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Multiple Endocrine Neoplasia Type 2

Synonyms: MEN2, MEN2 Syndrome

, MD, PhD, FACP.

Author Information and Affiliations

Initial Posting: ; Last Update: August 15, 2019.

Estimated reading time: 49 minutes


Clinical characteristics.

Multiple endocrine neoplasia type 2 (MEN2) includes the following phenotypes: MEN2A, FMTC (familial medullary thyroid carcinoma, which may be a variant of MEN2A), and MEN2B. All three phenotypes involve high risk for development of medullary carcinoma of the thyroid (MTC); MEN2A and MEN2B involve an increased risk for pheochromocytoma; MEN2A involves an increased risk for parathyroid adenoma or hyperplasia. Additional features in MEN2B 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 MEN2B, early adulthood in MEN2A, and middle age in FMTC.


The diagnosis of MEN2 is established in a proband who fulfills existing clinical diagnostic 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 MEN2. Identification of a heterozygous germline RET pathogenic variant on molecular genetic testing establishes the diagnosis if clinical features are inconclusive.


Treatment of manifestations: Treatment for MTC is surgical removal of the thyroid gland and lymph node dissection. External beam radiation therapy or intensity-modulated radiation therapy 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, with 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 MEN2A or MEN2B, 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 MEN2 should be screened for pheochromocytoma prior to a planned pregnancy or as early as possible during an unplanned pregnancy.

Genetic counseling.

All MEN2 phenotypes are inherited in an autosomal dominant manner. The probability of a de novo pathogenic variant is 5% or less in index cases with MEN2A and 50% in index cases with MEN2B. 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 1
  • Multiple endocrine neoplasia type 2A (MEN2A)
  • Familial medullary thyroid carcinoma (FMTC)
  • Multiple endocrine neoplasia type 2B (MEN2B)

For synonyms and outdated names see Nomenclature.


For other genetic causes of these phenotypes see Differential Diagnosis.


Clinical diagnostic criteria for multiple endocrine neoplasia type 2 (MEN2) have been published [Kloos et al 2009]; see Establishing the Diagnosis.

Suggestive Findings

Multiple endocrine neoplasia type 2 (MEN2) includes the phenotypes MEN2A; familial medullary thyroid carcinoma (FMTC), which may itself be a variant of MEN2A; and MEN2B.

MEN2A 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.

MEN2B 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.

Establishing the Diagnosis

The diagnosis of MEN2 is established in a proband with the following clinical criteria. Identification of a heterozygous germline RET pathogenic variant by molecular genetic testing (see Table 1) establishes the diagnosis if clinical features are inconclusive.

Clinical criteria, as outlined by Kloos et al [2009]:

  • MEN2A 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.
  • FMTC is diagnosed in families with four or more cases of MTC in the absence of pheochromocytoma or parathyroid adenoma/hyperplasia.
  • MEN2B 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.

When the phenotypic and laboratory findings suggest the diagnosis of MEN2, molecular genetic testing approaches can include single-gene testing or use of a multigene panel.

Single-gene testing. Sequence analysis of RET detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected.

A cancer predisposition multigene panel that includes RET and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Table 1.

Molecular Genetic Testing Used in MEN2

Gene 1Method 2Proportion of Probands with a Pathogenic Variant 3 Detectable by Method
RET Sequence analysis 4, 5>98% 6, 7>95% 6, 8>98% 9
Sequence analysis of select exons98% 6, 1095% 6, 8
Targeted analysis for pathogenic variants 1198% 9

Since MEN2 occurs through a gain-of-function mechanism, gene-targeted deletion/duplication analysis (such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification [MLPA], and gene-targeted microarray designed to detect single-exon deletions or duplications to detect intragenic deletions or duplications) is not indicated.


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


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or 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.


Sequence analysis of all RET exons may be performed instead of sequencing of select exons. If sequencing of select exons has been previously performed with no pathogenic variant detected, a multigene panel including RET is recommended (see Establishing the Diagnosis).


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 13-16 appear to account for a small percentage of pathogenic variants in families with FMTC, with an important minority affecting codons 768 and 804.


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].


