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Endocrinology |
AP/HP, Hôpital Européen Georges Pompidou, Département de Génétique Moléculaire [A-P. G-R., C. R., M. C., V. N., P. K. V. K., X. J.]; INSERM U36, Collège de France [A-P. G-R., J. F., P. C., P-F. P., X. J.]; INSERM U393, Hôpital des Enfants Malades [P. R.]; and AP/HP, Hôpital Européen Georges Pompidou, Service d’Hypertension Artérielle [P. C., P-F. P.], Paris
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Several familial diseases, such as VHL4 disease, multiple endocrine neoplasia type 2, and NF1, predispose individuals to phaeochromocytoma (4 , 5) . However, the genes responsible for these three diseases account for only a small proportion of the genetic predisposition to isolated ASP (6) .
Two new susceptibility genes were recently identified, SDHD and SDHB, encoding subunits D and B of the mitochondrial SDH, respectively (7 , 8) . The mitochondrial SDH complex catalyzes the oxidation of succinate to fumarate in the Krebs’ cycle and feeds electrons to the respiratory chain ubiquinone pool. Mutations in these two genes have been reported in families with hereditary paraganglioma. SDHD mutations are mainly associated with HNPs, whereas SDHB mutations are reported in HNP, familial phaeochromocytomas, and ASP (9) . Neumann et al. (10) recently tested 271 patients with ASP and identified 23 patients with a germ-line mutation in the SDHD (n = 11, 4%) or SDHB (n = 12, 4.5%) genes.
Inactivating germ-line mutations in SDHD or SDHB genes may be associated with a somatic LOH, with the complete loss of SDH activity and the activation of the hypoxic/angiogenic pathway in the tumoral tissues (11 , 12) and with a malignant phenotype (12) . To assess the phenotypic consequences of such mutations, we analyzed a series of 84 patients with ASP, including 27 patients with extra-adrenal, malignant, and/or recurrent phaeochromocytomas. In addition to genetic analysis, we searched for somatic LOH, assayed SDH activity, and analyzed the vascular architecture phenotype, which has been shown to be strongly associated with malignancy (13) .
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Tissues and Blood Samples.
Written informed consent for germ-line and somatic DNA analysis was obtained from each subject, and the study was approved by an institutional review board (CCPPRB Paris-Cochin, July 1996). Peripheral DNA was obtained from venous blood samples. Among the 84 patients, 33 fresh phaeochromocytoma samples were obtained during surgery and immediately frozen in liquid nitrogen. Somatic (from phaeochromocytoma) and constitutive (from leukocytes) DNA was extracted according to standard protocols.
Genetic Testing of Germ-line DNA.
The four exons of the SDHD gene, the eight exons of the SDHB gene, the three exons of the VHL gene, and six exons (exons 10, 11, 13, 14, 15, and 16) of the RET gene were amplified and directly sequenced as described previously (11
, 12
, 14
, 15)
.
Search for LOH at 11q23 (PGL1) and 1p36 (PGL4).
LOH analysis was performed for the 33 tumor and germ-line DNA samples, using two flanking microsatellite markers at each locus: D11S5011 and D11S5019 for PGL1 (11q23) corresponding to the SDHD gene and D1S507 and D1S199 for PGL4 (1p36), corresponding to the SDHB gene. For the seven available (in all except P038) inherited SDHB tumors, we used 11 fluorescent oligonucleotides (D1S243, D1S468, D1S2694, D1S244, D1S2667, D1S507, D1S199, D1S478, D1S2674, D1S2749, and D1S513) overlapping a 60-cM region between 1p36.33 (telomere) and 1p34.3. For these seven tumors, LOH was confirmed using tumor DNA extracted from the phaeochromocytoma homogenates used for enzymatic studies in a second run of PGL4 locus analysis. Germ-line and tumor DNA was amplified using the following amplification temperatures: 54°C for D1S243 and D1S2694 (with 5% DMSO), 55°C for D1S199 (with 5% DMSO), 56°C for D1S468-D1S244-D1S2667-D1S478, and 58°C for D1S513-D1S2674-D1S2749-D1S507. The amplification products were analyzed with an ABI 3700 instrument (Applied Biosystems) and the GeneScan Analysis 3.5 software (ABI Prism).
Enzyme Assays.
Succinate cytochrome c reductase (complex II + III) and quinol cytochrome c reductase (complex III) activities were measured spectrophotometrically in phaeochromocytoma homogenates as described previously (16)
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Immunohistochemistry.
