Familial medullary thyroid carcinoma without associated endocrinopathies: A distinct clinical entity

Abstract

In an evaluation of 213 patients from 15 kindreds with familial medullary thyroid carcinoma (MTC), we detected 41 subjects from two kindreds (L and O) who had MTC but no extra-thyroidal manifestations (hyperparathyroidism, phaeochromocytomas or mucosal neuromas) of multiple endocrine neoplasia (MEN) type IIa or IIb. In screening 178 members of the L and O kindreds, we found no evidence that any of them had died from MTC. To assess whether the malignancy was relatively indolent in these families, 20 selected subjects from the two kindreds were compared with 33 MEN IIa subjects. Both groups had clinically occult disease which was diagnosed biochemically by documenting elevated plasma calcitonin (CT) levels following stimulation with intravenous calcium and pentagastrin. There were no differences in the peak stimulated plasma CT levels at the time of diagnosis (1055 +/- 236 pg/ml versus 1096 +/- 191 pg/ml) or the incidence of regional lymph node metastases (0/20 versus 1/33) in the two groups. The mean age at diagnosis, however, was significantly higher in patients of the L and O kindreds than in patients with MEN IIa (43.1 +/- 3.4 years versus 21.1 +/- 2.2 years; P less than 0.001) indicating that in the two kindreds the MTC either developed at a later age or grew more slowly. This study demonstrates that MTC may occur in a familial pattern distinct from its presentation as MEN IIa or MEN IIb. In this setting it appears to be the least aggressive form of MTC yet described.

RET gene mutations (genotype and phenotype) of multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma

“…7 FMTC is the mildest subtype and features MTC without any of the extrathyroid characteristics of the other MEN 2 subtypes. 9 FMTC, as it was originally described, is uncommon. Although some studies attribute up to 35% of MEN2 cases to FMTC, most families thought to have FMTC become MEN2A families when an isolated member develops either a pheochromocytoma or hyperparathyroidism.…”

Over-representation of a germline RET sequence variant in patients with sporadic medullary thyroid carcinoma and somatic RET codon 918 mutation

“…About 75% of all MTCs are believed to be sporadic (Bergholm et al, 1990;Raue et al, 1993), and the remaining 25% comprise the autosomal dominant multiple endocrine neoplasia type 2 (MEN 2) syndromes, MEN 2A, MEN 2B and familial MTC (Farndon et al, 1986;Schimke, 1984). Germline mutations of the RET protooncogene a ecting exons 10, 11, 13, 14, 15 and 16 have been found to be associated with MEN 2 (Bolino et al, 1995;Carlson et al, 1994;Donis-Keller et al, 1993;Eng et al, 1994Eng et al, , 1995Farndon et al, 1986;Gimm et al, 1997;Hofstra et al, 1994;Mulligan et al, 1993;Schimke, 1984; Smith et al, 1997). Speci®cally, germline mutation at codon 918 (M918T) in exon 16 is associated with 495% of MEN 2B , which is characterized by a more severe form of MTC and phaeochromocytoma occurring at a young age and classic stigmata such as ganglioneuromatosis and a marfanoid habitus.…”

A Rare Case of De novo C634G Germline Mutation of the RET Proto-Oncogene in a Patient With MEN 2A Syndrome With Aggressive Pheochromocytoma

“…Patients with MEN 2B syndrome do not develop parathyroid disease, but a particular phenotype including a marfanoid habitus, multiple mucosal ganglioneuromas, neurofibromas, and thickened corneal nerves define this syndrome. FMTC is the least aggressive subtype and is characterized only by MTC, inherited in an autosomal dominant fashion with a genetic penetrance of nearly 100% [3]. MEN 2 has a prevalence of nearly 2.5 per 100,000 in the general population, with the distribution of the three subtypes being 70-80% MEN 2A, 5% MEN 2B and 10-20% FMTC [4].…”