Polymerase Chain Reaction/Sequencing
Polymerase Chain Reaction/Sequencing
Useful when a pathogenic familial variant identifiable by sequencing is known
Related Test
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
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
Test Interpretation
Sensitivity/Specificity
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
-
Pathology and Genetics: Tumours of the Endocrine Organs.
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.
Book -
GeneReviews - Multiple Endocrine Neoplasia Type 2
Eng C. Multiple endocrine neoplasia type 2. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews, University of Washington; 1993-2020. [Last Update: Aug 2019; Accessed: Feb 2020]
Online -
22584709
Raue F, Frank-Raue K. Genotype-phenotype correlation in multiple endocrine neoplasia type 2. Clinics (Sao Paulo). 2012;67 Suppl 1(Suppl 1):69-75.
PubMed -
8981969
Schuffenecker I, Ginet N, Goldgar D, et al. 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):233-237.
PubMed -
7977365
Carlson KM, Bracamontes J, Jackson CE, et al. Parent-of-origin effects in multiple endocrine neoplasia type 2B. Am J Hum Genet. 1994;55(6):1076-1082.
PubMed -
19469690
Kloos RT, Eng C, Evans DB, et al. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid. 2009;19(6):565-612.
PubMed -
7595170
Mulligan LM, Marsh DJ, Robinson BG, et al. Genotype-phenotype correlation in multiple endocrine neoplasia type 2: report of the International RET Mutation Consortium. J Intern Med. 1995;238(4):343-346.
PubMed -
21552134
Moline J, Eng C. Multiple endocrine neoplasia type 2: an overview. Genet Med. 2011;13(9):755-764.
PubMed
Diagnostic test for MEN2