Diagnosis and Management of Pheochromocytoma in an Academic Hospital 3 Years After Formation of A Pheochromocytoma Interest Group

ObjectiveTo examine whether establishment of a pheochromocytoma interest group improves diagnosis and management of pheochromocytoma in an academic hospital.MethodsThe medical records of patients who had preoperative or pathologic diagnosis of pheochromocytoma at a large academic hospital from July 2007 to July 2010 were retrieved and pertinent information was gathered. Quality measures for diagnosis and management of pheochromocytoma before and after establishment of a pheochromocytoma interest group, and by group and nongroup physicians, were compared.ResultsBetween 2007 and 2010, 16 patients were confirmed to harbor pheochromocytoma. The rates of overdiagnosis and underdiagnosis were similar before and after establishment of the pheochromocytoma interest group (23%-25% vs 17%, respectively); however, after interest group formation, pheochromocytoma was excluded in 9 patients for whom other physicians recommended adrenalectomy. Compared with nonmembers, members of the pheochromocytoma interest group more frequently performed pheochromocytoma testing before adrenal biopsy or adrenalectomy in patients with adrenal masses (71% vs 13%), including those with suspected malignancy (50% vs 7%). After interest group formation, many more patients were optimally prepared preoperatively and advised on follow-up plan and genetic testing.ConclusionsFormation of a pheochromocytoma interest group significantly enhances the quality of diagnosis and management of pheochromocytoma. The key to the group’s success is its incorporation of members’ formal or informal opinions into the care of patients with suspected pheochromocytoma. This model may be applied to other rare endocrine diseases. (Endocr Pract. 2011;17:356-362)     

Does higher concordance in monozygotic twins than in dizygotic twins suggest a genetic component?

It is widely regarded that twins can be used as a natural experiment to subject hypotheses to empirical testing regarding the contributions of genetic factors to phenotypic variability in human traits, especially behavioral traits. In genetic epidemiology, a higher concordance rate in monozygotic (MZ) twins than in dizygotic (DZ) twins is often taken as prima facie evidence for a genetic component. While twins studies have been used to estimate the contributions of genetic factors to phenotypic variability in human traits, the corresponding methodology that allows the estimation entails several crucial assumptions. The most critical is that MZ and DZ twins are equally similar environmentally. Although MZ twins are genetically more similar than DZ twins, they are often environmentally more similar. This paper demonstrates that, even in the complete absence of any genetic factor and of any biases, the greater environmental similarity alone in MZ twins can result in higher concordance rate in MZ twins than in DZ twins. This is especially true when there are multiple environmental factors, which may have multiple exposure levels and/or interact strongly, although each of them may be of low risk. This may serve as a sobering antidote to the uncritical reliance on twin studies without examining the validity of the underlying assumptions.     

Targeting Heat Shock Protein 90 for the Treatment of Malignant Pheochromocytoma

Metastatic pheochromocytoma represents one of the major clinical challenges in the field of neuroendocrine oncology. Recent molecular characterization of pheochromocytoma suggests new treatment options with targeted therapies. In this study we investigated the 90 kDa heat shock protein (Hsp90) as a potential therapeutic target for advanced pheochromocytoma. Both the first generation, natural product Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin), and the second-generation synthetic Hsp90 inhibitor STA-9090 (ganetespib) demonstrated potent inhibition of proliferation and migration of pheochromocytoma cell lines and induced degradation of key Hsp90 clients. Furthermore, ganetespib induced dose-dependent cytotoxicity in primary pheochromocytoma cells. Using metastatic models of pheochromocytoma, we demonstrate the efficacy of 17-AAG and ganetespib in reducing metastatic burden and increasing survival. Levels of Hsp70 in plasma from the xenograft studies served as a proximal biomarker of drug treatment. Our study suggests that targeting Hsp90 may benefit patients with advanced pheochromocytoma.     

Hyperinsulinism after removal of a pheochromocytoma.

The finding of hypoglycemia after the surgical removal of a pheochromocytoma in two patients in a previous study led to monitoring of the serum glucose and plasma C-peptide levels in two other patients with a pheochromocytoma and one with unilateral adrenocortical hyperplasia. In the two patients with a pheochromocytoma endogenous insulin secretion, as measured by a C-peptide assay, was suppressed before removal of the tumours and resumed immediately after removal. The serum glucose levels decreased in these patients, but sufficient intravenous administration of glucose prevented postoperative hypoglycemia. In the patient with adrenocortical hyperplasia the plasma C-peptide level was not decreased before tumour removal, nor did it increase abruptly following removal. It therefore seems likely that the rapid fall in the serum glucose level following removal of a pheochromocytoma is caused by prompt resumption of beta-cell activity, with rebound hyperinsulinism.     

