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Multiple Endocrine Neoplasia Type 2

Synonyms: MEN 2, MEN2 Syndrome

, MS, LGC and , MD, PhD, FACP.

Author Information
, MS, LGC
Genomic Medicine Institute
Cleveland Clinic
Cleveland, Ohio
, MD, PhD, FACP
Genomic Medicine Institute
Cleveland Clinic
Department of Genetics and Genome Sciences
Case Western Reserve University School of Medicine
Cleveland, Ohio

Initial Posting: ; Last Update: June 25, 2015.

Summary

Clinical characteristics.

Multiple endocrine neoplasia type 2 (MEN 2) is classified into three subtypes: MEN 2A, FMTC (familial medullary thyroid carcinoma), and MEN 2B. All three subtypes involve high risk for development of medullary carcinoma of the thyroid (MTC); MEN 2A and MEN 2B have an increased risk for pheochromocytoma; MEN 2A has an increased risk for parathyroid adenoma or hyperplasia. Additional features in MEN 2B include mucosal neuromas of the lips and tongue, distinctive facies with enlarged lips, ganglioneuromatosis of the gastrointestinal tract, and a ‘marfanoid’ habitus. MTC typically occurs in early childhood in MEN 2B, early adulthood in MEN 2A, and middle age in FMTC.

Diagnosis/testing.

The diagnosis of MEN 2 is established in a proband who fulfills existing diagnostic clinical criteria. Molecular genetic testing to identify a heterozygous germline RET pathogenic variant is indicated in all individuals with a diagnosis of primary C-cell hyperplasia or MTC or a clinical diagnosis of MEN 2. Identification of a heterozygous germline RET pathogenic variant on molecular genetic testing establishes the diagnosis if clinical features are inconclusive.

Management.

Treatment of manifestations: Treatment for MTC is surgical removal of the thyroid gland and lymph node dissection. External beam radiation therapy (EBRT) or intensity-modulated radiation therapy (IMRT) can be considered for advanced locoregional disease. Kinase inhibitors may be used in metastatic MTC. Pheochromocytomas detected by biochemical testing and radionuclide imaging are removed by adrenalectomy. Primary hyperparathyroidism is treated with surgery to remove one or more parathyroid glands, or more rarely, medications to reduce parathyroid hormone secretion.

Prevention of primary manifestations: Prophylactic thyroidectomy for individuals with an identified germline RET pathogenic variant.

Prevention of secondary complications: Prior to any surgery in an individual with MEN 2A or MEN 2B, the presence of a functioning pheochromocytoma should be excluded by appropriate biochemical screening.

Surveillance: Annual measurement of serum calcitonin concentration to detect residual or recurrent MTC after thyroidectomy, even if thyroidectomy was performed prior to biochemical evidence of disease. Monitoring for possible hypoparathyroidism in all those who have undergone thyroidectomy and parathyroid autotransplantation. Annual biochemical screening for those with a germline RET pathogenic variant whose initial screening results are negative for pheochromocytoma.

Agents/circumstances to avoid: Dopamine D2 receptor antagonists and β-adrenergic receptor antagonists present a high risk for adverse reactions in individuals with pheochromocytoma.

Evaluation of relatives at risk: RET molecular genetic testing should be offered to all at-risk members of kindreds in which a germline RET pathogenic variant has been identified.

Pregnancy management: Women with MEN 2 should be screened for pheochromocytoma prior to a planned pregnancy, or as early as possible during an unplanned pregnancy.

Genetic counseling.

All MEN 2 subtypes are inherited in an autosomal dominant manner. The probability of a de novo pathogenic variant is 5% or less in index cases with MEN 2A and 50% in index cases with MEN 2B. Offspring of affected individuals have a 50% chance of inheriting the pathogenic variant. Prenatal testing for pregnancies at increased risk is possible if the RET pathogenic variant has been identified in an affected family member.

GeneReview Scope

Multiple Endocrine Neoplasia Type 2: Included Phenotypes
  • Multiple endocrine neoplasia type 2A (MEN 2A)
  • Familial medullary thyroid carcinoma (FMTC)
  • Multiple endocrine neoplasia type 2B (MEN 2B)

For synonyms and outdated names see Nomenclature.

Diagnosis

Suggestive Findings

Multiple endocrine neoplasia type 2 (MEN 2) includes the phenotypes MEN 2A, familial medullary thyroid carcinoma (FMTC), and MEN 2B.

MEN 2A should be suspected in individuals with one or more specific endocrine tumors - medullary thyroid carcinoma (MTC), pheochromocytoma, or parathyroid adenoma/hyperplasia.

FMTC should be suspected in families with more than one individual diagnosed with MTC in the absence of pheochromocytoma or parathyroid adenoma/hyperplasia.

MEN 2B should be suspected in individuals with distinctive facies including lip mucosal neuromas resulting in thick vermilion of the upper and lower lip, mucosal neuromas of the lips and tongue, medullated corneal nerve fibers, marfanoid habitus, and MTC.

Histologic, Biochemical, and/or Imaging Findings Suggestive Of MEN 2

Medullary thyroid carcinoma (MTC) and C-cell hyperplasia (CCH)

  • Histologic. MTC originates in calcitonin-producing cells (C-cells) of the thyroid gland. MTC is diagnosed histologically when nests of C-cells appear to extend beyond the basement membrane and to infiltrate and destroy thyroid follicles. Immunohistochemistry for calcitonin expression may be performed as a pathologic diagnostic adjunct.

    CCH is diagnosed histologically by the presence of an increased number of diffusely scattered or clustered C-cells. In MEN 2, the age of transformation from CCH to MTC varies with different germline RET pathogenic variants [Machens et al 2003].
  • Biochemical. MTC and CCH are suspected in the presence of an elevated plasma calcitonin concentration, a specific and sensitive marker. In provocative testing, plasma calcitonin concentration is measured before (basal level) and two and five minutes after intravenous administration of calcium (stimulated level). Other calcitonin secretagogues such as pentagastrin (available in Europe, limited in the US) are also used. A basal or stimulated calcitonin level of ≥100 pg/mL is an indication for surgery [Costante et al 2007, American Thyroid Association Guidelines Task Force 2009].

Pheochromocytoma

  • Biochemical. Pheochromocytoma is suspected when biochemical screening reveals elevated excretion of catecholamines and catecholamine metabolites (e.g., norepinephrine, epinephrine, metanephrine, and vanillylmandelic acid [VMA]) in plasma or 24-hour urine collections [Pacak et al 2005, Ilias & Pacak 2009]. In MEN 2, pheochromocytomas consistently produce epinephrine or epinephrine and norepinephrine [Ilias & Pacak 2009].
  • Imaging. Abdominal MRI and/or CT are performed if plasma or urinary catecholamine values are increased or if a pheochromocytoma is suspected clinically. MRI is more sensitive than CT in detection of a pheochromocytoma.

    [18F]-fluorodopamine ([18F]DA) PET is the best overall imaging modality in the localization of pheochromocytomas. If [18F]DA PET is unavailable, MIBG (123I- or 131I- metaiodobenzylguanidine) scintigraphy should be used to further evaluate individuals with biochemical or radiographic evidence of pheochromocytoma [Ilias et al 2008].

