The 3PAs: An Update on the Association of Pheochromocytomas, Paragangliomas, and Pituitary Tumors

Abstract

Pituitary adenomas (PA) and pheochromocytomas/paragangliomas (PHEO/PGL) are rare tumors. Although they may co-exist by coincidence, there is mounting evidence that genes predisposing in PHEO/PGL development, may play a role in pituitary tumorigenesis. In 2012, we described a GH-secreting PA caused by an SDHD mutation in a patient with familial PGLs and found loss of heterozygosity at the SDHD locus in the pituitary tumor, along with increased hypoxia-inducible factor 1α (HIF-1α) levels. Additional patients with PAs and SDHx defects have since been reported. Overall, prevalence of SDHx mutations in PA is very rare (0.3–1.8% in unselected cases) but we and others have identified several cases of PAs with PHEOs/PGLs, like our original report, a condition which we termed the 3 P association (3PAs). Interestingly, when 3PAs is found in the sporadic setting, no SDHx defects were identified, whereas in familial PGLs, SDHx mutations were identified in 62.5–75% of the reported cases. Hence, pituitary surveillance is recommended among patients with SDHx defects. It is possible that the SDHx germline mutation-negative 3PAs cases may be due to another gene, epigenetic changes, mutations in modifier genes, mosaicism, somatic mutations, pituitary hyperplasia due to ectopic hypothalamic hormone secretion or a coincidence. PA in 3PAs are mainly macroadenomas, more aggressive, more resistant to somatostatin analogues, and often require surgery. Using the Sdhb ^+/− mouse model, we showed that hyperplasia may be the first abnormality in tumorigenesis as initial response to pseudohypoxia. We also propose surveillance and follow-up approach of patients presenting with this association.

Key words

pituitary adenoma - pheochromocytoma - paraganglioma - succinate dehydrogenase

Publication History

Received: 13 March 2018

Accepted: 09 July 2018

Article published online:
01 October 2018

• References

• 1 WHO Classification of Tumours of Endocrine Organs WHO/IARC Classification of Tumours. Lloyd RV, Osamura RY, Klöppel GR. (eds) Volume 10 4th Edition WHO; 2017
• 2 Kantorovich V, Koch CA, Pacak K.Pheochromocytoma and Paraganglioma. Groot LJ, Chrousos G, Dungan K, Feingold KR, Grossman A, Hershman JM, Koch C, Korbonits M, McLachlan R, New M, Purnell J, Rebar R, Singer F, Vinik A, Ed Source Endotext. Available from https://www.ncbi.nlm.nih.gov/pubmed/25905361
• 3 Vicha A, Musil Z, Pacak K. Genetics of pheochromocytoma and paraganglioma syndromes: new advances and future treatment options. Curr Opin Endocrinol Diabetes Obes 2013; 20: 186-191
• 4 Baysal BE, Ferrell RE, Willett-Brozick JE, Lawrence EC, Myssiorek D, Bosch A, Van der Mey A, Taschner PEM, Rubinstein WS, Myers EN, Richard III CW, Cornelisse CJ, Devilee P, Devlin B. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 2000; 287: 848-851
• 5 Niemann S, Müller U. Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nat Genet 2000; 26: 268-270
• 6 Astuti D, Latif F, Dallol A, Dahia PLM, Douglas F, George E, Sköldberg F, Husebye ES, Eng C, Maher ER. Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J Hum Genet 2001; 69: 49-54
• 7 Burnichon N, Brière J-J, Libé R, Vescovo L, Rivière J, Tissier F, Jouanno E, Jeunemaitre X, Bénit P, Tzagoloff A, Rustin P, Bertherat J, Favier J, Gimenez-Roqueplo A-P. SDHA is a tumor suppressor gene causing paraganglioma. Hum Mol Genet 2010; 19: 3011-3020
• 8 McWhinney SR, Pasini B, Stratakis CA. Familial gastrointestinal stromal tumors and germ-line mutations. N Engl J Med 2007; 357: 1054-1056