Pathogenic variants in exons 10 and 11 [Eng et al 1996, Kloos et al 2009]


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

Clinical Characteristics

Clinical Description

The endocrine disorders observed in multiple endocrine neoplasia type 2 (MEN2) are: medullary thyroid carcinoma (MTC) and/or its precursor, C-cell hyperplasia (CCH); pheochromocytoma; and parathyroid adenoma or hyperplasia.


Clinical findings. MTC in persons with MEN2 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 mass or neck pain prior to age 35 years. Diarrhea (the most frequent systemic symptom) occurs in affected individuals with a plasma calcitonin concentration >10 ng/mL and implies a poor prognosis [Callender et al 2008].
  • Up to 70% of individuals with a palpable thyroid mass or diarrhea already have cervical lymph node metastases [Cohen & Moley 2003]. Metastatic spread to regional lymph nodes (i.e., parathyroid, paratracheal, jugular chain, and upper mediastinum) or to distant sites including the liver, lungs, or bone is also common in symptomatic individuals [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% had a germline RET pathogenic variant [Elisei et al 2007].

Biochemical findings. MTC and CCH are suspected in the presence of an elevated plasma calcitonin concentration, a sensitive and specific marker. In provocative testing, plasma calcitonin concentration is measured before (basal level), then 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, Kloos et al 2009].

Note: 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].

Histology. 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 MEN2, the age of transformation from CCH to MTC varies with different germline RET pathogenic variants [Machens et al 2003].


Clinical findings. Pheochromocytomas in individuals with MEN2 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 MEN2 [Boedeker et al 2009].
  • Although pheochromocytomas in individuals with MEN2 rarely metastasize, they can be lethal because of intractable hypertension or anesthesia-induced hypertensive crises.

Biochemical findings. 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 MEN2, pheochromocytomas consistently produce epinephrine or epinephrine and norepinephrine [Ilias & Pacak 2009].

Imaging. Abdominal MRI and/or CT is 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-labeled metaiodobenzylguanidine) scintigraphy should be used to further evaluate individuals with biochemical or radiographic evidence of pheochromocytoma [Ilias et al 2008]. 68Ga-DOTATATE-PET-CT results correlate best with biochemical parameters (reviewed in Neumann et al [2019]).

Parathyroid Abnormalities

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

Biochemical findings. 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].

MEN2 Phenotypes

MEN2 is classified into three phenotypes: MEN2A, FMTC (which is now considered a variant of MEN2A), and MEN2B (Table 2). All three phenotypes involve high risk for MTC; individuals with MEN2A and MEN2B are at increased risk for pheochromocytoma; individuals with MEN2A are at increased risk for parathyroid hyperplasia or adenoma. Classifying an individual or family by MEN2 phenotype is useful for determining prognosis and management.

Table 2.

Percent of Clinical Features by MEN2 Phenotype

PhenotypeMedullary Thyroid CarcinomaPheochromocytomaParathyroid Disease
MEN2A 95%50%20%-30%
FMTC 100%0%0%
MEN2B 100%50%Uncommon

MEN2A. The MEN2A phenotype constitutes approximately 70%-80% of cases of MEN2. MTC is generally the first manifestation of MEN2A. Since genetic testing for RET pathogenic variants has become available, it has become apparent that 95% of individuals with MEN2A develop MTC, about 50% develop pheochromocytoma, and about 20%-30% develop hyperparathyroidism (reviewed by Neumann et al [2019]).

Pheochromocytomas usually present after MTC or concomitantly; however, they are the first sign in 13%-27% of individuals with MEN2A [Inabnet et al 2000, Rodriguez et al 2008]. Pheochromocytomas in persons with MEN2A 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 MEN2A, the diagnosis of pheochromocytoma in an individual warrants further investigation for MEN2A [Neumann et al 2019].

Hyperparathyroidism (HPT) in MEN2A 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 [Kloos et al 2009].

A small number of families with MEN2A have pruritic cutaneous lichen amyloidosis, also known as cutaneous lichen amyloidosis. 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 phenotype constitutes approximately 10%-20% of cases of MEN2. By operational definition, MTC is the only clinical manifestation of FMTC. Currently, FMTC is viewed as a variant of MEN2A with decreased penetrance of pheochromocytoma and hyperparathyroidism, rather than a distinct subtype [Kloos et al 2009].