Parathyroid abnormalities

  • Biochemical. Parathyroid abnormalities are present when elevated serum calcium occurs simultaneously with elevated or high-normal parathyroid hormone (PTH).
  • Imaging. Postoperative parathyroid localizing studies with 99mTc-sestamibi scintigraphy may be helpful if hyperparathyroidism recurs. For preoperative adenoma localization, three-dimensional single-photon emission CT (SPECT) may also be used [Brenner & Jacene 2008].

Establishing the Diagnosis

The diagnosis of MEN 2 is established in a proband with the following clinical criteria. Identification of a heterozygous germline RET pathogenic variant on molecular genetic testing establishes the diagnosis if clinical features are inconclusive.

Clinical criteria

  • MEN 2A is diagnosed clinically by the occurrence of two or more specific endocrine tumors (medullary thyroid carcinoma [MTC], pheochromocytoma, or parathyroid adenoma/hyperplasia) in a single individual or in close relatives.
  • Familial medullary thyroid carcinoma (FMTC) is diagnosed in families with four or more cases of MTC in the absence of pheochromocytoma or parathyroid adenoma/hyperplasia.
  • MEN 2B is diagnosed clinically by the presence of early-onset MTC, mucosal neuromas of the lips and tongue, as well as medullated corneal nerve fibers, distinctive facies with enlarged lips, and an asthenic ‘marfanoid’ body habitus [American Thyroid Association Guidelines Task Force 2009].

Molecular genetic testing to identify a heterozygous germline RET pathogenic variant is indicated in all individuals with a diagnosis of primary C-cell hyperplasia or MTC or a clinical diagnosis of MEN 2. The algorithm for testing is summarized in the most recent American Thyroid Association MTC Practice Guidelines [American Thyroid Association Guidelines Task Force 2009]. Note: If clinical findings suggest a diagnosis of MEN 2 in an individual with no family history of the disorder, molecular genetic testing of RET is still indicated.

Molecular testing approaches can include select exon testing, single gene testing, and use of a multi-gene panel.

  • Select exon testing. The majority of pathogenic variants occur in exons 10, 11, and 13-16. Sequence analysis of select exons and targeted mutational analysis may be offered by some laboratories.
  • Single-gene testing. Sequence analysis of RET may be performed if no pathogenic variant is found by select exon testing.
    Note: Since MEN 2 occurs through a gain of function mechanism and large intragenic deletion or duplication has not been reported, testing for intragenic deletions or duplications is not indicated.
  • A multi-gene panel that includes RET and other genes of interest (see Differential Diagnosis) may also be considered, especially in the case of isolated or familial pheochromocytoma. Note: The genes included and sensitivity of multi-gene panels vary by laboratory and over time.

Table 1.

Molecular Genetic Testing Used in MEN 2

Gene 1Test Method 2Proportion of Probands with a Pathogenic Variant 3 Detectable by This Method
MEN 2AFMTCMEN 2B
RETSequence analysis 4>98% 5>95% 6, 7>98% 8
Sequence analysis of select exons98% 5, 995% 6, 7
Targeted analysis for pathogenic variants 1098% 8
1.
2.

Since MEN 2 occurs through a gain of function mechanism, gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications is not indicated. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect singl- exon deletions or duplications.

3.

See Molecular Genetics for information on allelic variants detected in this gene.

4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.
6.
7.

Pathogenic variants of codons 618, 620, and 634 each account for 20% to 30% of pathogenic variants. Other pathogenic variants in exons 5, 8, 10, 11, and 13 to 16 appear to account for a small percentage of pathogenic variants in families with FMTC, with an important minority affecting codons 768 and 804.

8.

Approximately 95% of individuals have a pathogenic variant at codon 918 in exon 16 [Eng et al 1996]. A pathogenic variant in exon 15 has been identified in several affected individuals [Gimm et al 1997, Smith et al 1997].

9.
10.

Pathogenic variants typically detected: p.Met918Thr, p.Ala883Phe. Note: Pathogenic variants included in a panel may vary by laboratory.

Test characteristics. See Clinical Utility Gene Card [Raue et al 2012] for information on test characteristics including sensitivity and specificity.

Clinical Characteristics

Clinical Description

The endocrine disorders observed in multiple endocrine neoplasia type 2 (MEN 2) are: medullary thyroid carcinoma (MTC) and/or its precursor, C-cell hyperplasia; pheochromocytoma; and parathyroid adenoma or hyperplasia.

MTC in persons with MEN 2 typically presents at a younger age than sporadic MTC and is more often associated with C-cell hyperplasia as well as multifocality or bilaterality. Symptoms of MTC include neck pain, a palpable neck mass, and/or diarrhea resulting from hypercalcitoninemia [Callender et al 2008]. Metastatic spread to cervical and regional lymph nodes (i.e., parathyroid, paratracheal, jugular chain, and upper mediastinum) or to distant sites including the liver, lungs, or bone is common and has often occurred in individuals with a palpable thyroid mass or diarrhea [Moley et al 1998, Cohen & Moley 2003]. About 25%-30% of all individuals with MTC have a germline RET pathogenic variant. In a large series of individuals with simplex medullary thyroid carcinoma (i.e., no known family history of MTC or personal history of other endocrine disease), approximately 7% were found to have a germline RET pathogenic variant [Elisei et al 2007].

Pheochromocytomas in individuals with MEN 2 are nearly always adrenal and often bilateral [Pomares et al 1998, Pacak et al 2005, Thosani et al 2013].

Individuals with a confirmed germline RET pathogenic variant who present with head and neck paraganglioma all have a personal and/or family history consistent with MEN 2 [Boedeker CC et al 2009].

Although pheochromocytomas in individuals with MEN 2 rarely metastasize, they can be lethal because of intractable hypertension or anesthesia-induced hypertensive crises.

Parathyroid abnormalities can range from benign parathyroid adenomas to clinically evident hyperparathyroidism with hypercalcemia and renal stones.

MEN 2 is classified into three clinical subtypes: MEN 2A, FMTC, and MEN 2B (Table 2). All three subtypes involve high risk for MTC; individuals with MEN 2A and MEN 2B are at increased risk for pheochromocytoma; individuals with MEN 2A are at increased risk for parathyroid hyperplasia or adenoma. Classifying an individual or family by MEN 2 subtype is useful for determining prognosis and management.

Table 2.

Percent of Clinical Features by MEN 2 Subtype

SubtypeMedullary Thyroid CarcinomaPheochromocytomaParathyroid Disease
MEN 2A95%50%20%-30%
FMTC100%0%0%
MEN 2B100%50%Uncommon

MEN 2A

The MEN 2A subtype constitutes approximately 70%-80% of cases of MEN 2. Since genetic testing for RET pathogenic variants has become available, it has become apparent that 95% of individuals with MEN 2A develop MTC, about 50% develop pheochromocytoma, and about 20%-30% develop hyperparathyroidism [Eng et al 1996].

MTC is generally the first manifestation of MEN 2A. Probands with MTC typically present with a neck mass or neck pain prior to age 35 years. Up to 70% of such individuals already have cervical lymph node metastases [Cohen & Moley 2003]. Diarrhea (the most frequent systemic symptom) occurs in affected individuals with a plasma calcitonin concentration >10 ng/mL and implies a poor prognosis. All individuals with an MTC-predisposing pathogenic variant who have not undergone prophylactic thyroidectomy demonstrate biochemical evidence of MTC by age 35 years [DeLellis et al 2004].

