Risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germline RET mutations located in exon 10

Karin Frank-Raue, Lisa A. Rybicki, Zoran Erlic, Heiko Schweizer, Aurelia Winter, Ioana Milos, Sergio P A Toledo, Rodrigo A. Toledo, Marcos R. Tavares, Maria Alevizaki, Caterina Mian, Heide Siggelkow, Michael Hüfner, Nelson Wohllk, Giuseppe Opocher, Šárka Dvořáková, Bela Bendlova, Małgorzata Czetwertynska, Elzbieta Skasko, Marta BarontiniGabriela Sanso, Christian Vorländer, Ana Luiza Maia, Attila Patocs, Thera P. Links, Jan Willem De Groot, Michiel N. Kerstens, Gerlof D. Valk, Konstanze Miehle, Thomas J. Musholt, Josefina Biarnes, Svetozar Damjanovic, Mihaela Muresan, Christian Wüster, Martin Fassnacht, Mariola Peczkowska, Christine Fauth, Henriette Golcher, Martin A. Walter, Josef Pichl, Friedhelm Raue, Charis Eng, Hartmut P H Neumann

Research output: Contribution to journalArticlepeer-review


Multiple endocrine neoplasia type 2 is characterized by germline mutations in RET. For exon 10, comprehensive molecular and corresponding phenotypic data are scarce. The International RET Exon 10 Consortium, comprising 27 centers from 15 countries, analyzed patients with RET exon 10 mutations for clinical-risk profiles. Presentation, age-dependent penetrance, and stage at presentation of medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism were studied. A total of 340 subjects from 103 families, age 4-86, were registered. There were 21 distinct single nucleotide germline mutations located in codons 609 (45 subjects), 611 (50), 618 (94), and 620 (151). MTC was present in 263 registrants, pheochromocytoma in 54, and hyperparathyroidism in 8 subjects. Of the patients with MTC, 53% were detected when asymptomatic, and among those with pheochromocytoma, 54%. Penetrance for MTC was 4% by age 10, 25% by 25, and 80% by 50. Codon-associated penetrance by age 50 ranged from 60% (codon 611) to 86% (620). More advanced stage and increasing risk of metastases correlated with mutation in codon position (609→620) near the juxtamembrane domain. Our data provide rigorous bases for timing of premorbid diagnosis and personalized treatment/prophylactic procedure decisions depending on specific RET exon 10 codons affected.

Original languageEnglish
Pages (from-to)51-58
Number of pages8
JournalHuman Mutation
Issue number1
Publication statusPublished - Jan 2011


  • Genotype-phenotype
  • Medullary thyroid carcinoma
  • MEN2
  • MEN2A
  • MEN2B
  • Pheochromocytoma
  • RET

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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