Serum chromogranin-alpha immunoradiometric assay in the diagnosis of pheochromocytoma

BACKGROUND: The diagnosis of pheochromocytoma is based on laboratory tests that demonstrate an increase in urinary excretion of catecholamines or their metabolites. Chromogranin A (CgA) is a member of the granin family and is widely distributed in neuroendocrine cells and particularly in chromaffin adrenal cells. Consequently, serum CgA increases in patients affected by pheochromocytoma and other diseases of the chromaffin system. AIM: This study investigated the performance of serum CgA assay in the diagnosis of pheochromocytoma and compared serum CgA with 24-hour urinary epinephrine (E), norepinephrine (NE), vanillylmandelic acid (VMA) and metanephrines (MNs). METHODS: We enrolled 15 patients with histologically proven pheochromocytoma; 100 healthy blood donors and 148 patients with essential hypertension were enrolled as controls. Serum CgA was assayed by a specific immunoradiometric method (IRMA). Urinary tests were done with high performance liquid chromatography (HPLC). RESULTS: Circulating CgA showed a higher sensitivity (1.00), specificity (0.96) and accuracy (0.96) than all other tests. Serum levels of CgA clearly increased from blood donors and patients with essential hypertension to patients with pheochromocytoma (p<0.0001). Furthermore, a strong relationship between serum CgA and tumor mass was found (p<0.0001). In conclusion, our data suggest that the CgA assay might be used as a single test for the diagnosis of pheochromocytoma.     

Acute Myocardial Infarction Attributable to Adrenergic Crises in a Patient with Pheochromocytoma and Neurofibromatosis 1

ObjectiveTo describe a rare case of acute myocardial infarction in a patient with neurofibromatosis 1 and pheochromocytoma and to review the literature on the coexistence of these 2 diseases, the causes of myocardial injury in patients with pheochromocytoma, and the utility of genetic testing and pheochromocytoma screening for those patients and their families.MethodsWe present a case report, including the detailed clinical, laboratory, and radiographic data, results of adrenal mass pathology, and results of coronary angiography. We also survey other relevant reports available in the literature.ResultsA 43-year-old woman with a history of longstanding hypertension, neurofibromatosis 1, headaches, sweating, and palpitations presented to the hospital with chest pain and shortness of breath. She was found to have an acute myocardial infarction and pulmonary edema, as well as a right adrenal mass. A pheochromocytoma was suspected, and phenoxybenzamine was added to her treatment regimen. Cardiac catheterization showed nonobstructive coronary disease. The levels of plasma catecholamine metabolites were extremely high. The patient underwent uncomplicated laparoscopic right adrenalectomy 2 weeks after this admission. Surgical pathology confirmed the diagnosis of pheochromocytoma.ConclusionAdrenergic crisis attributable to pheochromocytoma can result in acute myocardial infarction even in the absence of obstructive coronary disease. Inclusion of pheochromocytoma in the differential diagnosis of hypertension in patients with neurofibromatosis is very important and helps avoid mistakes in the management of such patients. (Endocr Pract. 2007;13:269-273)     

Observed frequency of monozygotic twinning in Holstein dairy cattle

Bonnier's equation is used to mathematically estimate the frequency of monozygotic (MZ) twinning in epidemiologic studies of twinning in dairy cattle; however, no empirical determination of MZ twinning has been reported in the literature. Our objectives were to empirically determine the frequency of MZ twinning in lactating Holstein cows and to compare this result with published estimates predicted using Bonnier's equation. Ear biopsies were collected from 107 sets of Holstein twins from six Wisconsin dairies resulting in 40 opposite-sex twins, 29 same-sex male twins, and 38 same-sex female twins. To empirically determine the frequency of MZ twinning, DNA extracted from ear biopsies collected from the 67 same-sex twins was PCR amplified using primers for a minimum of 5 polymorphic microsatellite DNA markers. Opposite-sex twins were classified as dizygotic (DZ) as well as same-sex twins differing in at least one microsatellite DNA marker. Same-sex twins were classified as MZ when all genotypes for a minimum of five markers were identical. Of the 67 same-sex twins, 62 were classified as DZ and 5 MZ resulting in a MZ twinning frequency of 7.5% of same-sex twins and 4.7% of all twins. The estimated frequency of MZ twinning in this population of twin calves using Bonnier's equation was 39.5% of same-sex twins and 24.7% of all twins. We concluded that MZ twinning occurred infrequently in Holstein cattle and perhaps less frequently than that reported in studies using Bonnier's equation to estimate MZ twinning.     