The paraffin blocks prepared for routine pathological examination of the tumors were obtained. They were cut into 7-µm-thick sections, which were mounted on silane-treated slides. Immunohistochemistry was performed with an anti-CD34 antibody (Immunotech, Marseille, France) and an anti-
-actin antibody (DAKO, Trappes, France) at dilutions of 1:100 and 1:1000, respectively. The protocol used has been described elsewhere (17)
and included a biotinylated secondary antibody (Vector Laboratories, Burlingame, CA), an avidin-biotin-peroxidase complex (Vectastain ABC Elite; Vector Laboratories), and diaminobenzidine as a chromogen for the peroxidase activity.
Statistical Analysis.
The characteristics of the patients are expressed as mean ± 1 SD for continuous variable and counts and percentages for discrete variables. Phenotypic differences in quantitative traits were assessed, according to genotype, by Student’s t test or ANOVA. Differences in distributions of qualitative traits according to genotype were assessed by standard 
2 analysis and Fisher’s exact test. Calculations were carried out with Statview version 5.0 (Abacus Concepts).
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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2. Germ-line DNA Analysis.
Sixteen (19%) of the 84 patients had germinal amino acid change in VHL, SDHD, or SDHB gene, but none (0%) had mutations in the RET proto-oncogene. Two (2.4%) had mutations in the VHL gene, six (7.1%) had coding polymorphisms in the SDHD gene, and eight (9.5%) had deleterious mutations in the SDHB gene (Table 1)
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The G12S amino acid change in the SDHD gene was identified in two patients (2.4%), one with a recurrent malignant phaeochromocytoma and the other with a benign form (Table 2)
. This amino acid change was also found in 5 of 94 control subjects (5.3%), a frequency consistent with a nonfunctional polymorphism. We also detected the noncoding SNP S68S described previously in four patients (5%), a proportion similar to that observed in controls (4.2%). This SNP was in linkage disequilibrium with G12S in 2 patients and present in 2 others patients with benign adrenal tumors. The H50R amino acid change mutation was found in 4 patients (4.7%), a proportion not significantly different from that observed in controls (1%). It should be noted that the patient with a urinary bladder phaeochromocytoma also harbored a deleterious mutation in the SDHB gene.
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and Fig. 1
). Three missense mutations (A43P, R46Q, and R46G) in exon 2 were detected in 4 patients, all with extra-adrenal or malignant forms of phaeochromocytoma. A43P was identified in a patient who first underwent surgery at the age of 29 years for an extra-adrenal phaeochromytoma (#P106) in the Zuckerkandl body. Three years later, this patient developed a recurrence of the primary tumor and multiple metastases (lymph node, pulmonary, and bone). The R46Q mutation was found in a 54-year-old woman with a large, highly vascularized adrenal tumor, which extended into the heart with multiple pulmonary metastases, a case reported previously (12)
. The same mutation was identified in a 28-year-old patient (#P188) with a right adrenal tumor (65 mm) that was difficult to treat by surgery because of extensive vascular connections with the aorta and a 50-mm tumor of the Zuckerkandl body. The R46G mutation was found in a 31-year-old woman with an apparently benign left adrenal phaeochromocytoma (#P195). The surgeon described a highly abnormal vascularization of this tumor, with a large arterio-venous plexus on its posterior face. Two frameshift mutations were detected in exon 6 of the SDHB gene in 3 patients. The deletion of cytosine at position 725 (725 del c) was observed in a 37-year-old man (#P107) operated of a phaeochromocytoma located in the urinary bladder but not followed up. The deletion of two nucleotides at positions 754 and 755 (754–755 del tg) was detected in two unrelated patients with malignant phaeochromocytomas. The first, a 38-year-old man (#P038), underwent surgery for phaeochromocytoma in the Zuckerkandl body and presented, 1 year later, a lymph node and bone metastases. The 2nd patient, a 24-year-old woman (#P117), also underwent surgery for phaeochromocytoma in the Zuckerkandl body and developed lymph node and thoracic bone metastases 3 years later. The last mutation was a missense mutation in exon 7 of the SDHB gene (R230C) that was detected in a 32-year-old man (#P109), who underwent surgery for an apparently benign left adrenal phaeochromocytoma, but who went on to develop bone and lymph node metastases 5 years later.
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3. Somatic DNA Analysis and Complex II Enzyme Assays.
