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Key Points

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  • Disease summary:

    • Multiple endocrine neoplasia type 2 (MEN2) is caused by a dominantly inherited or de novo activating (gain of function) mutation in the RET proto-oncogene.

    • MEN2A (95% of MEN2 cases) is characterized by the development of medullary thyroid carcinoma (MTC) in greater than 90% of affected patients, pheochromocytoma (PHEO) in up to 50% of cases, and/or primary hyperparathyroidism (PHPT) in up to 20% of mutation carriers. Depending on the specific RET mutation, cutaneous lichen amyloidosis (CLA) and Hirschsprung disease can also occur.

    • MEN2B (5% of MEN2 cases) is characterized by the universal and early development of MTC, high risk of PHEO (up to 50% of cases) and a highly penetrant, distinctive physical appearance.

    • A strong genotype-phenotype correlation exists in MEN2 such that MTC disease severity, the likelihood of developing PHEO and PHPT, and the age of disease onset can be estimated based on genetic testing results.

    • In RET mutation carriers, C-cell hyperplasia is the initial stage of tumor development that leads to microscopic noninvasive MTC (usually bilateral) and ultimately to lymph node and distant metastases due to frankly invasive carcinoma.

    • Familial MTC (FMTC) is currently considered to be a phenotypic variant of MEN2A with a high risk for MTC but decreased penetrance and/or delayed onset of the other neoplastic manifestations. There is significant overlap between RET mutations associated with FMTC and those of MEN2A.

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  • Hereditary basis:

    • MEN2A and MEN2B have an autosomal dominant inheritance pattern with almost complete penetrance of the MTC phenotype.

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  • Differential diagnosis:

    • There is no other genetic syndrome associated with the development of MTC. Other multiorgan system syndromes that include PHEO as a feature include von Hippel-Lindau disease, the familial paraganglioma syndromes, and neurofibromatosis type 1. Familial PHPT is most commonly associated with MEN1 but the differential diagnosis also includes familial isolated primary hyperparathyroidism, familial hypocalciuric hypercalcemia, and hyperparathyroidism-jaw tumor syndrome. Hirschsprung disease can be sporadic or associated with underlying chromosomal abnormalities and gene mutations, including inactivating (loss of function) RET mutations that are distinct from the MEN2-causing mutations. The differential diagnosis for the skeletal phenotype of MEN2B includes Marfan syndrome and homocystinuria; intestinal ganglioneuromatosis may also be associated with Cowden syndrome and type 1 neurofibromatosis.

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Diagnostic Criteria and Clinical Characteristics

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Diagnostic Criteria

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At least one of the following

  • One or more of the MEN2-associated endocrine tumors in a patient who has an identified germline mutation in the RET proto-oncogene

  • Identification of a known MEN2-causing germline mutation in the RET proto-oncogene, particularly with a positive family history of any of the known MEN2-related endocrine tumors

  • A diagnosis of MTC in a patient who has one or more close relatives with histologically confirmed MTC

  • A clinical diagnosis of MEN2 (prior to confirmation via genetic testing) would be highly suspected in a given patient with two or more of the endocrine tumors associated with MEN2 or a diagnosis of MTC in a ...

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