OBJECTIVE: Multiple endocrine neoplasia type 2A (MEN 2A) is a rare syndrome caused by RET germline mutations and has been associated with primary hyperparathyroidism (PHPT) in up to 30% of cases. Recommendations on RET screening in patients with apparently sporadic PHPT are unclear. We aimed to estimate the prevalence of cases presenting with PHPT as first manifestation among MEN 2A index cases and to characterize the former cases. DESIGN AND METHODS: An international retrospective multicenter study of 1085 MEN 2A index cases. Experts from MEN 2 centers all over the world were invited to participate. A total of 19 centers in 17 different countries provided registry data of index cases followed from 1974 to 2017. RESULTS: Ten cases presented with PHPT as their first manifestation of MEN 2A, yielding a prevalence of 0.9% (95% CI: 0.4-1.6). 9/10 cases were diagnosed with medullary thyroid carcinoma (MTC) in relation to parathyroid surgery and 1/10 was diagnosed 15 years after parathyroid surgery. 7/9 cases with full TNM data were node-positive at MTC diagnosis. CONCLUSIONS: Our data suggest that the prevalence of MEN 2A index cases that present with PHPT as their first manifestation is very low. The majority of index cases presenting with PHPT as first manifestation have synchronous MTC and are often node-positive. Thus, our observations suggest that not performing RET mutation analysis in patients with apparently sporadic PHPT would result in an extremely low false-negative rate, if no other MEN 2A component, specifically MTC, are found during work-up or resection of PHPT.

Aix Marseille Univ APHM INSERM MMG Laboratory of Molecular Biology Hospital La Conception Marseille France

Aix Marseille Université Institut National de la Santé et de la Recherche Médicale Marseille France

AP HP Sorbonne Université Laboratoire Commun de Biologie et Génétique Moléculaires Hôpital St Antoine and INSERM CRSA Paris France

Cancer Genetics Kolling Institute Royal North Shore Hospital and University of Sydney Sydney New South Wales Australia

Centro de Investigación Biomédica en Red de Enfermedades Raras Madrid Spain

Department of Breast and Endocrine Surgery National Hospital Organization Higashinagoya National Hospital Nagoya Japan

Department of Breast and Endocrine Surgery Tokyo Women's Medical University Tokyo Japan

Department of Clinical Research University of Southern Denmark Odense Denmark

Department of Endocrine Surgery Noguchi Thyroid Clinic and Hospital Foundation Beppu Oita Japan

Department of Endocrinology And Metabolic Diseases Ankara University School of Medicine Ankara Turkey

Department of Endocrinology Assistance Publique Hôpitaux de Marseille Hôpital de la Conception Centre de Référence des Maladies Rares de l'hypophyse HYPO Marseille France

Department of Endocrinology Endocrine Oncology Unit Instituto do Cancer do Estado de São Paulo Faculdade de Medicina da Universidade de São Paulo São Paulo Brazil

Department of Endocrinology University of Groningen University Medical Center Groningen Groningen Netherlands

Department of Hypertension Institute of Cardiology Warsaw Poland

Department of Medical Genetics and Genomics Sapporo Medical University School of Medicine Sapporo Japan

Department of Molecular Endocrinology Institute of Endocrinology Prague Czech Republic

Department of Nuclear Medicine and Endocrine Oncology Maria Sklodowska Curie National Research Institute of Oncology Gliwice Branch Gliwice Poland

Department of ORL Head and Neck Surgery and Audiology Odense University Hospital Odense Denmark

Department of Research Studies and Additional Projects Cancer Patients Aid Association Dr Vithaldas Parmar Research and Medical Centre Worli Mumbai India

Department of Surgery Kuma Hospital Kobe Hyogo Japan

Department of Surgical Oncology Institute of Oncology Ljubljana Slovenia

Endocrine Section Hospital del Salvador Santiago de Chile Department of Medicine University of Chile Santiago Chile

Endocrinology and Nutrition Department University Hospital 'La Paz' Madrid Spain

Endocrinology Unit Department of Medicine University of Padua Padua Italy

Fédération d'Endocrinologie Hospices Civils de Lyon Université Lyon 1 France

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

HAS SE Momentum Hereditary Endocrine Tumors Research Group Semmelweis University Budapest Hungary

