBG) scintigraphy, and measurement of plasma and urine catecholaminesand plasma chromogranin A. All the patients and subjects gaveinformed consent.
Analytic Methods
Serum calcitonin concentrations were measured at the time ofthe intravenous administration of 0.5 µg of pentagastrinper kilogram of body weight and two and five minutes thereafterby radioimmunoassay (RIA-mat Calcitonin I, Byk Sangtec, Dietzenbach,Germany). Serum parathyroid hormone was measured by immunoradiometricassay (IRMA PTH intact, Diagnostic Systems Laboratories, Webster,Tex.). Urinary norepinephrine, epinephrine, and vanilmandelicacid were measured by spectrofluorometry. Plasma norepinephrineand epinephrine were determined radioenzymatically. Plasma chromograninA was measured by radioimmunoassay10. Blood samples for thelast three of these measurements were obtained after the subjectshad been supine for 30 minutes. The mean (±2 SD) valuesfor these measurements in 43 subjects (26 women and 17 men witha mean [±SD] age of 34 ±16 years, none of whomhad symptoms, one of whom had hypertension, and all of whomhad negative MIBG scintigraphy, MRI of the retroperitoneum,or both) were as follows: urinary norepinephrine, 43 ±38µg 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 ±24µmol per day); plasma norepinephrine, 0.4 ±0.3ng per milliliter (2.4 ±1.9 nmol per liter); plasma epinephrine,0.08 ±0.05 ng per milliliter (0.43 ±0.28 nmolper liter); and chromogranin A, 18 ±37 ng per milliliter.Blood pressure was measured for 24 hours in patients with newlydetected pheochromocytomas with use of an automatic blot-pressuremonitor (SpaceLabs, Kaarst, Germany), with measurements obtainedevery 20 minutes from 8 a.m. to 8 p.m. and every 30 minutesfrom 8 p.m. to 8 a.m.
Imaging Procedures
Radiologic imaging was performed by persons aware that the patientsand subjects were at risk for MEN-2 or von Hippel-Lindau diseaseor for pheochromocytoma. Abdominal ultrasonography, CT, MRI,and MIBG scintigraphy were performed with standard techniques.Several generations of CT scanners were used; the slice thicknesswas 4 to 8 mm. For MRI (Tomikon R23 with 0.23 T, Bruker, Karlsruhe,Germany), both T1- and strongly T2-weighted axial and T2-weightedcoronal spin-echo sequences with a slice thickness of 8 mm wereobtained. Scintigraphy was performed 48 hours after the intravenousadministration 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 StatisticalPackage for Social Sciences (SPSS, Chicago). Groups of patientswith distinct types of pheochromocytomas (familial vs. sporadictumors, those associated with von Hippel-Lindau disease andthose associated with MEN-2) were compared by parametric andnonparametric tests (two-tailed t-tests, chi-square tests, orWilcoxon rank-sum tests), as applicable. P values less than0.05 were considered to indicate statistical significance.
Results
We studied all 82 patients with symptomatic pheochromocytomaswho were admitted to our institutions between January 1, 1971,and July 1, 1993. Patients were excluded if they already hada confirmed diagnosis of MEN-2 or von Hippel-Lindau disease.All the screening studies for MEN-2 and von Hippel-Lindau diseasewere performed in 63 patients, and some studies were performedin 10 patients; 9 patients died before screening and were studiedat autopsy. Three patients were found to be carriers of MEN-2,and 16 to be carriers of von Hippel-Lindau disease. Thus, 19patients (23 percent) had evidence of one of the two familialtumor syndromes. In the three patients with MEN-2, pheochromocytomawas detected first and C-cell disease afterward. In the 16 patientswith von Hippel-Lindau disease, pheochromocytoma was the firstsymptomatic lesion. In nine patients retinal angiomatosis wasdetected by screening, whereas six patients had a positive familyhistory of von Hippel-Lindau disease as the only indicationof the disease. Two patients with von Hippel-Lindau diseasewho presented with recurrent multifocal pheochromocytomas wereidentified only by family screening. In 12 families with vonHippel-Lindau disease, only pheochromocytoma, retinal angioma,and hemangioblastoma of the central nervous system were found,whereas renal-cell carcinoma occurred in two families with thisdisease.