The effect of pheochromocytoma treatment on subclinical inflammation and endocrine function of adipose tissue

The aim of our study was to evaluate the influence of surgical removal of pheochromocytoma on the endocrine function of adipose tissue and subclinical inflammation as measured by circulating C-reactive protein (CRP) levels. Eighteen patients with newly diagnosed pheochromocytoma were included into study. Anthropometric measures, biochemical parameters, serum CRP, leptin, adiponectin and resistin levels were measured at the time of diagnosis and six months after surgical removal of pheochromocytoma. Surgical removal of pheochromocytoma significantly increased body weight, decreased both systolic and diastolic blood pressure, fasting blood glucose and glycated hemoglobin levels. Serum CRP levels were decreased by 50 % six months after surgical removal of pheochromocytoma (0.49+/-0.12 vs. 0.23+/-0.05 mg/l, p<0.05) despite a significant increase in body weight. Serum leptin, adiponectin and resistin levels were not affected by the surgery. We conclude that increased body weight in patients after surgical removal of pheochromocytoma is accompanied by an attenuation of subclinical inflammation probably due to catecholamine normalization. We failed to demonstrate an involvement of the changes in circulating leptin, adiponectin or resistin levels in this process.     

Diminished circadian blood pressure rhythm in patients with asymptomatic normotensive pheochromocytoma

In our study, the circadian blood pressure (BP) rhythm was studied in subjects with asymptomatic and normotensive pheochromocytoma. We have therefore performed 24-hour BP monitoring not only in 6 subjects with asymptomatic pheochromocytoma, but also in 33 patients with symptomatic pheochromocytoma and in 10 normotensive subjects, who served as a control group. Circadian BP rhythm was expressed by assessing a relative night-time BP decline. We found a similar BP rhythm, catecholamine excretion and tumor size in subjects with both forms of pheochromocytoma. Subjects with asymptomatic pheochromocytoma had a significantly lower night-time systolic BP decline (P=0.01) and diastolic BP decline (P=0.006) than normotensive controls. We conclude that the attenuated night-time BP decline in normotensive and asymptomatic subjects with pheochromocytoma might be a possible sign of partial desensitization of the cardiovascular system to catecholamines.     

Why the healing gods are twins

The association of twins with health-giving powers is widespread in mythology, folklore, and religion. The Ashvins of the Rig-Veda, the classical Dioscuri, and the early Christian saints Cosmos and Damian are among the many examples of twins divinely empowered in the area of health and fertility. A characteristic set of attributes of twins recurs in different mythologies of wide distribution. In addition to healing, divine twins are often empowered with the ability to revive the dead, increase the fertility of man, animals, and crops, influence the weather, predict the future, and insure victory in battle. In some traditional societies these special attributes are thought to extend to all of the twins and their parents in the tribe.Ancient and primitive societies supposed that the birth of twins was associated with divine influence, the mother having been visited or otherwise affected by supernatural powers. A frequent explanation was that twins were the result of superfetation, a divine impregnation occurring along with that by the lawful husband. The specific powers of divine twins appear to be a reflection of the particular form of origin of twins through divine interference with the fertilization process. The twins thus share some of the powers of the divine parent, particularly those pertaining to fertility. Their dual paternity and its inherent competition is related to their martial interests as well as their ability to resolve ambivalent or ambiguous situations and predict outcomes.     

Studies on Dihydropteridine Reductase Activity in Pheochromocytoma Cells

Abstract— The activity of dihydropteridine reductase (DPR) in pheochromocytoma cells has been studied. The activity of this enzyme in crude extracts of pheochromocytoma cells is approximately 50 nmol/min/mg protein. This activity is very much greater than the activity of tyrosine 3-monooxygenase (TH) in these extracts and the rate of conversion of tyrosine to DOPA in intact pheochromocytoma cells. Incubation of the cells with 56 m m -K⁺ or with cholera toxin has previously been shown to increase the rate of catecholamine synthesis and to cause a stable activation of TH in the cells. These treatments do not produce a stable activation of DPR, as assayed in vitro. Methotrexate inhibits DPR activity in vitro with an I₅₀ of approximately 20 μ m , but has no effect on the rate of DOPA formation in intact pheochromocytoma cells. Therefore, DPR does not appear to be the rate-limiting enzyme in the pathway of catecholamine synthesis in pheochromocytoma cells. Moreover, the activities of DPR and of TH are not regulated coordinately in these cells.     

