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]

Literature Cited

• Angelousi A, Hayes AR, Chatzellis E, Kaltsas GA, Grossman AB. Metastatic medullary thyroid carcinoma: a new way forward. Endocr Relat Cancer. 2022;29:R85-R103. [PMC free article: PMC9175549] [PubMed: 35521769]
• Appetecchia M, Lauretta R, Barnabei A, Pieruzzi L, Terrenato I, Cavedon E, Mian C, Castagna MG, Elisei R, et al. Epidemiology of simultaneous medullary and papillary thyroid carcinomas (MTC/PTC): an Italian multicenter study. Cancers (Basel). 2019;11:1516. [PMC free article: PMC6826384] [PubMed: 31600997]
• Bartsch DK, Hasse C, Schug C, Barth P, Rothmund M, Höppner W. A RET double mutation in the germline of a kindred with FMTC. Exp Clin Endocrinol Diabetes. 2000;108:128-32. [PubMed: 10826520]
• Berard I, Kraimps JL, Savagner F, Murat A, Renaudin K, Nicolli-Sire P, Bertrand G, Moisan JP, Bezieau S. Germline-sequence variants S836S and L769L in the RE arranged during Transfection (RET) proto-oncogene are not associated with predisposition to sporadic medullary carcinoma in the French population. Clin Genet. 2004;65:150-2. [PubMed: 14984475]
• Berndt I, Reuter M, Saller B, Frank-Raue K, Groth P, Grussendorf M, Raue F, Ritter MM, Höppner W. A new hot spot for mutations in the ret protooncogene causing familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2A. J Clin Endocrinol Metab. 1998;83:770-4. [PubMed: 9506724]
• Boedeker CC, Erlic Z, Richard S, Kontny U, Gimenez-Roqueplo AP, Cascón A, Robledo M, de Campos JM, van Nederveen FH, de Krijger RR, Burnichon N, Gaal J, Walter MA, Reschke K, Wiech T, Weber J, Rückauer K, Plouin PF, Darrouzet V, Giraud S, Eng C, Neumann HP. Head and neck paragangliomas in von Hippel-Lindau disease and multiple endocrine neoplasia type 2. J Clin Endocrinol Metab. 2009;94:1938-44. [PMC free article: PMC2690424] [PubMed: 19336503]
• Borun P, Jerzy S, Ziemnicka K, Kubaszewski L, Lipinski D, