Multiple Endocrine Neoplasia type 2 and Familial Medullary Thyroid Carcinoma                                                                                                                     by Beth A. Pletcher, MD, February 2000

Recent advances in molecular genetics have lead to the discovery that MEN 2A, MEN 2B and familial medullary thyroid carcinoma (FMTC) are all associated with mutations of a single gene on the long arm of chromosome 10. This RET gene is a proto-oncogene and different mutations can lead to the variety of clinical findings associated with these clinically well-defined conditions. However, it has become apparent in recent times that there may be some overlap between mutations associated with MEN 2A and FMTC.

MEN 2A: is associated with MTC (onset in early adulthood), hyperplasia of the parathyroids or parathyroid adenoma as well as pheochromocytoma.

MEN 2B: is associated with MTC (onset in early childhood), pheochromocytoma and a number of unusual clinical findings including: coarse facial features with thick lips, mucosal neuromas- especially of the lips or tongue, gastrointestinal ganglioneuromas and a long, thin body habitus.

FMTC: is associated with MTC alone and the diagnosis is usually not made until later adult life.

Although molecular testing is quite useful in identifying individuals at risk for one of these three conditions, the family history and physical exam are important in assessing risk and whom to offer genetic testing. Since not all mutations are identified with current technologies, patients and providers must understand the chances for a false negative result and additional surveillance options available to them. Other factors such as probability of a "new mutation" in an index case and mutation detection rate must be considered on an individual basis. Since all three conditions are inherited as autosomal dominant traits, offspring of affected individuals are at 50% risk of inheriting the condition. While MTC is a relatively aggressive and difficult to treat cancer, early detection or presymptomatic identification of at risk individuals may go a long way in decreasing morbidity and mortality.

Over 95% of MEN 2A patients will have a positive family history compared to only 50% of MEN 2B patients. The clinical and laboratory diagnosis are augmented by the family history. MTC and C-cell hyperplasia can be identified by elevated calcitonin levels whereas pheochromocytoma may be suspected in at risk individuals with hypertension. However, the most sensitive screening test for a pheo is measurement of urinary catecholamines and their metabolites on a 24 hour sample. Screening for parathyroid abnormalities includes: measurement of serum calcium, parathyroid hormone level and urinary calcium to creatinine ratio.

For affected individuals, the mutation detection rates vary from 85% for FMTC to 95% for MEN 2A and MEN 2B. For families in which a specific mutation cannot be identified and there are several affected family members available for testing, linkage analysis may be used to identify presymptomatic carriers. Mutations in exons 10 and 11 account for most of the cases of MEN 2A and one single point mutation in exon 16 accounts for 95% of the MEN 2B mutations. There is a great deal of overlap between mutations causing MEN 2A and FMCT in exons 10 and 11, but two specific mutations (one in exon 13 and one in exon 14) are clearly associated with FMCT only.

When the clinical diagnosis is clear, based on laboratory testing or family history, mutation analysis should be first offered to affected individuals who have concerns about risks to their children or close relatives to see if a mutation can be identified. This is best done in the context of a counseling session that should include a discussion of the risks and benefits of DNA testing, medical management and surveillance options as well as informed consent. However, one of the more ambiguous scenarios is when the clinician is faced with a patient diagnosed with MTC, who has no known family history of thyroid cancer or other related condition. Since the majority (75-80%) of isolated MTC is sporadic, the question arises as to whether or not to offer mutation analysis to such individuals. If an individual is under 40 years of age at diagnosis or has multifocal MTC, DNA testing seems to be clearly indicated, especially if there are children at risk. Even though the data is not all in, numerous studies have demonstrated a small but real risk for germline mutations in sporadic MTC (estimates vary between 1 and 24%). In light of this, recently we have been offering molecular testing for RET mutations to all patients with MTC, realizing that the majority will not have a mutation identified. For these low risk patients with "sporadic MTC ", a negative molecular test can be quite reassuring and can greatly reduce risks for occurrence in their offspring. There are other centers who are not offering such testing routinely and clearly the jury is still out on which approach is best.

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