Multiple endocrine neoplasia type 2A due to an exon 8 (G533C) mutation in a large North American kindred

Medullary thyroid cancer, although most commonly sporadic, may be part of the multiple endocrine neoplasia type 2 (MEN2) syndromes, generally due to mutations in the RET proto-oncogene. The majority of these mutations are located in exons 10, 11, and 13-16. More rarely, mutations in other exons have been described. We report for the first time a family from the United States with a rare mutation involving exon 8 of the RET proto-oncogene, corresponding to a p.Gly533Cys substitution (G533C) leading to the development of MEN2A syndrome in several affected family members. This mutation had only been previously described in a large family in Brazil and in 7.75% of patients with apparently sporadic medullary thyroid cancer (MTC) in Greece.

Given a strong index of suspicion, a genetic analysis to evaluate for uncommon mutations in the RET proto-oncogene identified the presence of the G533C missense mutation, despite initial negative screening for common mutations. We describe a family with a total of 47 individuals from five generations with multiple members affected with this mutation.

Our data suggest that in patients with this mutation, pheochromocytoma is more common than previously reported, and that in some cases this mutation may be associated with a more aggressive phenotype than initially described.

MEN2A due to the G533C mutation in exon 8 may be more common and more aggressive than previously recognized. In patients with medullary thyroid cancer with negative screening for common mutations in the RET oncogene but a strong index of suspicion, DNA sequence analysis of less commonly involved exons should be considered.