Hereditary Endocrine Cancer Group Spanish National Cancer Research Center Madrid Spain

Laboratoire de Biochimie et Biologie Moléculaire CHU Angers Université d'Angers UMR CNRS 6015 INSERM U1083 MITOVASC Angers France

Laboratoire de Biochimie et Oncologie Moléculaire CHU Lille Lille France

Laboratoire de Génétique Moléculaire CHU Lyon Lyon France

Réseau TenGen Marseille France

Section for Preventive Medicine Medical Center University of Freiburg Faculty of Medicine Albert Ludwigs University of Freiburg Freiburg Germany

Service de Génétique AP HP Hôpital européen Georges Pompidou Paris France

Université de Paris PARCC INSERM Paris France

Zobrazit více v PubMed

Donis-Keller H, Dou S, Chi D, Carlson KM, Toshima K, Lairmore TC, Howe JR, Moley JF, Goodfellow P, Wells SA., Jr Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Human Molecular Genetics 1993. 2 851–856. (10.1093/hmg/2.7.851) PubMed DOI

Mulligan LM, Kwok JB, Healey CS, Elsdon MJ, Eng C, Gardner E, Love DR, Mole SE, Moore JK, Papi L. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature 1993. 363 458–460. (10.1038/363458a0) PubMed DOI

Carlson KM, Dou S, Chi D, Scavarda N, Toshima K, Jackson CE, Wells SA, Goodfellow PJ, Jr, Donis-Keller H. Single missense mutation in the tyrosine kinase catalytic domain of the RET protooncogene is associated with multiple endocrine neoplasia type 2B. PNAS 1994. 91 1579–1583. (10.1073/pnas.91.4.1579) PubMed DOI PMC

Hofstra RM, Landsvater RM, Ceccherini I, Stulp RP, Stelwagen T, Luo Y, Pasini B, Hoppener JW, van Amstel HK, Romeo G. A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature 1994. 367 375–376. (10.1038/367375a0) PubMed DOI

Eng C, Smith DP, Mulligan LM, Nagai MA, Healey CS, Ponder MA, Gardner E, Scheumann GF, Jackson CE, Tunnacliffe A. Point mutation within the tyrosine kinase domain of the RET proto-oncogene in multiple endocrine neoplasia type 2B and related sporadic tumours. Human Molecular Genetics 1994. 3 237–241. (10.1093/hmg/3.2.237) PubMed DOI

Eng C, Clayton D, Schuffenecker I, Lenoir G, Cote G, Gagel RF, van Amstel HK, Lips CJ, Nishisho I, Takai SI, et al. The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. JAMA 1996. 276 1575–1579. PubMed

Opsahl EM, Brauckhoff M, Schlichting E, Helset K, Svartberg J, Brauckhoff K, Maehle L, Engebretsen LF, Sigstad E, Groholt KK, et al. A Nationwide study of multiple endocrine neoplasia type 2A in Norway: predictive and prognostic factors for the clinical course of medullary thyroid carcinoma. Thyroid 2016. 26 1225–1238. (10.1089/thy.2015.0673) PubMed DOI

Mathiesen JS, Kroustrup JP, Vestergaard P, Stochholm K, Poulsen PL, Rasmussen ÅK, Feldt-Rasmussen U, Schytte S, Pedersen HB, Hahn CH, et al. Incidence and prevalence of multiple endocrine neoplasia 2A in Denmark 1901–2014: a nationwide study. Clinical Epidemiology 2018. 10 1479–1487. (10.2147/CLEP.S174606) PubMed DOI PMC

Mathiesen JS, Kroustrup JP, Vestergaard P, Madsen M, Stochholm K, Poulsen PL, Krogh Rasmussen Å, Feldt-Rasmussen U, Schytte S, Pedersen HB, et al. Incidence and prevalence of multiple endocrine neoplasia 2B in Denmark: a nationwide study. Endocrine-Related Cancer 2017. 24 L39–L42. (10.1530/ERC-17-0122) PubMed DOI

Znaczko A, Donnelly DE, Morrison PJ. Epidemiology, clinical features, and genetics of multiple endocrine neoplasia type 2B in a complete population. Oncologist 2014. 19 1284–1286. (10.1634/theoncologist.2014-0277) PubMed DOI PMC

