Endocrine Abstracts

Early 2005 we reported on a new insertion-deletion mutation (insTTCTdelG) at codon 666 (exon 11) of the RET proto-oncogene. The index patient, a 12 year old boy with locally metastasized MTC, inherited the mutation from his maternal grandfather. His mother had a basal calcitonin of 30 ng/l and underwent a prophylactic total thyroidectomy at age 48, showing C-cell hyperplasia in both lobes and early MTC with a maximum size of 1.5 mm. At age 82, his grandfather did not have clinical MTC. The early presentation in the index patient was explained by the additive effects of the maternal RET mutation and a functional coding polymorphism (G691S) in his paternal RET gene.

Since then, the codon 666 mutation was identified in 3 other unrelated families. The 3 index patients were a female with locally metastasized MTC at age 70; a 46 year old female with a 0.5 cm MTC incidentally found in a thyroid lobe, that was resected because of a large colloid cyst, and a male with a pheochromocytoma at age 48 and 2 small (2 and 8 mm) foci of MTC following screening for MEN-2a at age 54.

In all cases the family history was negative for MTC and pheochromocytoma. At present (10–2005), genetic testing in 3 of 4 families has identified 7 living carriers without clinical or biochemical evidence of MTC even at high age (range 23–83 yrs). All families originate from the same geographical region, suggesting a common founder for this unique MEN-2a mutation. Haplotype analysis to confirm this hypothesis is currently in progress.

The insertion-deletion mutation at codon 666 of the RET oncogene is thus associated with a low penetrance of MTC (< 40%) and of pheochromocytoma (<10%). These observations suggest that early prophylactic thyroidectomy in asymptomatic carriers has to be evaluated in the context of the type of RET mutation.