Multiple Endocrine Neoplasia Type 2

Abstract

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 pheo and primary hyperparathyroidism. Two different clinical variants of MEN 2 are known, MEN 2A with the subtype FMTC (familial medullary thyroid carcinoma) and MEN 2B. 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 three 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 multiple endocrine neoplasia (MEN 2) is caused by germ‐line 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. Two different clinical variants of MEN 2 are known, MEN 2A with the subtype FMTC and MEN 2B. 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 is based on a classification of the RET mutations into three risk levels utilising the genotype–phenotype correlation and measurement of basal calcitonin in addition. By prophylactic thyroidectomy at early ages before metastases occur, cure rate of MTC will be 100%. The analysis of the RET proto‐oncogene in MEN 2 was the first step in establishing the highly personalised approach to the diagnosis and treatment of MEN 2.