HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: ERC-08-0105v1 15/4/1035    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Milos, I. N Articles by Neumann, H. P H Search for Related Content PubMed PubMed Citation Articles by Milos, I. N Articles by Neumann, H. P H

¹ Section of Preventive Medicine, Department of Nephrology, University of Freiburg Medical Centre, Freiburg im Breisgau, Germany² Department of Endocrinology of the University of Medicine and Pharmacy ‘Victor Babes’, Timisoara, Romania³ Private Praxis for Endocrinology, Brückenstr. 21, Heidelberg, Germany⁴ Endocrine Section, Hospital del Salvador, Universidad de Chile, Santiago de Chile, Chile⁵ Endocrine Division, Thyroid Section, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil⁶ Institutos de Histología, Embriología y Patología Tiroidea, Universidad Nacional de Cuyo, Mendoza, Argentina⁷ Molecular Medicine Research Group, Hungarian Academy of Sciences and 2nd Department of Medicine, Semmelweis University, Budapest, Hungary⁸ Hereditary Endocrine Cancer Group, Spanish National Cancer Center, Madrid and ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain⁹ Endocrinology Unit, Hospital Dr Josep Trueta de Girona, Girona, Spain¹⁰ Centro de Investigaciones Endocrinológicas, Hospital de Niños R. Gutiérrez, Buenos Aires, Argentina¹¹ Department of Endocrinology, University Medical Center Groningen, Groningen, The Netherlands¹² Department of Molecular Endocrinology of the Institute of Endocrinology, Prague, Czech Republic¹³ Department of Hypertension, Institute of Cardiology, Warsaw, Poland¹⁴ , Department of Quantitative Health Sciences¹⁵ Genomic Medicine Institute, Lerner Research Institute and Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA

(Correspondence should be addressed to H P H Neumann who is now at Medizinische Universitätsklinik, Abteilung Innere Medizin 4, Sektion für Präventive Medizin, Hugstetter Street 55, D 79106 Freiburg, Germany; Email: hartmut.neumann{at}uniklinik-freiburg.de)

RET testing in multiple endocrine neoplasia type 2 for molecular diagnosis is the paradigm for the practice of clinical cancer genetics. However, precise data for distinct mutation-based risk profiles are not available. Here, we survey the clinical profile for one specific genotype as a model, TGC to TGG in codon 634 (C634W). By international efforts, we ascertained all available carriers of the RET C634W mutation. Age at diagnosis, penetrance, and clinical complications were analyzed for medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism (HPT), as well as overall survival. Our series comprises 92 carriers from 20 unrelated families worldwide. Sixty-eight subjects had MTC diagnosed at age 3–72 years (mean 29). Lymph node metastases were observed in 16 subjects aged 20–72 and distant metastases in 4 subjects aged 28–69. Forty-one subjects had pheochromocytoma detected at age 18–67 (mean 36). Amongst the 28 subjects with MTC and pheochromocytoma, six developed pheochromocytoma before MTC. Six subjects had HPT diagnosed at age 26–52 (mean 39). Eighteen subjects died; of the 16 with known causes of death, 8 died of pheochromocytoma and 4 of MTC. Penetrance for MTC is 52% by age 30 and 83% by age 50, for pheochromocytoma penetrance is 20% by age 30 and 67% by age 50, and for HPT penetrance is 3% by age 30 and 21% by age 50. These data provide, for the first time, RET C634W-specific neoplastic risk and age-related penetrance profiles. The data may facilitate risk assessment and genetic counseling.