Multiple Endocrine Neoplasia Type 2

Clinical characteristics.

Multiple endocrine neoplasia type 2 (MEN2) includes the following phenotypes: MEN2A, familial medullary thyroid carcinoma (FMTC, 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 of 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 or by identification of a heterozygous germline gain-of-function variant in RET on molecular genetic testing. Molecular genetic testing is recommended in all individuals with a clinical diagnosis due to genotype-specific surveillance and treatment recommendations and to allow family studies.

Management.

Targeted therapy: Prophylactic thyroidectomy for individuals with an identified germline RET pathogenic variant.

Supportive care: Measurement of plasma free metanephrines or 24-hour urine for fractionated metanephrines to evaluate for functioning pheochromocytoma prior to any surgery in individuals with MEN2A, MEN2B, or FMTC. Adrenalectomy prior to thyroidectomy in any individual with pheochromocytoma identified. 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 incomplete tumor resection or extrathyroidal extension with positive margins. Kinase inhibitors may be considered in those with metastatic MTC. Standard treatment for hypothyroidism following thyroidectomy. Treatment of hypertension prior to adrenalectomy or management of hypertension during surgery. Resection of pheochromocytomas 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.

Surveillance: Annual measurement of serum calcitonin concentration in those who have not had prophylactic thyroidectomy and to detect residual or recurrent MTC after thyroidectomy, even if thyroidectomy was performed prior to biochemical evidence of disease. Annual plasma free metanephrines or 24-hour urine for fractionated metanephrines for those with a germline RET pathogenic variant whose initial screening results are negative for pheochromocytoma. Annual albumin-corrected calcium or ionized calcium for individuals with MEN2A/FMTC whose initial screening results are negative for hyperparathyroidism. Age of initiation of surveillance for pheochromocytoma and hyperparathyroidism is determined by the specific germline RET pathogenic variant identified.

Agents/circumstances to avoid: Dopamine D₂ receptor antagonists and beta-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. When an individual with MEN2 refuses to notify at-risk family members, the physician should consider consulting a clinical ethicist to determine if the physician has the ethical obligation to warn the at-risk family members.

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. Up to 95% of individuals diagnosed with MEN2A and 50% of individuals diagnosed with MEN2B have an affected parent. (By definition, individuals with FMTC have multiple family members who are affected.) Approximately 5%-9% of individuals with MEN2A and 50% of individuals with MEN2B have the disorder as the result of a de novo germline pathogenic variant. Each child of an individual with MEN2 has a 50% chance of inheriting the RET pathogenic variant. Once the RET pathogenic variant has been identified in an affected family member, molecular genetic testing of at-risk asymptomatic family members and prenatal and preimplantation genetic testing for MEN2 are possible.

Suggestive Findings

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 tumor(s): 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 clinical diagnosis of MEN2 can be established in a proband based on clinical diagnostic criteria [Kloos et al 2009, Wells et al 2015, National Comprehensive Cancer Network 2022], or the molecular diagnosis can be established in a proband with suggestive findings and a heterozygous germline gain-of-function pathogenic (or likely pathogenic) variant in RET identified by molecular genetic testing (see Table 1). Molecular genetic testing is recommended in all individuals with a clinical diagnosis due to genotype-specific surveillance and treatment recommendations and to allow family studies.

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous RET variant of uncertain significance does not establish or rule out the diagnosis.

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

p.Cys609, p.Cys611, p.Cys618, and p.Cys620. Pathogenic variants involving the cysteine codons 609, 611, 618, and 620 in exon 10 of RET are associated with MEN2A, FMTC, and Hirschsprung disease [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].

p.Cys634. Any RET pathogenic variant at codon 634 in exon 11 results in a higher incidence of pheochromocytomas and HPT [Eng et al 1996, Yip et al 2003, Zbuk & Eng 2007, Wells et al 2015].

