Pheochromocytomas and extra-adrenal paragangliomas detected by screening in patients with SDHD-associated head-and-neck paragangliomas

in Endocrine-Related Cancer
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  • 1 Department of Endocrinology and Metabolic Diseases, Center of Human and Clinical Genetics, Department of Otorhinolaryngology, Department of Surgery, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands

Patients with SDHD-associated head-and-neck paragangliomas (HNP) are at risk for developing pheochromocytomas for which screening has been advised. To assess clinical, biochemical, and radiological outcomes of screening in a large single-center cohort of SDHD-positive patients with HNP and to address the necessity for repetitive follow-up, we evaluated 93 patients with SDHD-associated HNP (p.Asp92Tyr, p.Leu139Pro). Screening consisted of measurement of 24 h urinary excretion of catecholamines and/or their metabolites in duplicate, which was repeated with intervals of 2 years if initial biochemical screening was negative. In patients, in whom urinary excretion was above the reference limit, imaging studies with 123I-MIBG (metaiodobenzylguanidine) scintigraphy and magnetic resonance imaging (MRI) and/or computed tomography (CT) were performed. Pheochromocytomas and extra-adrenal paragangliomas were treated surgically after appropriate blockade. Median follow-up was 4.5 years (range 0.5–19.5 years). Twenty-eight out of the 93 patients were included in our study and underwent additional imaging for pheochromocytomas/extra-adrenal paragangliomas. In 11 out of the 28 patients intra-adrenal pheochromocytomas were found. Extra-adrenal paragangliomas were discovered in eight patients. These tumors were detected during initial screening in 63% of cases, whereas 37% were detected after repeated biochemical screening. One patient was diagnosed with a biochemically silent pheochromocytoma. The high prevalence of pheochromocytomas/extra-adrenal paragangliomas in patients with SDHD-associated HNP warrants regular screening for tumors in these patients. Paragangliomas that do not secrete catecholamines might be more prevalent than previously reported. Future studies will have to establish whether routine imaging studies should be included in the screening of SDHD mutation carriers, irrespective of biochemical screening.

Abstract

Patients with SDHD-associated head-and-neck paragangliomas (HNP) are at risk for developing pheochromocytomas for which screening has been advised. To assess clinical, biochemical, and radiological outcomes of screening in a large single-center cohort of SDHD-positive patients with HNP and to address the necessity for repetitive follow-up, we evaluated 93 patients with SDHD-associated HNP (p.Asp92Tyr, p.Leu139Pro). Screening consisted of measurement of 24 h urinary excretion of catecholamines and/or their metabolites in duplicate, which was repeated with intervals of 2 years if initial biochemical screening was negative. In patients, in whom urinary excretion was above the reference limit, imaging studies with 123I-MIBG (metaiodobenzylguanidine) scintigraphy and magnetic resonance imaging (MRI) and/or computed tomography (CT) were performed. Pheochromocytomas and extra-adrenal paragangliomas were treated surgically after appropriate blockade. Median follow-up was 4.5 years (range 0.5–19.5 years). Twenty-eight out of the 93 patients were included in our study and underwent additional imaging for pheochromocytomas/extra-adrenal paragangliomas. In 11 out of the 28 patients intra-adrenal pheochromocytomas were found. Extra-adrenal paragangliomas were discovered in eight patients. These tumors were detected during initial screening in 63% of cases, whereas 37% were detected after repeated biochemical screening. One patient was diagnosed with a biochemically silent pheochromocytoma. The high prevalence of pheochromocytomas/extra-adrenal paragangliomas in patients with SDHD-associated HNP warrants regular screening for tumors in these patients. Paragangliomas that do not secrete catecholamines might be more prevalent than previously reported. Future studies will have to establish whether routine imaging studies should be included in the screening of SDHD mutation carriers, irrespective of biochemical screening.

Introduction

Paragangliomas are frequently multifocal tumors arising from the neural crest cells associated with the autonomic nervous system. Traditionally, they are divided into head-and-neck paragangliomas (HNP) and paragangliomas located in the thorax and abdomen. Some paragangliomas produce excessive amounts of catecholamines, especially if they are located in the adrenals (pheochromocytoma). Familial paraganglioma syndromes are associated with germ-line mutations in the genes encoding subunits of mitochondrial complex II succinate dehydrogenase (SDH): SDHD, SDHC, and SDHB (van der Mey et al. 1989, Baysal et al. 2000, Niemann & Muller 2000, Astuti et al. 2001, Koch et al. 2002, Benn & Robinson 2006). These SDH-genes can behave as tumor suppressor genes and distinct genotype–phenotype relations have been described (Baysal et al. 2000, Koch et al. 2002, Neumann et al. 2004, Benn et al. 2006, Timmers et al. 2007b). Among these three genes, mutations in SDHD are the most frequent cause of familial HNP in The Netherlands (Baysal et al. 2000, Taschner et al. 2001, Neumann et al. 2004, van Houtum et al. 2005). Although malignant disease is most frequently associated with SDHB mutations (Neumann et al. 2004, Timmers et al. 2007b), we recently described patients with malignant disease associated with the SDHD-c.274G>T (p.Asp92Tyr) mutation (Havekes et al. 2007). Several studies have investigated genotype–phenotype correlations in SDHD mutation carriers and were most often multi-center referral based patients with diverse underlying SDHD mutations (Neumann et al. 2004, Benn et al. 2006).

In 2005, we reported that the prevalence of catecholamine excess in our SDHD-linked HNP patients was much higher than previously appreciated (van Houtum et al. 2005). At the time of that study, 15 out of 40 consecutive patients (37.5%) had elevated urinary catecholamine excretion and a pheochromocytoma/paraganglioma was ultimately identified in 8 out of these 15 patients (20%). In patients with SDHD-linked HNP without elevated levels of catecholamines or their metabolites, we repeat biochemical testing at intervals of 2 years. In recent years, we have followed 93 consecutive HNP patients associated with a SDHD mutation (p.Asp92Tyr, p.Leu139Pro); including the updated data of the 40 patients who were previously reported in the paper by van Houtum et al. This is one of the largest, single-center cohorts with SDHD-linked HNP. The aim of this study was to report the clinical, biochemical, and radiological outcomes in SDHD-positive patients with HNP who were screened for elevated levels of catecholamines and their metabolites. Furthermore, we address the need for repetitive follow-up in these patients.

