RET protein consists of an extracellular ligand-binding domain, a transmembrane domain, and an intracellular domain, which contains two tyrosine kinase subdomains (TK1 and TK2) that are involved in the activation of several intracellular signal transduction pathways. There is a correlation between specific mutations and specific disease phenotypes (1). Mutations in RET exons 10 (codons 609, 611, 618, and 620) or 11 (codons 630 or 634), are seen in the majority of

Inhibitors,research,lifescience,medical MEN2A and FMTC (Familial medullary thyroid cancer) cases resulting in alterations in the cysteine-rich region of the RET protein’s extracellular domain. A mutation in codon 634 in exon 11 is the most common genetic Selleckchem Transferase inhibitor defect in this disorder and is strongly associated with hyperparathyroidism and pheochromocytoma (PC) in MEN2A. Mutations in codons 768 (exon 13), 804 (exon 14) and 891 (exon 15),

which result in changes in the intracellular tyrosine kinase domains, are found Inhibitors,research,lifescience,medical only in FMTC (2). In MEN 2B patients, the mutation involves codon 918 in exon 16 in 95% of cases and, rarely, codon 883 in exon 15 with resultant change in either methionine or alanine, respectively, in the tyrosine kinase domain of RET (3). Germaine to our patient and her family, in the rare cases where MEN 2A Inhibitors,research,lifescience,medical and HD co-exist, germline RET mutations most often involve exon 10 (1),(4), especially codon 618 or 620 (1),(5). This association poses a scientific Inhibitors,research,lifescience,medical dilemma, as the mutations in MEN are gain of function mutations with RET acting as a dominantly acting oncogene (6),(7) and those of HD result in loss of function (8),(9). However, a unifying hypothesis has been suggested in that mutations in exon 10 result in a relatively weaker activation

Inhibitors,research,lifescience,medical of the RET protein kinase, perhaps just sufficient to cause MTC. A concurrent decrease in the total number of receptor molecules on the cell surface possibly results in insufficient numbers of receptors for normal gangliogenesis and migration and/or for the prevention of inappropriate apoptosis, with oxyclozanide HD as a result (10),(11). This case teaches us a number of important lessons. Firstly, that all patients with a history of HD should consider screening for RET mutations (it should be noted that RET mutations are the predominant but only one of a number of possible causes of HD) (12),(13), as there is a well established association between HD and MEN2A. If present, this could facilitate early diagnosis of MEN2A with resultant thyroidectomy prior to the onset of MTC or at least prior to the development of metastatic disease. Equally, it is desirable that all patients with MTC should be tested for germline RET mutations in accordance with 2009 American Thyroid Association Guidelines for Management of MTC (14).