An atypical coincidence of endocrine tumors was found in a 34-year-oldwoman 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 basophilicanterior pituitary adenoma. The results of screening for bothsyndromes in the woman's relatives were normal, and the tumorwas classified as a sporadic pheochromocytoma. No other patientswith atypical tumors were found in this series, and no patienthad evidence of neurofibromatosis type 1.
Seventy-nine subjects at risk for pheochromocytoma (Figure 1)were screened in the prospective part of the study. Forty-twounsuspected tumors were found in 36 of these subjects (Table 1),27 of whom had von Hippel-Lindau disease and 9 of whom hadMEN-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 normotensivesubjects had 24-hour blood-pressure measurements; only 4 hadepisodes of hypertension. The sensitivity of the tests usedto detect pheochromocytoma was as follows: urinary norepinephrine,86 percent; urinary epinephrine, 53 percent; urinary vanilmandelicacid, 64 percent; plasma norepinephrine, 58 percent; plasmaepinephrine, 33 percent; plasma chromogranin A, 52 percent;abdominal ultrasonography, 40 percent; abdominal CT, 76 percent;abdominal MRI, 95 percent; and MIBG scintigraphy, 95 percent.
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.
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 MIBGscintigraphy; of these subjects, three rejected surgery, andthe six who had normotension even when their blood pressurewas measured for 24 hours decided to have regular follow-up.Three tumors were nonfunctional -- e.g., the subjects had normal24-hour blood-pressure values, and all their biochemical valueswere normal. Eleven percent of the subjects found to have pheochromocytomashad normal catecholamine values in urine and 36 percent hadnormal values in plasma. The majority of false negative resultswere found in the subjects who had small or extraadrenal tumors(Table 1). Eleven extraadrenal pheochromocytomas were foundin 10 subjects, and six of these tumors were not detected byeither ultrasonography or CT. Three adrenal tumors not detectedby CT measured 1.0 to 2.3 cm in diameter. Seventeen of 31 adrenaltumors 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 weredetected. By MRI, all tumors showed high signal intensity inT2-weighted images (Figure 2) and intermediate intensity inT1-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; urinarynorepinephrine, 95 percent; urinary epinephrine, 98 percent;urinary vanilmandelic acid, 91 percent; plasma norepinephrine,97 percent; plasma epinephrine, 94 percent; and plasma chromograninA, 95 percent.
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 sporadictumors, 24 carriers of MEN-2, and 43 carriers of von Hippel-Lindaudisease) in which 185 pheochromocytomas were found. The familialpheochromocytomas were found in patients identified as carriersin the unselected series, subjects identified during screeningfor pheochromocytoma, and affected relatives of the carriers.Among the patients with symptomatic pheochromocytomas, thosewith sporadic as compared with familial tumors at the time ofdiagnosis were significantly younger (P<0.001) (Figure 3,Table 2). Multifocal tumors were more common in patients withfamilial tumors than in those with sporadic tumors (P<0.001),and they were more common in families with MEN-2 than in familieswith von Hippel-Lindau disease (P = 0.02). Age at the time ofdiagnosis was similar in the families with MEN-2 and those withvon Hippel-Lindau disease. The frequency of extraadrenal tumorswas similar in the various groups. Thirty-one patients had bilateraladrenal tumors, 19 of them detected metachronously and 12 detectedsynchronously. The interval before the detection of the contralateraltumor was as long as 31 years (mean, 10). The pheochromocytomawas malignant in only 7 of 63 patients with sporadic tumorsand in none of the 67 patients with von Hippel-Lindau diseaseor MEN-2. Metastases were found in the lung (five patients),liver (five patients), skeletal system (three patients), lymphnodes (two patients), and central nervous system (two patients).