• 9 Gill AJ, Hes O, Papathomas T, Šedivcová M, Tan PH, Agaimy A, Andresen PA, Kedziora A, Clarkson A, Toon CW, Sioson L, Watson N, Chou A, Paik J, Clifton-Blight RJ, Robinson BG, Benn DE, Hills K, Maclean F, Niemeijer ND, Vlatkovic L, Hartmann A, Corssmit EPM, van Leenders GJLH, Przbycin C, McKenney J, Magi-Galluzzi CM, Yilmaz A, Yu D, Nicoli KD, Yong JL, Sibony M, Yakirevich E, Fleming S, Chow CW, Miettinen M, Michal M, Trpkov K. Succinate dehydrogenase (SDH)-deficient renal carcinoma: a morphologically distinct entity: a clinicopathologic series of 36 tumors from 27 patients. Am J Surg Pathol 2014; 38: 1588-1602
• 10 Ozluk Y, Taheri D, Matoso A, Sanli O, Berker NK, Yakirevich E, Yakirevich E, Balasubramanian S, Ross JS, Ali SM, Netto GJ. Renal carcinoma associated with a novel succinate dehydrogenase A mutation: A case report and review of literature of a rare subtype of renal carcinoma. Hum Pathol 2015; 46: 1951-1955
• 11 Vanharanta S, Buchta M, McWhinney SR, Virta SK, Peçzkowska M, Morrison CD, Lehtonen R, Januszewicz A, Järvinen H, Juhola M, Mecklin J-P, Pukkala E, Herva R, Kiuru M, Nupponen NN, Aaltonen LA, Neumann HPH, Eng C. Early-onset renal cell carcinoma as a novel extraparaganglial component of SDHB-associated heritable paraganglioma. Am J Hum Genet 2004; 74: 153-159
• 12 Ricketts C, Woodward ER, Killick P, Morris MR, Astuti D, Latif F, Maher ER. Germline SDHB mutations and familial renal cell carcinoma. J Natl Cancer Inst 2008; 100: 1260-1262
• 13 Niemeijer ND, Papathomas TG, Korpershoek E, De Krijger RR, Oudijk L, Morreau H, Bayley J-P, Hes FJ, Jansen JC, Dinjens WNM, Corssmit EPM. Succinate dehydrogenase (SDH)-deficient pancreatic neuroendocrine tumor expands the SDH-related tumor spectrum. J Clin Endocrinol Metab 2015; 100: E1386-E1393
• 14 Ni Y, Zbuk KM, Sadler T, Patocs A, Lobo G, Edelman E, Platzer P, Orloff MS, Waite KA, Eng C. Germline mutations and mariants in the succinate dehydrogenase genes in Cowden and Cowden-like syndromes. Am J Hum Genet 2008; 83: 261-268
• 15 Xekouki P, Pacak K, Almeida M, Wassif CA, Rustin P, Nesterova M, Sierra MDLL, Matro J, Ball E, Azevedo M, Horvath A, Lyssikatos C, Quezado M, Patronas N, Ferrando B, Pasini B, Lytras A, Tolis G, Stratakis CA. Succinate dehydrogenase (SDH) D subunit (SDHD) inactivation in a growth-hormone-producing pituitary tumor: A new association for SDH?. J Clin Endocrinol Metab 2012; 97: E357-E366
• 16 Jochmanová I, Yang C, Zhuang Z, Pacak K. Hypoxia-inducible factor signaling in pheochromocytoma: Turning the rudder in the right direction. J Natl Cancer Inst 2013; 105: 1270-1283
• 17 Xekouki P, Stratakis CA. Succinate dehydrogenase (SDHx) mutations in pituitary tumors: Could this be a new role for mitochondrial complex II and/or Krebs cycle defects?. Endocr Relat Cancer 2012; 19: C33-C40
• 18 Gill AJ, Toon CW, Clarkson A, Sioson L, Chou A, Winship I, Robinson BG, Benn DE, Clifton-Bligh RJ, Dwight T. Succinate dehydrogenase deficiency is rare in pituitary adenomas. Am J Surg Pathol 2014; 38: 560-566
• 19 Evenepoel L, Papathomas TG, Krol N, Korpershoek E, de Krijger RR, Persu A, Dinjens WNM. Toward an improved definition of the genetic and tumor spectrum associated with SDH germ-line mutations. Genet Med 2015; 17: 610-620
• 20 Niemeijer ND, Rijken JA, Eijkelenkamp K, van der Horst-Schrivers ANA, Kerstens MN, Tops CM, van Berkel A, Timmers HJ, Kunst HPM, Leemans CR, Bisschop PH, Dreijerink KM, van Dooren M, Bayley J-P, Pereira AM, Jansen J, Hes FJ, Hense E, Corssmit EP. The phenotype of SDHB germline mutation carriers: a nationwide study. Eur J Endocrinol 2017; 177: 115-125
