Multiple Endocrine Neoplasia Type 2

Abstract Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant hereditary cancer syndrome caused by missense gain‐of‐function mutations of the RET proto‐oncogene on chromosome 10. It has a strong penetrance of medullary thyroid carcinoma (MTC) and can be associated with bilateral pheochromocytoma and primary hyperparathyroidism. The specific RET mutation may suggest a predilection towards a particular phenotype and clinical course, with strong genotype–phenotype correlations. Recommendations on the timing of prophylactic thyroidectomy and extent of surgery are based on classification of RET mutations into risk levels according to genotype–phenotype correlations. By earlier identification of patients with hereditary MTC, the presentation changed from clinical tumours to preclinical disease resulting in a high cure rate of affected patients with much better prognosis. Key Concepts: The hereditary cancer syndrome (MEN 2) is caused by germline activating mutations of the RET ‐proto‐oncogene. Hereditary medullary thyroid carcinoma (MTC) is the most common manifestation of multiple endocrine neoplasia type 2 (MEN 2) syndrome. Genetic testing detects nearly 100% of mutation carriers. Three different clinical variants of MEN 2 are known, MEN 2A, MEN 2B and FMTC. Each variant of MEN 2 results from different RET gene mutations with a good genotype–phenotype correlation. Recommendation for the timing of prophylactic thyroidectomy and extent of surgery are based on a classification into four risk levels utilising the genotype–phenotype correlation. If prophylactic thyroidectomy is done at early ages cure rate will be 100% and improves significantly long‐term outcome and prognosis of these patients. Pheochromocytomas usually present after MTC or concomitantly, rarely it can be the first manifestation of MEN 2A, lifelong annual biochemical screening is necessary in carriers at risk.