Pheochromocytomas usually present after MTC or concomitantly; however, they are the first sign in 13%-27% of individuals with MEN 2A [Inabnet et al 2000, Rodriguez et al 2008]. Pheochromocytomas in persons with MEN 2A are diagnosed at an earlier age, have subtler symptoms, and are more likely to be bilateral than sporadic tumors [Pomares et al 1998, Pacak et al 2005]. Malignant transformation occurs in about 4% of cases [Modigliani et al 1995]. Since pheochromocytoma can be the first manifestation of MEN 2A, the diagnosis of pheochromocytoma in an individual warrants further investigation for MEN 2A [Inabnet et al 2000, Neumann et al 2002].

Hyperparathyroidism (HPT) in MEN 2A is typically mild and may range from a single adenoma to marked hyperplasia. Most individuals with hyperparathyroidism have no symptoms; however, hypercalciuria and renal calculi may occur [Brandi et al 2001]. HPT usually presents many years after the diagnosis of MTC; the average age at onset is 38 years [American Thyroid Association Guidelines Task Force 2009].

A small number of families with MEN 2A have pruritic cutaneous lichen amyloidosis (PCLA), also known as cutaneous lichen amyloidosis (CLA). This lichenoid skin lesion is located over the upper portion of the back and may appear before the onset of MTC [Seri et al 1997].

FMTC

The FMTC subtype constitutes approximately 10%-20% of cases of MEN 2. By operational definition MTC is the only clinical manifestation of FMTC. The age of onset of MTC is later in FMTC and the penetrance of MTC is lower than that observed in MEN 2A and MEN 2B [Eng et al 1996, Machens et al 2001, Machens & Dralle 2006, Zbuk & Eng 2007, American Thyroid Association Guidelines Task Force 2009]. To avoid erroneously disregarding a risk for pheochromocytoma, strict criteria should be met before a family is classified as having FMTC. In the past, some believed that a kindred with FMTC should have more than ten members with a RET pathogenic variant and multiple individuals with a RET pathogenic variant over age 50 years, and all members should have an adequate medical history demonstrating absence of pheochromocytoma or hyperparathyroidism [Brandi et al 2001].

Today, FMTC is typically viewed as a variant of MEN 2A with decreased penetrance of pheochromocytoma and hyperparathyroidism, rather than a distinct subtype [American Thyroid Association Guidelines Task Force 2009].

MEN 2B

The MEN 2B subtype accounts for approximately 5% of cases of MEN 2. MEN 2B is characterized by the early development of an aggressive form of MTC in all affected individuals [Skinner et al 1996]. Individuals with MEN 2B who do not undergo thyroidectomy before age one year are likely to develop metastatic MTC at an early age. Prior to intervention with early prophylactic thyroidectomy, the average age of death in individuals with MEN 2B was 21 years.

Pheochromocytomas occur in 50% of individuals with MEN 2B; about half are multiple and often bilateral. Individuals with undiagnosed pheochromocytoma may die from a cardiovascular hypertensive crisis perioperatively.

Clinically significant parathyroid disease is absent in MEN 2B.

Individuals with MEN 2B may be identified in infancy or early childhood by the presence of mucosal neuromas on the anterior dorsal surface of the tongue, palate, or pharynx and a distinctive facial appearance. The lips become prominent (or ‘blubbery’) over time, and submucosal nodules may be present on the vermilion border of the lips. Neuromas of the eyelids may cause thickening and eversion of the upper eyelid margins. Prominent thickened corneal nerves may be seen by slit lamp examination.

About 40% of affected individuals have diffuse ganglioneuromatosis of the gastrointestinal tract. Associated symptoms include abdominal distension, megacolon, constipation, or diarrhea. In one study of 19 individuals with MEN 2B, 84% reported gastrointestinal symptoms beginning in infancy or early childhood [Wray et al 2008].

About 75% of affected individuals have a marfanoid habitus, often with kyphoscoliosis or lordosis, joint laxity, and decreased subcutaneous fat. Proximal muscle wasting and weakness can also be seen.

Genotype-Phenotype Correlations

Pathogenic variants involving the cysteine codons 609, 618, and 620 in exon 10 of RET are associated with MEN 2A, FMTC, and HSCR1 [Mulligan et al 1994, Decker et al 1998, Romeo et al 1998, Inoue et al 1999, Takahashi et al 1999]. A pathogenic variant in one of these codons, is detected in about 10% of families with MEN 2A and more than 50% of families with FMTC; these pathogenic variants are associated with low transforming activity of RET [Takahashi et al 1998, Hansford & Mulligan 2000].

RET germline pathogenic variant, p.Met918Thr, is only associated with MEN 2B; however, somatic pathogenic variants at this codon are frequently observed in MTC in individuals with no known family history of MTC, and are over-represented in individuals with sporadic MTC who have a particular germline RET variant, c.2439C>T (p.Ser836Ser) [Gimm et al 1999].

Any RET pathogenic variant at codon 634 in exon 11 results in a higher incidence of pheochromocytomas and hyperparathyroidism [Eng et al 1996, Yip et al 2003, Zbuk & Eng 2007, American Thyroid Association Guidelines Task Force 2009].

  • A report of 12 Brazilian families indicated that p.Cys634Arg is associated with a higher probability of having metastases at diagnosis than other codon 634 pathogenic variants [Puñales et al 2003].
  • Codon 634 pathogenic variants are also associated with development of cutaneous lichen amyloidosis [Seri et al 1997]. Among 25 individuals from three families with a codon 634 pathogenic variant, 36% had cutaneous lichen amyloidosis [Verga et al 2003].
  • While 25% of FMTC kindreds harbor a pathogenic variant in codon 634, p.Cys634Arg pathogenic variants are virtually absent in this subtype [Hansford & Mulligan 2000, Zbuk & Eng 2007].

Pathogenic variants at codons 768, 804, and 891 that were initially only associated with MTC have subsequently been found in families with MEN 2A [Jimenez et al 2004a, Aiello et al 2005, Schulte et al 2010].

  • Initially thought to be associated with MTC only, pathogenic variants at codon 804 in exon 14 (e.g., p.Val804Leu and p.Val804Met) were subsequently identified in individuals with pheochromocytoma [Nilsson et al 1999, Høie et al 2000, Gibelin et al 2004, Jimenez et al 2004a].
  • Disease expression of pathogenic variants at codon 804 has been shown to be highly variable, even within the same family [Feldman et al 2000, Frohnauer & Decker 2000]. Some individuals with such pathogenic variants have MTC at age five years and fatal metastatic MTC at age 12 years, whereas other individuals with the same pathogenic variant have been shown to have normal thyroid histology at age 27 years, normal biochemical screening at age 40 years, and no clinical evidence of MTC at age 86 years.
  • In another large family with a high level of consanguinity, biochemical testing indicated expression of thyroid disease in individuals homozygous but not heterozygous for p.Val804Met [Lecube et al 2002].
  • Cutaneous lichen amyloidosis in the background of a p.Val804Met pathogenic variant has been reported in one individual [Rothberg et al 2009].

One study suggests that in addition to their association with MTC, pathogenic variants in codons 790 or 804 may be associated with papillary thyroid carcinoma [Brauckhoff et al 2002]. In a large Italian family, 40% of family members with a p.Val804Met pathogenic variant who were examined in detail had concomitant medullary and papillary thyroid carcinoma [Shifrin et al 2009].