The age of onset of MTC is later in FMTC and the penetrance of MTC is lower than that observed in MEN2A and MEN2B [Eng et al 1996, Machens et al 2001, Machens & Dralle 2006, Zbuk & Eng 2007, Kloos et al 2009]. To avoid erroneously dismissing a risk for pheochromocytoma, strict criteria should be met before a family is classified as having FMTC (see Establishing the Diagnosis, Clinical criteria).

MEN2B. The MEN2B phenotype accounts for approximately 5% of cases of MEN2. MEN2B is characterized by the early development of an aggressive form of MTC in all affected individuals [Skinner et al 1996]. Individuals with MEN2B 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 median age of death in individuals with MEN2B was 25 years (range: 0.5-66) [Castinetti et al 2019].

Pheochromocytomas occur in 50% of individuals with MEN2B; about half are multiple and often bilateral. Individuals with an undiagnosed pheochromocytoma may die from a cardiovascular hypertensive crisis perioperatively.

Clinically significant parathyroid disease is absent in MEN2B.

Individuals with MEN2B may be identified in infancy or early childhood by a distinctive facial appearance and the presence of mucosal neuromas on the anterior dorsal surface of the tongue, palate, or pharynx. 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 distention, megacolon, constipation, or diarrhea. In one study of 19 individuals with MEN2B, 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 MEN2A, 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 MEN2A 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 MEN2B; however, somatic pathogenic variants at this codon are frequently observed in MTC in individuals with no known family history of MTC, and are overrepresented in individuals with sporadic MTC who have the RET germline variant p.Ser836 [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, Kloos et al 2009].

Pathogenic variants at codons 768, 804, and 891 that were initially only associated with MTC have subsequently been found in families with MEN2A [Jimenez et al 2004a, Aiello et al 2005, Schulte et al 2010].

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 [Kloos et al 2009]. 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 Table 3 and Surveillance).


The penetrance for MTC, pheochromocytoma, and parathyroid disease varies by MEN2 phenotype (see Table 2).


MEN2A is also referred to as Sipple syndrome.

Mucosal neuroma syndrome is a synonym for MEN2B. MEN2B was initially called Wagenmann-Froboese syndrome [Morrison & Nevin 1996].


The prevalence of MEN2 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, have a later age of onset, and lack C-cell hyperplasia (CCH) [Kloos et al 2009].

DNA analysis of MTC tissue revealed a 40%-50% incidence of somatic RET variants in the absence of a RET germline pathogenic variant [Schilling et al 2001, de Groot et al 2006, Dvorakova et al 2008, Elisei et al 2008]. The somatic p.Met918Thr variant is the most common; 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 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 MEN2.

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 germline 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, multigene panels may also be considered for individuals with no syndromic features.

Evaluation of biochemical features can help differentiate MEN2-associated pheochromocytoma. Pacak et al [2005] compared biochemical profiles for inherited and sporadic pheochromocytoma and found that MEN2 can be ruled out in pheochromocytomas that exclusively produce normetanephrine.

Multiple endocrine neoplasia type 1 (MEN1). This endocrinopathy is genetically and clinically distinct from MEN2; the similar nomenclature for MEN1 and MEN2 may cause confusion. MEN1 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]. MEN1 is caused by a germline pathogenic variant in MEN1 and inherited in an autosomal dominant manner.

Multiple endocrine neoplasia type 4 (MEN4). While pheochromocytomas developed in the MENX rat model, humans with pathogenic variants in CDKN1B tend to have a phenotype similar to MEN1, with a high incidence of pituitary tumors and primary hyperparathyroidism [Lee & Pellegata 2013].


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with multiple endocrine neoplasia type 2 (MEN2), the following evaluations are recommended if they have not already been completed:

  • Referral to an endocrinologist
  • Consultation with a clinical geneticist and/or genetic counselor
  • Biochemical evaluations:
    • Plasma calcitonin
    • Plasma catecholamines and metanephrines
    • Serum calcium and parathyroid hormone
  • Evaluation for metastatic disease in individuals with MTC
    • CT with contrast for chest and abdomen
    • MRI of liver in the presence of 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 [Kloos et al 2009, National Comprehensive Cancer Network 2015]. Current NCCN guidelines recommend consideration of therapeutic external beam radiation therapy or intensity-modulated radiation therapy for incomplete tumor resection or extrathyroidal extension with positive margins [National Comprehensive Cancer Network 2015]. Several kinase inhibitors – vandetanib, cabozantinib, and BLU-667 – have improved progression-free survival and in some cases cause disease regression in unresectable or advanced metastatic MTC [Elisei et al 2013, Wells et al 2013, Subbiah et al 2018].

