Genetic and clinical features of multiple endocrine neoplasia types 1 and 2

Abstract

Multiple endocrine neoplasia (MEN) are clinical inherited syndromes affecting different endocrine glands. Three different patterns of MEN syndromes can occur (MEN 1, MEN 2A, and MEN 2B). MEN syndromes are very rare, affect all ages and both sexes are equally affected. MEN 1 is characterized by the neoplastic transformation of the parathyroid glands, pancreatic islets, anterior pituitary, and gastrointestinal tract. Heterozygous MEN 1 germline mutations have been detected in about 70-80% of patients with MEN 1. The mutations are scattered throughout the entire genomic sequence of the gene. MEN 1 patients are characterized by variable clinical features, thus suggesting the lack of a genotype-phenotype correlation. Therapeutical approaches are different according to the different endocrinopathies. The prognosis is generally good if adequate treatment is provided. In MEN 2 syndromes, the medullary thyroid cancer (MTC) is almost invariably present and can be associated with pheochromocytoma (PHEO) and/or multiple adenomatosis of parathyroid glands with hyperparathyroidism (PHPT). The different combination of the endocrine neoplasia gives origin to 3 syndromes: MEN 2A, MEN 2B, and FMTC. The clinical course of MTC varies considerably in the three syndromes. It is very aggressive in MEN 2B, almost indolent in the majority of patients with FMTC and with variable degrees of aggressiveness in patients with MEN 2A. Activating germline point mutations of the RET protooncogene are present in 98% of MEN 2 families. A strong genotype-phenotype correlation has been observed and a specific RET mutation may be responsible for a more or less aggressive clinical course. The treatment of choice for primary MTC is total thyroidectomy with central neck lymph nodes dissection. Nevertheless, 30% of MTC patients, especially in MEN 2B and 2A, are not cured by surgery. Recently, developed molecular therapeutics that target the RET pathway have shown very promising activity in clinical trials of patients with advanced MTC. MEN 2 prognosis is strictly dependent on the MTC aggressiveness and thus on the success of the initial treatment.

Figure 1

Prevalence of MEN 1 endocrine and nonendocrine manifestations. *Data obtained by a study on a series of 74 patients with MEN1 [8] and on a study determining the frequency of skin lesions in a series of 32 patients with MEN1 [9] Abbreviations: VIPoma-vasoactive intestinal peptide secreting tumor; PRLoma, prolactin secreting tumor; GHoma, growth hormone secreting tumor; ACTH, adrenocorticotropic hormone secreting tumor, ECLoma, enterochromaffin-like tumour.

Figure 2

Predicted functional partners of menin generated by the protein interaction database STRING v.9.0. Evidences for these associations derive from experiments (pink lines), homology data (violet lines), predictions by text data mining (green lines), and information obtained from databases (light blue lines). The loss of one or more of these interactions might contribute to the development of MEN 1 syndrome by different mechanisms.

Figure 3

Pedigree of an Italian kindred positive for a germline MEN 1 missense mutation (T344R) in exon 10 (unpublished data). Generation numbers are represented by Roman numerals and individual numbers are in Arabic numerals. The proband, II-3, presents all the main MEN 1 endocrine manifestations; the sister, II-2, does not present pituitary lesions, but has nonendocrine lesions, such as a tumor of CNS and an angioma. Proband's mother, I-2, has only primary hyperparathyroidism, supporting the lack for a genotype-phenotype correlation.

Figure 4

Prevalence rates of the three MEN 2 phenotypes in the International RET Consortium series (a) and in an Italian series (b). A higher prevalence of the FMTC phenotype was observed in the Italian series with respect to that reported by the International Consortium, which was based on cases collected up to 1994-1995.