The cognitive and identity development of twins at 16 years of age: a follow-up study of 32 twin pairs.

This is a follow up study of twins within the Stockholm area, including 32 families and their twins attending grade nine. The twins have been followed from birth to 16 years of age. The main purpose of this study from its inception was to assess mental and cognitive development at different ages. Another aim was to see how the twins who were born prematurely are developing during the school ages. A third aim has been to gain a deeper insight into the relationship between co-twins and the development of their identities, which is the focus of this paper. Several ability tests have been used, as well as questionnaires about interests, attitudes toward school, and leisure activities. At the 16-year follow-up, a psychological method, the Wartegg drawing test, designed to examine identity, ego strength, dependency, ambition, anxiety, willpower, creativity, empathy and coping strategies has been used. The results indicate that it is difficult for twins to develop independence and a positive identity, as they have to emancipate themselves both from their parents and from their co-twins. Some differences in identity, anxiety and ambition were observed between female and male twins, MZ and DZ twins, preterm and fullterm twins. Prematurity, sex and zygosity no longer had any relation to cognitive development at 16 years of age.     

Plasma adrenomedullin concentrations in patients with adrenal pheochromocytoma.

BACKGROUND: The hypotensive peptide adrenomedullin was first isolated in extracts of human pheochromocytoma. There is, however, no information available on the behaviour of circulating adrenomedullin or on the correlation with catecholamines in patients with pheochromocytoma. OBJECTIVES: 1) to investigate whether plasma adrenomedullin levels were changed in 10 patients with pheochromocytoma when compared to 21 healthy subjects and 16 patients with essential hypertension; 2) to determine whether or not adrenomedullin has a counter-regulatory role in catecholamine excess in pheochromocytoma or is responsible for hemodynamic modifications before and after tumour resection; 3) to determine tissue distribution of iradrenomedullin in the pheochromocytoma. METHODS: Plasma adrenomedullin and catecholamine levels were measured in all patients with pheochromocytoma before and four weeks after tumour removal. In the four patients undergoing resection of tumours, plasma levels of adrenomedullin were measured at different time-points during surgery. RESULTS: The mean plasma adrenomedullin concentrations ( SD) in patients with pheochromocytoma (37.9 +/- 6pg/ml) were significantly higher (p<0.0001) than those in normal subjects (13.7 +/- 6.1 pg/mI) and patients with essential hypertension (22.5 +/- 9.lpg/ml). Adrenomedullin levels correlated with plasma noradrenaline (r = 0.516, p = 0.0124). In all patients with pheochromocytoma, plasma adrenomedullin concentrations decreased after removal of tumours (from 37.9 +/- 6 to 10.9 +/- 4.6 pg/ml; p < 0.0001). In the four patients studied during surgery, baseline plasma adrenomedullin and noradrenaline levels were markedly elevated, and increased significantly with tumour manipulation, decreasing 24 hours after operation. Adrenal medulla cells surrounding the pheochromocytoma site stained for ir-adrenomedullin, whereas only isolated cells of pheochromocytoma stained for the peptide. CONCLUSIONS: This study demonstrates that circulating adrenomedullin is increased in pheochromocytoma, and is also correlated with plasma noradrenaline levels. Adrenomedullin may represent an additional biochemical parameter for clinical monitoring of patients with pheochromocytoma.     

Malignant Pheochromocytoma Secreting Vasoactive Intestinal Peptide and Response to Sunitinib: A Case Report and Literature Review

ObjectiveMalignant pheochromocytoma is rare and may be sporadic or have a genetic basis. Vasoactive intestinal peptide (VIP)-secreting pheochromocytoma has rarely been described in the literature, and treatment remains challenging in the absence of well-controlled randomized trials. The hypoxia-inducible factor – vascular endothelial growth factor axis has been implicated in pheochromocytoma when associated with germline Von-Hippel-Lindau (VHL) or succinate dehydrogenase (SDH) mutations, suggesting potential clinical activity of sunitinib in this setting.MethodsWe present a case report of a patient with a VIP-secreting malignant pheochromocytoma manifested as severe watery diarrhea, with an exquisite clinical response to sunitinib. We review this rare clinical entity and the potential role of sunitinib in this context.ResultsA 51-year-old male initially presented with a pheochromocytoma causing symptoms related to norepinephrine excess. He underwent adrenalectomy, which resulted in complete resolution of his symptoms. Three years later, he developed multifocal metastatic disease from his primary tumor, showing immunohistochemical evidence of VIP production accompanied by severe watery diarrhea and hypokalemia. The patient had a rapid, complete, and durable clinical response to sunitinib, but with only a minor radiological response and without significant toxicity. Genetic testing was negative for germline mutations in VHL, SDHB, SDHC, SDHD, transmembrane protein 127 (TMEM127) and for neurofibromatosis type 1 (NF-1).ConclusionTo the best of our knowledge, this is the first report of a case of malignant VIP-producing pheochromocytoma that was responsive to sunitinib.     

