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J Clin Endocrinol Metab. 2010 Mar;95(3):1318-27. doi: 10.1210/jc.2009-1355. Epub 2010 Jan 15.

High penetrance of pheochromocytoma associated with the novel C634Y/Y791F double germline mutation in the RET protooncogene.

Author information

1
Faculdade de Medicina da Universidade de São Paulo, Avenida Dr. Arnaldo, 455, 5 degrees andar, Cerqueira César, 012406-903, São Paulo, Brazil. toldo@usp.br

Abstract

CONTEXT:

Previous studies have shown that double RET mutations may be associated with unusual multiple endocrine neoplasia type 2 (MEN 2) phenotypes.

OBJECTIVE:

Our objective was to report the clinical features of patients harboring a previously unreported double mutation of the RET gene and to characterize this mutation in vitro.

PATIENTS:

Sixteen patients from four unrelated families and harboring the C634Y/Y791F double RET germline mutation were included in the study.

RESULTS:

Large pheochromocytomas measuring 6.0-14 cm and weighing up to 640 g were identified in the four index cases. Three of the four tumors were bilateral. High penetrance of pheochromocytoma was also seen in the C634Y/Y791F-mutation-positive relatives (seven of nine, 77.7%). Of these, two cases had bilateral tumors, one presented with multifocal tumors, two cases had large tumors (>5 cm), and one case, which was diagnosed with a large (5.5 x 4.5 x 4.0 cm) pheochromocytoma, reported early onset of symptoms of the disease (14 yr old). The overall penetrance of pheochromocytoma was 84.6% (11 of 13). Development of medullary thyroid carcinoma in our patients seemed similar to that observed in patients with codon 634 mutations. Haplotype analysis demonstrated that the mutation did not arise from a common ancestor. In vitro studies showed the double C634Y/Y791F RET receptor was significantly more phosphorylated than either activated wild-type receptor or single C634Y and Y791F RET mutants.

CONCLUSIONS:

Our data suggest that the natural history of the novel C634Y/Y791F double mutation carries a codon 634-like pattern of medullary thyroid carcinoma development, is associated with increased susceptibility to unusually large bilateral pheochromocytomas, and is likely more biologically active than each individual mutation.

PMID:
20080836
DOI:
10.1210/jc.2009-1355
[Indexed for MEDLINE]
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