Patients and methods

We reviewed data of all consecutive HNP patients who visited the outpatient clinic at the Department of Endocrinology since 1988. The Leiden University Medical Center is a tertiary referral center for HNP. Systematic screening for SDHD mutations was performed in those HNP patients, who agreed upon genetic testing. HNP patients who had a SDHD mutation or who had a direct family member in whom a SDHD mutation was ascertained were eligible for inclusion. Urine was collected over 24 h in duplicate under strict dietary regulations and after changing antihypertensive medication to doxazosine or withdrawal of interfering medication for several weeks. If levels of catecholamines and/or their respective O-methylated metabolites were above the reference limits (i.e., any value above the upper reference limit), additional imaging studies using 123I-MIBG (metaiodobenzylguanidine), computed tomography (CT), and/or magnetic resonance imaging (MRI) were performed to identify the source of catecholamine overproduction. Since 2002, the initial diagnostic protocol was improved, by implementing a standard evaluation protocol with 2-year intervals.

In ninety-three out of 154 consecutive patients with HNP the SDHD mutations (p.Asp92Tyr, p.Leu139Pro) were ascertained or documented to be present in a direct family member. Thirty-three out of the 93 patients had increased excretion of urinary catecholamines and/or the O-methylated metabolites at some point during follow-up and underwent further diagnostic imaging. Although one patient revealed no elevated levels of catecholamine excretion, imaging studies were performed and a pheochromocytoma was subsequently diagnosed (patient 8). Therefore, this patient was included in our study, in total 34 patients. Four patients with increased catecholamine and/or catecholamine metabolite excretion were excluded, because increased levels were found to be caused by tricyclic antidepressants, β-blockers and/or cannabis prior to urine collection (with normalization after cessation of medication and/or drugs). Two other patients with increased excretion were excluded because the suspected small pheochromocytomas had not yet been histologically confirmed. The clinical presentations, the biochemical phenotypes, and outcome of diagnostic imaging of these 28 remaining SDHD (p.Asp92Tyr, p.Leu139Pro) patients are described in this report.

Laboratory tests

Epinephrine, norepinephrine, and dopamine excretion in 24 h urine collections were quantified by reversed HPLC by an electrochemical detector. Inter- and intra-assay coefficients of variations (CV) for epinephrine were 4.3–9.0% ranging from high to low levels. For norepinephrine these data are 2.7–3.6% and for dopamine 3.1–4.8%. Vanillylmandelic acid (VMA) in urine was measured using HPLC with fluorometric detection with inter- and intra-assay CV of 2.4–9.1%. Since 2005, samples have been tested for the O-methylated catecholamine metabolites (metanephrine, normetanephrine, and 3-methoxy-tyramine) at the University Medical Center Groningen as well (Wolthers et al. 1997). Reference ranges were: norepinephrine 0.06–0.47 μmol/24 h, epinephrine <0.16 μmol/24 h, dopamine 0.46–3.40 μmol/24 h, VMA<30 μmol/24 h, metanephrine 33–90 μmol per mol creatinine, normetanephrine 64–260 μmol per mol creatinine, and 3-methoxy-tyramine 45–197 μmol per mol creatinine. Prior to germ-line mutation testing informed consent was obtained from each patient. SDHD mutation analysis was performed by restriction digestion as described by Taschner et al. (2001).

Results

HNP were present in all patients, because the presence of HNP was an inclusion criterion. All patients, except four (patients 11, 18, 21, and 26), had a positive family history for HNP. The median duration of follow-up was 4.5 year (range 0.5–19.5 years). Mean age at presentation for first screening was 46.2±12.9 years. Imaging studies for pheochromocytomas and extra-adrenal paragangliomas were performed in 28 out of the 93 SDHD mutation carriers (Tables 1 and 2).

Table 1

Head-and-neck paraganglioma patients with SDHD (c.274G>T or c.416T>C) mutations and catecholamine and/or catecholamine metabolite excretion

No.Sex, age (years)aHypertensionStart screening (years)Diagnosis (years)bComorbidity
1M, 64+19972004Sleep apnea
2M, 3520012001
3F, 40+19982005
4M, 61+20062006Macro-prolactinoma, sleep apnea
5M, 60+20022006Gastric myoleioblastoma
6F, 62c+19882002
7M, 24+19881988
M, 3919881994d
8F, 48+19881988eType 2 diabetes mellitus
9M, 30+19901990
10M, 33+20042005Anxiety disorder
M, 3520042006d
11F, 4320022003
12M, 3220072007Anxiety disorder
13M, 34+20032004
14M, 4020072007
15M, 6120022004
16M, 64c+19982006
17F, 42c20052006Graves' disease
18M, 4320032006
19F, 67c+20052005Meningioma
20M, 40+2003
21M, 45+2004
22M, 25+1989
23F, 352002
24F, 492000
25F, 64+2003
26M, 342005
27M, 472005Graves' disease
28F, 52+2006

M, male; F, female.

Age at first diagnosis of increased catecholamine and/or metabolite excretion.

Year of pheochromocytoma or paraganglioma diagnosis.

Previously published by Havekes et al.

Second episode due to glomus tumor.

Imaging for pheochromocytoma performed without having increased catecholamine and/or metabolite excretion at that time.

Table 2

Cause of increased catecholamine and/or catecholamine metabolite excretion, imaging results and histopathology

