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Multiple Endocrine Neoplasia Type 2

    Table 3. Percentage of Patients with Clinical Features of MEN2 by Subtype continued...

    Mutations at codon 634 (ATA-level C) are by far the most frequent finding in families with MEN2A. One study of 477 RET carriers showed that 52.1% had the C634R mutation, 26.0% carried the C634Y mutation, and 9.1% had the C634G mutation.[62] In general, mutations at codon 634 are associated with pheochromocytomas and PHPT.[62,118] Until recently, MEN2A with cutaneous lichen amyloidosis (CLA) had been seen almost exclusively in patients with mutations at codon 634.[62,64,119] However, a recent report described MTC and CLA in an individual previously thought to have FMTC due to a codon 804 mutation.[120] Codon 634 mutations have also been described in FMTC but are almost exclusively C634Y.[62]

    In summary, ATA-level D and level 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%).[62,121] Individuals with codon 634 mutations (but not codon 883 or 918 mutations) also have an increased risk of PHPT.[62]

    ATA-level B mutations, located in exon 10 of the RET gene, include mutations at codons 609, 611, 618, 620, and 630. These mutations involve cysteine residues in the extracellular domain of the RET protein and have been seen in families with MEN2A and those with MTC only (FMTC).[20,62,76,122,123,124,125,126] The risk of MTC in individuals with ATA-level B mutations is approximately 95% to 100%; the risk of pheochromocytoma and hyperparathyroidism is lower than that seen in ATA-level A mutations. In a 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 suggestive of MEN2. The authors attributed this to the relatively short follow-up time, incomplete screening of family members, or the method of ascertainment (population-based).[33] Another large study of 390 exon 10 mutation carriers showed an age-related risk of pheochromocytoma for individuals carrying any exon 10 mutation of 23.1% by age 50 years and 33% by age 60 years. Overall prevalence of pheochromocytoma was 17%. This study reported a 3.9% risk of developing hyperparathyroidism by age 60 years.[127]

    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 years.[62,128,129,130,131,132] Although pheochromocytoma and PHPT are not commonly associated with level A mutations, they have been described.[132]

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