• 21 Guerrero Pérez F, Lisbona Gil A, Robledo M, Iglesias P, Vilabona Artero C. Pituitary adenoma associated with pheochromocytoma/paraganglioma: A new form of multiple endocrine neoplasia. Endocrinol Nutr 2016; 63: 506-508
• 22 Dénes J, Swords F, Rattenberry E, Stals K, Owens M, Cranston T, Xekouki P, Moran L, Kumar A, Wassif C, Fersht N, Baldeweg SE, Morris D, Lightman S, Agha A, Rees A, Grieve J, Powell M, Boguszewski CL, Dutta P, Thakker RV, Srirangalingam U, Thompson CJ, Druce M, Higham C, Davis J, Eeles R, Stevenson M, O’Sullivan B, Taniere P, Skordilis K, Gabrovska P, Barlier A, Webb SM, Aulinas A, Drake WM, Bevan JS, Preda C, Dalantaeva N, Ribeiro-Oliveira A, Garcia IT, Yordanova G, Iotova V, Evanson J, Grossman AB, Trouillas J, Ellard S, Stratakis CA, Maher ER, Roncaroli F, Korbonits M. Heterogeneous genetic background of the association of pheochromocytoma/paraganglioma and pituitary adenoma: Results from a large patient cohort. J Clin Endocrinol Metab 2015; 100: E531-E541
• 23 Dénes JSF, Xekouki P, Kumar AV, Maher ER, Ferscht N, Grieve J, Baldeweg SE, Stratakis CA, Korbonits M. Familial pituitary adenoma and paraganglioma syndrome—a novel type of multiple endocrine neoplasia. In: 94th Annual Meeting of The Endocrine Society: 2012; 203 (OR41-2)
• 24 Dwight T, Mann K, Benn DE, Robinson BG, McKelvie P, Gill AJ, Winship I, Clifton-Bligh RJ. Familial SDHA mutation associated with pituitary adenoma and pheochromocytoma/paraganglioma. J Clin Endocrinol Metab 2013; 98: E1103-E1108
• 25 Papathomas TG, Gaal J, Corssmit EPM, Oudijk L, Korpershoek E, Heimdal K, Bayley JP, Morreau H, van Dooren M, Papaspyrou K, Schreiner T. Non-pheochromocytoma (PCC)/paraganglioma (PGL) tumors in patients with succinate dehydrogenase-related PCC-PGL syndromes: A clinicopathological and molecular analysis. Eur J Endocrinol 2014; 170: 1-12
• 26 Xekouki P, Szarek E, Bullova P, Giubellino A, Quezado M, Mastroyannis SA, Mastorakos P, Wassif CA, Raygada M, Rentia N, Dye L. Pituitary adenoma with paraganglioma/pheochromocytoma (3PAs) and succinate dehydrogenase defects in human and mice. J Clin Endocrinol Metab 2015; 100: E710-E719
• 27 De Sousa SM, McCabe MJ, Wu K, Roscioli T, Gayevskiy V, Brook K, Rawlings L, Scott HS, Thompson TJ, Earls P, Gill AJ. Germline variants in familial pituitary tumour syndrome genes are common in young patients and families with additional endocrine tumours. Eur J Endocrinol 2017; 176: 635-644
• 28 Marx S, Spiegel AM, Skarulis MC, Doppman JL, Collins FS, Liotta LA. Multiple endocrine neoplasia type 1: clinical and genetic topics. Annals of internal medicine 1998; 129: 484-494
• 29 Okada R, Shimura T, Tsukida S, Ando J, Kofunato Y, Momma T, Yashima R, Koyama Y, Suzuki S, Takenoshita S. Concomitant existence of pheochromocytoma in a patient with multiple endocrine neoplasia type 1. Surg Case Rep 2016; 2: 84
• 30 Trump D, Farren B, Wooding C, Pang JT, Besser GM, Buchanan KD, Edwards CR, Heath DA, Jackson CE, Jansen S, Lips K. Clinical studies of multiple endocrine neoplasia type 1 (MEN1). QJM 1996; 89: 653-670
• 31 Jamilloux Y, Favier J, Pertuit M, Delage-Corre M, Lopez S, Teissier M-P, Mathonnet M, Galinat S, Barlier A, Archambeaud F. A MEN1 syndrome with a paraganglioma. Eur J Hum Genet 2014; 22: 283-285
• 32 Dackiw APB, Cote GJ, Fleming JB, Schultz PN, Stanford P, Vassilopoulou-Sellin R, Evans DB, Gagel RF, Lee JE. Screening for MEN1 mutations in patients with atypical endocrine neoplasia. Surgery 1999; 126: 1097-1104