The American Thyroid Association Guidelines Task Force has classified pathogenic variants based on their risk for aggressive MTC [American Thyroid Association Guidelines Task Force 2009] (Table 3).

The classification may be used in (1) predicting phenotype and in (2) recommendations regarding the ages at which to (a) perform prophylactic thyroidectomy and (b) begin biochemical screening for pheochromocytoma and hyperparathyroidism (see Surveillance).

Table 3.

Risk for Aggressive MTC Based on Genotype

ATA 1 Risk LevelPathogenic Variants 2, 3
Level D
(highest risk)
p.Ala883Phe
p.Met918Thr
p.Val804Met+p.Glu805Lys 4
p.Val804Met+p.Tyr806Cys 4
p.Val804Met+p.Ser904Cys 4
Level Cp.Cys634Arg/Gly/Phe/Ser/Trp/Tyr
Level Bp.Cys609Phe/Arg/Gly/Ser/Tyr
p.Cys611Arg/Gly/Phe/Ser/Trp/Tyr
p.Cys618Arg/Gly/Phe/Ser/Tyr
p.Cys620Arg/Gly/Phe/Ser/Trp/Tyr
p.Cys630Arg/Phe/Ser/Tyr
p.Asp631Tyr
p.633/9 bp dup
p.634/12 bp dup
p.Val804Met+p.Val778Ile 4
Level Ap.Arg321Gly
p.531/9 bp dup
p.532 dup
p.Cys515Ser
p.Gly533Cys
p.Arg600Gln
p.Lys603Glu
p.Tyr606Cys
p.635/insert ELCR;p.Thr636Pro
p.Lys666Glu
p.Glu768Asp
p.Asn777Ser
p.Leu790Phe
p.Val804Leu/Met
p.Gly819Lys
p.Arg833Cys
p.Arg844Gln
p.Arg866Trp
p.Ser891Ala
p.Arg912Pro
1.

ATA = American Thyroid Association

2.

p.Ser649Leu and p.Tyr791Phe have been removed from this list as they have been reclassified as polymorphisms [Erlic et al 2010].

3.

Pathogenic variant designations have not been edited by GeneReviews staff and may not be standard nomenclature.

4.

Pathogenic variants in cis configuration on one allele

Penetrance

The penetrance for MTC, pheochromocytoma, and parathyroid disease varies by MEN 2 subtype (see Table 2).

Nomenclature

MEN 2A is also referred to as Sipple syndrome.

Mucosal neuroma syndrome is a synonym for MEN 2B. MEN 2B was initially called Wagenmann-Froboese syndrome [Morrison & Nevin 1996].

Prevalence

The prevalence of MEN 2 has been estimated at 1:35,000 [DeLellis et al 2004].

Differential Diagnosis

MTC in individuals with no family history of MTC. Medullary thyroid carcinoma accounts for approximately 10% of new cases of thyroid cancer diagnosed annually in the US. Sporadic MTC tends to be unifocal, occur at a later age of onset, and lack C-cell hyperplasia (CCH) [American Thyroid Association Guidelines Task Force 2009].

DNA analysis of MTC tissue revealed a 40%-50% incidence of somatic RET pathogenic variants in the absence of a germline pathogenic variant [Schilling et al 2001, de Groot et al 2006, Dvorakova et al 2008, Elisei et al 2008]. The p.Met918Thr pathogenic variant is the most common; pathogenic variants at other codons as well as small in-frame deletions have been reported [de Groot et al 2006]. Tumors with a somatic codon 918 pathogenic variant appear to be more aggressive [Schilling et al 2001, Elisei et al 2008].

C-cell hyperplasia (CCH). CCH associated with a positive calcitonin stimulation test occurs in about 5% of the general population. Serum calcitonin levels may be elevated in persons with chronic renal failure, sepsis, neuroendocrine tumors of the lung or gastrointestinal tract, hypergastrinemia, mastocytosis, autoimmune thyroid disease, and type 1A pseudohypoparathyroidism [Costante et al 2009].

Secondary CCH has been described occasionally in the setting of aging and hyperparathyroidism. Secondary CCH rarely transforms to MTC and is not related to MEN 2.

Pheochromocytoma. Up to 25% of individuals with pheochromocytoma and no known family history of pheochromocytoma have a heterozygous pathogenic variant in one of several genes: RET, VHL, SDHD, or SDHB [Neumann et al 2002, Bryant et al 2003, Neumann et al 2004]. Approximately 5% of individuals with nonsyndromic pheochromocytoma and no family history of pheochromocytoma were heterozygous for a RET pathogenic variant [Neumann et al 2002].Other pheochromocytoma susceptibility genes including SDHC, TMEM127, MAX, and SDHA further expand the differential diagnosis for nonsyndromic paraganglioma and pheochromocytoma [Peczkowska et al 2008, Burnichon et al 2009, Bayley et al 2010, Burnichon et al 2010, Qin et al 2010, Comino-Méndez et al 2011, Vandy et al 2011]. An algorithm for prioritizing which gene(s) to test is outlined by Erlic et al [2009], Neumann et al [2009], and Welander et al [2011]. However, multi-gene panels may also be considered for individuals with no syndromic features.

Evaluation of biochemical features can help differentiate MEN 2-associated pheochromocytoma. Pacak et al [2005] compared biochemical profiles for inherited and sporadic pheochromocytoma and found that MEN 2 can be ruled out in pheochromocytomas that exclusively produce normetanephrine.

  • VHL (von Hippel Lindau) syndrome. Any individual presenting with a pheochromocytoma should be evaluated for von Hippel Lindau (VHL) syndrome [Erlic et al 2009]. VHL syndrome is characterized by pheochromocytoma, renal cell carcinoma, cerebellar and spinal hemangioblastoma, and retinal angioma.

    Some families with apparent autosomal dominant pheochromocytoma have a germline VHL pathogenic variant in the absence of other clinical manifestations of VHL syndrome [Inabnet et al 2000]. Neumann et al [2002] identified germline VHL pathogenic variants in 11% of individuals with nonsyndromic pheochromocytoma and no family history of pheochromocytoma. However, a US-based study found no pathogenic variants in VHL in individuals with nonsyndromic pheochromocytoma or paraganglioma [Fishbein et al 2013].
  • Hereditary paraganglioma-pheochromocytoma syndrome. Pathogenic variants in the succinate dehydrogenase genes SDHA, SDHB, SDHC, SDHD, and SDHAF2 cause hereditary paraganglioma-pheochromocytoma syndrome. Early studies found that approximately 8.5% of individuals with apparently non-familial nonsyndromic pheochromocytoma have been shown to have a pathogenic variant in one of the genes (SDHD or SDHB) encoding the succinate dehydrogenase subunits that cause the hereditary paraganglioma-pheochromocytoma syndromes [Neumann et al 2002, Neumann et al 2004]. While head and neck paragangliomas are common in individuals with hereditary paraganglioma-pheochromocytoma syndrome, they are extremely rare in MEN 2 [Boedeker et al 2009]. Although pathogenic variants in SDHC initially were thought to only cause head/neck paragangliomas, several cases of SDHC-associated pheochromocytoma have been reported in the literature [Peczkowska et al 2008, Burnichon et al 2009, Vandy et al 2011]. Korpershoek et al [2011] found an SDHA germline pathogenic variant in 3% of individuals with apparently sporadic paragangliomas and pheochromocytomas. The gene SDHAF2 is a rare cause of hereditary head/neck paraganglioma and is not associated with pheochromocytoma [Bayley et al 2010].
  • TMEM127 associated susceptibility to pheochromocytoma (OMIM 613403). Recent studies estimate that 1%-2% of individuals with familial or non-familial pheochromocytoma have a germline TMEM127 pathogenic variant [Yao et al 2010, Abermil et al 2012]. A few individuals with a germline TMEM127 pathogenic variant have paragangliomas of the head/neck or at extra-adrenal sites [Neumann et al 2011].
  • MAX associated susceptibility to pheochromocytoma. (OMIM 154950). A MAX germline pathogenic variant is seen in approximately 1% of individuals with familial or non-familial pheochromocytoma [Burnichon et al 2012a]. Pheochromocytomas in individuals with MAX pathogenic variants are often bilateral [Burnichon et al 2012b].
  • Neurofibromatosis type 1. Pheochromocytomas are observed on occasion in neurofibromatosis type 1 (NF1). Most individuals with NF1 could be diagnosed based on clinical features including multiple café-au-lait macules, neurofibromas, Lisch nodules, axillary or inguinal freckling, and/or positive family history.
  • Polycythemia and paraganglioma/pheochromocytoma. HIF2A/EPAS1, PHD1, and PHD2 pathogenic variants have been identified in individuals with polycythemia and paraganglioma [Lorenzo et al 2013, Taïeb et al 2013, Yang et al 2015].

