Abstract
A patient with an apparent sporadic medullary thyroid carcinoma was tested for RET germline mutations by Sanger sequencing of RET exons 10, 11, and 13-16. The patient was heterozygous for two known mutations causative of Multiple Endocrine Neoplasia type 2 disorder, and both mutations were within codon 620 of RET exon 10, c.1859G > T (p.C620F) and c.1860C > G (p.C620W). In order to determine if these adjacent mutations were in cis or in trans, an unlabeled probe method and high-resolution melting analysis were utilized. The mutations were confirmed to occur in cis, representing a novel mutation, c.1859_1860delinsTG (p.C620L). Sanger sequencing of parental samples did not identify any changes at codon 620, so the p.C620L mutation is also de novo. The early age of onset for medullary thyroid carcinoma and the presence of lymph node metastasis in this patient suggests individuals with the p.C620L mutation should be treated and screened (for pheochromocytomas and parathyroid hyperplasia) as Multiple Endocrine Neoplasia type 2 patients with other RET codon 620 mutations (American Thyroid Association risk level B).
Highlights
Multiple endocrine neoplasia type 2 (MEN2, OMIM 171400) is an autosomal dominant inherited disorder with the hallmark symptom of medullary thyroid carcinoma (MTC)
The patient was heterozygous for two known mutations causative of Multiple Endocrine Neoplasia type 2 disorder, and both mutations were within codon 620 of RET exon 10, c.1859G > T (p.C620F) and c.1860C > G (p.C620W)
MEN2 consists of three syndromes: familial medullary thyroid carcinoma (FMTC; have MTC only), MEN2A (MTC, Pheochromocytoma, and parathyroid hyperplasia) and MEN2B (MTC, Pheochromocytoma, and other characteristic findings) [1,2,3]
Summary
Multiple endocrine neoplasia type 2 (MEN2, OMIM 171400) is an autosomal dominant inherited disorder with the hallmark symptom of medullary thyroid carcinoma (MTC). It is hypothesized that cysteine residue substitution disrupts the intramolecular disulfide bond, allowing the unpaired partner cysteine to aberrantly create a disulfide bond between the mutant RET monomers, resulting in ligandindependent RET dimerization and activation [5,6,7]. Mutations at these four codons have been detected in patients with MEN2A or FMTC, and the age of disease onset is variable ranging from childhood to adulthood (see the MEN2 RET database: www.arup.utah.edu/database/MEN2/MEN2_welcome.ph p [4])
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