**5. Medullary Thyroid Cancer as Part of MEN2 Syndromes**

About one-third of MTCs are hereditary, presenting as multicentric and bilateral, in contrast with sporadic cases that are a single unilateral tumor [133,134]. They present as part of MEN2A (70–80%), MEN2B (5%), or familial MTC (FMTC) (10–20%). The first inherited subtype of MTC, MEN2A, consists of primary hyperparathyroidism, pheochromocytoma and MTC in which it can occur early in life (approximately 5 years of age) in contrast with sporadic cases that presents between 15 and 20 years [134,135]. MEN2B is characterized by pheochromocytoma, MTC and non-endocrine diseases such as mucosal neuromas, intestinal tumors (most commonly ganglioneuromas) and Marfanoid habitus [135]. In the case of FMTC, only the thyroid gland is affected, but in a significant number of relatives in the same family, usually between the ages of 20 and 40 [135–137]. Activating germline *RET* mutations have been identified as the main cause of up to 98% of hereditary MTCs and up to half of sporadic cases [138]. Depending on the mutated residue within the RET protein, the phenotype may differ [139–142]. Families with two or more members with MTC are referred for genetic counseling and screening, if positive they undergo further testing for hyperparathyroidism and pheochromocytoma [2,143,144]. In the case of sporadic MTCs, somatic *RET* mutations, particularly M918T, has been shown to be associated with more aggressive disease and worse prognosis [144,145].