• 33 Daly AF, Castermans E, Oudijk L, Guitelman MA, Beckers P, Potorac I, Neggers SJ, Sacre N, van der Lely AJ, Bours V, de Herder WW. Pheochromocytomas and pituitary adenomas in three patients with MAX exon deletions. Endocr Relat Cancer 2018; 25: L37-L42
• 34 Roszko KL, Blouch E, Blake M, Powers JF, Tischler AS, Hodin R, Sadow P, Lawson EA. Case Report of a prolactinoma in a patient with a novel MAX mutation and bilateral pheochromocytomas. J Endoc Soc 2017; 1: 1401-1407
• 35 Kantorovich V, King KS, Pacak K. SDH-related pheochromocytoma and paraganglioma. Best Pract Res Clin Endocrinol Metab 2010; 24: 415-424
• 36 Ziegler CG, Brown JW, Schally AV, Erler A, Gebauer L, Treszl A, Young L, Fishman LM, Engel JB, Willenberg HS, Petersenn S. Expression of neuropeptide hormone receptors in human adrenal tumors and cell lines: antiproliferative effects of peptide analogues. Proc Natl Acad Sci U S A 2009; 106: 15879-15884
• 37 Freddi S, Arnaldi G, Fazioli F, Scarpelli M, Appolloni G, Mancini T, Kola B, Bertagna X, Mantero F, Collu R, Boscaro M. Expression of growth hormone-releasing hormone receptor splicing variants in human primary adrenocortical tumours. Clin Endocrinol 2005; 62: 533-538
• 38 Ueberberg B, Unger N, Sheu SY, Walz MK, Schmid KW, Saeger W, Mann K, Petersenn S. Differential expression of ghrelin and its receptor (GHS-R1a) in various adrenal tumors and normal adrenal gland. Horm Metab Res 2008; 40: 181-188
• 39 O’Toole SM, Dénes J, Robledo M, Stratakis CA, Korbonits M. The association of pituitary adenomas and phaeochromocytomas or paragangliomas. Endocr Relat Cancer 2015; 22: T105-T122
• 40 Zhang H, Bosch-Marce M, Shimoda LA, Yee ST, Jin HB, Wesley JB, Gonzalez FJ, Semenza GL. Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J Biol Chem 2008; 283: 10892-10903
• 41 Zakeri Z, Lockshin RA. Cell death: history and future. Adv Exp Med Biol 2008; 615: 1-11
• 42 Lee JG, Shin JH, Shim HS, Lee CY, Kim DJ, Kim YS, Chung KY. Autophagy contributes to the chemo-resistance of non-small cell lung cancer in hypoxic conditions. Respir Res 2015; 16: 138
• 43 Chaachouay H, Fehrenbacher B, Toulany M, Schaller M, Multhoff G, Rodemann HP. AMPK-independent autophagy promotes radioresistance of human tumor cells under clinical relevant hypoxia in vitro. Radiother Oncol 2015; 116: 409-416
• 44 van Nederveen FH, Gaal J, Favier J, Korpershoek E, Oldenburg RA, de Bruyn EM, Sleddens HF, Derkx P, Rivière J, Dannenberg H, Petri BJ. An immunohistochemical procedure to detect patients with paraganglioma and phaeochromocytoma with germline SDHB, SDHC, or SDHD gene mutations: a retrospective and prospective analysis. Lancet Oncol 2009; 10: 764-771
• 45 Gill AJ, Benn DE, Chou A, Clarkson A, Muljono A, Meyer-Rochow GY, Richardson AL, Sidhu SB, Robinson BG, Clifton-Bligh RJ. Immunohistochemistry for SDHB triages genetic testing of SDHB, SDHC, and SDHD in paraganglioma-pheochromocytoma syndromes. Hum Pathol 2010; 41: 805-814
• 46 Richter S, Peitzsch M, Rapizzi E, Lenders JW, Qin N, De Cubas AA, Schiavi F, Rao JU, Beuschlein F, Quinkler M, Timmers HJ. Krebs cycle metabolite profiling for identification and stratification of pheochromocytomas/paragangliomas due to succinate dehydrogenase deficiency. J Clin Endocrinol Metab 2014; 99: 3903-3911
• 47 Ryland GL, Doyle MA, Goode D, Boyle SE, Choong DYH, Rowley SM, Li J, Bowtell DD, Tothill RW, Campbell IG, Gorringe KL. Loss of heterozygosity: what is it good for?. BMC Med Genom 2015; 8: 45
• 48 Grogan RH, Pacak K, Pasche L, Huynh TT, Greco RS. Bilateral Adrenal Medullary Hyperplasia Associated With an SDHB Mutation. J Clin Oncol 2011; 29: E200-E202