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 membersof 10 families with MEN-2 and 14 families with von Hippel-Lindaudisease (Figure 1). Eighty-three percent of the 29 carriersof MEN-2 had pheochromocytomas. The tumor was the only manifestationof MEN-2 in seven subjects (24 percent), all of whom had normalpentagastrin tests and normal concentrations of serum parathyroidhormone. Seventy-two percent of 60 carriers of von Hippel-Lindaudisease had pheochromocytoma. The associated lesions were retinalangiomas (Figure 4) in 31 subjects, with blindness in 7 (unilateralin 6 and bilateral in 1); hemangioblastoma of the central nervoussystem in 10 subjects (Figure 5); and renal-cell carcinoma in2. Pheochromocytoma was the only manifestation of von Hippel-Lindaudisease in 23 subjects (38 percent).
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.
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 disorderswith an autosomal dominant pattern of inheritance -- MEN-2 andvon Hippel-Lindau disease. Establishing either of these diagnosesis important for the patient and the family, because the riskof other tumors involves not only the index patient but alsothe whole family, and early detection of the components of thetwo syndromes is important for successful management. In particular,hemangioblastoma of the central nervous system and metastaticrenal cancer in von Hippel-Lindau disease, medullary thyroidcancer in MEN-2, and pheochromocytoma in both syndromes arelife-threatening conditions; in addition, retinal angiomas cancause loss of vision in von Hippel-Lindau disease3,9. Therefore,we studied unselected patients with pheochromocytoma who wereseen over a period of 22.5 years in order to identify theirtumors as manifestations of MEN-2 or von Hippel-Lindau disease.
Twenty-three percent of the 82 patients with pheochromocytomaswere found to be gene carriers of MEN-2 or von Hippel-Lindaudisease -- more than four times the percentage usually consideredto be carriers among such patients11. Our figure may representthe lower limit of incidence, since 12 percent of the patientsunderwent incomplete screening and another 11 percent had autopsiesin which the eyes were not examined for retinal angiomas orthe thyroid gland for C-cell hyperplasia. Most (nearly 20 percent)were carriers of von Hippel-Lindau disease -- an unexpectedbut plausible result, since 53 percent of patients with thisdisease who had pheochromocytomas had no other lesion, whereasretinal angiomas, the most frequent finding in the remaining47 percent, were mostly asymptomatic and were found by screening.This previously unsuspected high risk for von Hippel-Lindaudisease is understandable, since no biochemical test to identifycarriers is available. Complete screening presupposes well-equippedand well-staffed centers and is costly and time-consuming forboth patient and physician. Screening for von Hippel-Lindaudisease is warranted, however, because of the risk of hemangioblastomaof the central nervous system; this tumor, which has an excellentprognosis if it is recognized and removed promptly,12 developedin 17 percent of the carriers.
In MEN-2, measurement of serum calcitonin after the administrationof pentagastrin is the standard screening test13. Twenty-fourpercent of carriers of MEN-2 had only pheochromocytoma, andthree of the tumors were extraadrenal, representing so-far-unknownphenotypes. Although rare in MEN-2, extraadrenal tumors werefrequent 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 whenthe familial tumors were detected and the higher frequency ofmultifocal tumors in patients with familial tumors. There seemsto be a very low incidence of malignant pheochromocytoma inpatients with familial syndromes; none of the 67 carriers ofMEN-2 and von Hippel-Lindau disease who had pheochromocytomashad distant metastases, as compared with 7 of the 63 patientswith sporadic pheochromocytomas. These results confirm otherreports that malignant pheochromocytoma is rare in von Hippel-Lindaudisease (with four cases reported7,14,15) and in MEN-2 (withone case16).
Pancreatic islet-cell tumors, although rare in von Hippel-Lindaudisease,9,17 have been reported in association with pheochromocytomaas a separate entity18. Only one patient in this study had thisphenotype, 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 than1 percent19. A few kindreds with pheochromocytoma alone havebeen reported,20,21 but they may ultimately be reclassifiedas having von Hippel-Lindau disease or MEN-2.