Wells SA, Jr, Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF, Lee N, Machens A, Moley JF, Pacini F, et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid 2015. 25 567–610. (10.1089/thy.2014.0335) PubMed DOI PMC

Kloos RT, Eng C, Evans DB, Francis GL, Gagel RF, Gharib H, Moley JF, Pacini F, Ringel MD, et al. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid 2009. 19 565–612. (10.1089/thy.2008.0403) PubMed DOI

Brandi ML, Gagel RF, Angeli A, Bilezikian JP, Beck-Peccoz P, Bordi C, Conte-Devolx B, Falchetti A, Gheri RG, Libroia A, et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. Journal of Clinical Endocrinology and Metabolism 2001. 86 5658–5671. (10.1210/jcem.86.12.8070) PubMed DOI

Traugott AL, Moley JF. Multiple endocrine neoplasia type 2: clinical manifestations and management. Cancer Treatment and Research 2010. 153 321–337. (10.1007/978-1-4419-0857-5_18) PubMed DOI

Raue F, Kraimps JL, Dralle H, Cougard P, Proye C, Frilling A, Limbert E, Llenas LF, Niederle B. Primary hyperparathyroidism in multiple endocrine neoplasia type 2A. Journal of Internal Medicine 1995. 238 369–373. (10.1111/j.1365-2796.1995.tb01212.x) PubMed DOI

Kraimps JL, Denizot A, Carnaille B, Henry JF, Proye C, Bacourt F, Sarfati E, Dupond JL, Maes B, Travagli JP, et al. Primary hyperparathyroidism in multiple endocrine neoplasia type IIa: retrospective French multicentric study. Groupe d’Etude des Tumeurs a Calcitonine. World Journal of Surgery 1996. 20 808–812; discussion 812. (10.1007/s002689900123) PubMed DOI

Lebeault M, Pinson S, Guillaud-Bataille M, Gimenez-Roqueplo AP, Carrie A, Barbu V, Pigny P, Bezieau S, Rey JM, Delvincourt C, et al. Nationwide French study of RET variants detected from 2003 to 2013 suggests a possible influence of polymorphisms as modifiers. Thyroid 2017. 27 1511–1522. (10.1089/thy.2016.0399) PubMed DOI

Imai T, Uchino S, Okamoto T, Suzuki S, Kosugi S, Kikumori T, Sakurai A. & MEN Consortium of Japan. High penetrance of pheochromocytoma in multiple endocrine neoplasia 2 caused by germ line RET codon 634 mutation in Japanese patients. European Journal of Endocrinology 2013. 168 683–687. (10.1530/EJE-12-1106) PubMed DOI

Romei C, Mariotti S, Fugazzola L, Taccaliti A, Pacini F, Opocher G, Mian C, Castellano M, degli Uberti E, Ceccherini I, et al. Multiple endocrine neoplasia type 2 syndromes (MEN 2): results from the ItaMEN network analysis on the prevalence of different genotypes and phenotypes. European Journal of Endocrinology 2010. 163 301–308. (10.1530/EJE-10-0333) PubMed DOI

Maciel RMB, Camacho CP, Assumpcao LVM, Bufalo NE, Carvalho AL, de Carvalho GA, Castroneves LA, de Castro FM, Jr, Ceolin L, Cerutti JM, et al. Genotype and phenotype landscape of MEN2 in 554 medullary thyroid cancer patients: the BrasMEN study. Endocrine Connections 2019. 8 289–298. (10.1530/EC-18-0506) PubMed DOI PMC

Mathiesen JS, Kroustrup JP, Vestergaard P, Stochholm K, Poulsen PL, Rasmussen ÅK, Feldt-Rasmussen U, Gaustadnes M, Orntoft TF, van Overeem Hansen T, et al. Distribution of RET mutations in multiple endocrine neoplasia 2 in Denmark 1994-2014: a Nationwide Study. Thyroid 2017. 27 215–223. (10.1089/thy.2016.0411) PubMed DOI PMC

Bergant D, Hocevar M, Besic N, Glavac D, Korosec B, Caserman S. Hereditary medullary thyroid cancer in Slovenia – genotype-phenotype correlations. Wiener Klinische Wochenschrift 2006. 118 411–416. (10.1007/s00508-006-0636-8) PubMed DOI