• 49 Weber A, Hoffmann MM, Neumann HPH, Erlic Z. Somatic mutation analysis of the SDHB, SDHC, SDHD, and RET genes in the clinical assessment of sporadic and hereditary pheochromocytoma. Horm Cancer 2012; 3: 187-192
• 50 Pasini B, McWhinney SR, Bei T, Matyakhina L, Stergiopoulos S, Muchow M, Boikos SA, Ferrando B, Pacak K, Assie G, Baudin E. Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD. Eur J Hum Genet 2008; 16: 79-88
• 51 Haller F, Moskalev EA, Faucz FR, Barthelmeß S, Wiemann S, Bieg M, Assie G, Bertherat J, Schaefer IM, Otto C, Rattenberry E. Aberrant DNA hypermethylation of SDHC: a novel mechanism of tumor development in Carney triad. Endocr Relat Cancer 2014; 21: 567-577
• 52 Buffet A, Smati S, Mansuy L, Ménara M, Lebras M, Heymann MF, Simian C, Favier J, Murat A, Cariou B, Gimenez-Roqueplo AP. Mosaicism in HIF2A-related polycythemia-paraganglioma syndrome. J Clin Endocrinol Metab 2014; 99: E369-E373
• 53 Lecoq AL, Zizzari P, Hage M, Decourtye L, Adam C, Viengchareun S, Veldhuis JD, Geoffroy V, Lombès M, Tolle V, Guillou A. Mild pituitary phenotype in 3- and 12-month-old Aip-deficient male mice. J Endocrinol 2016; 231: 59-69
• 54 Lloyd RV, Ruebel KH, Zhang S, Jin L. Pituitary hyperplasia in glycoprotein hormone alpha subunit-, p18(INK4C)-, and p27(kip-1)-null mice: analysis of proteins influencing p27(kip-1) ubiquitin degradation. Am J Pathol 2002; 160: 1171-1179
• 55 Donangelo I, Gutman S, Horvath E, Kovacs K, Wawrowsky K, Mount M, Melmed S. Pituitary tumor transforming gene overexpression facilitates pituitary tumor development. Endocrinology 2006; 147: 4781-4791
• 56 Bai F, Chan HL, Smith MD, Kiyokawa H, Pei X-H. p19Ink4d is a tumor suppressor and controls pituitary anterior lobe cell proliferation. Mol Cell Biol 2014; 34: 2121-2134
• 57 Gaston-Massuet C, Andoniadou CL, Signore M, Jayakody SA. Increased Wingless (Wnt) signaling in pituitary progenitor/stem cells gives rise to pituitary tumors in mice and humans. Proc Natl Acad Sci U S A 2011; 108: 11482-11487
• 58 Trivellin G, Daly AF, Faucz FR, Yuan B, Rostomyan L, Larco DO, Schernthaner-Reiter MH, Szarek E, Leal LF, Caberg JH, Castermans E. Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation. N Engl J Med 2014; 371: 2363-2374
• 59 Stergiopoulos SG, Abu-Asab MS, Tsokos M, Stratakis CA. Pituitary pathology in Carney complex patients. Pituitary 2004; 7: 73-82
• 60 Villa C, Lagonigro MS, Magri F, Koziak M, Jaffrain-Rea ML, Brauner R, Bouligand J, Junier MP, Di Rocco F, Sainte-Rose C, Beckers A. Hyperplasia-adenoma sequence in pituitary tumorigenesis related to aryl hydrocarbon receptor interacting protein gene mutation. Endocr Relat Cancer 2011; 18: 347-356
• 61 Jochmanová I, Zhuang Z, Pacak K. Pheochromocytoma: Gasping for air. Horm Cancer 2015; 6: 191-205
• 62 Szarek E, Ball ER, Imperiale A, Tsokos M, Faucz FR, Giubellino A, Moussallieh FM, Namer IJ, Abu-Asab MS, Pacak K, Taïeb D. Carney triad, SDH-deficient tumors, and Sdhb+/- mice share abnormal mitochondria. Endocr Relat Cancer 2015; 22: 345-352
• 63 Grandemange S, Herzig S, Martinou JC. Mitochondrial dynamics and cancer. Seminars Cancer Biol 2009; 19: 50-56
• 64 Bristow RG, Hill RP. Hypoxia and metabolism. Hypoxia, DNA repair and genetic instability. Nat Rev Cancer 2008; 8: 180-192
• 65 Lenders JWM, Duh Q-Y, Eisenhofer G, Gimenez-Roqueplo A-P, Grebe SKG, Murad MH, Naruse M, Pacak K, Young Jr. WF. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2014; 99: 1915-1942
• 66 Plouin PF, Amar L, Dekkers OM, Fassnacht M, Gimenez-Roqueplo AP, Lenders JWM, Lussey-Lepoutre C, Steichen O. European Society of Endocrinology Clinical Practice Guideline for long-term follow-up of patients operated on for a phaeochromocytoma or a paraganglioma. Eur J Endocrinol 2016; 174: G1-G10