• 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 have a pathogenic variant in codon 634, p.Cys634Arg pathogenic variants are virtually absent in this subtype [Hansford & Mulligan 2000, Zbuk & Eng 2007].

p.Leu790, p.Val804. In addition to an association with MTC, pathogenic variants in codons 790 or 804 may be associated with papillary thyroid carcinoma [Brauckhoff et al 2002]. In an additional study of 24 individuals with a germline RET pathogenic variant and concomitant MTC and papillary thyroid cancer, p.Val804Met was the most frequently reported variant at 33% [Appetecchia et al 2019].

p.Val804. 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 has been reported in one individual [Rothberg et al 2009].

p.Met918Thr. 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 a RET germline variant affecting p.Ser836 [Gimm et al 1999].

The American Thyroid Association Guidelines Task Force has classified pathogenic variants based on their risk for aggressive MTC [Wells et al 2015]. The classification may be used in (1) predicting phenotype and (2) recommendations regarding the ages at which to (a) perform prophylactic thyroidectomy and (b) begin biochemical screening for pheochromocytoma and HPT (see Table 6 and Surveillance).

Penetrance

Penetrance of some RET pathogenic variants is incomplete, as the incidence of 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 MEN2, the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 8 are recommended [Wells et al 2015, Neumann et al 2019, National Comprehensive Cancer Network 2022].

Agents/Circumstances to Avoid

Dopamine D₂ receptor antagonists (e.g., metoclopramide and veralipride) and beta-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 [Robson et al 2015]. Predictive genetic testing in asymptomatic at-risk relatives for MEN2 promotes earlier diagnosis and implementation of appropriate screening and surveillance. This has the potential to improve clinical outcomes by allowing for prophylactic removal of the thyroid gland prior to malignant transformation of C-cell hyperplasia, earlier diagnosis of MTC if already present, and earlier diagnosis of additional phenotypes including pheochromocytoma and hyperparathyroidism (HPT). Evaluations can include:

• Molecular genetic testing if the RET 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 child with a germline RET pathogenic variant suggests that molecular genetic testing should be performed even earlier when possible [Machens et al 2004].
  • Familial medullary thyroid carcinoma (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 [Wells et al 2015, National Comprehensive Cancer Network 2022].
• 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
  • Annual albumin-corrected calcium or ionized calcium for HPT
  • Annual measurement of plasma free metanephrines or 24-hour urine for fractionated metanephrines as appropriate [Wells et al 2015] 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 [Wells et al 2015].

Therapies Under Investigation

Clinical trials of multikinase inhibitors such as sorafenib, sunitinib, and regorafenib are currently under way. National Comprehensive Cancer Network and American Thyroid Association guidelines recommend consideration of clinical trial participation for individuals who fail standard treatment with a tyrosine kinase inhibitor such as vandetanib or cabozantinib [Wells et al 2015, National Comprehensive Cancer Network 2022]. Newer RET-selective inhibitors including selpercatinib (LOXO-292) & pralsetinib (BLU-667) are now approved as second-line treatment for metastatic MTC after failure of first-line multikinase inhibitors (see Treatment of Manifestations).

Sorafenib is FDA approved for use in renal cell and hepatocellular carcinoma. A meta-analysis including eight clinical trials and 101 individuals with metastatic MTC treated with sorafenib demonstrated a partial response of 21% and 58% stable disease [Vuong et al 2019]. 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].

Clinical trials of immune checkpoint inhibitors such as pembrolizumab, nivolumab, and ipilimumab are currently under way [Lorch et al 2020, Angelousi et al 2022]. National Comprehensive Cancer Network guidelines recommend consideration of pembrolizumab for individuals with metastatic, tumor mutational burden-high disease that has progressed on first-line treatment [National Comprehensive Cancer Network 2022].