Multiple endocrine neoplasia type 1 (MEN 1). This endocrinopathy is genetically and clinically distinct from MEN 2; the similar nomenclature for MEN 1 and MEN 2 may cause confusion. MEN 1 is characterized by a triad of pituitary adenomas, pancreatic islet cell tumors, and parathyroid disease consisting of hyperplasia or adenoma. Affected individuals can also have adrenal cortical tumors, carcinoid tumors, and lipomas [Giraud et al 1998]. MEN 1 is caused by a germline pathogenic variant in MEN1 and inherited in an autosomal dominant manner.

Multiple endocrine neoplasia type 4 (MEN 4). While pheochromocytomas developed in the MENX rat model, humans with pathogenic variants in CDKN1B tend to have a phenotype similar to MEN 1 with a high incidence of pituitary tumors and primary hyperparathyroidism [Lee & Pellegata 2013].

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with multiple endocrine neoplasia type 2 (MEN 2), the following evaluations are recommended:

  • Referral to an endocrinologist
  • Consultation with a medical geneticist and/or genetic counselor
  • Biochemical evaluations
    • Plasma calcitonin
    • Plasma catecholamines and metanephrines
    • Serum calcium and parathyroid hormone
  • Workup to evaluate for metastatic disease in individuals with MTC
    • CT with contrast for chest and abdomen
    • MRI of liver with nodal disease or calcitonin >400 pg/mL

Treatment of Manifestations

Medullary thyroid carcinoma (MTC). Standard treatment for MTC is surgical removal of the thyroid and lymph node dissection [American Thyroid Association Guidelines Task Force 2009, National Comprehensive Cancer Network 2015]. Current NCCN guidelines recommend consideration of therapeutic external beam radiation therapy (EBRT) or intensity-modulated radiation therapy (IMRT) for incomplete tumor resection or extrathyroidal extension with positive margins [National Comprehensive Cancer Network 2015]. Two kinase inhibitors – vandetanib and cabozantinib – have been shown to improve progression-free survival and in some cases cause disease regression in unresectable or advanced metastatic MTC [Elisei et al 2013, Wells et al 2013].

All individuals who have undergone thyroidectomy need thyroid hormone replacement therapy.

Autotransplantation of parathyroid tissue is not typically performed at the time of thyroidectomy unless there is evidence of hyperparathyroidism [American Thyroid Association Guidelines Task Force 2009].

Pheochromocytomas detected by biochemical testing and radionuclide imaging are removed by adrenalectomy, which may be performed using video-assisted laparoscopy. Historically, some specialists recommended bilateral adrenalectomy at the time of demonstration of tumor on just a single adrenal gland because of the strong probability that the other adrenal gland would develop a tumor within ten years. However, because of the risk for adrenal insufficiency and Addisonian crisis following bilateral adrenalectomy, most experts now recommend unilateral adrenalectomy in unilateral tumors and cortical-sparing adrenal surgery with close monitoring of the remnant tissue in persons with one remaining adrenal gland or bilateral pheochromocytoma [American Thyroid Association Guidelines Task Force 2009].

Hypertensive treatment prior to adrenalectomy involves the use of α- and β-adrenergic receptor blockade [Pacak et al 2005].

Parathyroid adenoma or hyperplasia diagnosed at the time of thyroidectomy is treated either with resection of the visibly enlarged parathyroid gland(s), subtotal parathyroidectomy, or total parathyroidectomy with forearm autograft [American Thyroid Association Guidelines Task Force 2009]. However, in most individuals with MEN 2A, hyperparathyroidism is diagnosed many years after thyroidectomy.

Individuals with biochemical evidence of primary hyperparathyroidism who have undergone prior thyroidectomy should have preoperative localization with excision of the localized hypertrophied parathyroid glands and forearm autotransplantation.

Therapy with medications to control primary hyperparathyroidism should be considered in individuals with a high risk for surgical mortality, limited life expectancy, or persistent or recurrent primary hyperparathyroidism after one or more surgical attempts [American Thyroid Association Guidelines Task Force 2009].

Prevention of Primary Manifestations

Prophylactic thyroidectomy is the primary preventive measure for individuals with an identified germline RET pathogenic variant [Cohen & Moley 2003, American Thyroid Association Guidelines Task Force 2009].

Prophylactic thyroidectomy is safe for all age groups; however, the timing of the surgery is controversial [Moley et al 1998]. According to the consensus statement from the American Thyroid Association Guidelines Task Force, the age at which prophylactic thyroidectomy is performed can be guided by the codon position of the RET pathogenic variant (Table 4, Genotype-Phenotype Correlations) [American Thyroid Association Guidelines Task Force 2009]. However, these guidelines continue to be modified as more data become available.

Table 4.

Risk for Aggressive MTC Based on Genotype and Recommended Interventions

ATA 1 Risk LevelPathogenic Variants 2, 3Age of Prophylactic SurgeryAge to Begin Screening
For PHEOFor HPT 4
Level D
(highest risk)
p.Ala883Phe
p.Met918Thr
p.Val804Met+p.Glu805Lys 5
p.Val804Met+p.Tyr806Cys 5
p.Val804Met+p.Ser904Cys 5
As soon as possible in 1st year of life8 yrsNA
Level Cp.Cys634Arg/Gly/Phe/Ser/Trp/Tyr<5 yrs8 yrs8 yrs
Level Bp.Cys609Phe/Arg/Gly/Ser/Tyr
p.Cys611Arg/Gly/Phe/Ser/Trp/Tyr
p.Cys618Arg/Gly/Phe/Ser/Tyr
p.Cys620Arg/Gly/Phe/Ser/Trp/Tyr
p.Cys630Arg/Phe/Ser/Tyr
p.Asp631Tyr
p.633/9 bp dup
p.634/12 bp dup
p.Val804Met+p.Val778Ile 5
Consider <5 yrs; may delay if criteria met 5Codon 630 pathogenic variant: 8 yrs
All others: 20 yrs
Codon 630 pathogenic variant: 8 yrs
All others: 20 yrs
Level Ap.Arg321Gly
p.531/9 bp dup
p.532 dup
p.Cys515Ser
p.Gly533Cys
p.Arg600Gln
p.Lys603Glu
p.Tyr606Cys
p.635/insert ELCR;p.Thr636Pro
p.Lys666Glu
p.Glu768Asp
p.Asn777Ser
p.Leu790Phe
p.Val804Leu/Met
p.Gly819Lys
p.Arg833Cys
p.Arg844Gln
p.Arg866Trp
p.Ser891Ala
p.Arg912Pro
May delay beyond age 5 yrs if criteria met 620 yrs20 yrs
1.

