The penetrance of MEN2 pheochromocytoma is not only determined by RET mutations

in Endocrine-Related Cancer
Authors:
Frederic Castinetti Department of Endocrinology Aix Marseille University, CNRS UMR7286 La Conception Hospital, Hopitaux de Marseille, Marseille, France

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Ana Luiza Maia Thyroid Section, Endocrinology Division, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

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Mariola Peczkowska Department of Hypertension, Institute of Cardiology, Warsaw, Poland

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Marta Barontini Center for Endocrinological Investigations, Hospital de Ninos R Gutierrez, Buenos Aires, Argentina

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Kornelia Hasse-Lazar Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska Curie Memorial Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland

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Thera P Links Department of Endocrinology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands

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Rodrigo A Toledo Department of Endocrinology, University of Sao Paulo School of Medicine, Sao Paulo, Brazil

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Sarka Dvorakova Department of Molecular Endocrinology, Institute of Endocrinology, Prague, Czech Republic

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Caterina Mian Operative Unit of the Endocrinology Department of Medicine (DIMED), University of Padova, Padova, Italy

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Maria Joao Bugalho Hospital de Santa Maria – CHLN, Lisboa, Portugal

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Stefania Zovato Department of Medicine (DIMED), University of Padova, Padova, Italy

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Maria Alevizaki Endocrine Unit Evgenideion Hospital and Department of Medical Therapeutics, Alexandra Hospital, Athens University School of Medicine, Athens, Greece

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Andrei Kvachenyuk Institute of Endocrinology, Kiev, Ukraine

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Birke Bausch 2nd Department of Medicine, University Medical Centre, Albert Ludwigs University of Freiburg, Freiburg, Germany

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Paola Loli Department of Endocrinology, Ospedale Niguarda Cà Granda, Milan, Italy

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Simona R Bergmann Division of Endocrinology and Diabetology, Faculty of Medicine, Philipps University of Marburg, Marburg, Germany

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Attila Patocs Molecular Medicine Research Group, HSA-SE ‘Lendület’ Hereditary Endocrine Tumor Research Group, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary

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Marija Pfeifer Department of Endocrinology, University Medical Center Ljubljana, Ljubljana, Slovenia

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Josefina Biarnes Costa Hospital Universitari de Girona, Gerencia Territorial Girona, Institut Català de la Salut, Girona, Spain

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Ernst von Dobschuetz Department of Visceral Surgery, University Medical Centre, Albert Ludwigs University of Freiburg, Freiburg, Germany

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Claudio Letizia Department of Internal Medicine and Medical Specialties, University La Sapienza, Rome, Italy

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Gerlof Valk Department of Internal Medicine, University Medical Centre Utrecht, Utrecht, Netherlands

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Marcin Barczynski Department of Endocrine Surgery, Third Chair of General Surgery, Jagiellonian University, Medical College, Krakow, Poland

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Malgorzata Czetwertynska Department of Endocrinology, Maria Sklodowska Curie Memorial Center and Institute of Oncology, Warsaw, Poland

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John T M Plukker Department of Surgery, University Medical Centre, Groningen, Netherlands

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Paola Sartorato Department of Internal Medicine, General Hospital, Montebelluna, Treviso, Italy

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Tomas Zelinka 3rd Department of Medicine, Department of Endocrinology and Metabolism, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic

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Petr Vlcek Department of Nuclear Medicine and Endocrinology, Second Faculty of Medicine, Charles University, Prague, Czech Republic

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Svetlana Yaremchuk Institute of Otolaryngology NAMS of Ukraine, Kiev, Ukraine

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Georges Weryha Department of Endocrinology, University Hospital, Nancy, France

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Letizia Canu Department of Experimental and Clinical Biomedical Sciences, Endocrinology Unit, University of Florence, Florence, Italy

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Nelson Wohllk Endocrine Section, Universidad de Chile, Hospital del Salvador, Santiago de Chile, Chile

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Frederic Sebag Department of Endocrine Surgery, Aix-Marseille University, La Conception Hospital, Marseille, France

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Martin K Walz Department of Surgery and Center of Minimally Invasive Surgery, Kliniken Essen-Mitte, Essen, Germany

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Charis Eng Genomic Medicine Institute, Lerner Research Institute and Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA

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Hartmut P H Neumann Section for Preventive Medicine, Department of Nephrology and General Medicine, University Medical Centre, Albert Ludwigs University of Freiburg, Freiburg, Germany

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Dear Editor,

Multiple endocrine neoplasia type 2 (MEN2) is a rare syndrome subdivided into 2 main entities: MEN2A and MEN2B (Donis-Keller et al. 1993, Mulligan et al. 1993, Eng et al. 1996). Genetic results can predict the natural history of medullary thyroid carcinoma (MTC) depending on the mutation of RET. This is the basis for ATA guidelines giving different ages to perform early thyroidectomy in such patients (Wells et al. 2015). MEN2A and MEN2B are also characterized by the occurrence of pheochromocytoma (PHEO), though less frequent than MTC. PHEO is a chromaffin tumor arising from the medullar zone of the adrenals and responsible for mortality if left undiagnosed (Lenders et al. 2005). Precise comparative large-scale epidemiological data on PHEO penetrance in different geographical zones are however missing in the literature as the majority of published studies were coming from a single Center or a single country.

To further describe the natural history of MEN2A PHEO, investigators from South America (Argentina, Chile, Brazil), Southern Europe (Italy, Spain, Portugal, Greece), Western Europe (France, Germany, The Netherlands) and Central Europe (Ukraine, Poland, Slovenia, Czech Republic) were contacted and asked to retrospectively collect demographic, clinical and genetic data about PHEO in MEN2 patients carrying mutations in exons 10 and 11 of RET. The aim was to better characterize the main epidemiological characteristics of MEN2 PHEO in these 4 different geographical areas. Follow-up policy was the same for all Centres: plasma and/or urinary metanephrine measurements were performed in symptomatic patients or in asymptomatic patients every 6–12 months depending on each investigator; imaging was done systematically when metanephrine concentrations increased, and every 3–5 years in patients with normal metanephrine values based upon investigators’ decision. In accordance with the institutional review board, all patients provided signed written informed consent for genetics and analyses of the results. Exceptions for this second point were the centers in Groningen and Utrecht in the Netherlands, and Lisbon in Portugal, where the participants’ identities were anonymized and protected by unique codes that were known only by two dedicated data managers; therefore, no further institutional review board approval was needed at these centers. The database was established from November 1, 2012 to October 1, 2013. Full characterization of the database was previously reported (Castinetti et al. 2014). Patients included in the database were enrolled at the participating centers from 1968 to 2013. Patients included in the database had to be diagnosed as carriers of germline pathogenic mutations of RET. Additionally, first-degree relatives with histologically proven MTC and PHEO (defined by the association of increased urinary or plasma metanephrines and adrenal tumor) were included.

Continuous variables are presented as median (IQR). Age-dependent penetrance estimates of PHEO were performed with the Kaplan–Meier method: we compared disease-free survival with the log-rank analysis. Statistical comparisons of quantitative data were performed with Student’s t test or ANOVA. For dichotomous data, χ2 test was used. All statistical tests were two sided, and P values of less than 0.05 were considered significant. Analyses were done with PRISM 6 software (GraphPad Software, 2014).

The cohort included 812 patients (446 females, 366 males) with MEN2A due to RET mutations in exons 10 and 11. Genetic analysis of the whole cohort showed that 239 patients (29%) carried exon 10 mutations and 573 patients (71%) exon 11 mutations (RET 634 codon). At last follow-up, 462 patients (56.9%) were presenting with at least 1 PHEO, while 350 (43.1%) were safe of PHEO (with negative biochemistry) at a median age of 35 years (min, 6; max, 87). Among the 462 patients with at least 1 PHEO, 412 carried mutations in exon 11 (71.9% of the 573 patients with RET 634) while 50 carried mutations in exon 10 (20.9% of 239 patients) (P < 0.001 for exon 10 vs exons 11). Median age at first diagnosis was 42 (IQR, 17) and 34 (IQR, 18) years for exons 10 and 11 respectively (P < 0.001 for exon 10 vs exons 11, data not shown). At least 1 pheochromocytoma was observed in 50% of patients with exon 11 by age 38 years, while the same penetrance was observed in 50% of patients with exon 10 by age 65 (P < 0.0001, data not shown). At last follow-up, 290 patients (62.8%) had bilateral pheochromocytoma: 210 (72.5%) presented synchronous bilateral pheochromocytoma, while 80 (27.5%) presented metachronous bilateral pheochromocytoma after a median time of 72 months (IQR, 84). Among these 290 patients, 270 carried exon 11 (93.1%) while 20 carried exon 10 (6.9%) (P < 0.001). Interestingly, among patients with exon 10 and 11 mutations, there was no significant difference in the median age at first diagnosis of pheochromocytoma whatever the codon or the amino-acid substitution (P = 0.207, data not shown).