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 [Kloos et al 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 [Kloos et al 2009, Neumann et al 2019].

Hypertensive treatment prior to adrenalectomy often involves the use of α- and β-adrenergic receptor blockade [Pacak et al 2005], although some centers do not pretreat with α-blockade and use nitroprusside to control blood pressure during surgery [Neumann et al 2019].

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 [Kloos et al 2009]. However, in most individuals with MEN2A, 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 [Kloos et al 2009].

Prevention of Primary Manifestations

Prophylactic thyroidectomy is the primary preventive measure for individuals with an identified germline RET pathogenic variant [Cohen & Moley 2003, Kloos et al 2009].

Prophylactic thyroidectomy is safe for all age groups; however, the timing of the surgery is controversial [Moley et al 1998]. According to the American Thyroid Association Guidelines Task Force consensus statement, the age at which prophylactic thyroidectomy is performed can be guided by the codon position of the RET pathogenic variant (see Table 3 and Genotype-Phenotype Correlations) [Kloos et al 2009]. However, these guidelines continue to be modified as more data become available.

Table 3.

Risk for Aggressive MTC Based on Genotype and Recommended Interventions

ATA Risk LevelPathogenic Variants 1Age of Prophylactic SurgeryAge to Begin Screening
Level D
(highest risk)
p.[Val804Met;Glu805Lys] 2
p.[Val804Met;Tyr806Cys] 2
p.[Val804Met];Ser904Cys] 2
As soon as possible in 1st year of life8 yrsNA
Level Cp.Cys634Arg
<5 yrs8 yrs8 yrs
Level Bp.Cys609Phe
p.Asp631Tyrp.Cys634_Thr636dup (p.633/9 bp dup 3)
p.Lys634_Arg635insHisGluLeuCys (p.634/12 bp dup 3)
p.[Val804Met;Val778Ile] 2
Consider <5 yrs; may delay if criteria met 4Codon 630 pathogenic variant: 8 yrs
All others: 20 yrs
Codon 630 pathogenic variant: 8 yrs
All others: 20 yrs
Level Ap.Arg321Gly
p.Glu529_Cys531dup (p.531/9 bp dup 3)
p.635/insert ELCR;p.Thr636Pro
May delay beyond age 5 yrs if criteria met 420 yrs20 yrs

Adapted from Kloos et al [2009]

ATA = American Thyroid Association; HPT = hyperparathyroidism; MTC = medullary thyroid carcinoma; PHEO = pheochromocytoma


See Molecular Genetics, Table 5 for details of pathogenic variants.


Two variants identified in a DNA sequence or a protein that derive from one chromosome (in cis)


Variant designation that does not conform to current naming conventions


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 [Kloos et al 2009] should begin at age:

  • Six months for children with MEN2B;
  • Three to five years for children with MEN2A or FMTC.

Caution should be used in interpreting calcitonin results for children younger than age three years, especially those younger than age six months [Kloos et al 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 MEN2A or MEN2B. 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].


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 germline 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 [Kloos et al 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, Kloos et al 2009, Neumann et al 2019]. Women with MEN2 should be screened for pheochromocytoma prior to a planned pregnancy, or as early as possible during an unplanned pregnancy [Kloos et al 2009, Neumann et al 2019]. Other screening studies, such as scintigraphy or positron emission tomography, may be warranted in some individuals.

  • MEN2A. Annual biochemical screening beginning at age eight years has been recommended for individuals with a pathogenic variant in codons 630 and 634 and at age 20 years for a pathogenic variant in all other codons [Kloos et al 2009].
  • FMTC. Screening as for MEN2A is indicated, as not all families classified as FMTC are MTC-only [Moers et al 1996].
  • MEN2B. Annual screening should begin at age eight years [Kloos et al 2009].