心肌酶谱、动态心电图及冠状动脉CT血管造影诊断嗜铬细胞瘤儿茶酚胺性心脏损害价值研究

摘要 目的：探讨心肌酶谱、动态心电图及冠状动脉CT血管造影诊断嗜铬细胞瘤儿茶酚胺性心脏损害的临床价值。方法：收集2013年1月-2020年4月在我院诊断为嗜铬细胞瘤患者114例,其中嗜铬细胞瘤儿茶酚胺性心脏损害的患者27例。所有患者均完善术前常规检查（血常规、胸片、动态心电图）、心肌酶谱、心脏超声、冠状动脉CTA等临床资料,并收集患者一般临床资料,如血压、临床症状等。结果：114例嗜铬细胞瘤患者中,27例患者存在嗜铬细胞瘤儿茶酚胺性心脏损害。嗜铬细胞瘤儿茶酚胺性心脏损害患者一般临床资料与嗜铬细胞瘤无儿茶酚胺性心脏损害的患者差异无统计学意义（P＞0.05）。嗜铬细胞瘤儿茶酚胺性心脏损害以高血压为主要表现,临床症状表现多样,可伴有头痛、心悸、多汗三联征表现。114例患者中,26例患者出现心肌酶谱升高,36例患者存在不同程度的心电图异常、24例患者冠状动脉CTA异常,嗜铬细胞瘤儿茶酚胺性心脏损害患者在心肌酶谱、动态心电图及冠状动脉CTA异常例数与嗜铬细胞瘤无儿茶酚胺性心脏损害患者中差异均有统计学意义（P＜0.05）。114例患者中心肌酶谱或心电图或冠状动脉CTA异常的患者总共56例,其中嗜铬细胞瘤儿茶酚胺性心脏损害患者23例,嗜铬细胞瘤无儿茶酚胺性心脏损害患者有33例,差异有统计学意义（P＜0.05）。嗜铬细胞瘤儿茶酚胺性心脏损害患者中,心律失常最为常见。结论：嗜铬细胞瘤儿茶酚胺性心脏损害患者心肌酶谱、动态心电图及冠状动脉CTA均可存在异常表现,但特异性、敏感性不高,三者同时综合分析可以提高临床诊断。     

Metacarpo-phalangeal and ring creases in twins

Metacarpo-phalangeal creases including the ring crease were studied on the middle finger of Japanese twins. The mean of differences and the correlation coefficient of the ring crease index as well as fine morphological features showed that the similarity between twins is greater in monozygotic twins than in dizygotic ones. The intrapair similarity in monozygotic twins is almost the same as that between right and left hands of an individual. For the diagnosis of zygosity this trait will be available.     

Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma

The pheochromocytomas are an important cause of secondary hypertension. Although pheochromocytoma susceptibility may be associated with germline mutations in the tumor-suppressor genes VHL and NF1 and in the proto-oncogene RET, the genetic basis for most cases of nonsyndromic familial pheochromocytoma is unknown. Recently, pheochromocytoma susceptibility has been associated with germline SDHD mutations. Germline SDHD mutations were originally described in hereditary paraganglioma, a dominantly inherited disorder characterized by vascular tumors in the head and the neck, most frequently at the carotid bifurcation. The gene products of two components of succinate dehydrogenase, SDHC and SDHD, anchor the gene products of two other components, SDHA and SDHB, which form the catalytic core, to the inner-mitochondrial membrane. Although mutations in SDHC and in SDHD may cause hereditary paraganglioma, germline SDHA mutations are associated with juvenile encephalopathy, and the phenotypic consequences of SDHB mutations have not been defined. To investigate the genetic causes of pheochromocytoma, we analyzed SDHB and SDHC, in familial and in sporadic cases. Inactivating SDHB mutations were detected in two of the five kindreds with familial pheochromocytoma, two of the three kindreds with pheochromocytoma and paraganglioma susceptibility, and 1 of the 24 cases of sporadic pheochromocytoma. These findings extend the link between mitochondrial dysfunction and tumorigenesis and suggest that germline SDHB mutations are an important cause of pheochromocytoma susceptibility.     

