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GeneDx
207 Perry Parkway
Gaithersburg, MD 20877
Phone: 301-519-2100
Fax: 301-519-2892
E-mail: [email protected]
www.genedx.com
Test Information Sheet
RET Gene Analysis in Multiple Endocrine Neoplasia Type 2A and
Multiple Endocrine Neoplasia Type 2B
(Familial Medullary Thyroid Cancer, included)
Also known as: MEN2A; Pheochromocytoma and amyloid-producing medullary thyroid carcinoma; PTC syndrome;
Sipple syndrome; FMTC; Thyroid carcinoma, familial medullary; MTC; MEN2B; Neuromata, mucosal, with
endocrine tumors; Mucosal neuroma syndrome; Wagenmann-Froboese syndrome
Mendelian Inheritance in Man Number: 171400 (Multiple Endocrine Neoplasia 2A); 155240 (Familial Medullary
Thyroid Carcinoma); 162300 (Multiple Endocrine Neoplasia 2B); 164761 (RET gene)
Clinical features:
The endocrine disorders observed in MEN2 are medullary thyroid carcinoma (MTC) and/or its precursor, C-cell
hyperplasia; pheochromocytoma; and parathyroid adenoma or hyperplasia. MEN2 traditionally has been classified
into three clinical subtypes: MEN2A, FMTC, and MEN2B. All three subtypes involve high risk for MTC; MEN2A
and MEN2B have an increased risk for pheochromocytoma; MEN 2A has an increased risk for parathyroid
hyperplasia or adenoma. Although all three subtypes are caused by mutations in the RET gene, classifying an
individual or family by MEN2 subtype is useful for determining prognosis and management.
The clinical diagnosis of MEN2A is made when an individual has two or more specific endocrine tumors:
medullary carcinoma of the thyroid (>95%), pheochromocytoma (50%), or parathyroid adenoma/hyperplasia (2030%). Prophylactic thyroidectomy in childhood is recommended when a RET mutation is identified.
FMTC (Familial Medullary Thyroid Carcinoma) is diagnosed in families with four cases of medullary thyroid
carcinoma (MTC) in the absence of pheochromocytoma or parathyroid adenoma. The medullary thyroid cancer
associated with FMTC is typically later onset and may be subclinical; therefore, in some families RET genetic
testing may be necessary to differentiate sporadic medullary thyroid cancer from FMTC.
MEN2B is characterized by multiple mucosal neuromas of the lips, tongue, and conjunctiva. Patients often have a
tall, thin, Marfanoid body habitus. Muscle wasting and weakness are a complication. Gastrointestinal symptoms
secondary to ganglioneuromas and colonic diverticula are observed. MEN2B is associated with an increased risk of
malignancy, including pheochromocytoma (50% of patients) and medullary thyroid carcinoma (100% penetrance).
RET gene mutations also are associated with another distinct disorder, Hirschsprung disease (see separate
information sheet for clinical information and for GeneDx testing information), and in approximately 10% of
isolated pheochromocytoma.
Inheritance pattern: Autosomal dominant; de novo mutations are estimated to occur in 5% of MEN2A cases and 50%
of MEN2B cases.
Reasons for referral:
1. Confirmation of a clinical diagnosis
2. Determination of appropriate screening and surgical management
3. Genetic counseling
4. Identification of at-risk family members
5. Prenatal diagnosis
Test method:
Information Sheet on MEN2A and MEN2B
Page 1 of 2
GeneDx Revision Date: 8/13
Analysis is performed by bi-directional sequencing of exons 1-20 of the RET gene. Mutations found in the first
person of a family to be tested are confirmed by repeat analysis using sequencing, restriction fragment analysis, or
another appropriate method.