In the prospective part of our study we screened affected membersof families with MEN-2 and von Hippel-Lindau disease and theirfirst-degree relatives, patients who had only retinal angiomas,and patients with multifocal pheochromocytomas and found anunexpectedly high number of pheochromocytomas. Thirty-six ofthe 79 subjects at risk (46 percent) had a total of 42 tumors.Some subjects reported contacts with physicians who had foundintermittent or persistent hypertension but did not considerpheochromocytoma. On the other hand, 24-hour blood-pressuremeasurements were normal in 15 of these subjects. No biochemicaltest was completely diagnostic for pheochromocytoma in thisstudy. However, in contrast to other studies,22 this study foundthat plasma catecholamine measurements did not have a high sensitivity,and urinary norepinephrine values more than twice as high asthe upper limit of normal, which was regarded as very suggestiveof pheochromocytoma,23 were found in only 64 percent. The besttest was the measurement of urinary norepinephrine excretion,with a sensitivity of 86 percent. Remarkably, urinary norepinephrine,epinephrine, and vanilmandelic acid excretion and plasma norepinephrineand epinephrine concentrations were normal in 11 percent and36 percent of the 36 subjects, respectively. Plasma chromograninA, a new marker for pheochromocytoma,24 had a sensitivity ofonly 52 percent. Tumor size and chromogranin A were correlated(23 subjects, r = 0.70, with 4 subjects omitted who had extensiveregressive alterations of tumor tissue), confirming an earlierstudy,25 and most of the normal values were found in subjectswith small tumors. Therefore, both radiologic imaging and biochemicaltests are essential for the detection of pheochromocytoma.
The screening part of the study tests the methods used to detectpheochromocytoma, because it was carried out prospectively andin a high-risk population. As compared with other studies, themost obvious discrepancy was the lower sensitivity of ultrasonography(40 percent vs. 90 to 95 percent23,26), whereas the sensitivitiesof abdominal CT (76 percent vs. 70 to 98 percent22,23,27), MIBGscintigraphy (95 percent vs. 78 to 96 percent22,28) and abdominalMRI (95 percent vs. 86 to 100 percent22,23,27) were similarto the values in those reports. The report that high signalintensity in T2-weighted MRI is diagnostic for pheochromocytoma29was confirmed in this series. Excellent documentation was obtainedin both the transverse and the coronal planes; the latter seemseven more suitable for the detection of extraadrenal lesions.
On the basis of this study, we recommend that every patientwith a pheochromocytoma be screened for both MEN-2 and von Hippel-Lindaudisease by the pentagastrin test, the measurement of serum parathyroidhormone, ophthalmoscopy, MRI of the brain, CT of the kidneysand pancreas, and ultrasonography of the testes. Careful pedigreeevaluation is essential, since pheochromocytoma may be the onlyabnormality in gene carriers of MEN-2 or von Hippel-Lindau disease.Since the presence of multiple pheochromocytomas is a strikingsign of the familial syndromes, screening should be extendedto first-degree relatives of such patients, even if they areasymptomatic. If MEN-2 or von Hippel-Lindau disease is diagnosed,screening of the patient's family should include investigationsfor pheochromocytoma. For that purpose, a combined biochemicaland radiologic approach using measurement of 24-hour urine norepinephrineexcretion and MRI is most effective.
