Familial medullary carcinoma prevention, risk evaluation, and RET in children of families with MEN2.

UNLABELLED: The ability to predict the risk of MEN2 and medullary thyroid carcinoma (MTC) by genetic RET proto-oncogene analysis has provided an essential tool in identifying patients in whom thyroid cancer can be prevented by prophylactic thyroidectomy but emphasizes the need for clear policy guidelines. Children of families with RET cysteine mutations (exons 10, 11, 13, and 16) may develop early metastatic tumours and require prophylactic thyroidectomy. The 918 mutation associated with MEN2B is associated with early aggressive behaviour and distant metastatic spread. This has led to active screening of affected families underlining the need for specific intervention strategies.

AIM: To evaluate the risk to children of families with MEN2 and to assess the risk and determine the treatment.

METHODS: Twenty-five patients from 10 families with MEN2 phenotypes were screened for RET mutations. Polymerase chain reaction amplification was performed on all 21 exons of the RET proto-oncogene, followed by heteroduplex single-strand conformation polymorphism (HEX-SSCP) analysis. Polymerase chain reaction products demonstrating variation in the HEX-SSCP gels were subjected to automated DNA sequencing analysis.

RESULTS: Eleven significant RET mutations were detected in affected families. Eight index cases received initial thyroidectomy for established MTC (plus 2 advised). In the family members screened, 3 prophylactic thyroidectomies (2 with early MTC) were performed and a further 2 recommended. An exon 10 C620W missense mutation (the "Janus" gene) was detected in a patient with Hirschsprung's disease plus 1 family member.

CONCLUSION: RET analysis of MEN has revolutionized the management of children of families with MEN2 and allowed surgical prediction and prophylaxis to take place. The presence of an exon 10 C620W mutation in association with Hirschsprung's disease was difficult to assess. We suggest possible guidelines for management of families with MTC and the role of genetic testing in their evaluation.