LOH analysis was performed on the 33 available tumors (all of the SDHB-inherited tumors except P#038) and the corresponding germ-line DNA samples using two microsatellite markers at the SDHD (11q23) and SDHB (1p36) loci (Table 4)
. Chromosome 11q23 LOH was found in 7 (21%) cases, all corresponding to benign adrenal tumors. Chromosome 1p36 LOH was found in 16 (48%) cases, half of them corresponding to extra-adrenal or malignant tumors. Among these 8 cases, 7 had a germ-line SDHB mutation. The combination of an SDHB germ-line mutation and chromosome 1p36 LOH was associated in six of seven cases with extra-adrenal location or malignancy (86%), and all germ-line SDHB mutations were associated with a 1p LOH (P = 0.002).
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. It was not possible to distinguish benign adrenal (#P195) or extra-adrenal phaeochromocytomas that were not followed-up (#P107, #P188) from malignant tumors.
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-actin antibodies for the identification of vascular smooth muscle cells with those obtained for three benign adrenal SDHB mutation-negative phaeochromocytomas. As expected, control tumors displayed a normal vascular pattern with small capillaries regularly distributed throughout the tumor sample (Fig. 2A–C
). In contrast, the malignant SDHB mutation-positive tumors displayed the archetypal irregular motifs described previously (#P106, Fig. 2G
; #P183, Fig. 2H
; and #P038, Fig. 2I
). The apparently benign adrenal (#P195, Fig. 2E
) or extra-adrenal but not followed-up SDHB mutation-positive phaeochromocytomas (#P188, Fig. 2D
and #P107, Fig. 2F
) also displayed an irregular architecture. Although less stereotypical than for #P106, #P183, and #P038, the change in vascular morphology observed (arcs, networks, and parallel structures) was similar to that observed in invasive malignant tumors.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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One of the most striking features of our results is the higher frequency of mutations in SDHB (9.5%) than in other genes implicated in phaeochromocytoma. In particular, we found no mutation in the RET gene and only 2 (2.4%) mutations in the VHL gene. These results contrast with those observed by the Freiburg-Warsaw-Columbus Pheochromocytoma Study Group, who obtained mutation frequencies of 5% for RET and 11% for VHL in 271 individuals with ASP (10) . A likely explanation is that we included only patients without a family history of VHL or NEM2, without retinal hemangioblastomas, and with normal thyrocalcitonin levels after pentagastrin testing. In Neumann’s report, 12 of the 13 patients positive for mutations of RET developed medullary thyroid carcinoma during the follow-up period (10) . In the same study, 10 of the 30 carriers of VHL mutations presented associated features of VHL disease during follow-up. Finally, the low frequency of RET and VHL mutations in our patients with ASP is also consistent with previous reports for these diseases with the early onset of thyroid lesions almost always preceding phaeochromocytoma in MEN2A (19) and extra-adrenal lesions (mainly retinal hemangioblastomas, renal-cell carcinoma) in most VHL cases (except for the type 2C of the disease; Ref. 20 ).
The other surprising finding of our study was the difference in mutation frequency between the SDHB and SDHD genes. The proportion of SDHB genetic variations was high, but only two coding polymorphisms (G12S and H50R) and one silent (S68S) polymorphisms were identified in the SDHD gene. The possible functionality of the G12S variant has been subjected to some debate because this variant has been found in affected subjects (21, 22, 23) but also in phenotypically normal subjects (24) . Our results confirm that this mutation is probably a polymorphism because it was observed in similar proportions in subjects with ASP (2 of 84) and in a set of controls (5 of 94, P = 0.33). Similar debates have concerned the potential functionality of the H50R variant (22 , 23) , the original amino acid being conserved in the mouse SDHB gene. In our study, the marginal difference in the frequency of the H50R mutation in ASP (4 of 84) and control (1 of 94, P = 0.15) subjects leaves some room for speculation, although one of the four cases of ASP was more likely to be accounted for by one mutation in SDHB gene. We thus analyzed SDH activity in one phaeochromocytoma with a germ-line H50R mutation but without LOH at the SDHD locus (#P168). Succinate cytochrome c reductase (123 nmol/min/mg protein) and quinol cytochrome c reductase (234 nmol/min/mg protein) activities were normal, providing additional evidence that this nucleotide change results in the production of a functional protein. On the whole, the absence of deleterious mutations in the SDHD gene in our cohort contrasts with the frequency of such mutations (4%) reported by Neumann et al. (10) . This discrepancy may be partly accounted for by selection bias attributable to the absence of glomus tumors during follow-up and the expression of SDHD mutations principally as head and neck paragangliomas (25) . Our results are more in accordance with those obtained by Benn et al. (26) who did not find any SDHD but six SDHB mutations in 7 patients with familial or ASPs.
