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Genetic and clinical features of multiple endocrine neoplasia types 1 and 2
1Department of Endocrinology and Metabolism, University of Pisa, 56124 Pisa, Italy.
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.
Insights
Multiple endocrine neoplasia (MEN) are rare inherited syndromes affecting endocrine glands. MEN 1 involves parathyroid, pancreas, and pituitary tumors, while MEN 2 involves medullary thyroid cancer, with varying RET protooncogene mutations influencing prognosis.
Area of Science:
- Endocrinology
- Genetics
- Oncology
Background:
- Multiple endocrine neoplasia (MEN) are rare inherited syndromes impacting various endocrine glands.
- Three main types exist: MEN 1, MEN 2A, and MEN 2B, each with distinct clinical manifestations and genetic underpinnings.
- These syndromes affect all ages and sexes equally, necessitating comprehensive understanding for diagnosis and management.
Purpose of the Study:
- To delineate the clinical characteristics and genetic basis of MEN 1 and MEN 2 syndromes.
- To explore the genotype-phenotype correlations, particularly in MEN 2, and their impact on disease aggressiveness.
- To review current and emerging therapeutic strategies for MEN-associated endocrinopathies.
Main Methods:
- Review of existing literature on MEN 1 and MEN 2 syndromes, focusing on genetic mutations and clinical presentations.
- Analysis of genotype-phenotype correlations in MEN 2, specifically linking RET protooncogene mutations to medullary thyroid cancer (MTC) behavior.
- Examination of therapeutic approaches and treatment outcomes for various MEN-associated conditions.
Main Results:
- MEN 1 is associated with parathyroid, pancreatic islet, and pituitary tumors, with mutations in the MEN 1 gene found in 70-80% of patients, showing variable clinical features.
- MEN 2 syndromes (MEN 2A, MEN 2B, FMTC) invariably feature medullary thyroid cancer (MTC), often accompanied by pheochromocytoma or hyperparathyroidism.
- Activating RET protooncogene mutations are present in 98% of MEN 2 families, with strong genotype-phenotype correlations observed, influencing MTC aggressiveness. MEN 2B shows the most aggressive MTC.
- Surgical treatment for MTC is standard, but 30% of patients require further treatment, with emerging RET-targeted molecular therapies showing promise for advanced disease.
Conclusions:
- MEN syndromes require distinct diagnostic and management strategies based on their specific genetic profiles and affected endocrine glands.
- Understanding the RET protooncogene's role in MEN 2 is crucial for predicting MTC aggressiveness and guiding treatment decisions.
- While MEN 1 management focuses on individual endocrinopathies with generally good prognosis, MEN 2 management hinges on controlling MTC, with ongoing research into novel therapeutics for resistant cases.
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