Several studies have investigated peptide receptor radionuclide therapy (PRRT), targeting somatostatin receptors with radionuclides such as ¹⁷⁷lutetium, ⁹⁰yttrium, and ¹¹¹indium for individuals with advanced or metastatic MTC [Grossrubatscher et al 2020, Parghane et al 2020, Angelousi et al 2022]. A review of more than 200 individuals with MTC treated with PRRT with somatostatin analogs showed efficacy in treatment with a favorable radiologic response in greater than 60% of individuals [Grossrubatscher et al 2020]. Clinical trials investigating ¹⁷⁷lutetium and ⁹⁰yttrium are ongoing.

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 – MEN2A, familial medullary thyroid carcinoma (FMTC), and MEN2B – 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:
  • Up to 95% of individuals diagnosed with MEN2A have an affected parent.
  • By definition, individuals with FMTC have multiple family members who are affected.
  • 50% of individuals diagnosed with MEN2B have an affected parent.
• A proband with MEN2A or MEN2B may have the disorder as the result of a de novo germline RET pathogenic variant.
  • The proportion of individuals with MEN2A caused by a de novo germline pathogenic variant is approximately 5%-9% [Wells et al 2015].
  • The proportion of individuals with MEN2B caused by a de novo germline 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 MEN2A or MEN2B for manifestations of the disorder and to offer molecular genetic testing if the RET pathogenic variant has been identified in the proband (see Establishing the Diagnosis).
• If the proband has a known germline RET pathogenic variant that cannot be identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• 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 medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism.
• The family history of some individuals diagnosed with MEN2A or MEN2B may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, early death of the parent before onset of symptoms, or late onset of the disorder in the affected parent. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband).

Sibs of a proband. The risk to the sibs of a proband depends on the clinical/genetic status of the proband's parents.

• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• The penetrance for MTC, pheochromocytoma, and parathyroid disease varies by MEN2 subtype (see Table 2). Sibs who inherit a familial RET pathogenic variant typically manifest the same MEN2 subtype as other affected family members (see Genotype-Phenotype Correlations).
• If the proband has a known RET pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If the parents are clinically unaffected but their genetic status is unknown, sibs are still at increased risk for MEN2 because of the possibility of reduced penetrance in a parent or the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with MEN2 has a 50% chance of inheriting the 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, the parent's family members are at increased risk.

Related Genetic Counseling Issues

Testing of at-risk individuals

• Molecular genetic testing of at-risk asymptomatic family members is strongly recommended for all first-degree relatives of an affected person with an identified germline RET pathogenic variant. Predictive genetic testing in asymptomatic relatives at risk for MEN2 promotes earlier diagnosis and implementation of appropriate screening and surveillance. This has the potential to improve clinical outcomes by allowing for prophylactic removal of the thyroid gland prior to malignant transformation of C-cell hyperplasia, earlier diagnosis of MTC if already present, and earlier diagnosis of additional phenotypes including pheochromocytoma and hyperparathyroidism.
• Because early detection of at-risk individuals affects medical management, testing of asymptomatic children is beneficial [Robson et al 2015]. Molecular genetic testing should be performed in at-risk individuals by age five years in families with MEN2A and FMTC and as soon as possible after birth in families with MEN2B so that individuals with a RET pathogenic variant can receive appropriate preventative measures, surveillance, and treatment (see Management). When a known pathogenic variant is not identified, linkage analysis can be considered in families with more than one affected family member from different generations. Education and genetic counseling of at-risk children and their parents prior to genetic testing are appropriate.
• See also Management, Evaluation of Relatives at Risk for information on evaluating and screening at-risk relatives for the purpose of early diagnosis and treatment.

Individuals with simplex MTC and no identifiable RET germline pathogenic variant. The probability that the offspring of an individual with simplex MTC (i.e., no known family history of MTC) and no identifiable RET germline pathogenic variant would inherit a RET pathogenic variant is 0.15%-0.18% [Romei et al 2016]. This is based on empiric data indicating that 6%-7% of individuals with simplex MTC have a germline RET pathogenic variant and the possibility of a false negative molecular genetic test result in an individual with a germline RET pathogenic variant (the pathogenic variant detection rate for RET is approximately 95%).

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).

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). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the RET pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for MEN2 are possible.