In June 1993, missense mutations of the RET proto-oncogene wereidentified in 20 of 23 families with MEN-2A,30 and three differentrestriction-fragment rearrangements encompassing the identifiedgene for von Hippel-Lindau disease in 28 of 221 families withvon Hippel-Lindau disease have been reported31. These importantdiscoveries must, however, be confirmed by studies of additionalfamilies, and the introduction of genetic tests in place ofclinical screening cannot be recommended as long as such markersare not completely diagnostic. Furthermore, for MEN-2 the subtypeMEN-2B remains to be characterized. The finding of pheochromocytoma,retinal angiomatosis, and hemangioblastoma of the central nervoussystem in the absence of renal, pancreatic, and epididymal lesionsin 12 of the 14 families with von Hippel-Lindau disease, confirmingour previously reported clustering of manifestations,32 suggeststhe existence of a distinct subtype of von Hippel-Lindau diseasethat 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 ManfredLehmann, M.D., of the Department of Medicine; Mathias Langer,M.D., Berthold Wimmer, M.D., Jorg Laubenberger, M.D., ErnstMoser, M.D., Ph.D., and Carl Schumichen, M.D., of the Departmentof Radiology; Eduard Farthmann, M.D., of the Department of Surgery;Georg Hertting, M.D., of the Department of Pharmacology; andHans-Eckart Schaefer, M.D., and Norbert Bohm, M.D., of the Departmentof Pathology; to Gunter Mangold, M.D. (Community Hospital, Lahr),and Volker Hofmann, M.D. (St. Barbara Hospital, Halle an derSaale), for their support and cooperation in the Freiburg studyof von Hippel-Lindau disease; to Dieter Engelhardt, M.D. (Departmentof Endocrinology, University of Munich), and Soren Schroder,M.D. (Department of Pathology, University of Hamburg), for contributingdata on Family 3 with MEN-2; to Otto A. Muller, M.D. (HospitalRotes Kreuz, Munich), for data on Family 7 with MEN-2; to LotharHeuser, 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
Schimke RN. Multiple endocrine neoplasia: how many syndromes? Am J Med Genet 1990;37:375-383. [CrossRef][Medline]
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][Medline]
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][Medline]
Neumann HPH. Basic criteria for clinical diagnosis and genetic counselling in von Hippel-Lindau syndrome. Vasa 1987;16:220-226. [Medline]
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. [Free Full Text]
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. [Free Full Text]
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. [Medline]
Green JS, Bowmer MI, Johnson GJ. Von Hippel-Lindau disease in a Newfoundland kindred. Can Med Assoc J 1986;134:133-8, 146. [Abstract]
Lamiell JM, Salazar FG, Hsia YE. Von Hippel-Lindau disease affecting 43 members of a single kindred. Medicine (Baltimore) 1989;68:1-29. [Medline]
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. [Free Full Text]
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.
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. [Free Full Text]
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. [Medline]
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. [Free Full Text]
Sato Y, Waziri M, Smith W, et al. Hippel-Lindau disease: MR imaging. Radiology 1988;166:241-246. [Free Full Text]
Wilson RA, Ibanez ML. A comparative study of 14 cases of familial and nonfamilial pheochromocytomas. Hum Pathol 1978;9:181-188. [Medline]
Neumann HPH, Dinkel E, Brambs HJ, et al. Pancreatic lesions in the von Hippel-Lindau syndrome. Gastroenterology 1991;101:465-471. [Medline]
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. [Free Full Text]
Riccardi VM. Von Recklinghausen neurofibromatosis. N Engl J Med 1981;305:1617-1627. [Medline]
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.
Glowniak JV, Shapiro B, Sisson JC, et al. Familial extra-adrenal pheochromocytoma: a new syndrome. Arch Intern Med 1985;145:257-261. [Free Full Text]
Bravo EL. Pheochromocytoma: new concepts and future trends. Kidney Int 1991;40:544-556. [Medline]
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. [Medline]
O'Connor DT, Deftos LJ. Secretion of chromogranin A by peptide-producing endocrine neoplasms. N Engl J Med 1986;314:1145-1151. [Abstract]
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][Medline]
Yeh HC. Sonography of the adrenal glands: normal glands and small masses. AJR Am J Roentgenol 1980;135:1167-1177. [Abstract]
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. [Free Full Text]
Chatal JF, Charbonnel B. Comparison of iodobenzylguanidine imaging with computed tomography in locating pheochromocytoma. J Clin Endocrinol Metab 1985;61:769-772. [Free Full Text]
Reinig JW, Doppman JL, Dwyer AJ, Johnson AR, Knop RH. Adrenal masses differentiated by MR. Radiology 1986;158:81-84. [Free Full Text]
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][Medline]
Latif F, Tory K, Gnarra J, et al. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 1993;260:1317-1320. [Free Full Text]
Neumann HPH, Wiestler OD. Clustering of features of von Hippel-Lindau syndrome: evidence for a complex genetic locus. Lancet 1991;337:1052-1054. [CrossRef][Medline]
Gergics, P., Patocs, A., Toth, M., Igaz, P., Szucs, N., Liko, I., Fazakas, F., Szabo, I., Kovacs, B., Glaz, E., Racz, K.
