Germline mutations of the RET proto-oncogene cause three different cancer syndromes:
multiple endocrine neoplasia type 2A (MEN 2A), multiple endocrine neoplasia type 2B
(MEN 2B) and familial medullary thyroid carcinoma (FMTC). In the absence of biochemical
and/or clinical evidence of pheochromocytoma and hyperparathyroidism, patients with
MEN 2A disease display the same phenotype of FMTC disease, although prognosis and
clinical management in both affected and unaffected familial members are quite different.
We studied a family with hereditary MTC, whose proband was referred to us because
of enlarged cervical nodes and increased calcitonin serum levels 28 years after the
total thyroidectomy for MTC. Cervical node dissection was carried out and subsequently
the presence of MTC metastasis was histologically confirmed. A RET genomic mutation
at codon 634 (TGC→TTC) was identified in the proband and in seven out of 19 familial
members studied. Accordingly, a hereditary disease was suggested. However, the strong
association of RET mutation at codon 634 with the presence of pheochromocytoma in
MEN 2 disease suggested a more rigorous management in all gene carriers. Indeed, during
the follow-up pheochromocytoma was subsequently identified in the proband. This finding
suggests that all families with a pedigree suggestive of FMTC should be regarded at
risk from MEN 2A disease, at least when a critical mutation in the RET cysteine domain
is detected.
Key words:
Multiple Endocrine Neoplasia 2A (MEN 2A) - Familial Medullary Thyroid Carcinoma (FMTC)
- RET Proto-Oncogene - Mutation - Genetic Analysis
References
- 1
Schimke R N.
Genetic aspects of multiple endocrine neoplasia.
Ann Rev Med.
1984;
35
25-31
- 2
Schimke R N, Hartmann W H, Prout T E, Rimoin D L.
Syndrome of bilateral pheochromocytoma, medullary thyroid carcinoma and multiple neuromas:
a possible regulatory defect in the differentiation of cromaffin tissue.
N Engl J Med.
1968;
279
1-7
- 3
Farndon J R, Leight G S, Dilley W G, Baylin S B, Smallridge R C, Harrison T S, Wells S A
Jr.
Familial medullary thyroid carcinoma without associated endocrinopathies: a distinct
clinical entity.
Br J Surg.
1986;
73
278-281
- 4
Eng C, Clayton D, Schuffenecker I, Lenoir G, Cote G, Gagel R, van Hamstel H KP, Lips C JM,
Nishisho I, Takai S, Marsh D J, Robinson B G, Frank-Raue K, Raue F, Xue F, Noll W W,
Romei C, Pacini F, Fink M, Niederle B, Zedenius J, Nordenskiold M, Komminoth P, Hendy G N,
Gharib H, Thibodeau S N, Lacroix A, Frilling A, Ponder B AJ, Mulligan L M.
The relationship between specific RET proto-oncogene mutations and disease phenotype
in multiple endocrine neoplasia type 2.
JAMA.
1996;
276
1575-1579
- 5
Ponder B AJ.
The phenotype associated with ret mutations in the Multiple Endocrine Neoplasia type
2 syndrome.
Cancer Res.
1999;
59 (Suppl)
1736-1742
- 6
Moers A M, Landsvater R M, Schaap C, Jansen-Schillhorn van Veen J M, de Valk I A,
Blijiham J H, Hoppener J W, Vroom T M, van Amstel H K, Lips C J.
Familial medullary thyroid carcinoma: not a distinct entity? Genotype-phenotype correlation
in a large family.
Am J Med.
1996;
101
635-641
- 7
Takahashi M, Buma Y, lwamoto T, Inaguma Y, Ikeda H, Hiai H.
Cloning and expression of the RET proto-oncogene encoding a tyrosine kinase with two
potential transmembrane domains.
Oncogene.
1988;
3
571-578
- 8
Chiefari E, Russo D, Giuffrida D, Zampa G A, Meringolo D, Arturi F, Chiodini I, Bianchi D,
Attard M, Trischitta V, Bruno R, Giannasio P, Pontecorvi A, Filetti S.
Analysis of RET proto-oncogene abnormalities in patients with MEN 2A, MEN 2B, familial
or sporadic medullary thyroid carcinoma.
J Endocrinol Invest.
1998;
21
358-364
- 9
Russo D, Arturi F, Chiefari E, Meringolo D, Bianchi D, Bellanova B, Filetti S.
A case of metastatic medullary thyroid carcinoma: early identification before surgery
of a RET proto-oncogene somatic mutation in fine needle aspirate specimen.
J Clin Endocrinol Metab.
1997;
82
3378-3382
- 10
Baudin E, Lumbroso J, Schlumberger M, Leclere J, Giammarile F, Gardet P, Roche A,
Travagli J P, Parmentier C.
Comparison of octreotide scintigraphy and conventional imaging in medullary thyroid
carcinoma.
J Nucl Med.
1996;
37
912-916
- 11 Cryer P E.
Disease of Sympathetic-Chromaffin System. In: Felig P, Baxter JD, Frohman LA (III ed) Endocrinology and Metabolism. New York;
McGraw Hill, Inc. 1997
- 12
Learoyd D L, Twigg S M, Marsh D J, Robinson B G.
The pratical management of multiple endocrine neoplasia.
Trends Endocrinol Metab.
1995;
6
273-278
- 13
Chappuis-Flament S, Pasini A, De Vita G, Segouffin-Cariou C, Fusco A, Attie T, Lenoir G M,
Santoro M, Billaud M.
Dual effect on the RET receptor of MEN 2 mutations affecting specific extracytoplasmatic
cysteines.
Oncogene.
1998;
17
2851-2861
- 14
Libroia A, Verga U, Vecchi G, Banfi F, Zurleni F, Quadro L, Scurini C, Fattoruso O,
Colantuoni V.
Seventeen-year-long follow-up of a family affected by type 2A multiple endocrine neoplasia
(MEN 2A).
J Endocrinol Invest.
1998;
21
87-92
- 15
Gagel R F.
Unresolved issues in the genesis and management of multiple endocrine neoplasia type
2.
Horm Metab Res.
1997;
29
135-137
S. Filetti, M.D.
Cattedra di Endocrinologia
Dipartimento di Medicina Sperimentale e Clinica
Via T. Campanella, 115
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