ATA = American Thyroid Association

2.

p.Ser649Leu and p.Tyr791Phe have been removed from this list as they were reclassified as benign variants [Erlic et al 2010].

3.

Pathogenic variant designations have not been edited by GeneReviews staff and may not be standard nomenclature.

4.

HPT = Hyperparathyroidism

5.

Pathogenic variants in cis configuration on one allele

6.

Criteria: normal annual basal and or stimulated serum calcitonin; normal annual neck ultrasound examination; family history of less aggressive MTC

Thyroidectomy for C-cell hyperplasia, before progression to invasive MTC, may allow surgery to be limited to thyroidectomy with sparing of lymph nodes [Brandi et al 2001, Kahraman et al 2003].

For all individuals with a RET pathogenic variant who have not had a thyroidectomy, annual biochemical screening is recommended with immediate thyroidectomy if results are abnormal [Szinnai et al 2003].

Annual serum calcitonin screening [American Thyroid Association Guidelines Task Force 2009] should begin at age:

  • Six months for children with MEN 2B
  • Three to five years for children with MEN 2A or FMTC

Caution should be used in interpreting calcitonin results for children younger than age three years, especially those younger than age six months [American Thyroid Association Guidelines Task Force 2009].

Prophylactic thyroidectomy is not routinely offered to at-risk individuals in whom the disorder has not been confirmed.

Prevention of Secondary Complications

Prior to any surgery, the presence of a functioning pheochromocytoma should be excluded by appropriate biochemical screening in any individual with MEN 2A or MEN 2B. In a prospective study of at-risk family members with the pathogenic variant, 8% had pheochromocytoma detected at the same time as MTC [Nguyen et al 2001].

If pheochromocytoma is detected, adrenalectomy should be performed before thyroidectomy to avoid intraoperative catecholamine crisis [Lee & Norton 2000].

Surveillance

MTC. Approximately 50% of individuals diagnosed with MTC who have undergone total thyroidectomy and neck nodal dissections have recurrent disease [Cohen & Moley 2003]. Furthermore, thyroid glands removed from individuals with a RET pathogenic variant who had normal plasma calcitonin concentrations have been found to contain MTC [Skinner et al 1996]. Therefore, continued monitoring for residual or recurrent MTC is indicated after thyroidectomy, even if thyroidectomy is performed prior to biochemical evidence of disease.

The screening protocol for MTC after prophylactic thyroidectomy is an annual measurement of serum calcitonin [American Thyroid Association Guidelines Task Force 2009]. More frequent follow up is recommended for those with residual disease.

Hypoparathyroidism. All individuals who have undergone thyroidectomy and autotransplantation of the parathyroids need monitoring for possible hypoparathyroidism.

Pheochromocytoma. For individuals whose initial screening results are negative for pheochromocytoma, annual biochemical screening is recommended, followed by MRI and/or CT if the biochemical results are abnormal [Pacak et al 2005, American Thyroid Association Guidelines Task Force 2009]. Women with MEN 2 should be screened for pheochromocytoma prior to a planned pregnancy, or as early as possible during an unplanned pregnancy [American Thyroid Association Guidelines Task Force 2009]. Other screening studies, such as scintigraphy or positron emission tomography, may be warranted in some individuals.

Parathyroid adenoma or hyperplasia. Annual biochemical screening is recommended for affected individuals who have not had parathyroidectomy and parathyroid autotransplantation.

Agents/Circumstances to Avoid

Dopamine D2 receptor antagonists (e.g., metoclopramide and veralipride) and β-adrenergic receptor antagonists (β-blockers) have a high potential to cause an adverse reaction in individuals with pheochromocytoma.

Other medications including monoamine oxidase inhibitors, sympathomimetics (e.g., ephedrine), and certain peptide and corticosteroid hormones may also cause complications; tricyclic antidepressants are inconsistent in causing adverse reactions [Eisenhofer et al 2007].

Evaluation of Relatives at Risk

It is appropriate to evaluate apparently asymptomatic at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures. The American Society of Clinical Oncologists (ASCO) identifies MEN 2 as a Group 1 disorder, i.e., a well-defined hereditary cancer syndrome for which genetic testing is considered part of the standard management for at-risk family members [American Society of Clinical Oncology 2003]. Evaluations can include:

  • Molecular genetic testing if the pathogenic variant in the family is known:
    • MEN 2A. RET molecular genetic testing should be offered to at-risk children by age five years. The finding of MTC in the thyroid of a 12-month-old with a RET pathogenic variant suggests that molecular genetic testing should be performed even earlier when possible [Machens et al 2004].
    • FMTC. Recommendations for families with known FMTC are the same as for MEN 2A.
    • MEN 2B. RET molecular genetic testing should be performed as soon as possible after birth in all children known to be at risk [Brandi et al 2001].
  • The following screening of at-risk family members if the pathogenic variant in the family is not known:
    • Neck ultrasound examination and basal and/or stimulated calcitonin measurements for MTC
    • Albumin-corrected calcium or ionized calcium for hyperparathyroidism
    • Measurement of plasma or 24-hour urine metanephrines and normetanephrines as appropriate [American Thyroid Association Guidelines Task Force 2009] for pheochromocytoma

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Women with MEN 2 should be screened for pheochromocytoma prior to a planned pregnancy, or as early as possible during an unplanned pregnancy [American Thyroid Association Guidelines Task Force 2009].

Therapies Under Investigation

Clinical trials of multikinase inhibitors such as sorafenib, sunitinib, and ponatinib are currently underway. NCCN guidelines recommend consideration of clinical trial participation for individuals who fail standard treatment with vandetanib and cabozantinib [National Comprehensive Cancer Network 2015].

Sorafenib is FDA approved for use in renal cell and hepatocellular carcinoma. In a Phase II clinical trial of sorafenib, 16 individuals with sporadic MTC had a partial response (1/16) or stable disease (15/16) [Lam et al 2010]. A small Phase II trial of treatment with sunitinib demonstrated objective response in three (50%) of six individuals with metastatic MTC and stable disease in two individuals [Carr et al 2010]. Ponatinib has been shown to inhibit RET kinase activity and diminish medullary thyroid cancer in mice [De Falco et al 2013].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

All of the multiple endocrine neoplasia type 2 (MEN 2) subtypes are inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • The proportion of individuals with MEN 2 who have an affected parent varies by subtype:
    • MEN 2A
      • 95% of individuals diagnosed with MEN 2A have an affected parent. The penetrance for MTC, pheochromocytoma, and parathyroid disease varies by MEN 2 subtype (see Table 2).
      • A proband with MEN 2A may have the disorder as the result of a de novo germline RET pathogenic variant. The proportion of cases caused by a de novo germline pathogenic variant is approximately 5% [Schuffenecker et al 1997].
      • It is appropriate to evaluate the parents of an individual with MEN 2A for manifestations of the disorder and offer molecular genetic testing if the RET pathogenic variant has been identified in the proband (see Diagnosis, Establishing the Diagnosis).
    • FMTC. By definition, individuals with FMTC have multiple family members who are affected.
    • MEN 2B
      • 50% of individuals diagnosed with MEN 2B have an affected parent. The penetrance for MTC, pheochromocytoma, and parathyroid disease varies by MEN 2 subtype (see Table 2).
      • A proband with MEN 2B may have the disorder as the result of a de novo germline RET pathogenic variant [Carlson et al 1994].

