Germline RET V804M mutation associated with multiple endocrine neoplasia type 2A

Abstract

Rare mutation

RET Proto-Oncogene in Sardinia: V804M Is the Most Frequent Mutation and May Be Associated with FMTC/MEN-2A Phenotype

“…In contrast, heterozygous point mutations in codon 804 leading to a substitution of valine 804 by either leucine (V804L) or methionine (V804M) have been reported in several families with FMTC (22)(23)(24), while MEN-2A was very rarely observed. To our best knowledge, before our case, only Gibelin et al (9) reported a family in which a V804M mutation was associated to MEN-2A (MTC plus hyperparathyroidism) in one member. Thus, assuming that MEN-2A phenotype is a rare expression of V804M mutation, the high frequency of 804 codon mutations in Sardinia could also explain the reason why we also observed a patient with a MEN-2A phenotype.…”

RET codon 804 mutations in multiple endocrine neoplasia 2: genotype-phenotype correlations and implications in clinical management

“…The disease in these individuals tend to be aggressive as evidenced by regional lymph node involvement in approximately 90% of macrocarcinomas and up to 30% microcarcinomas (65). (69). A comparative analysis of clinical, biochemical and histopathological features was performed by Niccoli-Sire et al in 2001 between FMTC index cases harboring non-cysteine (exons 13-15) and cysteine RET mutations (exon 10) (47).…”

“…In contrast to majority of RET 804 (non-cysteine) mutation carriers who remain biochemically normal till the third decade of life (54), individuals with classical cysteine mutations (codon 634) show a positive pentagastrin test during the first decade of life (6,(62)(63)(64). Additional studies have also described HPTH in association with V804M (50,59,69,99) and V804L mutations (58,60). Their results differed from earlier findings in that the authors found no statistically significant difference between the groups in mean age at diagnosis and stage of C-cell disease including size of MTC (macroscopic or microscopic), bilaterality, presence of CCH and regional node involvement.…”

The optimal range of RET mutations to be tested: European comments to the guidelines of the American Thyroid Association

“…Finally, total agreement was also expressed regarding the ATA-R #15 which indicates to treat MEN 2B patients harboring codon 804 mutation associated to another mutation similarly to those with the more typical MEN 2B RET causing mutations. Indeed, data from the literature report that the phenotype associated to V804M mutation alone is mostly FMTC [8,9], though also MEN 2A cases have been described [9-11]. However, when this mutation is associated to another on the same allele (Y806C, S904C, E805K, V778I) the phenotype resembles that of MEN 2B [12-16].…”