(2009). Germline VHL gene mutations in Hungarian families with von Hippel-Lindau disease and patients with apparently sporadic unilateral pheochromocytomas. Eur J Endocrinol
161: 495-502
[Abstract][Full Text]
Srirangalingam, U., Khoo, B., Walker, L., MacDonald, F., Skelly, R. H, George, E., Spooner, D., Johnston, L. B, Monson, J. P, Grossman, A. B, Drake, W M, Akker, S. A, Pollard, P. J, Plowman, N., Avril, N., Berney, D. M, Burrin, J. M, Reznek, R. H, Kumar, V K A., Maher, E. R, Chew, S. L
(2009). Contrasting clinical manifestations of SDHB and VHL associated chromaffin tumours. Endocr Relat Cancer
16: 515-525
[Abstract][Full Text]
Yuan, W., Wang, W., Cui, B., Su, T., Ge, Y., Jiang, L., Zhou, W., Ning, G.
(2008). Overexpression of ERBB-2 was more frequently detected in malignant than benign pheochromocytomas by multiplex ligation-dependent probe amplification and immunohistochemistry. Endocr Relat Cancer
15: 343-350
[Abstract][Full Text]
Boyle, J. G., Davidson, D. F., Perry, C. G., Connell, J. M. C.
(2007). Comparison of Diagnostic Accuracy of Urinary Free Metanephrines, Vanillyl Mandelic Acid, and Catecholamines and Plasma Catecholamines for Diagnosis of Pheochromocytoma. J. Clin. Endocrinol. Metab.
92: 4602-4608
[Abstract][Full Text]
d'Herbomez, M., Forzy, G., Bauters, C., Tierny, C., Pigny, P., Carnaille, B., Pattou, F., Wemeau, J.-L., Rouaix, N.
(2007). An analysis of the biochemical diagnosis of 66 pheochromocytomas. Eur J Endocrinol
156: 569-575
[Abstract][Full Text]
Chew, F. S., Banks, K. P.
(2006). Imaging of Pheochromocytoma and Incidental Adrenal Lesions: Self-Assessment Module. Am. J. Roentgenol.
187: S467-S469
[Abstract][Full Text]
Jimenez, C., Cote, G., Arnold, A., Gagel, R. F.
(2006). Should Patients with Apparently Sporadic Pheochromocytomas or Paragangliomas be Screened for Hereditary Syndromes?. J. Clin. Endocrinol. Metab.
91: 2851-2858
[Abstract][Full Text]
Sullivan, J., Groshong, T., Tobias, J. D.
(2005). Presenting Signs and Symptoms of Pheochromocytoma in Pediatric-aged Patients. CLIN PEDIATR
44: 715-719
[Abstract]
Neumann, H. P. H., Pawlu, C., Peczkowska, M., Bausch, B., McWhinney, S. R., Muresan, M., Buchta, M., Franke, G., Klisch, J., Bley, T. A., Hoegerle, S., Boedeker, C. C., Opocher, G., Schipper, J., Januszewicz, A., Eng, C., for the European-American Paraganglioma Study Grou,
(2004). Distinct Clinical Features of Paraganglioma Syndromes Associated With SDHB and SDHD Gene Mutations. JAMA
292: 943-951
[Abstract][Full Text]
Kaltsas, G. A., Besser, G. M., Grossman, A. B.
(2004). The Diagnosis and Medical Management of Advanced Neuroendocrine Tumors. Endocr. Rev.
25: 458-511
[Abstract][Full Text]
Bryant, J., Farmer, J., Kessler, L. J., Townsend, R. R., Nathanson, K. L.
(2003). Pheochromocytoma: The Expanding Genetic Differential Diagnosis. JNCI J Natl Cancer Inst
95: 1196-1204
[Abstract][Full Text]
Bravo, E. L., Tagle, R.
(2003). Pheochromocytoma: State-of-the-Art and Future Prospects. Endocr. Rev.
24: 539-553
[Abstract][Full Text]
Taupenot, L., Harper, K. L., O'Connor, D. T.