        The proportion of MEN 2B caused by a de novo germline RET pathogenic variant is 50%.

        The majority of de novo pathogenic variants are paternal in origin, but maternal origin has been reported.
  • If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo germline pathogenic variant in the proband. Although no instances of germline mosaicism have been reported in MEN 2, it remains a possibility.
  • Recommendations for the evaluation of parents of a proband with a clinical diagnosis of MEN 2 and an undetectable RET pathogenic variant include thyroid ultrasound and biochemical screening for MTC, pheochromocytoma, and hyperparathyroidism.
  • The family history of some individuals diagnosed with MEN 2 may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disorder in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband’s parents.
  • If a parent of the proband has the germline RET pathogenic variant, the risk to the sibs of inheriting the variant is 50%.
  • The sibs of a proband with clinically unaffected parents are still at increased risk for MEN 2 because of the possibility of reduced penetrance in a parent.
  • If the RET pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism; germline mosaicism has not yet been reported.

Offspring of a proband

  • Each child of an individual with MEN 2 has a 50% chance of inheriting the RET pathogenic variant.
  • The probability that the offspring of an individual with simplex medullary thyroid carcinoma (MTC) (i.e., no known family history of MTC) and no identifiable RET germline pathogenic variant would inherit a RET pathogenic variant is 0.18% [Brandi et al 2001, Massoll & Mazzaferri 2004]. This is based on a 95% pathogenic variant detection rate and on empiric data that 7% of individuals with sporadic MTC have a germline RET pathogenic variant.

Other family members

  • The risk to other family members depends on the status of the proband's parents.
  • If a parent has a germline RET pathogenic variant, his or her family members are at increased risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Testing of at-risk individuals. Consideration of molecular genetic testing of at-risk family members is appropriate for surveillance (see Surveillance). Molecular genetic testing (see Establishing the Diagnosis) can be used for testing of at-risk relatives only if a germline pathogenic variant has been identified in the family. When a known pathogenic variant is not identified, linkage analysis (see Establishing the Diagnosis) can be considered in families with more than one affected family member from different generations. Because early detection of at-risk individuals affects medical management, testing of asymptomatic children is beneficial [American Society of Clinical Oncology 2003]. Education and genetic counseling of at-risk children and their parents prior to genetic testing are appropriate.

Genetic cancer risk assessment and counseling. For a comprehensive description of the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without molecular genetic testing, see Cancer Genetics Risk Assessment and Counseling – for health professionals (part of PDQ®, National Cancer Institute).

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with MEN 2 has the pathogenic variant or clinical evidence of the disorder, the RET pathogenic variant is likely de novo, or germline mosaicism exists. However, other possible non-medical explanations that could also be explored include alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption.

Family planning

  • The optimal time for determination of genetic risk and availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the RET pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory offering either testing of this gene or custom prenatal testing.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the RET pathogenic variant has been identified [American Thyroid Association Guidelines Task Force 2009].

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Association for Multiple Endocrine Neoplasia Disorders (AMEND)
    The Warehouse
    No 1 Draper Street
    Tunbridge Wells Kent TN4 0PG
    United Kingdom
    Phone: + 44 (0)1892 516076
    Email: info@amend.org.uk
  • Associazione Italiana Neoplasie Endocrine Multiple (AIMEN)
    Italy
    Phone: 39 800 177 526
    Fax: 39 0331 983343
    Email: aimento@libero.it
  • National Library of Medicine Genetics Home Reference
  • American Cancer Society (ACS)
    1599 Clifton Road Northeast
    Atlanta GA 30329-4251
    Phone: 800-227-2345 (toll-free 24/7); 866-228-4327 (toll-free 24/7 TTY)
  • CancerNetwork.com
  • National Cancer Institute (NCI)
    6116 Executive Boulevard
    Suite 300
    Bethesda MD 20892-8322
    Phone: 800-422-6237 (toll-free)
    Email: cancergovstaff@mail.nih.gov
  • NCBI Genes and Disease
  • Pheo Para Troopers
    To empower and support pheochromocytoma and paraganglioma patients through knowledge, a sense of community, and advocacy while sponsoring key initiatives in data collection, treatment, and patient care.
    PO Box 2064
    Kokomo IN 46904-2064
    Email: info@pheoparatroopers.org
  • AMEND Research Registry
    The Warehouse
    Draper Street
    Tunbridge Wells Kent TN4 0PG
    United Kingdom
    Phone: +44 1892 516076
    Email: jo.grey@amend.org.uk

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Multiple Endocrine Neoplasia Type 2: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for Multiple Endocrine Neoplasia Type 2 (View All in OMIM)

155240THYROID CARCINOMA, FAMILIAL MEDULLARY; MTC
162300MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIB; MEN2B
164761REARRANGED DURING TRANSFECTION PROTOONCOGENE; RET
171400MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIA; MEN2A

Gene structure. The RET proto-oncogene comprises 21 exons over 55 kb of genomic sequence. For a detailed summary of gene and protein information, see Table A, Gene.

Benign allelic variants. Benign variants as well as variants of uncertain significance have been described. See Table A, Locus Specific for a database of normal, uncertain, and pathogenic RET variants [Margraf et al 2009].

It is speculated that some rare variants (e.g., p.Val648Ile) may modify the phenotype when inherited with a pathogenic variant [Nunes et al 2002].

Evidence suggests that other rare allelic variants may be predisposition factors. For example, p.Gly691Ser and p.Ser904Ser may be low-penetrance risk factors for development of medullary thyroid carcinoma (MTC) [Robledo et al 2003, Elisei et al 2004] and may predispose individuals with a pathogenic variant to an earlier age of onset of MEN 2A [Gil et al 2002, Robledo et al 2003, Cardot-Bauters et al 2008]; however, this finding was not replicated in a larger study [Lesueur et al 2006]. The p.Ser836Ser variant has been associated with an increased risk for non-familial MTC in at least two studies [Gimm et al 1999, Ruiz et al 2001] but not in another [Berard et al 2004]. A meta-analysis of six allelic variants found a modest non-familial MTC association with p.Ser836Ser and a strong association with the promoter benign variant IVS1-126G>T [Figlioli et al 2013].

Although the variants p.Ser649Leu and p.Tyr791Phe were recently reclassified as non-pathogenic, it is unknown if they act as modifiers of risk [Erlic et al 2010].

At this time, there is insufficient data from association studies to direct individual patient care.

Pathogenic allelic variants. The major pathogenic variants are non-conservative substitutions located in one of six cysteine codons in the extracellular domain of the encoded protein. They include codons 609, 611, 618, and 620 in exon 10 and codons 630 and 634 in exon 11 [Takahashi et al 1998]. All of these variants have been identified in families with MEN 2A and some have been identified in families with FMTC. Pathogenic variants in these sites have been detected in 98% of families with MEN 2A [Eng et al 1996]. See Table A for a database of RET variants [Margraf et al 2009].