We subdivided the whole cohort of patients into 4 different geographical areas: South America (n = 268), Southern Europe (n = 178), Western Europe (n = 192) and Central Europe (n = 174) to determine the phenotypic characteristics of MEN2 pheochromocytoma in each area. There was a significant difference in the number of patients with pheochromocytoma and exons 10 (codon 620) and 11 (codon 634) mutations as shown in Table 1. At last follow-up (not significantly different between all areas), for exon 11, only 53% of patients had presented at least 1 pheochromocytoma in South America, while they were 75–81% in the other 3 areas (P = 0.038). There was a significant difference for unilateral and bilateral pheochromocytoma penetrance between South America and the 3 European areas: 50% of patients presented unilateral pheochromocytoma at 33, 36, 37 and 43 and bilateral pheochromocytoma at 44, 44, 45 and 61 years of age, respectively, in Southern Europe, Central Europe, Western Europe and South America (P < 0.0001, P = 0.0017 for South America vs other areas) (Fig. 1).

Figure 1
Figure 1

Bilateral pheochromocytoma penetrance in patients with RET 634 mutation based on geographic area. The table shows the number of subjects at risk initially, and then at 20 and 40 years of age. There was a significant difference in terms of penetrance depending on the geographical area (P < 0.0001 for unilateral PHEO, P = 0.0017 for bilateral PHEO).

Citation: Endocrine-Related Cancer 24, 8; 10.1530/ERC-17-0189

Table 1

Characteristics of pheochromocytoma based on geographic area.

Southern Europe Central Europe Western Europe South America P
Patients 185 174 190 263
Pheochromocytoma 93 (52%) 118 (68%) 141 (74%) 110 (41%) 0.038
 Unilateral 35 (38%) 44 (37%) 45 (32%) 44%) ns
 Bilateral 58 (62%) 74 (63%) 96 (68%) 56%) ns
  Synchronous 51 (88%) 48 (65%) 70 (73%) 42 (68%) 0.012
  Metachronous 7 (12%) 26 (35%) 26 (27%) 20 (32%) 0.016
Patients with mutations in
 Exon 10 17/90 (19%) 9/35 (25%) 15/36 (42%) 9/78 (12%) 0.021
 Exon 11 76/95 (81%) 109/139 (75%) 126/154 (81%) 101/185 (53%) 0.033
Patients with mutations in codon
 609 3/25 (12%) 3/10 (30%) 3/4 (75%) 0/0 ns
 611 2/2 (100%) 1/6 (17%) 3/3 (100%) 0/6 ns
 618 3/18 (17%) 3/11 (27%) 8/27 (30%) 4/17 (25%) ns
 620 9/45 (20%) 2/8 (25%) 1/2 (50%) 5/55 (9%) 0.049
 634 76/95 (80%) 109/139 (78%) 126/154 (81%) 101/185 (55%) 0.038
Mean age at last follow-up (years) (min–max) 45 (12–90) 42 (7–79) 51 (6–95) 43 (7–96) ns

Gender, male/female. For RET exon and codon lines, the rate represents the number of patients with pheochromocytoma vs the total number of patients.

Our data are of importance mainly because PHEO has progressively become the main MEN2A disease: Indeed, early thyroidectomy has modified the outcome of MEN2 patients in the way that endocrinologists taking care of familial cases identified by early genetic screening will mainly have to deal with PHEO follow-up and management (Waguespack et al. 2011). MEN2 PHEO can be diagnosed in a same way as sporadic PHEO with the main advantage of being usually discovered at an early stage due to the regular follow-up of MEN2 patients. We recently reported that patients with MEN2 PHEO could take benefit of adrenal sparing surgery, a technique aimed at sparing a piece of cortical tissue while taking off the PHEO, allowing for a normal post-surgical cortical function in more than 50% of patients (Castinetti et al. 2014). A proper follow-up of MEN2 patients is thus mandatory to optimize their treatment: as such, endocrinologists need to know perfectly the natural history of MEN2 PHEO, but specific series on pheochromocytoma are lacking (Imai et al. 2013, Thosani et al. 2013).