Our most important finding is that the presence of germ-line mutations in the SDHB gene, but not in the SDHD gene, are strongly associated with extra-adrenal phaeochromocytomas and confer a high risk of recurrence or malignancy. In the presence of an SDHB mutation, the odds ratio for an extra-adrenal tumor as a primary site is very high, 19.8 (95% confidence interval 2.9–213). If we consider only the 82 patients with a complete follow-up, the odds ratio for recurrence or malignancy was 19 (95% confidence interval 1.9–910). These odds ratios must clearly be interpreted with caution because of the small number of SDHB mutation-positive subjects but are high enough to warrant prospective evaluation of genetic analysis of this locus as a prognostic test for ASPs. This higher risk of malignancy and of tumor formation at an extra-adrenal site conferred by SDHB mutations is consistent with several previous observations. Neumann et al. (10) provided no information concerning malignancy for their 12 patients with SDHB mutations but stated that 50% of these patients presented extra-adrenal disease. A missense mutation (R242H) in exon 7 of the SDHB gene was recently identified in a proband with initial metastatic periadrenal and periaortic paragangliomas, followed by bone metastasis 29 years later (27) . Several abdominal paragangliomas were subsequently discovered in his 27-year-old son, who carried the same mutation. The strengths of our study are the longevity of our cohort (the 1st patient to undergo surgery did so in 1970), the systematic follow-up (8.8 +/-5.7 years) of all but 2 patients, and the high frequency of recurrent and malignant tumors (25%). Five patients with SDHB mutations clearly displayed a malignant phenotype. Two patients, one with two secreting tumors (adrenal and Zuckerkandl body) and the other with a phaeochromocytoma in the urinary bladder, were lost to follow-up. The only SDHB mutation-positive patient with an apparently benign phaeochromocytoma has been followed-up for only 18 months. We assessed the probability of malignancy for these three tumors by studying their vascular architecture. Angiogenesis is indeed a critical step in tumor growth and metastatic invasion. On the basis of our previous observation of a vascular pattern characteristic of malignant phaeochromocytomas (13) , we compared the vascular architecture of these three tumors with three benign adrenal SDHB mutation-negative and three clearly malignant SDHB mutation-positive phaeochromocytomas. The result was unequivocal, with an irregular pattern of vascularization and almost all of the characteristics of malignant status identified in the three tumors assessed.
What are the molecular causes of malignancy for the SDHB tumors? As reported previously for one patient with an SDHD mutation (11)
and for one with an SDHB mutation (12)
, all germ-line SDHB mutations were associated with somatic LOH at the SDHB locus from 1pter to 1p34.3 and with complete somatic loss of SDH activity. After SDH inactivation, the interruption of the Krebs’ cycle and its consequences for the induction of angiogenic genes, such as EPAS-1 and HIF-1 (11)
, and the generation of superoxides by the respiratory chain may all be involved in tumor formation (28)
. Germ-line mutations in FH, which encodes fumarate hydratase, were recently reported in a dominantly inherited syndrome associating uterine fibroids, skin leiomyomata, and papillary renal cell cancer (29)
. All these recent findings highlight the unexpected role of mitochondrial proteins in tumor pathogenesis.
It is also possible that another gene included in the chromosome 1p LOH is responsible for tumor formation. Several authors have suggested that chromosome 1p may carry tumor suppressor loci involved in phaeochromocytoma formation (30 , 31) . Two consensus LOH regions have been described in neuroblastoma, another neural crest-derived tumor: (a) one telomeric in 1p36 and (b) the other in 1p32–35. These LOH are usually screened as prognostic factors predictive of malignancy and used in treatment decisions (31) . In sporadic and familial phaeochromocytomas, Benn et al. (30) have suggested three possible regions of common somatic loss: PC1; PC2; and PC3. The SDHB gene is exactly midway (1p36–13) between PC2 and PC3, which are lost in the SDHB mutation-positive malignant phaeochromocytomas. Our data suggest that the SDHB gene may be one of these tumor suppressor genes.
In conclusion, this study emphasizes the clinical usefulness of genetic testing of all patients with phaeochromocytoma because genetic defects are relatively frequent even in apparently sporadic tumors. The presence of a germ-line SDHB mutation should be considered as a high-risk factor for malignancy and recurrence and should lead to appropriate clinical management and strict follow-up.