No.ParagangliomaMRI abdomenCT-scan abdomenMIBG positiveOctreotide scanHistopathologyMetastasis
1AdrenalEnlarged adrenal LAdrenal LGlomusPheo L (1.8 cm)
2AdrenalEnlarged adrenal RAdrenal R, glomus RPheo R (2.5×3.0 cm)
3AdrenalEnlarged adrenal LPheo L (2.2 cm)
4AdrenalEnlarged adrenal RAdrenal RPheo R (1.3 cm)
5AdrenalEnlarged adrenal LAdrenal LPheo L (1.9 cm)
6AdrenalEnlarged adrenal LAdrenal LGlomus, cranially of bladderPheo L (2 cm)+a
7AdrenalEnlarged adrenal LEnlarged adrenal LAdrenal LPheo L (4.5×2.7 cm)
Glomusb
8AdrenalcEnlarged adrenal LcEnlarged adrenal LcAdrenal L, glomuscGlomuscPheo L (1.5 cm)
9AdrenalEnlarged adrenal RAdrenal RPheo R (4.5 cm)
10AdrenalEnlarged adrenal LAdrenal LPheo L (1.6 cm)
Glomusb,dGlomus
11AdrenalEnlarged adrenal L (irregularly enlarged)Adrenal R (minimal uptake)Pheo L (1 cm) and cortical adenoma (1.5 cm)
12Extra-adrenalMedially of adrenal RRegion of adrenal RPGL
13Extra-adrenalPancreas/adrenal L/aortaRegion of adrenal LPGL
14Extra-adrenalPars horizontale duodenumAbdominal centerPGL
15Extra-adrenalParaaortal LNo thoracic lesionsPara aortic LGlomusPGL
16Extra-adrenalInferior vena cava RRegion of adrenal R,PGL (3.3 cm)+a
17BladderTumor bladderGlomusPGL (8 cm)+a
18MediastinalMediastinumGlomusWatch-and-wait
19MediastinalPulmonary massGlomusOrbitameningiomaPGL (thymus+lymph nodes)+a
20GlomusGlomus
21Glomus
22GlomusGlomus
23GlomusGlomusGlomus
24GlomusGlomus and minor uptake adrenal R
25GlomusGlomus
26GlomusdAdrenal L, glomusPGL
27GlomusAdrenal L, glomusGlomus
28Glomus; no extra adrenalParavertebral mass aortic bifurcation, differential diagnosis extra adrenal paragangliomaGlomus, no uptake in abdomenGlomusSchwannoma (no PGL)

L, left; R, right; Pheo, pheochromocytoma; PGL, paraganglioma; −, negative.

Previously published by Havekes et al.

Second episode by glomus tumor.

Imaging performed although no increased excretion of catecholamines and/or metabolites present.

Normalized excretion after removal glomus tumor.

Genetics

Most patients in the Leiden cohort have the SDHD-c.274G>T (p.Asp92Tyr) mutation, both in the included group and those without elevated catecholamine levels that were excluded from this study. Twenty-five out of the 28 SDHD-positive patients included in this study had the SDHD-c.274G>T (p.Asp92Tyr) mutation. Patients 1, 5, and 12 had a SDHD-c.416T>C (p.Leu139Pro) mutation.

Cause of elevated levels of catecholamines and/or catecholamine metabolites

Details are shown in Table 2. In 27 out of the 28 included patients, there was increased excretion of urinary catecholamines and/or their respective metabolites. In one female patient (number 8) additional radiological studies were ordered by her attending physician, though she did not reveal any catecholamine excess at repeated testing. Nonetheless, MRI imaging resulted in the detection of (an unexpected) pheochromocytoma, which was confirmed by pathological examination after surgical removal. In total, intra-adrenal paragangliomas (pheochromocytomas) were identified and after appropriate α-(and β-) blockade surgically removed and histologically confirmed in 11 out of the 28 patients. In six patients with elevated catecholamine and/or catecholamine metabolite excretion, extra-adrenal paragangliomas in abdomen or pelvis were found and surgically treated after appropriate blockade. Two patients (patients 18 and 19) were diagnosed with mediastinal paragangliomas, in which patient 19 was operated. In patient 28, the resected extra-adrenal lesion suspect for paraganglioma was diagnosed as schwannoma after histological investigation.

Ultimately, 11 patients with HNP and increased catecholamine and/or catecholamine metabolite excretion, no pheochromocytoma or extra-adrenal paraganglioma could be identified. Per exclusionem their catecholamine levels were attributed to the presence of glomus tumors (patients 7, 10, 20, 21, 22, 23, 24, 25, 26, 27, and 28). Uptake of 123I-MIBG in the glomus tumor was found in seven out of these patients. Patients 10 and 26 were operated for these glomus tumors, which resulted in normalization of excretion. Patients 7 and 10 had been previously treated for a pheochromocytoma and were later suspected of having elevated catecholamine and/or catecholamine metabolite levels caused by the glomus tumor as well.

Signs and symptoms

Palpitations were mentioned in 10 out of the 28 patients. Seven of these patients were later diagnosed with either a pheochromocytoma or an extra-adrenal paraganglioma. Hypertension was found in 17 out of the 28 patients included in this study (61%). Eight patients reported diaphoresis of which five had a pheochromocytoma or extra-adrenal paraganglioma. Headaches were only mentioned by two patients, both with a pheochromocytoma. Furthermore, HNP patients frequently reported hearing loss (34%), tinnitus (28%), and dysphonia (13%). Anxiety disorders were reported in four patients, obstructive sleep apnea in two patients, Graves' disease in two patients, and one patient (number 4) was treated for a macro-prolactinoma.

Biochemical profile of urinary catecholamines and/or catecholamine metabolites

The predominant biochemical phenotype of urinary catecholamines and their metabolites in our patients is shown in Table 3. Norepinephrine, VMA and, if tested, normetanephrine were most frequently elevated, whereas elevation of epinephrine was only detected in two patients, one of whom had a malignant bladder paraganglioma (number 17). However, metanephrines were negative in these two patients, indicating epinephrine could have been falsely elevated. As expected, the O-methylated metabolite normetanephrine was elevated in most patients with elevated norepinephrine. One patient (patient 24) had elevated excretion of normetanephrine, whereas the excretion of norepinephrine was normal. Patient 28 had elevated excretion of metanephrine with normal values for epinephrine. Excretion of 3-methoxy-tyramine was increased in 10 out of the 28 patients and was found in patients with pheochromocytomas, extra-adrenal paragangliomas, malignant disease or producing glomus tumors.

Table 3

Biochemical phenotype

Cause
PatientNEEDAVMANMNMN3MTPheoExtra-adrenal/Thor. PGLGlomus
1+++ooo+
2++ooo+
3++ooo+
4++
5+++
6+++aa+a+
7++ooo++b
8cooo+
9+++ooo+
10++ooo++b,d
11++ooo+
12++++
13++ooo+
14++++++
15++ooo+
16++ooo+
17+++++++
18++
19++++
20+ooo+
21++
22+++
23++++++
24++++
25+ooo+
26++ooo+d
27++++++
28+++++++

NE, norepinephrine; E, epinephrine; DA, dopamine; VMA, vanillyl mandelic acid; NMN, normetanephrine; MN, metanephrine; 3-MT, 3-methoxytyramine; PGL, paraganglioma; o, not performed.

