Risk Profiles and Penetrance Estimations in Multiple Endocrine Neoplasia Type 2A Caused by Germline RET Mutations Located in Exon 10
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Wohllk González, Nelson
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Risk Profiles and Penetrance Estimations in Multiple Endocrine Neoplasia Type 2A Caused by Germline RET Mutations Located in Exon 10
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Abstract
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.
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HUMAN MUTATION, Vol. 32, No. 1, 51–58, 2011
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