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 encodes a receptor tyrosine kinase with extracellular, transmembrane, and intracellular domains. The extracellular domain consists of a calcium-binding cadherin-like domain and a cysteine-rich domain. 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, RET kinase activation, and intracellular signaling whereby phosphorylated tyrosines become docking sites for intracellular signaling proteins [Salvatore et al 2021]. The RET tyrosine kinase catalytic core, which is located in the intracellular domain, causes downstream activation of the mitogen-activated protein (MAP) kinase signaling cascade [Salvatore et al 2021]. Pathogenic variants causing multiple endocrine neoplasia type 2 (MEN2) lead to constitutive activation (i.e., gain of function) of tyrosine kinase.

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, Wells et al 2015, Romei et al 2016, Elisei et al 2019]. All of these variants have been identified in families with MEN2A and some have been identified in families with familial medullary thyroid carcinoma (FMTC). Pathogenic variants in these sites have been detected in 98% of families with MEN2A [Eng et al 1996].

The risk for aggressive medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism can be estimated based on genotype (see Table 3 and Table 6).

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, Wells et al 2015]. A second pathogenic variant, p.Ala883Phe, resulting from a two-nucleotide indel, has been found in 2%-3% of individuals with MEN2B [Wells et al 2015, Salvatore et al 2021].

Two variants in cis configuration on one RET allele have been reported in individuals with MEN2B (see Table 9 for codon 804 in combination with 778, 805, 806, and 904) [Miyauchi et al 1999, Menko et al 2002, Cranston et al 2006, Wells et al 2015].

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, 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].

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 Hirschsprung disease (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].

Mechanism of disease causation. Gain of function. In MEN2A, the majority of pathogenic variants occur in the extracellular cysteine-rich domain, allowing for aberrant intermolecular disulfide bonds and resulting in ligand-independent RET kinase dimerization and subsequent constitutive activation of the RET kinase. In MEN2B, p.Met918Thr results in increased ATP binding and autophosphorylation and subsequent dimerization-independent activation of the RET kinase [Salvatore et al 2021].

Note: In contrast to the activating pathogenic variants in MEN2, pathogenic variants that cause HSCR result in a decrease in the transforming activity of RET because RET molecules are stuck in the endoplasmic reticulum and do not reach the cell surface [Iwashita et al 1996] (see Genetically Related Disorders).

Modifier and predisposition variants. 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 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.Ser904= 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.Ser904= and a strong association with the promoter benign variant IVS1-126G>T [Figlioli et al 2013]. Inactivating RET variants may provide a protective effect against the development of MEN2 phenotypes, such as c.73+9277T>C. This variant disrupts the RET gene enhancer and may counteract the constitutive RET activation seen in MEN2; it is rarely present in individuals with MEN2 [Borun et al 2012, Kaczmarek-Ryś et al 2018].

Author History

Charis Eng, MD, PhD, FACP (2010-present)

Jessica Marquard, MS, LGC; Cleveland Clinic (2010-2019)

Gilman Pitt, MD (2023-present)

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

• 10 August 2023 (sw) Comprehensive update posted live
• 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
• 21 January 2003 (me) Comprehensive update posted live
• 27 September 1999 (me) Review posted live
• October 1998 (gw) Original submission

Published Guidelines / Consensus Statements

• National Comprehensive Cancer Network. NCCN Guidelines: Neuroendocrine and Adrenal Tumors. NCCN website. Available online; purchase or subscription required. 2022. Accessed 7-5-23.
• Robson ME, Bradbury AR, Arun B, Domchek SM, Ford JM, Hampel HL, Lipkin SM, Syngal S, Wollins DS, Lindor NM. American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol. 2015;33:3660-7. [PubMed]
• Wells SA Jr, Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF, Lee N, Machens A, Moley JF, Pacini F, Raue F, Frank-Raue K, Robinson B, Rosenthal MS, Santoro M, Schlumberger M, Shah M, Waguespack SG, et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015;25:567-610. [PubMed]

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