Table 3. Percentage of Patients with Clinical Features of MEN2 by Subtype continued...
Genotype-Phenotype Correlations and Risk Stratification
Genotype-phenotype correlations in MEN2 are well-established and have long been used to guide clinicians in making medical management recommendations. Several groups have developed mutation-stratification tables based on clinical phenotype, age of onset, and aggressiveness of MTC.[23,25,76] This classification strategy was first put forth after the Seventh International Workshop on MEN in 2001, which provided guidelines for the age of genetic testing and prophylactic thyroidectomy. This stratification was revised by the American Thyroid Association (ATA). The original classification scheme provided three levels of risk based on the genetic mutation of an individual. The new guidelines by the ATA added a fourth category for codon 634 mutations, in recognition of their aggressive clinical course. The specific mutations and their ATA classification are summarized in Table 4 and Table 5 below. The ATA's classification scheme has not been prospectively validated as a basis for clinical decision-making.
ATA-level D mutations are the most aggressive and carry the highest risk of developing MTC. These mutations, which are typically seen in MEN2B, are associated with the youngest age at disease onset and the highest risk of mortality. ATA-level C mutations (codon 634) are associated with a slightly lower risk, yet the MTC in patients with these mutations is still quite aggressive and may present at an early age. ATA-level A and level B mutations are associated with a lower risk of aggressive MTC relative to the risk seen in level C and level D mutation carriers. However, the risk of MTC is still substantially elevated over the general population risk and consideration of risk-reducing thyroidectomy is warranted.
A European multicenter study of 207 RET mutation carriers supported previous suggestions that some mutations are associated with early-onset disease. For example, this study found that individuals with the C634Y mutation developed MTC at a significantly younger age (mean 3.2 years; 95% confidence interval [CI], 1.2–5.4) than individuals with the C634R mutation (mean 6.9 years; 95% CI, 4.9–8.8). In the former group of patients, risk-reducing thyroidectomy warrants consideration before the age of 5 years. Although limited by small numbers, the same study did not support a need for risk-reducing thyroidectomy in asymptomatic carriers of mutations in codons 609, 630, 768, 790, 791, 804, or 891 before the age of 10 years or for central lymph node dissection before the age of 20 years. Some authors suggest using these differences as the basis for decisions on the timing of risk-reducing thyroidectomy and the extent of surgery. Others have advocated using basal and stimulated calcitonin levels as a basis for determining the appropriate timing of thyroidectomy.
Mutations 883 and 918 have only been seen in MEN2B and are associated with the earliest age of onset and the most aggressive form of MTC.[107,108,109,110,111] Approximately 95% of individuals with MEN2B will have the M918T mutation.[107,108,109,112] As discussed above, 50% of individuals with MEN2B will develop pheochromocytoma but PHPT is rare. In addition to mutations at codons 883 and 918, some individuals with a MEN2B-like phenotype have been found to carry two germline mutations.[113,114,115,116,117] It is likely that as testing for RET becomes more common in clinical practice, additional double mutation phenotypes will be described.