• 67 Aghi MK, Chen CC, Fleseriu M, Newman SA, Lucas JW, Kuo JS, Barkhoudarian G, Farrell CJ, Sheehan J, Ziu M, Dunn IF. Congress of Neurological Surgeons Systematic Review and Evidence-Based Guidelines on the Management of Patients with Nonfunctioning Pituitary Adenomas: Executive Summary. Neurosurgery 2016; 79: 521-523
• 68 Katznelson L, Laws ER, Melmed S, Molitch ME, Murad MH, Utz A, Wass JA. Acromegaly: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2014; 99: 3933-3951
• 69 Melmed S, Casanueva FF, Hoffman AR, Kleinberg DL, Montori VM, Schlechte JA, Wass JA. Diagnosis and treatment of hyperprolactinemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2011; 96: 273-288
• 70 Nieman LK, Biller BMK, Findling JW, Murad MH, Newell-Price J, Savage MO, Tabarin A. Treatment of cushing’s syndrome: An endocrine society clinical practice guideline. J Clin Endocrinol Metab 2015; 100: 2807-2831
• 71 The Endocrine Society. Pituitary incidentaloma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2011; 96: 894-904
• 72 Casey RT, Warren AY, Martin JE, Challis BG, Rattenberry E, Whitworth J, Andrews KA, Roberts T, Clark GR, West H, Smith PS. Clinical and Molecular Features of Renal and Pheochromocytoma/Paraganglioma Tumor Association Syndrome (RAPTAS): Case Series and Literature Review. J Clin Endocrinol Metab 2017; 102: 4013-4022
• 73 Rostomyan L, Beckers A. Screening for genetic causes of growth hormone hypersecretion. Growth Horm IGF Res 2016; 30: 52-57
• 74 Goodwin S, McPherson JD, McCombie WR. Coming of age: ten years of next-generation sequencing technologies. Nat Rev Genet 2016; 17: 333-351
• 75 Beckers A. Means, motive, and opportunity: SDH mutations are suspects in pituitary tumors. J Clin Endocrinol Metab 2013; 98: 2274-2276
• 76 Gorospe L, Cabañero-Sánchez A, Muñoz-Molina GM, Pacios-Blanco RE, Ureña Vacas A, García-Santana E. An unusual case of mediastinal paraganglioma and pituitary adenoma. Surgery 2017; 162: 1338-1339
• 77 Efstathiadou ZA, Sapranidis M, Anagnostis P, Kita MD, Rosenthal EL. Unusual case of Cowden-like syndrome, neck paraganglioma, and pituitary adenoma. Head Neck 2014; 36: E12-E16
• 78 López-Jiménez E, De Campos JM, Kusak EM, Landa I, Leskelä S, Montero-Conde C, Leandro-Garcia LJ, Vallejo LA, Madrigal B, Rodríguez-Antona C, Robledo M, Cascón A. SDHC mutation in an elderly patient without familial antecedents. Clin Endocrinol 2008; 69: 906-910
• 79 Varsavsky M, Sebastián-Ochoa A, Torres Vela E. Coexistence of a pituitary macroadenoma and multicentric paraganglioma: a strange coincidence. Endocrinología y Nutrición 2013; 60: 154-156
• 80 Jeong YJ, Oh HK, Bong JG. Multiple endocrine neoplasia type 1 associated with breast cancer: A case report and review of the literature. Oncol Lett 2014; 8: 230-234
• 81 Langer P, Cupisti K, Bartsch DK, Nies C, Goretzki PE, Rothmund M, Röher HD. Adrenal Involvement in Multiple Endocrine Neoplasia Type 1. World J Surg 2002; 26: 891
• 82 Carty SE, Helm AK, Amico JA, Clarke MR, Foley TP, Watson CG, Mulvihill JJ, Marx S, Skogseid B. The variable penetrance and spectrum of manifestations of multiple endocrine neoplasia type 1. Surgery 1998; 124: 1106-1114
• 83 Heinlen JE, Buethe DD, Culkin DJ, Slobodov G. Multiple endocrine neoplasia 2a presenting with pheochromocytoma and pituitary macroadenoma. ISRN Oncology 2011; 1-4
• 84 Naziat A, Karavitaki N, Thakker R, Ansorge O, Sadler G, Gleeson F, Cranston T, McCormack A, Grossman AB, Shine B. Confusing genes: a patient with MEN2A and Cushing’s disease. Clin Endocrinol 2013; 78: 966-968
