Clinical Diagnosis And Genetic Testing

The diagnosis of the MEN 2 clinical subtypes relies on a combination of clinical findings, family history, and molecular genetic testing for RET gene mutation, which is recommended for all patients with sporadic MTC, pheochromocytoma (particularly if bilateral and/or before age 18), Hirschsprung's disease, and patients with physical features or gastrointestinal manifestation suggestive of MEN 2B. Genetic testing is also offered to first-degree relatives (before age 5 in MEN 2A and FMTC and before age 1 in MEN 2B) of RET mutation carriers to identify asymptomatic at-risk individuals for early prophylactic thyroidectomy, which could be curative when the disease is microscopic and localized to the thyroid gland. Genetic testing is generally done on DNA extracted from peripheral blood leucocytes for common mutations in exons 10 (codons 609, 611, 618, or 620), 11 (codon 634), and 16.[9] Because of the established genotypical-phenotypical correlation, RET mutation stratification has clinical and management implications.1-10-13-1 Hyperpara-thyroidism is most commonly associated with mutations in codon 634, less frequent with mutations in codons 609, 611, 618, 620, 790, and 791. Individuals with MEN 2B (mutation in codons Met918 in exon 16, Ala883 in exon 15, or 922) do not develop HPT. Pheochromo-cytoma has been reported in all RET mutations except codons 768, Val804met, and 891 and is most commonly associated with mutations in codon 634 (in exon 11) and 918. Mutations in codons 609, 768, 790, 791, and 891 are associated with the lowest risk for MTC, whereas mutations in codon 611, 618, 620, or 634 are associated with high risk for MTC. Mutations in codon 883, 918, or 922 are associated with the highest risk for aggressive MTC. Mutations in codons 609, 618, and 620 in exon 10 are associated with MEN A2, FMTC, or Hirschsprung's disease. Therefore germline mutation analysis of RET exon 10 containing these codons is indicated in all children with Hirschsprung's disease.

Mutation detection rate is summarized in Table 1. Various molecular methods used to detect mutations in RET include DNA sequencing, restriction enzymatic analyses, chemical cleavage mismatch, single-stranded conformational polymorphism (SSCP), and denaturing gradient gel electrophoresis (DGGE). Most recently, a multiplex PCR assay to amplify exons 10, 11, and 13 of the RET proto-oncogene has been developed. The multiplex PCR product is then analyzed on a modified mutation detection enhancement (MDE) matrix for heteroduplex identification and visualized with ethidium bromide.[14] Confirmation of the specific mutation can be achieved by restriction enzymatic digestion (if feasible) or by DNA sequencing.

Genetic testing should always be done in the setting of pre- and post-test genetic counseling, as endorsed by the American Society of Clinical Oncology in its position statement on genetic testing for hereditary cancer.[15] The process of genetic counseling includes providing risk assessment, educating patients about testing options, discussing the implications for medical management, and providing supportive counseling to the individual and their family.

Getting Started With Dumbbells

Getting Started With Dumbbells

The use of dumbbells gives you a much more comprehensive strengthening effect because the workout engages your stabilizer muscles, in addition to the muscle you may be pin-pointing. Without all of the belts and artificial stabilizers of a machine, you also engage your core muscles, which are your body's natural stabilizers.

Get My Free Ebook

Post a comment