Representing persistent malignant disease after 2005, previously described by Havekes et al.

Patients 8 and 11 were later diagnosed with catecholamine or catecholamine metabolite producing glomus as well.

Imaging performed without the presence of increased catecholamine or catecholamine metabolite excretion.

Normalized excretion of catecholamines and/or catecholamine metabolites after removal glomus tumor.

Imaging

No patients with negative imaging on whole-body MRI and/or CT have been diagnosed with a pheochromocytoma or an extra-adrenal paraganglioma during prolonged follow-up. MRI revealed one false-positive result in our series (patient 28), in whom the extra-adrenal lesion proved to be a schwannoma instead of a paraganglioma. In patients with pheochromocytomas and extra-adrenal paragangliomas combined, sensitivity and specificity of 123I-MIBG was 74 and 78% respectively. Positive and negative predictive values for pheochromocytoma and extra-adrenal lesions combined were 88 and 58% respectively. MIBG revealed false-negative results in five patients, three of whom had malignant and/or mediastinal disease. Furthermore, subtle or more intense MIBG uptake in HNP was frequently found (11 patients), either with or without abdominal uptake. Increased uptake was shown in 11 out of 12 patients on whom octreotide scintigraphy was performed.

Discussion

This large, single-center study evaluated screening for pheochromocytomas and extra-adrenal paragangliomas in 93 SDHD-associated (p.Asp92Tyr, p.Leu139Pro) HNP patients. This study confirms the high prevalence of both pheochromocytomas and extra-adrenal paragangliomas in SDHD (p.Asp92Tyr, p.Leu139Pro) mutation carriers (van Houtum et al. 2005). Excretion of urinary catecholamines and/or their O-methylated compounds above the upper reference limit was documented in 29% of the patients. Ultimately, pheochromocytomas or extra-adrenal paragangliomas were identified in 20% of all patients in addition to the HNP. Approximately, one-third of these pheochromocytomas or extra-adrenal paragangliomas were found only by repeated screening after a normal initial outcome. Our results not only document the clinical relevance of repetitive screening in SDHD mutation carriers but also suggest that there might be a larger role for imaging as a first-line investigation.

SDHD mutation carriers are at risk for developing pheochromocytomas and/or extra-adrenal paragangliomas. Van Houtum et al. (2005) have previously reported an increased prevalence of pheochromocytoma in a smaller subset of HNP patients in our center. In accordance with this previous publication, we found an increased prevalence of both pheochromocytomas and extra-adrenal paragangliomas. In addition, we were not able to find a clear correlation between clinical symptoms and the presence of pheochromocytoma or extra-adrenal paraganglioma. This lack of correlation with symptoms stresses the need for patients to undergo repeated screening. We included all SDHD-associated HNP patients with increased urinary excretion of catecholamines and/or their O-methylated metabolites (i.e., any value above the upper reference limit). Although the degree of elevation in catecholamine and/or catecholamine metabolite levels should be taken into account in the diagnostic algorithm for pheochromocytoma before initializing localization studies; less compelling biochemical evidence may justify imaging studies in those patients with a strong hereditary predisposition (Pacak et al. 2007). Elevations of norepinephrine, normetanephrine, and VMA excretion were most frequently found. Recently, evaluation of the biochemical phenotype of SDHB-associated malignant paragangliomas revealed hypersecretion of norepinephrine, normetanephrine, and dopamine (Timmers et al. 2007b). The reason for a different prevalence of dopamine excess in our study concerning SDHD-associated patients might not only be related to fewer cases of malignant disease, but also to the insensitive and non-specific nature of measuring urinary dopamine levels (Eisenhofer et al. 2005). The urinary excretion of the O-methylated metabolite of dopamine, 3-methoxytyramine, was increased in 10 out of the 28 patients, but could be present in a variety of patients with or without pheochromocytomas, extra-adrenal paragangliomas, malignant disease, and producing glomus tumors. Interestingly, the elevated levels of 3-methoxytyramine in our study could be a reflection of the fact that we used the presence of HNP as an inclusion criterion, because carotid bodies are known to use dopamine as a neurotransmitter (Koch et al. 2003, Jeffery et al. 2006, Minguez-Castellanos et al. 2007). We suspect HNP might continuously O-methylate dopamine and subsequently release methoxytyramine into the circulation, even in the absence of overt dopamine secretion. The clinical relevance of the measurement of 3-methoxy-tyramine remains to be further evaluated (Eisenhofer et al. 2005).

In contrast to adrenal and extra-adrenal sympathetic paragangliomas, paragangliomas arising from parasympathetic tissue (mainly in the head-and-neck) rarely produce significant amounts of catecholamines (Erickson et al. 2001, Koch et al. 2003, Pacak et al. 2007). Remarkably, in 11 cases (12% of all subjects) the glomus tumor itself was identified as the presumptive cause of catecholamine and/or catecholamine metabolite excretion after extensive investigations to exclude other paraganglioma locations. Unfortunately, false-positive results cannot be excluded with certainty because not all patients who were suspected to have catecholamine and/or catecholamine metabolite producing HNP were accessible for surgical removal. In addition, we suspect the false-positive results to be clustered in this group of HNP patients, since we have used the upper reference limit as a cut-off value to perform additional whole-body imaging and, therefore, the presence of other paragangliomas was virtually excluded by extensive imaging studies. However, in the two patients with suspected catecholamine and/or catecholamine metabolite excreting HNP, who were operated, the increased excretion rates returned to normal after surgery. In addition, in 7 of these 11 cases MIBG uptake was present in the HNP. Our results suggest that catecholamine and/or catecholamine metabolite excretion in SDHD mutation carriers might result from HNP more frequently than expected in HNP patients in general.

Furthermore, all our cases have the p.Asp92Tyr or p.Leu139Pro mutations. These are frequently occurring founder mutations in The Netherlands, whereas other reports described patients with different mutations in the SDHD gene. So far, it has not been reported that there are different clinical phenotypes associated with the different mutations within the SDHD gene. Importantly, since all SDHD gene mutation carriers could theoretically develop pheochromocytoma or paraganglioma irrespective of the presence of HNP, we advise the inclusion of all patients carrying these mutations in screening programs for both HNP and pheochromocytomas, even though at present it is unclear to which extent these patients will develop catecholamine excess in the absence of HNP. However, although unlikely, we cannot exclude the possibility that the reported phenotype may be related to these specific Dutch founder mutations and/or to unknown gene–environment interactions in The Netherlands.