Patocs A, Klein I, Szilvasi A, Gergics P, Toth M, Valkusz Z, Forizs E, Igaz P, Al-Farhat Y, Tordai A, et al. Genotype-phenotype correlations in Hungarian patients with hereditary medullary thyroid cancer. Wiener Klinische Wochenschrift 2006. 118 417–421. (10.1007/s00508-006-0635-9) PubMed DOI

Sharma BP, Saranath D. RET gene mutations and polymorphisms in medullary thyroid carcinomas in Indian patients. Journal of Biosciences 2011. 36 603–611. (10.1007/s12038-011-9095-0) PubMed DOI

Aydogan Bİ, Yuksel B, Tuna MM, Navdar Basaran M, Akkurt Kocaeli A, Ertorer ME, Aydin K, Guldiken S, Simsek Y, Cihan Karaca Z, et al. Distribution of RET mutations and evaluation of treatment approaches in hereditary medullary thyroid carcinoma in turkey. Journal of Clinical Research in Pediatric Endocrinology 2016. 8 13–20. (10.4274/jcrpe.2219) PubMed DOI PMC

Diaz RE, Wohllk N. Multiple endocrine neoplasia: the Chilean experience. Clinics 2012. 67 (Supplement 1) 7–11. (10.6061/clinics/2012(sup01)03) PubMed DOI PMC

Margraf RL, Crockett DK, Krautscheid PM, Seamons R, Calderon FR, Wittwer CT, Mao R. Multiple endocrine neoplasia type 2 RET proto-oncogene database: repository of MEN2-associated RET sequence variation and reference for genotype/phenotype correlations. Human Mutation 2009. 30 548–556. (10.1002/humu.20928) PubMed DOI

Mathiesen JS, Habra MA, Bassett JHD, Choudhury SM, Balasubramanian SP, Howlett TA, Robinson BG, Gimenez-Roqueplo AP, Castinetti F, Vestergaard P, et al. Risk profile of the RET A883F germline mutation: an international collaborative study. Journal of Clinical Endocrinology and Metabolism 2017. 102 2069–2074. (10.1210/jc.2016-3640) PubMed DOI

Castinetti F, Waguespack SG, Machens A, Uchino S, Hasse-Lazar K, Sanso G, Else T, Dvorakova S, Qi XP, Elisei R, et al. Natural history, treatment, and long-term follow up of patients with multiple endocrine neoplasia type 2B: an international, multicentre, retrospective study. Lancet: Diabetes and Endocrinology 2019. 7 213–220. (10.1016/S2213-8587(18)30336-X) PubMed DOI PMC

Khan AA, Hanley DA, Rizzoli R, Bollerslev J, Young JE, Rejnmark L, Thakker R, D’Amour P, Paul T, Van Uum S, et al. Primary hyperparathyroidism: review and recommendations on evaluation, diagnosis, and management. A Canadian and international consensus. Osteoporosis International 2017. 28. 1–19. (10.1007/s00198-016-3716-2) PubMed DOI PMC

Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL. & Trotti A. (eds). AJCC Cancer Staging Manual, 7th ed. New York, NY, USA: Springer, 2010.

Twigt BA, Scholten A, Valk GD, Rinkes IH, Vriens MR. Differences between sporadic and MEN related primary hyperparathyroidism; clinical expression, preoperative workup, operative strategy and follow-up. Orphanet Journal of Rare Diseases 2013. 8 50 (10.1186/1750-1172-8-50) PubMed DOI PMC

Schuffenecker I, Virally-Monod M, Brohet R, Goldgar D, Conte-Devolx B, Leclerc L, Chabre O, Boneu A, Caron J, Houdent C, et al. Risk and penetrance of primary hyperparathyroidism in multiple endocrine neoplasia type 2A families with mutations at codon 634 of the RET proto-oncogene. Groupe D’etude des Tumeurs a Calcitonine. Journal of Clinical Endocrinology and Metabolism 1998. 83 487–491. (10.1210/jcem.83.2.4529) PubMed DOI

Herfarth KK, Bartsch D, Doherty GM, Wells SA, Jr, Lairmore TC. Surgical management of hyperparathyroidism in patients with multiple endocrine neoplasia type 2A. Surgery 1996. 120 966–973; discussion 973–964. (10.1016/s0039-6060(96)80042-0) PubMed DOI

