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.

Diagnosis/testing.

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.

Management.

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.

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.

• Select-exon testing. The majority of pathogenic variants occur in exons 10, 11, and 13-16 (Table 3). Sequence analysis of select exons and targeted analysis for pathogenic variants may be offered by some laboratories.
  If no pathogenic variant is found by select-exon testing, full-gene sequencing of RET as part of a multigene panel should be considered next.
  Note: Since MEN2 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 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.

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.

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].

• 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 MEN2A [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 had 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 association with 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 [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).

Penetrance

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

Nomenclature

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].

Prevalence

The prevalence of MEN2 has been estimated at 1:35,000 [DeLellis et al 2004].

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.

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].

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 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:
  • MEN2A. 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 germline 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 MEN2A.
  • MEN2B. 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 [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.

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:

• MEN2A
  • 95% of individuals diagnosed with MEN2A have an affected parent. The penetrance for MTC, pheochromocytoma, and parathyroid disease varies by MEN2 subtype (see Table 2).
  • A proband with MEN2A 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 MEN2A 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.
• MEN2B
  • 50% of individuals diagnosed with MEN2B have an affected parent. The penetrance for MTC, pheochromocytoma, and parathyroid disease varies by MEN2 subtype (see Table 2).
  • A proband with MEN2B may have the disorder as the result of a de novo germline RET pathogenic variant [Carlson et al 1994]. The proportion of MEN2B 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.
  • It is appropriate to evaluate the parents of an individual with MEN2B 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).

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.

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].

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].

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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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