• 85 1000 Genomes Project Consortium. An integrated map of genetic variation from 1,092 human genomes. Nature. 2012; 491: 56
• 86 Koshy AN, Cheng VE, Sajeev JK, Venkataraman P, Profitis K. Bilateral pheochromocytoma and paraganglioma: a rare cause of cardiomyopathy. Eur Heart J Cardiovasc Imag 2016; 17: 705
• 87 Boguszewski CL, Fighera TM, Bornschein A, Marques FM, Dénes J, Rattenbery E, Maher ER, Stals K, Ellard S, Korbonits M. Genetic studies in a coexistence of acromegaly, pheochromocytoma, gastrointestinal stromal tumor (GIST) and thyroid follicular adenoma. Arq Bras Endocrinol Metabol 2012; 56: 507-512
• 88 Parghane RV, Agrawal K, Mittal BR, Shukla J, Bhattacharya A, Mukherjee KK. 68Ga DOTATATE PET/CT in a rare coexistence of pituitary macroadenoma and multiple paragangliomas. Clin Nuc Med 2014; 39: 91-93
• 89 Mumby C, Davis JRE, Trouillas J, Higham CE. Phaeochromocytoma and acromegaly: a unifying diagnosis. Endocrinol Diabetes Metab Case Rep 2014; 140036:
• 90 Sisson JC, Giordano TJ, Avram AM. Three endocrine neoplasms: an unusual combination of pheochromocytoma, pituitary adenoma, and papillary thyroid carcinoma. Thyroid 2012; 22: 430-436
• 91 Gatta-Cherifi B, Chabre O, Murat A, Niccoli P, Cardot-Bauters C, Rohmer V, Young J, Delemer B, Du Boullay H, Verger MF, Kuhn JM, Sadoul JL, Ruszniewski P, Beckers A, Monsaingeon M, Baudin E, Goudet P, Tabarin A. Adrenal involvement in MEN1. Analysis of 715 cases from the Groupe d’étude des Tumeurs Endocrines database. Eur J Endocrinol 2012; 166: 269-279
• 92 Zhang C, Ma G, Liu X, Zhang H, Deng H, Nowell J, Miao Q. Primary cardiac pheochromocytoma with multiple endocrine neoplasia. J Cancer Res Clin Oncol 2011; 137: 1289-1291
• 93 Yaylali GF, Akin F, Bastemir M, Yaylali YT, Ozden A. Phaeochromocytoma combined with subclinical Cushing’s syndrome and pituitary microadenoma. Clin Invest Med 2008; 31: 176-181
• 94 Breckenridge SM, Hamrahian AH, Faiman C, Suh J, Prayson R, Mayberg M. Coexistence of a pituitary macroadenoma and pheochromocytoma – a case report and review of the literature. Pituitary 2003; 6: 221-225
• 95 Dünser MW, Mayr AJ, Gasser R, Rieger M, Friesenecker B, Hasibeder WR. Cardiac failure and multiple organ dysfunction syndrome in a patient with endocrine adenomatosis. Acta Anaesthesiol Scand 2002; 46: 1161-1164
• 96 Sleilati GG, Kovacs KT, Honasoge M. Acromegaly and pheochromocytoma: report of a rare coexistence. Endocr Pract 2002; 8: 54-60
• 97 Baughan J, De Gara C, Morrish D. A rare association between acromegaly and pheochromocytoma. Am J Surg 2001; 182: 185-187
• 98 Khalil WKA, Vadasz J, Rigo E, Kardos L, Tiszlavicz L, Gaspar L. Pheochromocytoma combined with unusual form of Cushing’s syndrome and pituitary microadenoma. Eur J Endocrinol 1999; 141: 653-654
• 99 Teh BT, Hansen J, Svensson PJ, Hartley L. Bilateral recurrent phaeochromocytoma associated with a growth hormone-secreting pituitary tumour. Br J Surg 1996; 83: 1132
• 100 Azzarelli B, Felten S, Muller J, Miyamoto R, Purvin V. Dopamine in paragangliomas of the glomus jugulare. Laryngoscope 1988; 98: 573-578
• 101 Bertrand JH, Ritz P, Reznik Y, Grollier G, Potier JC, Evrad C, Mahoudeau JA. Sipple’s syndrome associated with a large prolactinoma. Clin Endocrinol 1987; 27: 607-614
• 102 Larraza-Hernandez O, Albores-Saavedra J, Benavides G, Krause LG, Perez-Merizaldi JC, Ginzo A. Multiple endocrine neoplasia. Pituitary adenoma, multicentric papillary thyroid carcinoma, bilateral carotid body paraganglioma, parathyroid hyperplasia, gastric leiomyoma, and systemic amyloidosis. Am J Clin Pathol 1982; 78: 527-532
