Interpretive Handbook

Test 80573 :
Multiple Endocrine Neoplasia Type 2 (2A, 2B, FMTC) Mutation Screen

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant cancer syndrome that has classically been divided into 3 subtypes: MEN 2A, MEN 2B, and familial medullary thyroid carcinoma (FMTC). The characteristic features of MEN 2A include multifocal medullary thyroid carcinoma (MTC), bilateral pheochromocytoma, and primary hyperparathyroidism. MEN 2B is characterized by MTC, pheochromocytoma, and multiple mucosal neuromas. Other features of MEN 2B include enlarged nerves of the gastrointestinal tract (ganglioneuromatosis), marfanoid habitus, hypotonia, and corneal nerve thickening. FMTC is diagnosed in families with four or more cases of MTC in the absence of pheochromocytoma or parathyroid involvement.


Age of onset is variable but may range from childhood to the seventh decade. For MEN 2A, there is incomplete penetrance with only about two thirds of gene carriers being symptomatic by age 70. Early diagnosis and appropriate surgical intervention can prevent metastatic MTC and can reduce the morbidity and mortality associated with MTC.


Biochemical screening can increase the detection rate in asymptomatic individuals with a family history of MEN 2. This testing involves the measurement of calcitonin with and without stimulation by calcium or pentagastrin to detect early signs of thyroid disease (hyperplasia of calcitonin-producing cells [C-cells] of the thyroid).


Missense mutations in the RET proto-oncogene (located on chromosome 10) are responsible for the variable phenotypes of MEN 2A, MEN 2B, and FMTC. The majority of mutations occur at conserved cysteine residues within exons 10 and 11. Additional mutations in exons 13, 14, 15 and 16 account for the preponderance of other RET mutations. Taken together, mutations in these codons account for approximately 98% of MEN 2A, >99% of MEN2B, and 96% of FMTC.


Although gain of function mutations in the RET proto-oncogene may result in MEN2, loss of function mutations have been reported in patients with Hirschsprung disease (HSCR). It has been reported that up to 50% of familial cases of HSCR and 3% to 35% of sporadic HSCR are due to RET germline mutations. However, most of the mutations that cause HSCR occur outside of the codons that are typically mutated in MEN2. Therefore, the absence of a mutation utilizing this test does not rule out the diagnosis of HSCR.

Useful For Suggests clinical disorders or settings where the test may be helpful

Confirmation of diagnosis of multiple endocrine neoplasia type 2 (MEN 2), MEN 2B, and familial medullary thyroid carcinoma (FMTC)


Documentation of germline mutation to distinguish FMTC from sporadic multifocal medullary thyroid carcinoma

Interpretation Provides information to assist in interpretation of the test results

An interpretive report will be provided.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

A small percentage of individuals who are carriers or have a diagnosis of multiple endocrine neoplasia type 2 (MEN2) may have a mutation that is not identified by this method (eg, mutations in other exons, promoter mutations). The absence of a mutation(s), therefore, does not eliminate the possibility of positive carrier status or the diagnosis of MEN2. For carrier testing, it is important to first document the presence of a RET proto-oncogene mutation in an affected family member.


In some cases, DNA alterations of undetermined significance may be identified.


Rare polymorphisms exist that could lead to false-negative or false-positive results. If results obtained do not match the clinical findings, additional testing should be considered.


A previous bone marrow transplant from an allogenic donor will interfere with testing. Call Mayo Medical Laboratories for instructions for testing patients who have received a bone marrow transplant.


Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors in our interpretation of results may occur if information given is inaccurate or incomplete.

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

An interpretive report will be provided.

Clinical References Provides recommendations for further in-depth reading of a clinical nature

1. Hansford J, Mulligan L: Multiple endocrine neoplasia type 2 and RET: from neoplasia to neurogenesis. J Med Genet 2000;37(11):817-827

2. Marini F, Falchetti A, Del Monte F, Carbonell Sala S, et al: Multiple endocrine neoplasia type 2. Orphanet J Rare Dis. 2006 Nov 14;1:45

3. Ruiz-Ferrer M. Fernandez RM. Antinolo G. et al: A complex additive model of inheritance for Hirschsprung disease is supported by both RET mutations and predisposing RET haplotypes. Gen Med 2006;8(11):704-710