The members of the COMETE Network were as follows: Youssef Anouar, INSERM U-413, Rouen; Ivan Bachelot, Service d’Endocrinologie, Hôpital Michallon, Grenoble; Erno Baviera, Laboratoire d’Anatomo-pathologie, Hôpital Saint Joseph, Paris; Chérif Beldjord, INSERM U-129, Institut Cochin, Paris; Xavier Bertagna, Institut Cochin, Paris; Jérôme Bertherat, Institut Cochin, Paris; Patrick Bruneval, Laboratoire d’Anatomo-Pathologie, HEGP, Paris; Olivier Chabre, Service d’Endocrinologie, Hôpital Michallon, Grenoble; Edmond Chambaz, INSERM U-244, Grenoble; Eric Clauser, INSERM U-36, Collège de France, Paris; Pierre Corvol, INSERM U-36, Collège de France, Paris; Catherine Delarue, INSERM U-413, Rouen; Jean-Marc Duclos, Service d’Urologie, Hôpital Saint Joseph, Paris; Jacques Epelbaum, INSERM U-159, Paris; Judith Favier, INSERM U-36, Collège de France, Paris; Jean-Jacques Feige, INSERM U-244, Grenoble; Jean-Marie Gasc, INSERM U-36, Collège de France, Paris; Anne-Paule Gimenez-Roqueplo, Département de Génétique, HEGP, Paris; Christine Gicquel, Laboratoire d’Explorations Fonctionnelles Endocriniennes, Hôpital Armand Trousseau, Paris; Xavier Jeunemaitre, Département de Génétique, HEGP, Paris; Jean-Marc Kuhn, Groupe Hospitalo-Universitaire de Recherche en Hormonologie, Rouen; Yves Le Bouc, Laboratoire d’Explorations Fonctionnelles Endocriniennes, Hôpital Armand Trousseau, Paris; Hervé Le Hir, CGM-CNRS, Gif-sur-Yvette; Hervé Lefebvre, INSERM U-413, Rouen; Albert Louvel, Laboratoire d’Anatomo-Pathologie, Hôpital Cochin, Paris; Pierre-François Plouin, Département d’Hypertension Artérielle, HEGP, Paris; Antoine Tabarin, Hopital du Haut-Leveque, CHU de Bordeaux; Claude Thermes, Centre de Génétique Moléculaire, CNRS A 9061, Gif-sur-Yvette; Pierre Thomopoulos, Clinique des Maladies Endocriniennes et Métaboliques, Hôpital Cochin, Paris; Hubert Vaudry, INSERM U-413, Rouen.
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FOOTNOTES |
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1 Supported by the Institut National de la Santé et de la Recherche Médicale and by PHRC Grant AOM 95201 for the COMETE Network. A-P. Gimenez-Roqueplo holds a Contrat Individuel d’Objectif from INSERM, and J. Favier holds a fellowship from La Ligue Contre le Cancer. 
2 To whom requests for reprints should be addressed, at Département de Génétique Moléculaire, Hôpital Européen Georges Pompidou, 20-40, rue Leblanc, 75015 Paris, France. Phone: 33 1 56 09 38 81; Fax: 33 1 56 09 38 84; E-mail: Anne-Paule.Gimenez{at}hop.egp.ap-hop-paris.fr
3 The members of the COMETE Network are listed in the Appendix.
4 The abbreviations used are: VHL, von Hippel-Lindau; ASP, apparently sporadic phaeochromocytoma; SDH, succinate dehydrogenase; LOH, loss of heterozygosity; COMETE, Cortical and Medullary adrenal Tumors; MEN, multiple endocrine neoplasia; NF1, neurofibromatosis type 1; HNP, head and/or neck paraganglioma.
Received 3/13/03. Revised 6/ 3/03. Accepted 6/ 4/03.