Although MIBG scanning is reported to have a sensitivity of 83–100% in the detection of benign pheochromocytomas in case finding studies, this sensitivity is considerably reduced in familial, extra-adrenal or malignant paragangliomas (Nielsen et al. 1996, van der Harst et al. 2001, Ilias et al. 2003, Lumachi et al. 2006). In our study, use of 123I-MIBG for detection of intra- and extra-adrenal paragangliomas combined revealed a sensitivity of only 74% in our cohort with mostly familial paragangliomas. However, as expected, the sensitivity rose to 83% when we investigated (intra-adrenal) pheochromocytomas separately. Furthermore, because our patients were detected using a routine screening protocol with the upper reference limit as a cut-off value, earlier detection of increased catecholamine or catecholamine metabolite excretion may have influenced sensitivity. Nonetheless, we found the combination of MRI and 123I-MIBG to be sufficient in most cases. Although Timmers et al. (2007a) recently reported the superiority of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) in the evaluation of metastatic paraganglioma, one might argue that in our cohort, because most of the paragangliomas were benign, the use of 18F-fluorodopamine or 18F-fluoro-dihydroxyphenylalanine (18F-FDOPA) PET would be more appropriate after negative MIBG imaging (Pacak et al. 2001, Hoegerle et al. 2002, Hoegerle et al. 2003, Mackenzie et al. 2007).

In our study, the sensitive and specific assays for O-methylated catecholamine metabolites (metanephrine and normetanephrine) were introduced for screening only in the last few years. Measurement of these metabolites in both plasma and urine is more sensitive for the diagnosis of pheochromocytoma than measurements of their parent catecholamines (Eisenhofer et al. 1998, Lenders et al. 2002, Sawka et al. 2003, Pacak et al. 2007). Although in our study, most patients had concordant results between the excretion of catecholamines, VMA, and their O-methylated metabolites, the relatively small number of (nor) metanephrine assays performed in our study limits the reliability of a comparison between those measurements. Although patients 24 and 28 had elevated levels of the O-methylated compounds (in patient 24 normetanephrine and in patient 28 metanephrine), their respective parent catecholamines were still within reference ranges, thus exemplifying their superior sensitivity. Although the later introduction of (nor-) metanephrine analyses in our study may have theoretically resulted in an underestimation of the prevalence of elevated levels catecholamines and their metabolites, and thus of the presence of paragangliomas/pheochromocytomas in the first period of the present study, this does not invalidate our conclusions with respect to the relevance of repetitive testing for catecholamines in these patients.

More challenging is the concept of the so-called ‘non-secreting’ or ‘biochemically silent’ paragangliomas (i.e., paragangliomas that do not secrete catecholamines and/or their metabolites). These tumors might not always be detected using our present standard approach starting with urine analysis. Inadvertently, patient 8 provided the proof for this hypothesis, by the finding of a pheochromocytoma, even though no increased urinary excretion of catecholamines or their metabolites had been found. We are not able to exclude the presence of paragangliomas outside the neck region in those patients with SDHD mutations who had levels of catecholamines and catecholamine metabolites within reference limits, because no imaging studies were performed in these patients. The possibility of non-secreting or mediastinal paragangliomas and the presently unclear consequences of missing one of these tumors in our SDHD-associated population (with low estimated malignancy rates of ∼2.5%; Havekes et al. 2007) will have to be taken into consideration. By contrast, because of high malignant potential, patients with an SDHB mutation are already subjected to repetitive anatomical imaging irrespective of catecholamine or catecholamine metabolite levels (Timmers et al. 2007b). Because we suspect undetected ‘non-secreting’ paragangliomas to be more frequent in SDHD carriers than hitherto reported, additional studies will have to establish the value of additional routine imaging studies in screening protocols of carriers of SDHD mutations, irrespective of concurrent catecholamines or their metabolites.

The results of the present study emphasize the need to screen all SDHD mutation carriers for increased catecholamine and catecholamine metabolite excretion on a regular basis. If this approach would not have been instituted, 7 out of the 19 patients, who were diagnosed with pheochromocytomas or extra-adrenal paragangliomas in our report would have been discharged from follow-up, or not have been subjected to screening at all. Because we suspect undetected ‘non-secreting’ paragangliomas to be more frequent in SDHD mutation carriers than previously reported, we advocate future studies to include MRI imaging of thorax, abdomen, and pelvis as primary or routine investigations, irrespective of biochemical results, in order to establish whether routine imaging procedures should be included in future guidelines.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

Acknowledgements

We would like to thank Edwin W Lai for his help in preparing this manuscript.

References

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  • Benn DE, Gimenez-Roqueplo AP, Reilly JR, Bertherat J, Burgess J, Byth K, Croxson M, Dahia PL, Elston M & Gimm O et al. 2006 Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes. Journal of Clinical Endocrinology and Metabolism 91 827836.

    • Search Google Scholar
    • Export Citation
  • Eisenhofer G, Keiser H, Friberg P, Mezey E, Huynh TT, Hiremagalur B, Ellingson T, Duddempudi S, Eijsbouts A & Lenders JW 1998 Plasma metanephrines are markers of pheochromocytoma produced by catechol-O-methyltransferase within tumors. Journal of Clinical Endocrinology and Metabolism 83 21752185.

    • Search Google Scholar
    • Export Citation
  • Eisenhofer G, Goldstein DS, Sullivan P, Csako G, Brouwers FM, Lai EW, Adams KT & Pacak K 2005 Biochemical and clinical manifestations of dopamine-producing paragangliomas: utility of plasma methoxytyramine. Journal of Clinical Endocrinology and Metabolism 90 20682075.

    • Search Google Scholar
    • Export Citation
  • Erickson D, Kudva YC, Ebersold MJ, Thompson GB, Grant CS, van Heerden JA & Young WF Jr 2001 Benign paragangliomas: clinical presentation and treatment outcomes in 236 patients. Journal of Clinical Endocrinology and Metabolism 86 52105216.

