Multiple Endocrine Neoplasia Type 2 (MEN2)
Multiple Endocrine Neoplasia Type 2 (MEN2) causes both malignant benign tumors of the endocrine system, the most common being medullary thyroid carcinoma (MTC). Non-endocrine tumors may also occur.
PrintMultiple Endocrine Neoplasia Type 2 (MEN2) causes both malignant benign tumors of the endocrine system, the most common being medullary thyroid carcinoma (MTC). Non-endocrine tumors may also occur.
Depending on the tissues involved, MEN2 can be divided into three subtypes: MEN2A, MEN2B, and familial medullary thyroid carcinoma (FMTC).
MEN2 is inherited in an autosomal dominant manner and is caused by germline mutations in the RET proto-oncogene. The Ambry Test: Multiple Endocrine Neoplasia Type 2 begins with Gene Sequence Analysis of exons 10, 11, and 13-16 of the RET gene. If no mutation is detected, the remaining exons are sequenced. Mutations in RET are detected in up to 98% of individuals with MEN2.
Genetic testing is a useful tool to differentiate sporadic MTC cases from those caused by MEN2, as there are screening and surgical interventions that can reduce morbidity and mortality in RET mutation carriers.
Multiple endocrine neoplasia type 2 (MEN2), also known as Sipple syndrome, is characterized by benign or malignant tumors of the endocrine system. The most common malignancy associated with MEN2 is medullary thyroid carcinoma (MTC). MEN2 is caused by mutations that result in the activation of the RET proto-oncogene and is inherited in an autosomal dominant manner. Tumors generally occur in the endocrine system, but may also occur in non-endocrine tissues. Depending on the tissues involved, MEN2 can be further subdivided into three subtypes: MEN2A, MEN2B, and familial medullary thyroid carcinoma (FMTC).1
MEN2A is characterized by MTC in 95% of cases, hyperparathyroidism in up to 30% of cases, and unilateral or bilateral pheochromocytomas in up to 50% of cases.1,2 Co-segregation of RET-related Hirschsprung’s disease and MEN2A has also been reported.3
MEN2B is the rarer but most aggressive of the MEN2 subtypes, causing up to 10% of MEN2 cases. Clinical manifestations consist of: MTC (100%) and pheochromocytoma (50%). MEN2B can be differentiated from MEN2A by a lack of hyperparathyroidism. Individuals affected with MEN2B also often exhibit a marfanoid habitus, bumpy lips and tongues as a result of neuromas,1,2 as well as intestinal ganglioneuromas in children.4
FMTC is the mildest of the subtypes and comprises about 5%-35% of MEN2 cases. Individuals are only affected with medullary thyroid carcinoma and do not exhibit any of the other typical MEN2 findings.1,2
Papillary thyroid carcinoma has been reported in patients with mutations in three specific codons of the RET gene.5
Genetic testing is an especially useful diagnostic tool to differentiate sporadic medullary thyroid carcinoma (MTC) cases from those affected with multiple endocrine neoplasia type 2 (MEN2). According to Brandi et al (2001), it is beneficial if an individual is identified to be a carrier of a RET mutation before they reach adulthood
as there are screening and surgical interventions that help diminish their mortality rate. It is recommended that even seemingly sporadic cases of MTC be tested for RET mutations, ideally before surgery, as undiagnosed pheochromocytomas can increase the risk of surgical complications.
The Ambry Test: Multiple Endocrine Neoplasia Type 2 (MEN2) begins with double-stranded automated sequencing in sense and antisense directions of exons 10, 11, and 13-16 of RET plus at least 20 bases into the 5’ and 3’ ends of the corresponding introns. If no mutation is detected, testing continues automatically with sequencing of the remaining exons plus at least 20 bases into the 5’ and 3’ ends of the corresponding introns.
Mutations in the RET gene account for up to 98% of individuals affected with MEN2.7 The Ambry Sequence: MEN2 is capable of detecting >99% of described mutations in RET.
Blood: Collect 3-5 cc from adult or 2 cc minimum from child into EDTA purple-top tube (first choice) or ACD yellow-top tube (second choice). Store at room temperature or refrigerate. Ship at room temperature.
Blood Spot: Call for availability.
Saliva: Collect 2 ml into Oragene™ DNA Self-Collection container. Store and ship at room temperature.
DNA: Send 20 μg in TE at 50-100 ng/μl. Store frozen and ship on ice or dry ice.
Prenatal: Prenatal testing is available. Please call an Ambry Genetic Counselor to discuss your case.
| Test Code | Technique | CPT Codes |
|---|---|---|
| 2640 | MEN Type 1 (MEN1 Gene Sequence Analysis) | 83891x1, 83894x8, 83898x7, 83904x14, 83909x14, 83912x1 |
| 2680 | MEN Type 2 (RET Gene Sequence Analysis | 83891x1, 83894x21, 83898x20, 83904x35, 83909x35, 83912x1 |
| Technique | Days |
|---|---|
| MEN Type 1 (MEN1 Gene Sequence Analysis) | 10-21 |
| MEN Type 2 (RET Gene Sequence Analysis | 10-21 |
1 Eng C et al. JAMA.1996; 276(19): 1575-1579.
2 Fraue F et al. Horm. 2009; 8(1): 23-23.
3 Moore SW et al. Pediatr Surg Int. 2008; 24:521-530.
4 Lora M et al. J Clin Endoclinol Metab. 2005; 90(7): 4383-4387.
5 Brauckhoff M et al. Thyroid. 2002; 12(7): 557-61.
6 Brandi ML et al. J Clin Endocrinol Metab. 2001; 86: 5658-5671.
7 Lodish MB et al. Expert Rev Anticancer Ther. 2009; 8(4): 625-632.