The risk of aggressive MTC, pheochromocytoma, and hyperparathyroidism can be estimated based on genotype. See Table 4 for management recommendations.

Approximately 95% of all individuals with the MEN 2B phenotype have a single nucleotide variant (SNV) in the tyrosine kinase domain of RET at codon 918 in exon 16, which substitutes a threonine for methionine [Eng et al 1996]. A second SNV at codon 883 has been found in 2%-3% of individuals with MEN 2B [Gimm et al 1997, Smith et al 1997]. Tandem RET pathogenic variants in codons 805, 806, and 904 in cis configuration with the p.Val804Met pathogenic variant have also been reported in individuals with MEN 2B [Miyauchi et al 1999, Menko et al 2002, Cranston et al 2006, American Thyroid Association Guidelines Task Force 2009].

In addition to the pathogenic variants in the cysteine residues in exons 10 and 11 that have been found in families with MEN 2A, pathogenic variants in codons 631, 768, 790, 804, 844, and 891, and others in exons 5, 8, 10, 11, and 13 to 16 have been identified in a small number of families [Hofstra et al 1997, Berndt et al 1998, American Thyroid Association Guidelines Task Force 2009].

A pathogenic variant at codon 603 was reported in one family and appeared to be associated with both MTC and papillary thyroid cancer [Rey et al 2001]. The pathogenic variant p.Arg912Pro appeared to be associated with FMTC in two families [Jimenez et al 2004b].

Small, in-frame duplications have been reported in four families [Höppner & Ritter 1997, Höppner et al 1998, Pigny et al 1999, Niccoli-Sire et al 2003].

Rare families with two pathogenic variants in cis configuration have been reported; for example, alteration of both codons 634 and 635 in one family with MEN 2A; alteration of both codons 804 and 844 in one family with FMTC [Bartsch et al 2000]; and alteration of codons 804 and 806 in an individual with MEN 2B [Miyauchi et al 1999].

Normal gene product. RET produces a receptor tyrosine kinase with extracellular, transmembrane, and intracellular domains. The extracellular domain consists of a calcium-binding cadherin-like region and a cysteine-rich region. The encoded protein plays a role in signal transduction by interaction with the glial-derived neurotropic factor (GDNF) family of ligands: GDNF, neurturin, persephin, and artemin. Ligand interaction is via the ligand-binding GDNF family receptors (GFRα) to which RET protein binds the encoded protein complexes. Formation of a complex containing two RET protein molecules leads to RET autophosphorylation and intracellular signaling whereby phosphorylated tyrosines become docking sites for intracellular signaling proteins [Santoro et al 2004]. The RET tyrosine kinase catalytic core, which is located in the intracellular domain, interacts with the docking protein FRS2 and causes downstream activation of the mitogen-activated protein (MAP) kinase signaling cascade [Manié et al 2001]. Normal tissues contain transcripts of several lengths [Takaya et al 1996].

Abnormal gene product. Pathogenic variants in codons in the cysteine-rich extracellular domain (609, 611, 618, 620, and 634) cause ligand-independent RET dimerization, leading to constitutive activation (i.e., gain of function) of tyrosine kinase [Takahashi et al 1998].

The pathogenic variant in codon 918 that causes 95% of the MEN 2B phenotype lies within the catalytic core of the tyrosine kinase and causes a constitutive activation (i.e., gain of function) of the RET kinase in its monomeric state, independent of the normal ligand-binding and dimerization steps [Takahashi et al 1998].

In contrast to the activating pathogenic variants in MEN 2, pathogenic variants that cause Hirschsprung disease (HSCR) result in a decrease in the transforming activity of RET [Iwashita et al 1996]. For families in which MEN 2A and HSCR cosegregate, models to explain how the same pathogenic variant can cause gain of function and loss of function have been proposed [Takahashi et al 1999].

Cancer and Benign Tumors

Fusion proteins. Approximately 20%-40% of papillary thyroid carcinoma is associated with somatic gene rearrangements that cause juxtaposition of the tyrosine kinase domain of RET to various gene partners [Tallini et al 1998, Santoro et al 2002, Puxeddu et al 2003].

References

Published Guidelines/Consensus Statements

  1. American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. Available online. 2003. Accessed 6-23-15.
  2. American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. Available online; registration or institutional access required. 2010. Accessed 6-23-15.

Literature Cited

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  2. Aiello A, Cioni K, Gobbo M, Collini P, Gullo M, Della Torre G, Passerini E, Ferrando B, Pilotti S, Pierotti MA, Pasini B. The familial medullary thyroid carcinoma-associated RET E768D mutation in a multiple endocrine neoplasia type 2A case. Surgery. 2005;137:574–6. [PubMed: 15855933]
  3. American Society of Clinical Oncology. American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility. J Clin Oncol. 2003;21:2397–406. [PubMed: 12692171]
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Suggested Reading

  1. Giraud S. Multiple endocrine neoplasia type 2 (MEN2). Atlas of Genetics and Cytogenetics in Oncology and Haematology. Available online. 2001. Accessed 6-23-15.
  2. Machens A, Lorenz K, Dralle H. Constitutive RET tyrosine kinase activation in hereditary medullary thyroid cancer: clinical opportunities. J Intern Med. 2009;266:114–25. [PubMed: 19522830]
  3. Ponder BAJ. Multiple endocrine neoplasia type 2. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). Chap 42. New York, NY: McGraw-Hill. Available online. 2014. Accessed 6-23-15.

Chapter Notes

Author History

Charis Eng, MD, PhD, FACP (2010-present)
Jessica Marquard, MS, LGC (2010-present)
Georgia L Wiesner, MD, MS, FACMG; Case Western Reserve University School of Medicine (1999-2010)
Karen Snow-Bailey, PhD, FACMG, FHGSA; Auckland City Hospital (1999-2006*)

*Karen Snow-Bailey died on September 10, 2006. The following is excerpted from a tribute by Stephen N Thibodeau, PhD, of the Mayo Clinic, Rochester, MN:

"Karen was well known to so many of us, as she was an active member of the Association for Molecular Pathology (AMP)....In 1993, Karen joined the medical staff at the Mayo Clinic, where she was responsible for codirecting the Molecular Genetics Laboratory in the Department of Laboratory Medicine and Pathology....In 2002, Karen returned to New Zealand to be closer to family and became an international presence. Importantly, she began to have a tremendous influence in the development of diagnostic genetics services both in New Zealand and Australia....Karen was a scientist, an educator, and an artist....We will all miss Karen as a colleague, as a mentor to many, as an individual who had a vision for the future, but most importantly, as a warm and compassionate friend who cared for others."

[Reprinted from J Mol Diagn 2007, 9:133 with permission from the American Society for Investigative Pathology and the Association for Molecular Pathology]

Revision History

  • 25 June 2015 (me) Comprehensive update posted live
  • 10 January 2013 (me) Comprehensive update posted live
  • 4 May 2010 (me) Comprehensive update posted live
  • 7 March 2005 (me) Comprehensive update posted to live Web site
  • 19 May 2004 (cd) Revision: Genetic Counseling
  • 21 January 2003 (me) Comprehensive update posted to live Web site
  • 27 September 1999 (me) Review posted to live Web site
  • October 1998 (gw) Original submission
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