    • Search Google Scholar
    • Export Citation
  • van der Harst E, de Herder WW, Bruining HA, Bonjer HJ, de Krijger RR, Lamberts SW, van de Meiracker AH, Boomsma F, Stijnen T & Krenning EP et al. 2001 [(123)I]metaiodobenzylguanidine and [(111)In]octreotide uptake in benign and malignant pheochromocytomas. Journal of Clinical Endocrinology and Metabolism 86 685693.

    • Search Google Scholar
    • Export Citation
  • Havekes B, Corssmit EP, Jansen JC, van der Mey AG, Vriends AH & Romijn JA 2007 Malignant paragangliomas associated with mutations in the succinate dehydrogenase D gene. Journal of Clinical Endocrinology and Metabolism 92 12451248.

    • Search Google Scholar
    • Export Citation
  • Hoegerle S, Nitzsche E, Altehoefer C, Ghanem N, Manz T, Brink I, Reincke M, Moser E & Neumann HP 2002 Pheochromocytomas: detection with 18F DOPA whole body PET – initial results. Radiology 222 507512.

    • Search Google Scholar
    • Export Citation
  • Hoegerle S, Ghanem N, Altehoefer C, Schipper J, Brink I, Moser E & Neumann HP 2003 18F-DOPA positron emission tomography for the detection of glomus tumours. European Journal of Nuclear Medicine and Molecular Imaging 30 689694.

    • Search Google Scholar
    • Export Citation
  • van Houtum WH, Corssmit EP, Douwes Dekker PB, Jansen JC, van der Mey AG, Brocker-Vriends AH, Taschner PE, Losekoot M, Frolich M & Stokkel MP et al. 2005 Increased prevalence of catecholamine excess and phaeochromocytomas in a well-defined Dutch population with SDHD-linked head and neck paragangliomas. European Journal of Endocrinology 152 8794.

    • Search Google Scholar
    • Export Citation
  • Ilias I, Yu J, Carrasquillo JA, Chen CC, Eisenhofer G, Whatley M, McElroy B & Pacak K 2003 Superiority of 6-[18F]-fluorodopamine positron emission tomography versus [131I]-metaiodobenzylguanidine scintigraphy in the localization of metastatic pheochromocytoma. Journal of Clinical Endocrinology and Metabolism 88 40834087.

    • Search Google Scholar
    • Export Citation
  • Jeffery J, Devendra D, Farrugia J, Gardner D, Murphy MJ, Williams R, Ayling RM & Wilkin TJ 2006 Increased urinary dopamine excretion in association with bilateral carotid body tumours – clinical, biochemical and genetic findings. Annals of Clinical Biochemistry 43 156160.

    • Search Google Scholar
    • Export Citation
  • Koch CA, Vortmeyer AO, Zhuang Z, Brouwers FM & Pacak K 2002 New insights into the genetics of familial chromaffin cell tumors. Annals of the New York Academy of Sciences 970 1128.

    • Search Google Scholar
    • Export Citation
  • Koch CA, Rodbard JS, Brouwers FM, Eisenhofer G & Pacak K 2003 Hypotension in a woman with a metastatic dopamine-secreting carotid body tumor. Endocrine Practice 9 310314.

    • Search Google Scholar
    • Export Citation
  • Lenders JW, Pacak K, Walther MM, Linehan WM, Mannelli M, Friberg P, Keiser HR, Goldstein DS & Eisenhofer G 2002 Biochemical diagnosis of pheochromocytoma: which test is best? Journal of the American Medical Association 287 14271434.

    • Search Google Scholar
    • Export Citation
  • Lumachi F, Tregnaghi A, Zucchetta P, Cristina MM, Cecchin D, Grassetto G & Bui F 2006 Sensitivity and positive predictive value of CT, MRI and 123I-MIBG scintigraphy in localizing pheochromocytomas: a prospective study. Nuclear Medicine Communications 27 583587.

    • Search Google Scholar
    • Export Citation
  • Mackenzie IS, Gurnell M, Balan KK, Simpson H, Chatterjee K & Brown MJ 2007 The use of 18-fluoro-dihydroxyphenylalanine and 18-fluorodeoxyglucose positron emission tomography scanning in the assessment of metaiodobenzylguanidine-negative phaeochromocytoma. European Journal of Endocrinology 157 533537.

    • Search Google Scholar
    • Export Citation
  • van der Mey AG, Maaswinkel-Mooy PD, Cornelisse CJ, Schmidt PH & van de Kamp JJ 1989 Genomic imprinting in hereditary glomus tumours: evidence for new genetic theory. Lancet 2 12911294.

    • Search Google Scholar
    • Export Citation
  • Minguez-Castellanos A, Escamilla-Sevilla F, Hotton GR, Toledo-Aral JJ, Ortega-Moreno A, Mendez-Ferrer S, Martin-Linares JM, Katati MJ, Mir P & Villadiego J et al. 2007 Carotid body autotransplantation in Parkinson disease: a clinical and positron emission tomography study. Journal of Neurology, Neurosurgery, and Psychiatry 78 825831.

    • Search Google Scholar
    • Export Citation
  • Neumann HP, Pawlu C, Peczkowska M, Bausch B, McWhinney SR, Muresan M, Buchta M, Franke G, Klisch J & Bley TA et al. 2004 Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. Journal of the American Medical Association 292 943951.

    • Search Google Scholar
    • Export Citation
  • Nielsen JT, Nielsen BV & Rehling M 1996 Location of adrenal medullary pheochromocytoma by I-123 metaiodobenzylguanidine SPECT. Clinical Nuclear Medicine 21 695699.

    • Search Google Scholar
    • Export Citation
  • Niemann S & Muller U 2000 Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nature Genetics 26 268270.

  • Pacak K, Eisenhofer G, Carrasquillo JA, Chen CC, Li ST & Goldstein DS 2001 6-[18F]fluorodopamine positron emission tomographic (PET) scanning for diagnostic localization of pheochromocytoma. Hypertension 38 68.

    • Search Google Scholar
    • Export Citation
  • Pacak K, Eisenhofer G, Ahlman H, Bornstein SR, Gimenez-Roqueplo AP, Grossman AB, Kimura N, Mannelli M, McNicol AM & Tischler AS 2007 Pheochromocytoma: recommendations for clinical practice from the First International Symposium. October 2005. Nature Clinical Practice. Endocrinology & Metabolism 3 92102.

