Advances in Genetic Screening for Multiple Endocrine Neoplasia Type 2 and the Implications for Management of Children at Risk

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Abstract
There has been a continual evolution in our knowledge of the MEN 2 syndromes since the initial classification was made nearly 40 years ago [1]. The first level of understanding was a complete description of the clinical components of the syndrome and the pattern of inheritance. Following this, methods were devised to prospectively screen families known to be at risk [2]. These screening methods, which identified the components of the syndrome before clinically overt symptoms became present, greatly improved the therapeutic outcome for patients with this syndrome. Until recently, the molecular defect responsible for the MEN 2 syndrome was not known. There is now considerable evidence implicating activating point mutations of the RET proto-oncogene as the initiating defect for MEN 2A and the familial medullary thyroid carcinoma (FMTC) variant of the MEN 2 syndrome [3, 4]. These data will influence the management of families at risk for this syndrome, with the end result that a definitive diagnosis will be possible from a single blood sample obtained as early as the prenatal period of life. This development effectively places the prospective management decisions for patients with this syndrome into the hands of those caring for the pediatric population. This review will summarize key points from the evolution of knowledge of the MEN 2 syndrome with a focus on incorporating the newest genetic information into clinical practice. The MEN 2 syndrome was originally described as the association of pheochromocytoma with cancer of the thyroid gland [1]. The syndrome has now been categorized into four variants, which are MEN 2A, MEN 2B, FMTC, and a variant of MEN 2A that is associated with a skin disorder known as cutaneous lichen amyloidosis (CLA). The incidence of the clinical manifestations associated with each of these variants is summarized in Table 1. Of note is that in MEN 2A, the most common variant, medullary thyroid carcinoma (MTC) is associated with pheochromocytoma and parathyroid hyperplasia, whereas in MEN 2B, parathyroid hyperplasia is absent [5]. Unique to MEN 2B is a Marfanoid habitus and diffuse ganglioneuromatosis of the alimentary tract and ocular system [6]. FMTC lacks the other components of this syndrome [7]. In the variant of MEN 2A that is associated with CLA, a pruritic skin rash is caused by the deposition of keratin-like peptides into the dermal-epidermal junction [8, 9]. (C) Lippincott-Raven Publishers.

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