Multiple Endocrine Neoplasia Type 2 (MEN2)

Multiple Endocrine Neoplasia Type 2 (MEN2) causes both malignant and benign tumors of the endocrine system, the most common being medullary thyroid carcinoma (MTC). 

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Multiple Endocrine Neoplasia Type 2 (MEN2) causes both malignant and benign tumors of the endocrine system, the most common being medullary thyroid carcinoma (MTC). 

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MEN2 is associated with a high lifetime risk for medullary thyroid cancer (MTC), pheochromocytoma (PCC), and parathyroid adenoma or hyperplasia, depending on the subtype.  It is inherited in an autosomal dominant manner and caused by germline mutations in the RET proto-oncogene.  Depending on the tissues involved, MEN2 is divided into three subtypes: MEN2A, MEN2B, and familial medullary thyroid carcinoma (FMTC).  Genetic analysis of RET 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.

Disease Name 
Multiple Endocrine Neoplasia Type 2 (MEN2)
MEN2A (Sipple Syndrome)
MEN2B (Mucosal Neuroma Syndrome)
Familial Medullary Thyroid Carcinoma (FMTC)
Disease Information 

MEN2 is characterized by benign or malignant tumors of the endocrine system. The most common malignancy associated with MEN2 is MTC. MEN2 is caused by mutations that activate 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 is further subdivided into three subtypes: MEN2A, MEN2B, and FMTC [1].

MEN2A is characterized by MTC in 95% of cases, hyperparathyroidism in up to 30% of cases, and unilateral or bilateral PCC in up to 50% of cases [1, 2]. Co-segregation of RET-related Hirschsprung 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. Risk for MTC is 100% and for PCC is 50%. MEN2B can be differentiated from MEN2A by a lack of hyperparathyroidism. Individuals affected with MEN2B also often have a marfanoid habitus, distinctive facial characteristics with enlarged lips [4], mucosal neuromas of the lips and tongue [1, 2, 4], as well as childhood intestinal ganglioneuromas [5].

FMTC is the mildest of the subtypes and comprises about 5-35% of MEN2 cases. Individuals are usually only affected with MTC and do not exhibit any of the other typical MEN2 findings [1, 2].

Papillary thyroid carcinoma has also been reported in patients with mutations in codons 790 and 804 of the RET gene [6].

Testing Benefits & Indication 

Genetic testing is an especially useful diagnostic tool to differentiate sporadic MTC cases from those with MEN2, as it directly impacts medical management. According to Brandi et al., it is beneficial if an individual is identified to be a carrier of a RET mutation before they reach adulthood, as screening and surgical interventions can help diminish their mortality rate [7, 8]. It is also recommended that all patients with MTC be offered testing for germline RET mutations, ideally before surgery; undiagnosed pheochromocytomas can increase the risk of surgical complications [7, 8]. 

Test Description 

RET coding exons1-20 and well into the 5’ and 3’ ends of all the introns and untranslated regions are analyzed by sequencing. Clinically significant intronic findings beyond 5 base pairs are always reported. Intronic variants of unknown or unlikely clinical significance are not reported beyond 5 base pairs from the splice junction. Genomic deoxyribonucleic acid (gDNA) is isolated from the patient’s specimen using standardized methodology and quantified. Sequence enrichment of the targeted coding exons and adjacent intronic nucleotides is carried out by a bait-capture methodology, using long biotinylated oligonucleotide probes followed by polymerase chain reaction (PCR) and next generation sequencing (NGS). Sanger sequencing is performed for any regions missing or with insufficient read depth coverage for reliable heterozygous variant detection. Reportable small insertions and deletions, potentially homozygous variants, variants in regions complicated by pseudogene interference, and single nucleotide variant calls not satisfying 100x depth of coverage and 40% het ratio thresholds are verified by Sanger sequencing.10 

Mutation Detection Rate 

Mutations in the RET gene account for up to 98% of individuals affected with MEN2 (clinical sensitivity) [9]. Ambry’s RET analysis can detect >99.9% of described mutations in the gene, when present (analytic sensitivity). 

Specimen Requirements 

Complete specimen requirements are available here or by downloading the PDF found above in the Quick Links section at the top of this page.

Turnaround Time 
TEST CODE Technique CALENDAR DAYS
2680 RET Gene Sequence  14-21

 

Specialty 
Genes 
RET
Techniques 
References 
  1. Eng C, et al. The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. JAMA. 1996. 276(19): p. 1575-9.
  2. Raue F and Frank-Raue K. Genotype-phenotype relationship in multiple endocrine neoplasia type 2. Implications for clinical management. Hormones (Athens). 2009. 8(1): p. 23-8.
  3. Moore SW and Zaahl MG. Multiple endocrine neoplasia syndromes, children, Hirschsprung's disease and RET. Pediatr Surg Int. 2008. 24(5): p. 521-30.
  4. Moline J and Eng C. Multiple Endocrine Neoplasia Type 2, in GeneReviews(R), R.A. Pagon. et al. Editors. 1993: Seattle (WA).
  5. Lora MS, et al. Adrenal ganglioneuromas in children with multiple endocrine neoplasia type 2: a report of two cases. J Clin Endocrinol Metab. 2005. 90(7): p. 4383-7.
  6. Brauckhoff M, et al. Papillary thyroid carcinoma in patients with RET proto-oncogene germline mutation. Thyroid. 2002. 12(7): p. 557-61.
  7. Brandi ML, et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab. 2001. 86(12): p. 5658-71.
  8. American Thyroid Association Guidelines Task F, et al. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid. 2009. 19(6): p. 565-612.
  9. Lodish MB and Stratakis CA. RET oncogene in MEN2, MEN2B, MTC and other forms of thyroid cancer. Expert Rev Anticancer Ther. 2008. 8(4): p. 625-32.
  10. Mu W, et al. Sanger confirmation is required to achieve optimal sensitivity and specificity in next-generation sequencing panel testing. J Mol Diagn. 2016. 18(6):923-932.