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Diagnosis and Treatment |

Genetic Testing in the Diagnosis and Management of Multiple Endocrine Neoplasia Type II

Gregory A. Ledger, MD; Sundeep Khosla, MD; Noralane M. Lindor, MD; Stephen N. Thibodeau, PhD; and Hossein Gharib, MD
[+] Article, Author, and Disclosure Information

From the Mayo Clinic and the Mayo Foundation, Rochester, Minnesota. Requests for Reprints: Hossein Gharib, MD, Mayo Clinic, 200 First Street SW, Rochester, MN 55905.

Copyright ©2004 by the American College of Physicians

Ann Intern Med. 1995;122(2):118-124. doi:10.7326/0003-4819-122-2-199501150-00008
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Purpose: To review significant advances in the early diagnosis and treatment of medullary thyroid carcinoma in patients with the multiple endocrine neoplasia II (MEN II) syndromes, advances made possible by the application of recently discovered genetic information.

Data Sources: Recently published English-language literature on linkage analysis and DNA analysis in the MEN II syndromes.

Study Selection: Articles on familial and sporadic forms of medullary thyroid carcinoma; pentagastrin-calcitonin determination; and genetic testing.

Data Extraction: Information from recent studies on 1) the usefulness and limitations of genetic testing, especially DNA and linkage analysis, in the early diagnosis of the familial form of thyroid carcinoma and 2) the correlation between the results of genetic testing and the results of biochemical screening.

Data Synthesis: Medullary thyroid carcinoma accounts for most of the morbidity and mortality among patients with the familial medullary thyroid carcinoma syndromes. Multiple endocrine neoplasia IIa and IIb and familial medullary thyroid carcinoma are inherited conditions with autosomal dominance and incomplete penetrance. Traditionally, diagnosis of and screening for these conditions have been done using pentagastrin stimulation tests and plasma calcitonin determinations. Recent genetic mapping, however, has assigned the genes responsible for these tumors to the pericentromeric region of chromosome 10. Available data suggest that mutations in exon 10, 11, or 16 of the RET proto-oncogene are responsible for MEN IIa and IIb and familial non-MEN medullary thyroid carcinoma. Thus, genetic testing can identify affected members of a kindred and will probably lead to early thyroidectomy and possible cure for gene carriers.

Conclusions: Early studies confirm the usefulness of DNA analysis in the diagnosis and treatment of patients with familial forms of medullary thyroid carcinoma. We review changes in the diagnosis and treatment of these patients and offer a strategy for operative intervention based on results of genetic testing.


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Figure 1.
Schematic representation of the RET proto-oncogene showing the different domains of the transmembrane tyrosine kinase receptor protein.[21]

Mutations in multiple endocrine neoplasia type IIa (MEN IIa) and familial medullary thyroid carcinoma (FMTC) occur in exons 10 and 11 at one of five codons encoding a cysteine. Patients with multiple endocrine neoplasia type IIb (MEN IIb) have a mutation within exon 16 at codon 918 within the catalytic core of the tyrosine kinase domain. (Modified from Eng and colleagues . By permission of Oxford University Press.).

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Figure 2.
Algorithm suggesting sequence of tests in a patient with medullary thyroid carcinoma (MTC), family screen, and management based on results of genetic testing.

Thyroidectomy is recommended for all persons predicted to be gene carriers by either direct DNA mutation analysis or linkage-based testing. Dashed line represents an alternative, less desirable course, when surgical decision is based on follow-up evaluation with pentagastrin tests. *Indicates further evaluation dictated by adequacy of markers to exclude gene carriers. CT = calcitonin; LA = linkage analysis.

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