    • Search Google Scholar
    • Export Citation
  • Sawka AM, Jaeschke R, Singh RJ & Young WF Jr 2003 A comparison of biochemical tests for pheochromocytoma: measurement of fractionated plasma metanephrines compared with the combination of 24-hour urinary metanephrines and catecholamines. Journal of Clinical Endocrinology and Metabolism 88 553558.

    • Search Google Scholar
    • Export Citation
  • Taschner PE, Jansen JC, Baysal BE, Bosch A, Rosenberg EH, Brocker-Vriends AH, Der Mey AG, van Ommen GJ, Cornelisse CJ & Devilee P 2001 Nearly all hereditary paragangliomas in The Netherlands are caused by two founder mutations in the SDHD gene. Genes, Chromosomes and Cancer 31 274281.

    • Search Google Scholar
    • Export Citation
  • Timmers HJ, Kozupa A, Chen CC, Carrasquillo JA, Ling A, Eisenhofer G, Adams KT, Solis D, Lenders JW & Pacak K 2007a Superiority of fluorodeoxyglucose positron emission tomography to other functional imaging techniques in the evaluation of metastatic SDHB-associated pheochromocytoma and paraganglioma. Journal of Clinical Oncology 25 22622269.

    • Search Google Scholar
    • Export Citation
  • Timmers HJ, Kozupa A, Eisenhofer G, Raygada M, Adams KT, Solis D, Lenders JW & Pacak K 2007b Clinical presentations, biochemical phenotypes, and genotype–phenotype correlations in patients with succinate dehydrogenase subunit B-associated pheochromocytomas and paragangliomas. Journal of Clinical Endocrinology and Metabolism 92 779786.

    • Search Google Scholar
    • Export Citation
  • Wolthers BG, Kema IP, Volmer M, Wesemann R, Westermann J & Manz B 1997 Evaluation of urinary metanephrine and normetanephrine enzyme immunoassay (ELISA) kits by comparison with isotope dilution mass spectrometry. Clinical Chemistry 43 114120.

    • Search Google Scholar
    • Export Citation

 

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  • Astuti D, Latif F, Dallol A, Dahia PL, Douglas F, George E, Skoldberg F, Husebye ES, Eng C & Maher ER 2001 Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. American Journal of Human Genetics 69 4954.

    • Search Google Scholar
    • Export Citation
  • Baysal BE, Ferrell RE, Willett-Brozick JE, Lawrence EC, Myssiorek D, Bosch A, van der MA, Taschner PE, Rubinstein WS & Myers EN et al. 2000 Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 287 848851.

    • Search Google Scholar
    • Export Citation
  • Benn DE & Robinson BG 2006 Genetic basis of phaeochromocytoma and paraganglioma. Best Practice and Research. Clinical Endocrinology and Metabolism 20 435450.

    • Search Google Scholar
    • Export Citation
  • Benn DE, Gimenez-Roqueplo AP, Reilly JR, Bertherat J, Burgess J, Byth K, Croxson M, Dahia PL, Elston M & Gimm O et al. 2006 Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes. Journal of Clinical Endocrinology and Metabolism 91 827836.

    • Search Google Scholar
    • Export Citation
  • Eisenhofer G, Keiser H, Friberg P, Mezey E, Huynh TT, Hiremagalur B, Ellingson T, Duddempudi S, Eijsbouts A & Lenders JW 1998 Plasma metanephrines are markers of pheochromocytoma produced by catechol-O-methyltransferase within tumors. Journal of Clinical Endocrinology and Metabolism 83 21752185.

    • Search Google Scholar
    • Export Citation
  • Eisenhofer G, Goldstein DS, Sullivan P, Csako G, Brouwers FM, Lai EW, Adams KT & Pacak K 2005 Biochemical and clinical manifestations of dopamine-producing paragangliomas: utility of plasma methoxytyramine. Journal of Clinical Endocrinology and Metabolism 90 20682075.

    • Search Google Scholar
    • Export Citation
  • Erickson D, Kudva YC, Ebersold MJ, Thompson GB, Grant CS, van Heerden JA & Young WF Jr 2001 Benign paragangliomas: clinical presentation and treatment outcomes in 236 patients. Journal of Clinical Endocrinology and Metabolism 86 52105216.

    • Search Google Scholar
    • Export Citation
  • van der Harst E, de Herder WW, Bruining HA, Bonjer HJ, de Krijger RR, Lamberts SW, van de Meiracker AH, Boomsma F, Stijnen T & Krenning EP et al. 2001 [(123)I]metaiodobenzylguanidine and [(111)In]octreotide uptake in benign and malignant pheochromocytomas. Journal of Clinical Endocrinology and Metabolism 86 685693.

    • Search Google Scholar
    • Export Citation
  • Havekes B, Corssmit EP, Jansen JC, van der Mey AG, Vriends AH & Romijn JA 2007 Malignant paragangliomas associated with mutations in the succinate dehydrogenase D gene. Journal of Clinical Endocrinology and Metabolism 92 12451248.

    • Search Google Scholar
    • Export Citation
  • Hoegerle S, Nitzsche E, Altehoefer C, Ghanem N, Manz T, Brink I, Reincke M, Moser E & Neumann HP 2002 Pheochromocytomas: detection with 18F DOPA whole body PET – initial results. Radiology 222 507512.

    • Search Google Scholar
    • Export Citation
  • Hoegerle S, Ghanem N, Altehoefer C, Schipper J, Brink I, Moser E & Neumann HP 2003 18F-DOPA positron emission tomography for the detection of glomus tumours. European Journal of Nuclear Medicine and Molecular Imaging 30 689694.

    • Search Google Scholar
    • Export Citation
  • van Houtum WH, Corssmit EP, Douwes Dekker PB, Jansen JC, van der Mey AG, Brocker-Vriends AH, Taschner PE, Losekoot M, Frolich M & Stokkel MP et al. 2005 Increased prevalence of catecholamine excess and phaeochromocytomas in a well-defined Dutch population with SDHD-linked head and neck paragangliomas. European Journal of Endocrinology 152 8794.

    • Search Google Scholar
    • Export Citation
  • Ilias I, Yu J, Carrasquillo JA, Chen CC, Eisenhofer G, Whatley M, McElroy B & Pacak K 2003 Superiority of 6-[18F]-fluorodopamine positron emission tomography versus [131I]-metaiodobenzylguanidine scintigraphy in the localization of metastatic pheochromocytoma. Journal of Clinical Endocrinology and Metabolism 88 40834087.