Our study emphasizes the fact that RET mutation is not the only determinant of the natural history of PHEO in MEN2. Indeed, we report for the first time a different natural history of MEN2 PHEO between Europe and South America. As all the centers had the same policy in terms of PHEO follow-up, this difference cannot be explained by different diagnostic approaches. The difference is highly significant: 50% of Central Europe patients will have a PHEO by age 33 years, while it is only by the age of 43 years that the same percent will be obtained in South America. More importantly from a management viewpoint, a delay of more than 15 years was observed between the age at which patients would present bilateral PHEO (and thus a definite adrenal insufficiency when treated by bilateral adrenalectomy) in Europe vs South America. This could be due to modifier variants in RET or in another gene: Siqueira and coworkers had suggested that RET polymorphisms (L769L, S836S, and G691S/S904S) might modify the natural history of MEN2 PHEO: patients with 2 of these polymorphisms indeed presented a younger age at diagnosis (Siqueira et al. 2014). Protective alleles could also explain this different natural history: protective alleles are rare and potentially ancestry specific, and in our cohort, they could be identified in patients from South America. To further ascertain this hypothesis, large multiethnic studies should be performed. Finally, one further explanation could also be the influence of the environment, but this remains hypothetical for MEN2.

To conclude, the differences reported in this study thus suggest that the natural history of MEN2 PHEO could be influenced by modifying factors (genetic or environmental). Future studies should be aimed at better defining these factors, now that the main epidemiological characteristics of MEN2 PHEO have been well defined.

Declaration of interest

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

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector, except for S Dovorakova (Grant AZV 16-32665A).

Acknowledgements

The authors would like to thank the following physicians for fruitful discussions: Gabriela Sansó (Buenos Aires, Argentina), Thomas Cuny (Nancy, France), Debora R Siqueira (Porto Alegre, Brazil), Malgorzata Szperl (Warsaw, Poland), Barbara Jarzab (Gliwice, Poland), Hans H G Verbeek (Groningen, Netherlands), Sergio P A Toledo (Sao Paulo, Brazil), Flavia L Coutinho (Sao Paulo, Brazil), Massimo Mannelli (Florence, Italy), Monica Recasens (Girona, Spain), Lea Demarquet (Nancy, France), Luigi Petramala (Rome, Italy), Francesca Schiavi (Padova, Italy), Giuseppe Opocher (Padova, Italy), Andrzej Januszewicz (Warsaw, Poland), Jean-Francois Henry, Thierry Brue and Bernard Conte-Devolx (Marseille, France). Charis Eng and Hartmut PH Neumann: Co-senior authors.

References

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    • Crossref
    • PubMed
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    • Export Citation
  • Donis-Keller H, Dou S, Chi D, Carlson KM, Toshima K, Lairmore TC, Howe JR, Moley JF, Goodfellow P & Wells SA Jr 1993 Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Human Molecular Genetics 2 851856. (doi:10.1093/hmg/2.7.851)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Eng C, Clayton D, Schuffenecker I, Lenoir G, Cote G, Gagel RF, van Amstel HK, Lips CJ, Nishisho I & Takai SI et al. 1996 The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. JAMA 276 15751579. (doi:10.1001/jama.1996.03540190047028)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Imai T, Uchino S, Okamoto T, Suzuki S, Kosugi S, Kikumori T & Sakurai AJapan MENCo 2013 High penetrance of pheochromocytoma in multiple endocrine neoplasia 2 caused by germ line RET codon 634 mutation in Japanese patients. European Journal of Endocrinology 168 683687. (doi:10.1530/EJE-12-1106)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lenders JW, Eisenhofer G, Mannelli M & Pacak K 2005 Phaeochromocytoma. Lancet 366 665675. (doi:10.1016/S0140-6736(05)67139-5)