(2003). The Chromogranin-Secretogranin Family. NEJM
348: 1134-1149
[Full Text]
Koch, C. A., Pacak, K., Chrousos, G. P.
(2002). The Molecular Pathogenesis of Hereditary and Sporadic Adrenocortical and Adrenomedullary Tumors. J. Clin. Endocrinol. Metab.
87: 5367-5384
[Abstract][Full Text]
Baysal, B E
(2002). Hereditary paraganglioma targets diverse paraganglia. J. Med. Genet.
39: 617-622
[Abstract][Full Text]
Kashyap, A S, Kashyap, S
(2002). von Hippel-Lindau disease complicated by pheochromocytoma. Postgrad. Med. J.
78: 443-443
[Full Text]
Baghai, M., Thompson, G. B., Young, W. F. Jr, Grant, C. S., Michels, V. V., van Heerden, J. A.
(2002). Pheochromocytomas and Paragangliomas in von Hippel-Lindau Disease: A Role for Laparoscopic and Cortical-Sparing Surgery. Arch Surg
137: 682-689
[Abstract][Full Text]
Neumann, H. P., Bausch, B., McWhinney, S. R., Bender, B. U., Gimm, O., Franke, G., Schipper, J., Klisch, J., Altehoefer, C., Zerres, K., Januszewicz, A., Smith, W. M., Munk, R., Manz, T., Glaesker, S., Apel, T. W., Treier, M., Reineke, M., Walz, M. K., Hoang-Vu, C., Brauckhoff, M., Klein-Franke, A., Klose, P., Schmidt, H., Maier-Woelfle, M., Peczkowska, M., Szmigielski, C., Eng, C., the Freiburg-Warsaw-Columbus Pheochromocytoma Stud,
(2002). Germ-Line Mutations in Nonsyndromic Pheochromocytoma. NEJM
346: 1459-1466
[Abstract][Full Text]
Dluhy, R. G.
(2002). Pheochromocytoma -- Death of an Axiom. NEJM
346: 1486-1488
[Full Text]
Weise, M., Merke, D. P., Pacak, K., Walther, M. M., Eisenhofer, G.
(2002). Utility of Plasma Free Metanephrines for Detecting Childhood Pheochromocytoma. J. Clin. Endocrinol. Metab.
87: 1955-1960
[Abstract][Full Text]
Neumann, H. P.H., Reincke, M., Eng, C., Conlin, P. R.
(2001). Case 13-2001: Genetic Testing in Pheochromocytoma. NEJM
345: 547-548
[Full Text]
d'Herbomez, M., Gouze, V., Huglo, D., Nocaudie, M., Pattou, F., Proye, C., Wemeau, J.-L., Marchandise, X.
(2001). Chromogranin A Assay and 131I-MIBG Scintigraphy for Diagnosis and Follow-Up of Pheochromocytoma. JNM
42: 993-997
[Abstract][Full Text]
Maxwell, P. H., Buckley, C., Gleadle, J. M., Mason, P. D.
(2001). Nasty shock after an anti-emetic. Nephrol Dial Transplant
16: 1069-1072
[Full Text]
Eisenhofer, G., Walther, M. M., Huynh, T.-T., Li, S.-T., Bornstein, S. R., Vortmeyer, A., Mannelli, M., Goldstein, D. S., Linehan, W. M., Lenders, J. W. M., Pacak, K.
(2001). Pheochromocytomas in von Hippel-Lindau Syndrome and Multiple Endocrine Neoplasia Type 2 Display Distinct Biochemical and Clinical Phenotypes. J. Clin. Endocrinol. Metab.
86: 1999-2008
[Abstract][Full Text]
Salmenkivi, K., Arola, J., Voutilainen, R., Ilvesmäki, V., Haglund, C., Kahri, A. I., Heikkilä, P., Liu, J.
(2001). Inhibin/Activin {beta}B-Subunit Expression in Pheochromocytomas Favors Benign Diagnosis. J. Clin. Endocrinol. Metab.
86: 2231-2235
[Abstract][Full Text]
Plouin, P.-F., Duclos, J.-M., Soppelsa, F., Boublil, G., Chatellier, G.
(2001). Factors Associated with Perioperative Morbidity and Mortality in Patients with Pheochromocytoma: Analysis of 165 Operations at a Single Center. J. Clin. Endocrinol. Metab.
86: 1480-1486
[Abstract][Full Text]
Hirsch, N. P., Murphy, A., Radcliffe, J. J.
(2001). Neurofibromatosis: clinical presentations and anaesthetic implications. Br J Anaesth
86: 555-564
[Abstract][Full Text]
Bender, B. U., Gutsche, M., Gläsker, S., Müller, B., Kirste, G., Eng, C., Neumann, H. P. H.
(2000). Differential Genetic Alterations in von Hippel-Lindau Syndrome-Associated and Sporadic Pheochromocytomas. J. Clin. Endocrinol. Metab.
85: 4568-4574
[Abstract][Full Text]
Gimm, O., Armanios, M., Dziema, H., Neumann, H. P. H., Eng, C.
(2000). Somatic and Occult Germ-line Mutations in SDHD, a Mitochondrial Complex II Gene, in Nonfamilial Pheochromocytoma. Cancer Res.
60: 6822-6825
[Abstract][Full Text]
Eisenhofer, G., Lenders, J. W.M., Linehan, W. M., Walther, M. M., Goldstein, D. S., Keiser, H. R.
(1999). Plasma Normetanephrine and Metanephrine for Detecting Pheochromocytoma in von Hippel-Lindau Disease and Multiple Endocrine Neoplasia Type 2. NEJM
340: 1872-1879
[Abstract][Full Text]
Sandur, S., Dasgupta, A., Shapiro, J. L., Arroliga, A. C., Mehta, A. C.
(1999). Thoracic Involvement With Pheochromocytoma: A Review. Chest
115: 511-521
[Abstract][Full Text]
de Lorgeril, M., Salen, P., Martin, J.-L., Monjaud, I., Boucher, P., Mamelle, N.
(1998). Mediterranean Dietary Pattern in a Randomized Trial: Prolonged Survival and Possible Reduced Cancer Rate. Arch Intern Med
158: 1181-1187
[Abstract][Full Text]
Brauch, H., Hoeppner, W., Jahnig, H., Wohl, T., Engelhardt, D., Spelsberg, F., Ritter, M. M.
(1997). Sporadic Pheochromocytomas Are Rarely Associated with Germline Mutations in the vhl Tumor Suppressor Gene or the ret Protooncogene. J. Clin. Endocrinol. Metab.
82: 4101-4104
[Abstract][Full Text]
Plouin, P.-F., Chatellier, G., Fofol, I., Corvol, P.
(1997). Tumor Recurrence and Hypertension Persistence After Successful Pheochromocytoma Operation. Hypertension
29: 1133-1139
[Abstract][Full Text]
Neumann, H. P.H., Eng, C., Mulligan, L. M.
(1996). Von Hippel-Lindau Disease and Pheochromocytoma-Reply. JAMA
275: 840-840
[Abstract]
Neumann, H. P. H., Eng, C., Mulligan, L. M., Glavac, D., Zauner, I., Ponder, B. A. J., Crossey, P. A., Maher, E. R., Brauch, H.
(1995). Consequences of Direct Genetic Testing for Germline Mutations in the Clinical Management of Families With Multiple Endocrine Neoplasia, Type II. JAMA
274: 1149-1151
[Abstract]
Gagel, R. F., Neumann, H. P.H.
(1994). Pheochromocytoma, Multiple Endocrine Neoplasia Type 2, and von Hippel-Lindau Disease. NEJM
330: 1090-1091
[Full Text]
Hoegerle, S., Nitzsche, E., Altehoefer, C., Ghanem, N., Manz, T., Brink, I., Reincke, M., Moser, E., Neumann, H. P. H.
(2002). Pheochromocytomas: Detection with 18F DOPA Whole-Body PET3Initial Results. Radiology
222: 507-512
[Abstract][Full Text]
A correction has been published: N Engl J Med 1994;331(22):1535.
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