Test sensitivity:
The largest international study to date identified germline RET mutations in 95% of patients with a clinical
diagnosis of MEN2A, 87% of patients with FMTC, and 94% of patients with MEN2B.1 One large study identified
a germline RET mutation in 35 of 481 (7.3%) of individuals with apparently sporadic MTC2, while other smaller
studies have found germline RET mutations in 0-22.7% of apparently sporadic MTC cases.3,4,5
Mutation spectrum:
In MEN2A, nearly all mutations occur in exons 10 and 11 of the RET gene. Mutations at the codon Cys634
position occur in ~85% of families. Mutations of Cysteine residues at amino acid positions 609, 611, 618, and 620
account for most of the remaining identifiable mutations in these exons. Patients with FMTC have exhibited a
number of different mutations in the RET gene, most of which occur in exons 10, 11, 13, or 14.1,6 A single
mutation in exon 16, Met918Thr, has been identified in 95% (or more) of patients with MEN2B, and a mutation
affecting the Ala883 codon in exon 15 has been reported in 2-4% of cases.7,8 Missense and nonsense codon
changes are most frequent. Evidence for genotype-phenotype correlation involving specific Cysteine codons has
been established, one notable relationship existing between mutations at the Cys634 codon and a higher incidence
of pheochromocytomas and hyperparathyroidism.9
Specimen Requirements and Shipping/Handling:
• Blood: A single tube with 1-5 mL whole blood in EDTA. Ship overnight at ambient temperature, using a cool
pack in hot weather. Specimens may be refrigerated for 7 days prior to shipping.
• Buccal Brushes: When sending a buccal sample, use a GeneDx buccal kit (others not accepted). Submit by
mail. Buccal brushes are not accepted on children under 6 months of age.
• Prenatal Diagnosis: For prenatal testing for a known mutation in the RET gene, please refer to the
specimen requirements table on our website at: http://www.genedx.com/test-catalog/prenatal/. Ship
specimen overnight at ambient temperature, using a cool pack in hot weather.
Required Forms:
• Sample Submission (Requisition) Form – complete all pages
• Payment Options Form or Institutional Billing Instructions
For test codes, prices, CPT codes, and turn-around-times, please refer to the test catalog page on our
website: www.genedx.com
References Cited:
(1) Mulligan, L.M. et al., Genotype-phenotype correlation in multiple endocrine neoplasia type 2: report of the International RET
Mutation Consortium. J Intern Med. 238: 343-6, 1995.
(2) Elisei, R et al., RET genetic screening in patients with medullary thyroid cancer and their relatives: Experience with 807 individuals at
one center. J Clin Endocrinol Metab 92(12)4725-4729, 2007.
(3) Heshmati HM, et al. Genetic testing in medullary thyroid carcinoma syndromes: mutation types and clinical significance. Mayo Clin
Proc 72(5):430-436, 1997.
(4) Wiench M et al. Estimation of risk of inherited medullary thyroid carcinoma in apparent sporadic patients. J Clin Oncol 19(5):13741380, 2001.
(5) Shirahama S et al. Mutational analysis of the RET proto-oncogene in 71 Japanese patients with medullary thyroid carcinoma. J Hum
Genet 43:101-106, 1998.
(6) Mulligan, L.M. et al., Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN 2A and FMTC. Nat
Genet. 6: 70-4, 1994.
(7) Eng, C. et al., Point mutation within the tyrosine kinase domain of the RET-proto-oncogene in multiple endocrine neoplasia type 2B
and related sporadic tumors. Hum Mol Genet. 3: 237-41, 1994.
(8) Gimm, O. et al., Germline dinucleotide mutation in codon 883 of the RET proto-oncogene in multiple endocrine neoplasia type 2B
without codon 918 mutation. J Clin Endocrinol Metab. 82: 3902-4, 1997.
(9) Yip, L. et al., Multiple Endocrine Neoplasia Type 2: Evaluation of the Genotype-Phenotype Relationship. Arch Surg. 138: 409-16,
2003.
Information Sheet on MEN2A and MEN2B
Page 2 of 2
GeneDx Revision Date: 8/13