• 103 Meyers DH. Association of phaeochromocytoma and prolactinoma. MJA 1982; 1: 13-14
• 104 Blumenkopf B, Boekelheide K. Neck paraganglioma with a pituitary adenoma. Case report. J Neurosurg 1982; 57: 426-429
• 105 Anderson RJ, Lufkin EG, Sizemore GW, Carney JA, Sheps SG, Silliman YE. Acromegaly and pituitary adenoma with phaeochromocytoma: a variant of multiple endocrine neoplasia. Clin Endocrinol 1981; 14: 605-612
• 106 Myers JH, Eversman JJ. Acromegaly, hyperparathyroidism, and pheochromocytoma in the same patient. A multiple endocrine disorder. Arch Intern Med 1981; 141: 1521-1522
• 107 Alberts WM, McMeekin JO, George JM. Mixed multiple endocrine neoplasia syndromes. JAMA 1980; 244: 1236-1237
• 108 Janson KL, Roberts JA, Varela M. Multiple endocrine adenomatosis: in support of the common origin theories. J Urol 1978; 119: 161-165
• 109 Manger WM, Gifford RW. Studies on 38 patients with pheochromocytoma in whom catecholamines were determined. In: Pheochromocytoma. New York, NY: Springer; 1977: 276-295
• 110 Melicow MM. One hundred cases of pheochromocytoma (107 tumors) at the Columbia-Presbyterian Medical Center, 1926–1976: a clinicopathological analysis. Cancer 1977; 40: 1987-2004
• 111 Kadowaki S, Baba Y, Kakita T, Yamamoto H, Fukase M, Goto Y, Seino Y, Kato Y, Matsukara S, Imura H. A case of acromegaly associated with pheochromocytoma [in Japanese]. Saishin Igaku 1976; 31: 1402-1409
• 112 Farhi F, Dikman SH, Lawson W, Cobin RH, Zak FG. Paragangliomatosis associated with multiple endocrine adenomas. Arch Pathol Lab Med 1976; 100: 495-498
• 113 Berg B, Biörklund A, Grimelius L, Ingemansson S, Larsson LI, Stenram U, Akerman M. A new pattern of multiple endocrine adenomatosis: chemodectoma, bronchial carcinoid, GH-producing pituitary adenoma, and hyperplasia of the parathyroid glands, and antral and duodenal gastrin cells. Acta Med Scand 1976; 200: 321-326
• 114 Wolf LM, Duduisson M, Schrub JC, Metayer J, Laumonier R. Sipple’s syndrome associated with pituitary and parathyroid adenomas. Ann Endocrinol 1972; 33: 455-463
• 115 Miller GL, Wynn J. Acromegaly, pheochromocytoma, toxic goiter, diabetes mellitus, and endometriosis. Arch Intern Med 1971; 127: 299-303
• 116 Steiner A, Goodman A, Powers S. Study of a kindred with pheochromocytoma, medullary thyroid carcinoma, hyperparathyroidism and Cushing’s disease: multiple endocrine neoplasia, type 2. Medicine 1968; 47: 371-409
• 117 Kahn MT, Mullon DA. Phoechromocytoma without hypertension. Report of a patient with acromegaly JAMA 1964; 188: 74-75
• 118 German WJ, Flanigan S. Pituitary adenomas: a follow-up study of the Cushing series. Clin Neurosurg 1964; 10: 72-81
• 119 Iversen K. Acromegaly associated with phaeochromocytoma. Acta Med Scand 1952; 142: 1-5
• 120 Bayley JP, Devilee P, Taschner PEM. The SDH mutation database: an online resource for succinate dehydrogenase sequence variants involved in pheochromocytoma, paraganglioma and mitochondrial complex II deficiency. BMC Med Genet 2005; 6: 39
• 121 Benn DE, Gimenez-Roqueplo A-P, Reilly JR, Bertherat J, Burgess J, Byth K, Croxson M, Dahia PLM, Elston M, Henley OGD, Herman P, Murday V, Niccoli-Sire P, Pasieka JL, Rohmer V, Tucker K, Jeunemaitre X, Marsh DJ, Plouin PF, Robinson BG. Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes. J Clin Endocrinol Metab 2006; 91: 827-836
• 122 Ni Y, He X, Chen J, Moline J, Mester J, Orloff MS, Ringel MD, Eng C. Germline SDHx variants modify breast and thyroid cancer risks in Cowden and Cowden-like syndrome via FAD/NAD-dependant destabilization of p53. Hum Mol Genet 2012; 21: 300-310