Howe JR, Norton JA, Wells SA., Jr Prevalence of pheochromocytoma and hyperparathyroidism in multiple endocrine neoplasia type 2A: results of long-term follow-up. Surgery 1993. 114 1070–1077. PubMed

Frank-Raue K, Leidig-Bruckner G, Lorenz A, Rondot S, Haag C, Schulze E, Buchler M, Raue F. Hereditary variants of primary hyperparathyroidism – MEN1, MEN2, HPT-JT, FHH, FIHPT. Deutsche Medizinische Wochenschrift 2011. 136 1889–1894. (10.1055/s-0031-1286358) PubMed DOI

Machens A, Dralle H. Advances in risk-oriented surgery for multiple endocrine neoplasia type 2. Endocrine-Related Cancer 2018. 25 T41–T52. (10.1530/ERC-17-0202) PubMed DOI

Sarika HL, Papathoma A, Garofalaki M, Saltiki K, Pappa T, Pazaitou-Panayiotou K, Anastasiou E, Alevizaki M. Genetic screening of patients with medullary thyroid cancer in a referral center in Greece during the past two decades. European Journal of Endocrinology 2015. 172 501–509. (10.1530/EJE-14-0817) PubMed DOI

Machens A, Lorenz K, Sekulla C, Hoppner W, Frank-Raue K, Raue F, Dralle H. Molecular epidemiology of multiple endocrine neoplasia 2: implications for RET screening in the new millenium. European Journal of Endocrinology 2013. 168 307–314. (10.1530/EJE-12-0919) PubMed DOI

Giacche M, Panarotto A, Tacchetti MC, Tosini R, Campana F, Mori L, Cappelli C, Pirola I, Lombardi D, Pezzola DC, et al. p.Ser891Ala RET gene mutations in medullary thyroid cancer: phenotypical and genealogical characterization of 28 apparently unrelated kindreds and founder effect uncovering in Northern Italy. Human Mutation 2019. 40 926–937. (10.1002/humu.23754) PubMed DOI

Elisei R, Tacito A, Ramone T, Ciampi R, Bottici V, Cappagli V, Viola D, Matrone A, Lorusso L, Valerio L, et al. Twenty-five years experience on RET genetic screening on hereditary MTC: an update on the prevalence of germline RET mutations. Genes 2019. 10 698 (10.3390/genes10090698) PubMed DOI PMC

Mathiesen JS, Kroustrup JP, Vestergaard P, Stochholm K, Poulsen PL, Rasmussen ÅK, Feldt-Rasmussen U, Gaustadnes M, Orntoft TF, Rossing M, et al. Founder effect of the RET(C611Y) mutation in multiple endocrine neoplasia 2A in Denmark: a nationwide study. Thyroid 2017. 27 1505–1510. (10.1089/thy.2017.0404) PubMed DOI

Cunha LL, Lindsey SC, Franca MIC, Sarika L, Papathoma A, Kunii IS, Cerutti JM, Dias-da-Silva MR, Alevizaki M, Maciel RMB. Evidence for the founder effect of RET533 as the common Greek and Brazilian ancestor spreading multiple endocrine neoplasia 2A. European Journal of Endocrinology 2017. 176 515–519. (10.1530/EJE-16-1021) PubMed DOI

Martins-Costa MC, Cunha LL, Lindsey SC, Camacho CP, Dotto RP, Furuzawa GK, Sousa MS, Kasamatsu TS, Kunii IS, Martins MM, et al. M918V RET mutation causes familial medullary thyroid carcinoma: study of 8 affected kindreds. Endocrine-Related Cancer 2016. 23 909–920. (10.1530/ERC-16-0141) PubMed DOI

Machens A, Lorenz K, Weber F, Dralle H. Geographic epidemiology of MTC families: unearthing European ancestral heritage. Endocrine-Related Cancer 2018. 25 L27–L30. (10.1530/ERC-17-0514) PubMed DOI

Machens A, Lorenz K, Dralle H. Peak incidence of pheochromocytoma and primary hyperparathyroidism in multiple endocrine neoplasia 2: need for age-adjusted biochemical screening. Journal of Clinical Endocrinology and Metabolism 2013. 98 E336–E345. (10.1210/jc.2012-3192) PubMed DOI