    • Search Google Scholar
    • Export Citation
  • Jeffery J, Devendra D, Farrugia J, Gardner D, Murphy MJ, Williams R, Ayling RM & Wilkin TJ 2006 Increased urinary dopamine excretion in association with bilateral carotid body tumours – clinical, biochemical and genetic findings. Annals of Clinical Biochemistry 43 156160.

    • Search Google Scholar
    • Export Citation
  • Koch CA, Vortmeyer AO, Zhuang Z, Brouwers FM & Pacak K 2002 New insights into the genetics of familial chromaffin cell tumors. Annals of the New York Academy of Sciences 970 1128.

    • Search Google Scholar
    • Export Citation
  • Koch CA, Rodbard JS, Brouwers FM, Eisenhofer G & Pacak K 2003 Hypotension in a woman with a metastatic dopamine-secreting carotid body tumor. Endocrine Practice 9 310314.

    • Search Google Scholar
    • Export Citation
  • Lenders JW, Pacak K, Walther MM, Linehan WM, Mannelli M, Friberg P, Keiser HR, Goldstein DS & Eisenhofer G 2002 Biochemical diagnosis of pheochromocytoma: which test is best? Journal of the American Medical Association 287 14271434.

    • Search Google Scholar
    • Export Citation
  • Lumachi F, Tregnaghi A, Zucchetta P, Cristina MM, Cecchin D, Grassetto G & Bui F 2006 Sensitivity and positive predictive value of CT, MRI and 123I-MIBG scintigraphy in localizing pheochromocytomas: a prospective study. Nuclear Medicine Communications 27 583587.

    • Search Google Scholar
    • Export Citation
  • Mackenzie IS, Gurnell M, Balan KK, Simpson H, Chatterjee K & Brown MJ 2007 The use of 18-fluoro-dihydroxyphenylalanine and 18-fluorodeoxyglucose positron emission tomography scanning in the assessment of metaiodobenzylguanidine-negative phaeochromocytoma. European Journal of Endocrinology 157 533537.

    • Search Google Scholar
    • Export Citation
  • van der Mey AG, Maaswinkel-Mooy PD, Cornelisse CJ, Schmidt PH & van de Kamp JJ 1989 Genomic imprinting in hereditary glomus tumours: evidence for new genetic theory. Lancet 2 12911294.

    • Search Google Scholar
    • Export Citation
  • Minguez-Castellanos A, Escamilla-Sevilla F, Hotton GR, Toledo-Aral JJ, Ortega-Moreno A, Mendez-Ferrer S, Martin-Linares JM, Katati MJ, Mir P & Villadiego J et al. 2007 Carotid body autotransplantation in Parkinson disease: a clinical and positron emission tomography study. Journal of Neurology, Neurosurgery, and Psychiatry 78 825831.

    • Search Google Scholar
    • Export Citation
  • Neumann HP, Pawlu C, Peczkowska M, Bausch B, McWhinney SR, Muresan M, Buchta M, Franke G, Klisch J & Bley TA et al. 2004 Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. Journal of the American Medical Association 292 943951.

    • Search Google Scholar
    • Export Citation
  • Nielsen JT, Nielsen BV & Rehling M 1996 Location of adrenal medullary pheochromocytoma by I-123 metaiodobenzylguanidine SPECT. Clinical Nuclear Medicine 21 695699.

    • Search Google Scholar
    • Export Citation
  • Niemann S & Muller U 2000 Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nature Genetics 26 268270.

  • Pacak K, Eisenhofer G, Carrasquillo JA, Chen CC, Li ST & Goldstein DS 2001 6-[18F]fluorodopamine positron emission tomographic (PET) scanning for diagnostic localization of pheochromocytoma. Hypertension 38 68.

    • Search Google Scholar
    • Export Citation
  • Pacak K, Eisenhofer G, Ahlman H, Bornstein SR, Gimenez-Roqueplo AP, Grossman AB, Kimura N, Mannelli M, McNicol AM & Tischler AS 2007 Pheochromocytoma: recommendations for clinical practice from the First International Symposium. October 2005. Nature Clinical Practice. Endocrinology & Metabolism 3 92102.

    • Search Google Scholar
    • Export Citation
  • Sawka AM, Jaeschke R, Singh RJ & Young WF Jr 2003 A comparison of biochemical tests for pheochromocytoma: measurement of fractionated plasma metanephrines compared with the combination of 24-hour urinary metanephrines and catecholamines. Journal of Clinical Endocrinology and Metabolism 88 553558.

    • Search Google Scholar
    • Export Citation
  • Taschner PE, Jansen JC, Baysal BE, Bosch A, Rosenberg EH, Brocker-Vriends AH, Der Mey AG, van Ommen GJ, Cornelisse CJ & Devilee P 2001 Nearly all hereditary paragangliomas in The Netherlands are caused by two founder mutations in the SDHD gene. Genes, Chromosomes and Cancer 31 274281.

    • Search Google Scholar
    • Export Citation
  • Timmers HJ, Kozupa A, Chen CC, Carrasquillo JA, Ling A, Eisenhofer G, Adams KT, Solis D, Lenders JW & Pacak K 2007a Superiority of fluorodeoxyglucose positron emission tomography to other functional imaging techniques in the evaluation of metastatic SDHB-associated pheochromocytoma and paraganglioma. Journal of Clinical Oncology 25 22622269.

    • Search Google Scholar
    • Export Citation
  • Timmers HJ, Kozupa A, Eisenhofer G, Raygada M, Adams KT, Solis D, Lenders JW & Pacak K 2007b Clinical presentations, biochemical phenotypes, and genotype–phenotype correlations in patients with succinate dehydrogenase subunit B-associated pheochromocytomas and paragangliomas. Journal of Clinical Endocrinology and Metabolism 92 779786.

    • Search Google Scholar
    • Export Citation
  • Wolthers BG, Kema IP, Volmer M, Wesemann R, Westermann J & Manz B 1997 Evaluation of urinary metanephrine and normetanephrine enzyme immunoassay (ELISA) kits by comparison with isotope dilution mass spectrometry. Clinical Chemistry 43 114120.

    • Search Google Scholar
    • Export Citation