Cardiac Abnormalities Associated with Pheochromocytoma and other Adrenal Tumors

ObjectiveTo study the specific cardiac abnormalities associated with pheochromocytoma and to suggest a strategy for evaluating cardiac function in patients with pheochromocytoma.MethodsIn this case-control study, we reviewed pathology records of patients seen at Cedars-Sinai Medical Center between 1997 and 2007; patients with adrenal or extra-adrenal pheochromocytoma and those with nonfunctioning benign or malignant adrenal tumors were identified. Patients with functioning adrenal adenomas that secreted cortisol or aldosterone were excluded. Clinical history, imaging, pathology, biochemical test results, electrocardiographic findings, and echocardiographic findings were compared between patients with pheochromocytoma and patients with nonfunctioning adrenal tumors.ResultsThe charts of 22 patients with pheochromocytoma and 35 patients with nonfunctioning adrenal tumors were included. No perioperative mortality was observed. The average age of patients with pheochromocytoma was similar to that of control patients (51.9 ± 3.9 years vs 60.2 ± 2.5 years, respectively), as was the number of patients with known cardiovascular diseases (2 [9%] in the pheochromocytoma group vs 5 [14%] in the control group). Two patients with pheochromocytoma (9%) exhibited myocardial damage. Abnormal electrocardiographic findings were present in 16 patients with pheochromocytoma (73%) and in 17 control patients (49%) (P = .1). QTc was prolonged in patients with pheochromocytoma compared with control patients (448.3 ± 9.7 ms vs 424.7 ± 4.5 ms, respectively; P = .02) and was correlated with levels of norepinephrine and normetanephrine, but not with levels of epinephrine and metanephrine or tumor size. ST-T abnormalities were present in 11 patients with pheochromocytoma (50%) and in 8 control patients (23%) (P = .04). Echocardiographic findings were normal in most patients with pheochromocytoma; abnormal left ventricular wall motion was documented in 3 patients with long QTc.ConclusionsThe specific electrocardiographic findings in patients with pheochromocytoma are prolonged QTc and ST-T abnormalities. Performing an electrocardiogram in patients with pheochromocytoma would be prudent. Echocardiography would be useful to examine LV wall motion in patients with long QTc. Coronary artery disease should be excluded in patients with significant ST- T changes. (Endocr Pract. 2009;15:10-16)     

An IGF-I promoter polymorphism modifies the relationships between birth weight and risk factors for cardiovascular disease and diabetes at age 36

BACKGROUND: Biochemical testing for pheochromocytoma by measurement of fractionated plasma metanephrines is limited by false positive rates of up to 18% in people without known genetic predisposition to the disease. The plasma normetanephrine fraction is responsible for most false positives and plasma normetanephrine increases with age. The objective of this study was to determine if we could improve the specificity of fractionated plasma measurements, by statistically adjusting for age. METHODS: An age-adjusted metanephrine score was derived using logistic regression from 343 subjects (including 33 people with pheochromocytoma) who underwent fractionated plasma metanephrine measurements as part of investigations for suspected pheochromocytoma at Mayo Clinic Rochester (derivation set). The performance of the age-adjusted score was validated in a dataset of 158 subjects (including patients 23 with pheochromocytoma) that underwent measurements of fractionated plasma metanephrines at Mayo Clinic the following year (validation dataset). None of the participants in the validation dataset had known genetic predisposition to pheochromocytoma. RESULTS: The sensitivity of the age-adjusted metanephrine score was the same as that of traditional interpretation of fractionated plasma metanephrine measurements, yielding a sensitivity of 100% (23/23, 95% confidence interval [CI] 85.7%, 100%). However, the false positive rate with traditional interpretation of fractionated plasma metanephrine measurements was 16.3% (22/135, 95% CI, 11.0%, 23.4%) and that of the age-adjusted score was significantly lower at 3.0% (4/135, 95% CI, 1.2%, 7.4%) (p < 0.001 using McNemar's test). CONCLUSION: An adjustment for age in the interpretation of results of fractionated plasma metanephrines may significantly decrease false positives when using this test to exclude sporadic pheochromocytoma. Such improvements in false positive rate may result in savings of expenditures related to confirmatory imaging.