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

  • MEN2A. Screening should start at age eight years for individuals with a pathogenic variant in codons 630 and 634, and by age 20 years for individuals with other RET pathogenic variants [Kloos et al 2009].
  • FMTC. Periodic screening should begin at age 20 years [Kloos et al 2009].
  • MEN2B. Screening is unnecessary as individuals with MEN2B are not at increased risk for hyperparathyroidism.

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 MEN2 as a Group 1 disorder: 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:
  • 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 [Kloos et al 2009] for pheochromocytoma

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

Pregnancy Management

Women with MEN2 should be screened for pheochromocytoma prior to a planned pregnancy, or as early as possible during an unplanned pregnancy [Kloos et al 2009].

Therapies Under Investigation

Clinical trials of multikinase inhibitors such as sorafenib, sunitinib, and ponatinib are currently under way. NCCN and ATA guidelines recommend consideration of clinical trial participation for individuals who fail standard treatment with a tyrosine kinase inhibitor such as vandetanib and cabozantinib [National Comprehensive Cancer Network 2015, Wells et al 2015]. Newer agents such as BLU-667 are showing promise as well.

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 in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of 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; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

All of the multiple endocrine neoplasia type 2 (MEN2) subtypes are inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband. The proportion of individuals with MEN2 who have an affected parent varies by subtype:

If the pathogenic variant found in the proband cannot be detected in the 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 MEN2, it remains a possibility.

Recommendations for the evaluation of parents of a proband with a clinical diagnosis of MEN2 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 MEN2 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 MEN2 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 been reported.

Offspring of a proband

  • Each child of an individual with MEN2 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 – health professional version (part of PDQ®, National Cancer Institute).

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with MEN2 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 including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and availability of prenatal/preimplantation genetic 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. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

Once the RET pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for MEN2 are possible [Kloos et al 2009].

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.


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)
    United Kingdom
    Email: info@amend.org.uk
  • Associazione Italiana Neoplasie Endocrine Multiple (AIMEN 1 & 2)
    Phone: 347 4561588
    Email: info@aimen.it
  • MedlinePlus
  • American Cancer Society
    Phone: 800-227-2345
  • American Multiple Endocrine Neoplasia Support
    Phone: 865-283-5842
    Email: Info@amensupport.org
  • CancerNetwork.com
  • National Cancer Institute (NCI)
    Phone: 800-422-6237
    Email: NCIinfo@nih.gov
  • NCBI Genes and Disease
  • Pheo Para Alliance
    Our mission is to empower patients with pheochromocytoma or paraganglioma, their families and medical professionals through advocacy, education and a global community of support, while helping to advance research that accelerates treatments and cures.
  • AMEND Research Registry
    Association for Multiple Endocrine Neoplasia Disorders
    United Kingdom
    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

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
RET 10q11​.21 Proto-oncogene tyrosine-protein kinase receptor ret RET database RET RET

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

Table B.

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


Molecular Pathogenesis

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]. Pathogenic variants causing MEN2 lead to constitutive activation (i.e., gain of function) of tyrosine kinase.

Gene structure. The RET proto-oncogene comprises 20 exons; the first exon is noncoding (NM_020975.5). Normal tissues contain transcripts of several lengths [Takaya et al 1996]. The variant NM_020975.5 is the longest transcript and encodes the longer isoform (a), also known as Ret51. For a detailed summary of gene and protein information, see Table A, Gene.

Putative benign/modifier/predisposition variants. Benign variants as well as variants of uncertain significance have been described. See Table A, Locus Specific for a database of 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.Ser904= 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 MEN2A [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.Ser836= variant has been associated with an increased risk for nonfamilial 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 nonfamilial MTC association with p.Ser836= 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, whether they act as modifiers of risk is not known [Erlic et al 2010].

Table 4.

Putative RET Benign/Modifier/Predisposition Variants Discussed in This GeneReview

Predicted Protein ChangeDNA Nucleotide ChangeReference Sequences
p.Val648Ilec.1842G>A NM_020975​.5
p.Ser836= 1c.2508C>T
p.Ser904= 1c.2712C>G

Designates that protein has not been analyzed, but no change in the amino acid is expected

Pathogenic variants. The most common 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 MEN2A and some have been identified in families with FMTC. Pathogenic variants in these sites have been detected in 98% of families with MEN2A [Eng et al 1996]. See Table A for a database of RET variants [Margraf et al 2009].