Raue F, Bruckner T, Frank-Raue K. Long-term outcomes and aggressiveness of hereditary medullary thyroid carcinoma: 40 years of experience at one center. Journal of Clinical Endocrinology and Metabolism 2019. 104 4264–4272. (10.1210/jc.2019-00516) PubMed DOI

Machens A, Lorenz K, Weber F, Dralle H. Genotype-specific progression of hereditary medullary thyroid cancer. Human Mutation 2018. 39 860–869. (10.1002/humu.23430) PubMed DOI

Mathiesen JS, Kroustrup JP, Vestergaard P, Stochholm K, Poulsen PL, Rasmussen ÅK, Feldt-Rasmussen U, Schytte S, Londero SC, Pedersen HB, et al. Survival and long-term biochemical cure in medullary thyroid carcinoma in Denmark 1997–2014: a nationwide study. Thyroid 2019. 29 368–377. (10.1089/thy.2018.0564) PubMed DOI PMC

Machens A, Dralle H. Surgical treatment of medullary thyroid cancer. Recent Results in Cancer Research 2015. 204 187–205. (10.1007/978-3-319-22542-5_9) PubMed DOI

Censi S, Cavedon E, Watutantrige-Fernando S, Barollo S, Bertazza L, Manso J, Iacobone M, Nacamulli D, Galuppini F, Pennelli G, et al. Unique case of a large indolent medullary thyroid carcinoma: time to reconsider the medullary thyroid adenoma entity? European Thyroid Journal 2019. 8 108–112. (10.1159/000494675) PubMed DOI PMC

Opsahl EM, Akslen LA, Schlichting E, Aas T, Brauckhoff K, Hagen AI, Rosenlund AF, Sigstad E, Groholt KK, Jorgensen LH, et al. The role of calcitonin in predicting the extent of surgery in medullary thyroid carcinoma: a nationwide population-based study in Norway. European Thyroid Journal 2019. 8 159–166. (10.1159/000499018) PubMed DOI PMC

Schuffenecker I, Ginet N, Goldgar D, Eng C, Chambe B, Boneu A, Houdent C, Pallo D, Schlumberger M, Thivolet C, et al. Prevalence and parental origin of de novo RET mutations in multiple endocrine neoplasia type 2A and familial medullary thyroid carcinoma. Le Groupe d’Etude des Tumeurs a Calcitonine. American Journal of Human Genetics 1997. 60 233–237. PubMed PMC

Castinetti F, Maia AL, Peczkowska M, Barontini M, Hasse-Lazar K, Links TP, Toledo RA, Dvorakova S, Mian C, Bugalho MJ, et al. The penetrance of MEN2 pheochromocytoma is not only determined by RET mutations. Endocrine-Related Cancer 2017. 24 L63–L67. (10.1530/ERC-17-0189) PubMed DOI

Frank-Raue K, Rybicki LA, Erlic Z, Schweizer H, Winter A, Milos I, Toledo SP, Toledo RA, Tavares MR, Alevizaki M, et al. Risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germline RET mutations located in exon 10. Human Mutation 2011. 32 51–58. (10.1002/humu.21385) PubMed DOI

Milos IN, Frank-Raue K, Wohllk N, Maia AL, Pusiol E, Patocs A, Robledo M, Biarnes J, Barontini M, Links TP, et al. Age-related neoplastic risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germ line RET Cys634Trp (TGC>TGG) mutation. Endocrine-Related Cancer 2008. 15 1035–1041. (10.1677/ERC-08-0105) PubMed DOI

Machens A, Niccoli-Sire P, Hoegel J, Frank-Raue K, van Vroonhoven TJ, Roeher HD, Wahl RA, Lamesch P, Raue F, Conte-Devolx B, et al. Early malignant progression of hereditary medullary thyroid cancer. New England Journal of Medicine 2003. 349 1517–1525. (10.1056/NEJMoa012915) PubMed DOI

Eng C, Mulligan LM, Smith DP, Healey CS, Frilling A, Raue F, Neumann HP, Ponder MA, Ponder BA. Low frequency of germline mutations in the RET proto-oncogene in patients with apparently sporadic medullary thyroid carcinoma. Clinical Endocrinology 1995. 43 123–127. (10.1111/j.1365-2265.1995.tb01903.x) PubMed DOI

Modigliani E, Vasen HM, Raue K, Dralle H, Frilling A, Gheri RG, Brandi ML, Limbert E, Niederle B, Forgas L. Pheochromocytoma in multiple endocrine neoplasia type 2: European study. The Euromen Study Group. Journal of Internal Medicine 1995. 238 363–367. (10.1111/j.1365-2796.1995.tb01211.x) PubMed DOI

Mulligan LM, Marsh DJ, Robinson BG, Schuffenecker I, Zedenius J, Lips CJ, Gagel RF, Takai SI, Noll WW, Fink M. Genotype-phenotype correlation in multiple endocrine neoplasia type 2: report of the International RET Mutation Consortium. Journal of Internal Medicine 1995. 238 343–346. (10.1111/j.1365-2796.1995.tb01208.x) PubMed DOI

Mulligan LM, Eng C, Healey CS, Clayton D, Kwok JB, Gardner E, Ponder MA, Frilling A, Jackson CE, Lehnert H. Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN 2A and FMTC. Nature Genetics 1994. 6 70–74. (10.1038/ng0194-70) PubMed DOI

Mulligan LM, Eng C, Attie T, Lyonnet S, Marsh DJ, Hyland VJ, Robinson BG, Frilling A, Verellen-Dumoulin C, Safar A. Diverse phenotypes associated with exon 10 mutations of the RET proto-oncogene. Human Molecular Genetics 1994. 3 2163–2167. (10.1093/hmg/3.12.2163) PubMed DOI

Castinetti F, Qi XP, Walz MK, Maia AL, Sanso G, Peczkowska M, Hasse-Lazar K, Links TP, Dvorakova S, Toledo RA, et al. 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 2014. 15 648–655. (10.1016/S1470-2045(14)70154-8) PubMed DOI

Bilezikian JP, Bandeira L, Khan A, Cusano NE. Hyperparathyroidism. Lancet 2018. 391 168–178. (10.1016/S0140-6736(17)31430-7) PubMed DOI

Verbeek HH, de Groot JWB, Sluiter WJ, Muller Kobold AC, van den Heuvel ER, Plukker JT, Links TP. Calcitonin testing for detection of medullary thyroid cancer in people with thyroid nodules. Cochrane Database of Systematic Reviews 2020. 3 CD010159 (10.1002/14651858.CD010159.pub2) PubMed DOI PMC

Opsahl EM, Akslen LA, Schlichting E, Aas T, Brauckhoff K, Hagen AI, Rosenlund AF, Sigstad E, Groholt KK, Maehle L, et al. Trends in diagnostics, surgical treatment, and prognostic factors for outcomes in medullary thyroid carcinoma in Norway: a nationwide population-based study. European Thyroid Journal 2019. 8 31–40. (10.1159/000493977) PubMed DOI PMC

Machens A, Dralle H. Surgical cure rates of sporadic medullary thyroid cancer in the era of calcitonin screening. European Journal of Endocrinology 2016. 175 219–228. (10.1530/EJE-16-0325) PubMed DOI

Saltiki K, Rentziou G, Stamatelopoulos K, Georgiopoulos G, Stavrianos C, Lambrinoudaki E, Alevizaki M. Small medullary thyroid carcinoma: post-operative calcitonin rather than tumour size predicts disease persistence and progression. European Journal of Endocrinology 2014. 171 117–126. (10.1530/EJE-14-0076) PubMed DOI

Elisei R, Romei C. Calcitonin estimation in patients with nodular goiter and its significance for early detection of MTC: European comments to the guidelines of the American Thyroid Association. Thyroid Research 2013. 6 (Supplement 1) S2 (10.1186/1756-6614-6-S1-S2) PubMed DOI PMC

Skandarajah A, Barlier A, Morlet-Barlat N, Sebag F, Enjalbert A, Conte-Devolx B, Henry JF. Should routine analysis of the MEN1 gene be performed in all patients with primary hyperparathyroidism under 40 years of age? World Journal of Surgery 2010. 34 1294–1298. (10.1007/s00268-009-0388-5) PubMed DOI