Hereditary Forms

Thyroid Factor

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In about 25% of cases the medullary thyroid carcinoma is one of the components of the multiple endocrine neoplasia type 2 syndrome, which is an autosomal dominant inherited syndrome with a variable degree of expressivity and an age-related penetrance. As shown in Table 21.1, three different hereditary syndromes can be classified according to the involved organs: (a) multiple endocrine neopla-

Table 21.1 Prevalence of different endocrine neoplasia and other clinical manifestations in MEN2 syndromes

Figure 21.2 Classification and relative prevalence of different forms of medullary thyroid carcinoma according to RET genetic screening and clinical manifestations.

sia type 2A (MEN2A), a syndrome consisting of medullary thyroid carcinoma, pheochromocy-toma, and parathyroid neoplasia [17]; (b) MEN2B, a syndrome consisting of medullary thyroid carcinoma, pheochromocytoma, muco-sal neuromas,and ganglioneuromatosis [18]; (c) familial medullary thyroid carcinoma (FMTC), which is characterized by the presence of an inheritable medullary thyroid carcinoma with no apparent association with other endocrine neoplasia [19]. After the introduction of RET genetic screening, the relative prevalence of the FMTC syndrome has been found to be much higher (from 10% to 50% of all MEN syndromes) (Figure 21.2). The increased number of FMTC cases is mainly due to the high number of apparently sporadic medullary thyroid carcinomas demonstrated to be familial cases by the RET mutation analysis [20,21].

The clinical appearance of medullary thyroid carcinoma in MEN syndromes is that of a thyroid nodular disease, similar to that of the sporadic form with the exception that it is usually bilateral, multicentric, and almost invariably associated with C-cell hyperplasia [22-24]. The clinical course of the medullary thyroid carcinoma varies considerably in the three syndromes. It is very aggressive and almost invariably unfavorable in MEN2B, with affected patients rarely surviving after adolescence. It is most indolent in the majority of patients with the FMTC form and shows variable degrees of aggressiveness in patients with MEN2A. Different types of RET gene mutations account for different biological behavior [25-28] and separate therapeutic protocols have been defined for the treatment of medullary thyroid carcinoma occurring in the three different syndromes [29].

Between 10% and 30% of patients with MEN2A develop hyperparathyroidism during the third to fourth decades of life. The clinical findings are superimposable on those of the sporadic form of hyperparathyroidism and very often no specific symptoms are present. At variance with the sporadic form, multiple parathyroid hyperplasia or adenomatosis is most commonly found [17,30]. Hyperparathyroidism has only occasionally been reported in patients with MEN2B [18].

About 50% of MEN2A and 40-45% of MEN2B patients develop pheochromocytoma, which shares the same characteristics in both syndromes. Contrary to the sporadic form of pheochromocytoma, the adrenal tumors of MEN syndromes are usually bilateral and mul-ticentric. However, the two adrenal glands are rarely simultaneously involved and a mean period of 10 years usually elapses between the development of the tumor in the two glands.

The MEN2B syndrome is characterized by the association with mucosal neuromas, which are mainly located on the distal tongue and sub-conjunctival areas, and ganglioneuromatosis affecting the gastrointestinal tract. MEN2B patients may be easily recognized on physical examination by the typical marfanoid habitus characterized by thin and inappropriately long extremities and pectus excavatum [18,31-33]. Thick lips and eyelids are frequently observed in the presence of mucosal neuromas, and are usually clearly evident when eyes and mouth are explored (Figure 21.3). Gastrointestinal disorders due to the intestinal neuromas throughout the intestinal tract, including obstructive symptoms, cramping and diarrhea, are frequently observed in early childhood.

An association with cutaneous lichen amyloi-dosis (CLA), a characteristically a pigmented and itchy skin lesion specifically localized in the interscapular region of the back (Figure 21.4),

Figure 21.3 Clinical features of MEN2B syndrome. A Characteristic mucosal neurinomas of subconjunctivas are apparent. B Characteristic mucosal neurinomas of the distal part of the tongue are apparent. C Characteristic thick lips and marfanoid habitus. D Thick lips and mucosal neurinomas.

Figure 21.3 Clinical features of MEN2B syndrome. A Characteristic mucosal neurinomas of subconjunctivas are apparent. B Characteristic mucosal neurinomas of the distal part of the tongue are apparent. C Characteristic thick lips and marfanoid habitus. D Thick lips and mucosal neurinomas.

Figure 21.4 Cutaneous lichen amyloidosis (CLA) in a patient affected by MEN2A.The figure shows the characteristic location in the interscapular regions.

has been reported in less than 10% of MEN2A families [34,35]. The development of CLA may precede the development of the medullary thyroid carcinoma: thus, when present it is almost invariably diagnostic of MEN2A and may be considered a predictor of the syndrome.

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