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Do all patients with RET mutations associated with multiple endocrine neoplasia type 2 require surgery?

Nature Clinical Practice Endocrinology & Metabolism volume 1, pages 60–61 (2005)Cite this article

The advent of genetic testing for hereditary forms of medullary thyroid cancer (MTC) has revolutionized the management of families with multiple endocrine neoplasia type 2 (MEN2). Screening the RET proto-oncogene for mutations has the highest specificity and sensitivity (>98%) of genetic testing in any of the hereditary cancer syndromes,1 and analysis must include exons 10, 11, 13, 14, 15 and 16. RET mutation screening should be performed on all new, seemingly sporadic cases of MTC. The penetrance of MTC in RET-mutation-positive patients is over 95%, but the age-specific penetrance varies according to the mutation. Interestingly, approximately 25% of patients with Hirschsprung's disease have 'loss-of-function' RET mutations. In the past decade, genotype–phenotype analysis in MEN2 has led to refinements of the management guidelines that should now allow tailoring of therapy to the specific MEN2 genotype. Controversy still exists regarding the timing and extent of surgical treatment and in this Viewpoint we discuss our approach to these decisions.

There are three distinct but overlapping MEN2 syndromes: MEN2A, MEN2B and familial MTC. MEN2A is most commonly caused by RET mutations in the cysteine codons of the extracellular and transmembrane domains of exons 10 and 11, but can also be caused by more rare intracellular mutations. Mutations at codon 634 in exon 11 are the most frequent in MEN2A (>60%) and correlate with a phenotype of MTC with pheochromocytoma in 50% of cases, and MTC with hyperparathyroidism in 15%.2 In these families MTC often arises in the first decade of life and age-related penetrance is not influenced by the amino acid substituted at codon 634.1,3 In MEN2A families with mutations in exon 10 or the intracellular domain, pheochromocytoma is less prevalent and MTC rarely presents before the age of 10 years. Rare mutations in exons 13–15, including codon 768 in exon 13, correlate with the familial MTC phenotype without pheochromocytoma or hyperparathyroidism; this form of MTC rarely develops before the age of 20 years. Other mutations associated with familial MTC include some of those at codons 618 and 620 in exon 10. Although exon 13 mutations at codon 804 were initially thought to cause familial MTC, there are now reports of late-onset pheochromocytoma in these families.4 Codon 804 mutations were also thought to correlate with less aggressive or later onset MTC, but this theory remains controversial: the multicenter European Multiple Endocrine Neoplasia study (EUROMEN)3 suggested that lymph-node metastases are not seen in the first two decades of life, but another study reported metastatic MTC in a 6-year-old child with a codon 804 mutation.5

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Authors and Affiliations

  1. Endocrinologist and a Senior Lecturer in Medicine, Royal North Shore Hospital and the University of Sydney, Australia

    Diana L Learoyd

  2. Endocrinologist and a Professor of Medicine at the Cancer Genetics Laboratory of the Kolling Institute and the Department of Endocrinology, Royal North Shore Hospital and the University of Sydney, Australia

    Bruce G Robinson

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  1. Diana L Learoyd
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Correspondence to Diana L Learoyd.

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Learoyd, D., Robinson, B. Do all patients with RET mutations associated with multiple endocrine neoplasia type 2 require surgery?. Nat Rev Endocrinol 1, 60–61 (2005). https://doi.org/10.1038/ncpendmet0045

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