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C. Jimenez, G. Cote, A. Arnold, and R. F. Gagel Should Patients with Apparently Sporadic Pheochromocytomas or Paragangliomas be Screened for Hereditary Syndromes? J. Clin. Endocrinol. Metab., August 1, 2006; 91(8): 2851 - 2858. [Abstract] [Full Text] [PDF]
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E. R Woodward and E. R Maher Von Hippel-Lindau disease and endocrine tumour susceptibility. Endocr. Relat. Cancer, June 1, 2006; 13(2): 415 - 425. [Abstract] [Full Text] [PDF]
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 E. R. Maher Genetics of phaeochromocytoma Br. Med. Bull., June 1, 2006; 79-80(1): 141 - 151. [Abstract] [Full Text] [PDF]
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W. F. Young Jr and A. L. Abboud Paraganglioma--all in the family. J. Clin. Endocrinol. Metab., March 1, 2006; 91(3): 790 - 792. [Full Text] [PDF]
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D. E. Benn, A.-P. Gimenez-Roqueplo, J. R. Reilly, J. Bertherat, J. Burgess, K. Byth, M. Croxson, P. L. M. Dahia, M. Elston, O. Gimm, et al. Clinical Presentation and Penetrance of Pheochromocytoma/Paraganglioma Syndromes J. Clin. Endocrinol. Metab., March 1, 2006; 91(3): 827 - 836. [Abstract] [Full Text] [PDF]
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 L. Amar, J. Bertherat, E. Baudin, C. Ajzenberg, B. Bressac-de Paillerets, O. Chabre, B. Chamontin, B. Delemer, S. Giraud, A. Murat, et al. Genetic Testing in Pheochromocytoma or Functional Paraganglioma J. Clin. Oncol., December 1, 2005; 23(34): 8812 - 8818. [Abstract] [Full Text] [PDF]
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P.J. Pollard, J.J. Briere, N.A. Alam, J. Barwell, E. Barclay, N.C. Wortham, T. Hunt, M. Mitchell, S. Olpin, S.J. Moat, et al. Accumulation of Krebs cycle intermediates and over-expression of HIF1{alpha} in tumours which result from germline FH and SDH mutations Hum. Mol. Genet., August 1, 2005; 14(15): 2231 - 2239. [Abstract] [Full Text] [PDF]
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L Simi, R Sestini, P Ferruzzi, M S Gagliano, F Gensini, M Mascalchi, L Guerrini, C Pratesi, P Pinzani, G Nesi, et al. Phenotype variability of neural crest derived tumours in six Italian families segregating the same founder SDHD mutation Q109X J. Med. Genet., August 1, 2005; 42(8): e52 - e52. [Abstract] [Full Text] [PDF]
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A. Cascon, A. Cebrian, M. Pollan, S. Ruiz-Llorente, C. Montero-Conde, R. Leton, R. Gutierrez, F. Lesueur, R. L. Milne, O. Gonzalez-Albarran, et al. Succinate Dehydrogenase D Variants Do Not Constitute a Risk Factor for Developing C Cell Hyperplasia or Sporadic Medullary Thyroid Carcinoma J. Clin. Endocrinol. Metab., April 1, 2005; 90(4): 2127 - 2130. [Abstract] [Full Text] [PDF]
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G. Eisenhofer, D. S. Goldstein, P. Sullivan, G. Csako, F. M. Brouwers, E. W. Lai, K. T. Adams, and K. Pacak Biochemical and Clinical Manifestations of Dopamine-Producing Paragangliomas: Utility of Plasma Methoxytyramine J. Clin. Endocrinol. Metab., April 1, 2005; 90(4): 2068 - 2075. [Abstract] [Full Text] [PDF]
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L. Amar, A. Servais, A.-P. Gimenez-Roqueplo, F. Zinzindohoue, G. Chatellier, and P.-F. Plouin Year of Diagnosis, Features at Presentation, and Risk of Recurrence in Patients with Pheochromocytoma or Secreting Paraganglioma J. Clin. Endocrinol. Metab., April 1, 2005; 90(4): 2110 - 2116. [Abstract] [Full Text] [PDF]
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G. Eisenhofer, S. R Bornstein, F. M Brouwers, N.-K. V Cheung, P. L Dahia, R. R de Krijger, T. J Giordano, L. A Greene, D. S Goldstein, H. Lehnert, et al. Malignant pheochromocytoma: current status and initiatives for future progress Endocr. Relat. Cancer, September 1, 2004; 11(3): 423 - 436. [Abstract] [Full Text] [PDF]
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B E Baysal, J E Willett-Brozick, P A A Filho, E C Lawrence, E N Myers, and R E Ferrell An Alu-mediated partial SDHC deletion causes familial and sporadic paraganglioma J. Med. Genet., September 1, 2004; 41(9): 703 - 709. [Full Text] [PDF]
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 H. P. H. Neumann, C. Pawlu, M. Peczkowska, B. Bausch, S. R. McWhinney, M. Muresan, M. Buchta, G. Franke, J. Klisch, T. A. Bley, et al. Distinct Clinical Features of Paraganglioma Syndromes Associated With SDHB and SDHD Gene Mutations JAMA, August 25, 2004; 292(8): 943 - 951. [Abstract] [Full Text] [PDF]
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