In summary, ATA-level D and C mutations confer the highest risk of MTC (about 95% lifetime risk) with a more aggressive disease course. There is an increased risk of pheochromocytoma (up to 50%).[49,107] Individuals with codon 634 mutations (but not codon 883 or 918 mutations) also have an increased risk of PHPT.
ATA-level B mutations involve cysteine residues in the extracellular domain of the RET protein and are seen in families with either MEN 2A or FMTC.[19,49,63,108,109,110,111,112] In a report of 477 RET mutation carriers, mutations at codons 609, 611, 618, and 620 were seen in 30 families with MEN 2A and 18 families with FMTC. In another large series of 518 probands with MTC undergoing RET testing, most individuals with codon 609, 611, 618, 620, or 630 mutations had only MTC and no other features suggesting MEN 2. This could be a result of the relatively short follow-up time, incomplete screening of family members, or the method of ascertainment (population-based).
Individuals with ATA-level A mutations have a lower, albeit still elevated, lifetime risk of MTC. MTC associated with these mutations tends to follow a more indolent course and have a later age at onset, although there are several reports of individuals with ATA-level A mutations who developed MTC before age 20.[49,114,115,116,117,118] Although pheochromocytoma and PHPT are not commonly associated with level A mutations, they have been described.
In addition to the mutations categorized in Table 2, a number of rare or novel RET mutations have been described. Some of these represent mutations that lead to an FMTC or MEN 2 phenotype. Others may represent low penetrance alleles or modifying alleles that confer only a modest risk of developing MTC. Still others may be benign polymorphisms of no clinical significance. A variety of approaches, including segregation analyses, in silico analyses, association studies, as well as functional assays, can be employed to determine the functional and clinical significance of a given genetic variant. An online, publicly available RET mutation database repository was recently developed and includes a complete list of mutations and their associated pathogenicity, phenotype and other associated clinical information and literature references.
Risk-reducing thyroidectomy and parathyroidectomy with reimplantation of one or more parathyroid glands into the neck or nondominant forearm is a preventive option for all subtypes of MEN 2. To implement this management strategy, biochemical screening to identify CCH and/or genetic testing to identify persons who carry causative RET mutations is needed to identify candidates for risk-reducing surgery (see below). The optimal timing of surgery, however, is controversial. Current recommendations are based on clinical experience and vary for different MEN 2 subtypes, as noted in Table 2.