MULTIPLE ENDOCRINE NEOPLASIA TYPE 2A
MTC is the most frequent complication of MEN 2A and occurs in more than 95 % of clinically affected patients. PC develops in about 50 % of patients, but there are interfamilial variations in predisposition, and the variations in the frequency of PC have been correlated with specific RET mutations (Eng et al. 1996a, b; Zbuk and Eng 2007; Frank-Raue et al. 2011).
Similarly, the incidence of HPT, which occurs in 15–30 % of patients, is also correlated with allelic variation (Eng et al. 1996a, b; Schuffenecker et al. 1998; Zbuk and Eng 2007). MTC is almost always the first manifestation of MEN 2A. Clinical epidemiologic studies suggested that about 25 % of all MTC presentations are MEN 2 and are characterized by C cell hyperplasia. MTC arise from these parafollicular C cells, which derive from the neural crest, and secrete calcitonin. Other hormones may also be secreted by this Tumours, including adrenocorticotropic hormone (ACTH), melanocyte- stimulating hormone (MSH), prolactin, serotonin, VIP, somatostatin, prostaglandins, and gastrin, so the symptomatology may be complex. About one-third of patients with MTC develop diarrhea, which resolves on removal of the thyroid gland. MEN 2A-related MTCs often present clinically between 20 and 40 years of age, and up to a quarter present with cervical lymphadenopathy. They may metastasize to liver, lungs, and bone. Over 90 % of MEN 2A-related PC are bilateral and multifocal, and occur, on average, about 8 years after MTC, with a mean age at diagnosis of 37 years (Howe et al. 1993), and are bilateral in approximately 50 % of affected patients. In the recent past, many believed that PC rarely precedes MTC, but population- based registries of PC have shown that germline RET mutations can be found in individuals with PC only (Neumann et al. 2002). However, extra-adrenal or malignant PC is infrequent in MEN 2. Up to 50 % of patients with PC are asymptomatic, and a rise in urinary catecholamines and vanillylmandelic acid (VMA) may be a late feature. Hypertension may develop, but paroxysmal hypertension, especially related to postural changes, is more typical of PC.
An increase in the adrenaline–noradrenaline ratio in the urine may be noted earlier, as would serum chromogranin-A levels. Although clinical penetrance for MEN 2A is incomplete (approximately 45 % at age of 50 years and 60–75 % at age of 70 years), hyperplasia of thyroid C cells, which is the precursor of MTC, has a much earlier age at onset. C cell hyperplasia may be detected in asymptomatic mutation carriers by such biochemical screening tests and increases the apparent penetrance of MEN 2A to 93 % at age of 31 years (Easton et al. 1989).