Molecular genetic analysis was performed in 276 families with medullary thyroid carcinoma (31 familial and 245 apparently sporadic), 29 patients with apparently sporadic pheochromocytoma, and 122 families with Hirschsprung’s disease (a total of 427 families and unrelated individuals). The RET Y791F variant was found in 31 patients from 10 families — an allele frequency of 1.2% in these cases. The authors do not list any controls to compare this to.
The authors observe high variability in type of disease and age of onset; while most cases are summarized as late onset and high cure rates, the authors report two patients carrying this variant with aggressive tumors. The authors conclude: “Despite the fact that the mutation was categorized as the least-high risk mutation, we tend to agree with recommendation to perform prophylactic total thyroidectomy in all carriers of the mutation regardless of calcitonin levels, ideally before 10 years of age.”
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These authors perform a more extensive survey of controls in addition to examining cases and report this variant in 8 out of 1000 controls (0.8%) and in 13 out of 1475 patients in the European-American Pheochromocytoma-Paraganglioma registry. An additional four(?) relatives of these patients were discovered also to be carriers. 15 of these patients and relatives carrying Y791F were re-evaluated and found to have no family history or additional MEN 2 features.
The authors observe that prior reports had smaller (or lacked) control populations, sporadic cases and a lack of familial evidence. They also observe the variant does not segregate with the disease in their study.
The authors conclude that, in contrast to its prior treatment, this variant is not a Mendelian mutation responsible for MEN 2.