  • Mulligan LM, Kwok JB, Healey CS, Elsdon MJ, Eng C, Gardner E, Love DR, Mole SE, Moore JK & Papi L et al. 1993 Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature 363 458460. (doi:10.1038/363458a0)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Siqueira DR, Ceolin L, Ferreira CV, Romitti M, Maia SC, Maciel LM & Maia AL 2014 Role of RET genetic variants in MEN2-associated pheochromocytoma. European Journal of Endocrinology 170 821828. (doi:10.1530/EJE-14-0084)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Thosani S, Ayala-Ramirez M, Palmer L, Hu MI, Rich T, Gagel RF, Cote G, Waguespack SG, Habra MA & Jimenez C 2013 The characterization of pheochromocytoma and its impact on overall survival in multiple endocrine neoplasia type 2. Journal of Clinical Endocrinology and Metabolism 98 E1813E1819. (doi:10.1210/jc.2013-1653)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Waguespack SG, Rich TA, Perrier ND, Jimenez C & Cote GJ 2011 Management of medullary thyroid carcinoma and MEN2 syndromes in childhood. Nature Reviews Endocrinology 7 596607. (doi:10.1038/nrendo.2011.139)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wells SA, Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF, Lee N, Machens A, Moley JF & Pacini F et al. 2015 Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid 25 567610. (doi:10.1089/thy.2014.0335)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

 

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  • Bilateral pheochromocytoma penetrance in patients with RET 634 mutation based on geographic area. The table shows the number of subjects at risk initially, and then at 20 and 40 years of age. There was a significant difference in terms of penetrance depending on the geographical area (P < 0.0001 for unilateral PHEO, P = 0.0017 for bilateral PHEO).

  • Castinetti F, Qi XP, Walz MK, Maia AL, Sanso G, Peczkowska M, Hasse-Lazar K, Links TP, Dvorakova S & Toledo RA et al. 2014 Outcomes of adrenal-sparing surgery or total adrenalectomy in phaeochromocytoma associated with multiple endocrine neoplasia type 2: an international retrospective population-based study. Lancet Oncology 15 648655. (doi:10.1016/S1470-2045(14)70154-8)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Donis-Keller H, Dou S, Chi D, Carlson KM, Toshima K, Lairmore TC, Howe JR, Moley JF, Goodfellow P & Wells SA Jr 1993 Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Human Molecular Genetics 2 851856. (doi:10.1093/hmg/2.7.851)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Eng C, Clayton D, Schuffenecker I, Lenoir G, Cote G, Gagel RF, van Amstel HK, Lips CJ, Nishisho I & Takai SI et al. 1996 The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. JAMA 276 15751579. (doi:10.1001/jama.1996.03540190047028)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Imai T, Uchino S, Okamoto T, Suzuki S, Kosugi S, Kikumori T & Sakurai AJapan MENCo 2013 High penetrance of pheochromocytoma in multiple endocrine neoplasia 2 caused by germ line RET codon 634 mutation in Japanese patients. European Journal of Endocrinology 168 683687. (doi:10.1530/EJE-12-1106)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lenders JW, Eisenhofer G, Mannelli M & Pacak K 2005 Phaeochromocytoma. Lancet 366 665675. (doi:10.1016/S0140-6736(05)67139-5)

  • Mulligan LM, Kwok JB, Healey CS, Elsdon MJ, Eng C, Gardner E, Love DR, Mole SE, Moore JK & Papi L et al. 1993 Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature 363 458460. (doi:10.1038/363458a0)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Siqueira DR, Ceolin L, Ferreira CV, Romitti M, Maia SC, Maciel LM & Maia AL 2014 Role of RET genetic variants in MEN2-associated pheochromocytoma. European Journal of Endocrinology 170 821828. (doi:10.1530/EJE-14-0084)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Thosani S, Ayala-Ramirez M, Palmer L, Hu MI, Rich T, Gagel RF, Cote G, Waguespack SG, Habra MA & Jimenez C 2013 The characterization of pheochromocytoma and its impact on overall survival in multiple endocrine neoplasia type 2. Journal of Clinical Endocrinology and Metabolism 98 E1813E1819. (doi:10.1210/jc.2013-1653)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Waguespack SG, Rich TA, Perrier ND, Jimenez C & Cote GJ 2011 Management of medullary thyroid carcinoma and MEN2 syndromes in childhood. Nature Reviews Endocrinology 7 596607. (doi:10.1038/nrendo.2011.139)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wells SA, Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF, Lee N, Machens A, Moley JF & Pacini F et al. 2015 Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid 25 567610. (doi:10.1089/thy.2014.0335)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation