Multiple Endocrine Neoplasia Type 2

Diagnostic test for MEN2

Familial Mutation, Targeted Sequencing 2001961
Method: Polymerase Chain Reaction/Sequencing

Useful when a pathogenic familial variant identifiable by sequencing is known

Related Test
Hereditary Cancer Panel, Sequencing and Deletion/Duplication 2012032
Method: Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray

Confirm diagnosis of a hereditary cancer syndrome with personal or family history consistent with features of more than one cancer syndrome

Multiple endocrine neoplasia type 2 (MEN2) is a rare hereditary syndrome caused by pathogenic variants in the RET gene. MEN2 can be further classified into subtypes MEN2A, MEN2B, and familial medullary thyroid cancer (FMTC). All MEN2 types have an increased risk of medullary thyroid cancer (MTC). MEN2A (70-80% of MEN2 cases) is also associated with benign parathyroid adenomas, adrenal gland tumors (pheochromocytoma), and nerve cell tumors (ganglioneuromatosis). MEN2B is associated with more aggressive MTC that can occur during childhood and with benign neuromas often found in the mucous membranes. Pheochromocytomas develop in approximately 50% of individuals with MEN2B. FMTC is considered a variant of MEN2A and is characterized as multiple cases (often four or more) of MTC in a family, without the presence of pheochromocytomas or hyperparathryoidism.

Disease Overview

Prevalence

1/35,000 

Symptoms

MEN2 has three defined subtypes 

  • MEN2A: 70-80% of cases
    • Early onset MTC: typically prior to 35 years
    • Pheochromocytoma
    • Parathyroid adenoma/hyperplasia
  • MEN2B: ~5% of cases
    • Early onset MTC: childhood
    • Pheochromocytoma
    • Mucosal abnormalities
    • Gastrointestinal ganglioneuromatosis
    • Eye abnormalities: eg, corneal nerve thickening
    • Skeletal abnormalities: eg, marfanoid body
  • FMTC: 10-20% of cases
    • Associated with MTC only
    • FMTC is considered a variant of MEN2A and is characterized as multiple cases (often four or more) of MTC in a family, without the presence pheochromocytomas or hyperparathryoidism

Genetics

Gene

RET

Inheritance

Autosomal dominant

Penetrance

  • Clinical course differs between subtypes
  • Penetrance of MTC 
    • 95% for MEN2A
    • Nearly 100% for FMTC and MEN2B

De novo Pathogenic Variants

  • 5% of MEN2A 
  • 50% of MEN2B pathogenic variants 

Test Interpretation

Sensitivity/Specificity

  • Clinical sensitivity
  • Analytical sensitivity/specificity: 99%

Results

  • Positive: one RET pathogenic variant detected
    • Confirms diagnosis and etiology
  • Negative: no RET pathogenic variants detected
    • MEN2A, MEN2B, or FMTC is unlikely, but not excluded
  • Inconclusive: RET variant detected, but whether variant is benign or pathogenic is unknown

Limitations

  • Not evaluated
    • Regulatory region variants
    • Deep intronic variants
    • Large deletions/duplications
    • RET exons other than 5, 8, 10, 11, 13-16
  • Diagnostic errors can occur due to rare sequence variations
References 
  1. DeLellis RA, Lloyd RV, Heitz PU. Pathology and Genetics: Tumours of the Endocrine Organs. World Health Organization Classification of Tumours Series, Vol 8. Lyon, France: IARC Press, 2004.
  2. Marquard J, Eng C. Multiple Endocrine Neoplasia Type 2. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, editors. GeneReviews, University of Washington, 1993-2019. Seattle, WA [Last Update: Jun 2015; Accessed: Jul 2019]
  3. Raue F, Frank-Raue K. Genotype-phenotype correlation in multiple endocrine neoplasia type 2. Clinics (Sao Paulo). 2012; 67 Suppl 1: 69-75. PubMed
  4. Schuffenecker I, Ginet N, Goldgar D, Eng C, Chambe B, Boneu A, Houdent C, Pallo D, Schlumberger M, Thivolet C, Lenoir GM. Prevalence and parental origin of de novo RET mutations in multiple endocrine neoplasia type 2A and familial medullary thyroid carcinoma. Am J Hum Genet. 1997; 60(1): 233-7. PubMed
  5. Carlson KM, Bracamontes J, Jackson CE, Clark R, Lacroix A, Wells SA, Goodfellow PJ. Parent-of-origin effects in multiple endocrine neoplasia type 2B. Am J Hum Genet. 1994; 55(6): 1076-82. PubMed
  6. American Thyroid Association Guidelines Task Force, Kloos RT, Eng C, Evans DB, Francis GL, Gagel RF, Gharib H, Moley JF, Pacini F, Ringel MD, Schlumberger M, Wells SA. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid. 2009; 19(6): 565-612. PubMed
  7. Mulligan LM, Marsh DJ, Robinson BG, Schuffenecker I, Zedenius J, Lips CJ, Gagel RF, Takai SI, Noll WW, Fink M. Genotype-phenotype correlation in multiple endocrine neoplasia type 2: report of the International RET Mutation Consortium. J Intern Med. 1995; 238(4): 343-6. PubMed
  8. Moline J, Eng C. Multiple endocrine neoplasia type 2: an overview. Genet Med. 2011; 13(9): 755-64. PubMed
Related Information 
Multiple Endocrine Neoplasias - MEN

Last Update: August 2019