The risk for aggressive MTC, pheochromocytoma, and hyperparathyroidism can be estimated based on genotype. See Table 3 for management recommendations.

Approximately 95% of all individuals with the MEN2B phenotype have a pathogenic variant 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 pathogenic variant, p.Ala883Phe, resulting from a two-nucleotide indel, has been found in 2%-3% of individuals with MEN2B [Gimm et al 1997, Smith et al 1997].

Two variants in cis configuration on one RET allele have been reported in individuals with MEN2B (see Table 5 for codon 804 in combination with 778, 805, 806, and 904) [Miyauchi et al 1999, Menko et al 2002, Cranston et al 2006, Kloos et al 2009].

In addition to the pathogenic variants in the cysteine residues in exons 10 and 11 that have been found in families with MEN2A, pathogenic variants in codons 631, 768, 790, 804, 844, and 891, and others in exons 5, 8, 10, 11, and 13-16, have been identified in a small number of families [Hofstra et al 1997, Berndt et al 1998, Kloos et al 2009, Wells et al 2015].

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 MEN2A; 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 MEN2B [Miyauchi et al 1999].

For families in which MEN2A 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].

Table 5.

RET Pathogenic Variants Discussed in This GeneReview

ATA Risk LevelPredicted Protein Change
(Alias 1)
DNA Nucleotide Change
(Alias 1)
Level D
(highest risk)
p.Ala883Phec.2647_2648delGCinsTT NM_020975​.5
p.[Val804Met;Glu805Lys] 2c.[2410G>T; c.2413G>A] 2
p.[Val804Met;Tyr806Cys] 2c.[2410G>T;2417A>G] 2
p.[Val804Met;Ser904Cys] 2c.[2410G>T;2711C>G] 2
Level Cp.Cys634Argc.1900C>T
Level Bp.Cys609Phec.1826G>T
(633/9 bp dup)
(634/12 bp dup)
p.[Val804Met;Val778Ile] 2c.[2410G>T;c.2332G>A] 2
Level Ap.Gly321Arg
(531/9 bp dup)
p.635/insert ELCR;p.Thr636Pro

Adapted from Kloos et al [2009]

ATA = American Thyroid Association

See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org).

Variant designations are updated to current naming conventions; therefore, not all directly correlate to the nomenclature in their original publications.


Variant designation that does not conform to current naming conventions


Two variants identified in a DNA sequence or a protein that derive from one chromosome (in cis)

Normal gene product. The transcript variant NM_020975.5 encodes NP_066124.1, the 1,114-amino acid proto-oncogene tryrosine-protein kinase receptor RET isoform (a) precursor, also known as Ret 51. For RET function, see Molecular Pathogenesis. For a detailed summary of gene, transcript, and protein information, see Table A, Gene.

Abnormal gene product. Pathogenic variants in the cysteine-rich extracellular domain (codons 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 MEN2B 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 MEN2, pathogenic variants that cause Hirschsprung disease result in a decrease in the transforming activity of RET [Iwashita et al 1996] (see Genetically Related Disorders).

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].

Somatic RET variants, in the absence of a germline pathogenic RET variant, are found in medullary thyroid carcinoma of individuals without a family history of MTC and in sporadic pheochromocytoma (see Differential Diagnosis, MTC in individuals with no family history of MTC; Pheochromocytoma).


Published Guidelines / Consensus Statements

  • American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. 2003.
  • American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. Available online. 2010. Accessed 2-23-22.

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Chapter Notes

Author History

Charis Eng, MD, PhD, FACP (2010-present)
Jessica Marquard, MS, LGC; Cleveland Clinic (2010-2019)
Karen Snow-Bailey, PhD, FACMG, FHGSA; Auckland City Hospital (1999-2006*)
Georgia L Wiesner, MD, MS, FACMG; Case Western Reserve University School of Medicine (1999-2010)

*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

  • 15 August 2019 (ma) Comprehensive update posted live
  • 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 live
  • 19 May 2004 (cd) Revision: Genetic Counseling
  • 21 January 2003 (me) Comprehensive update posted live
  • 27 September 1999 (me) Review posted live
  • October 1998 (gw) Original submission
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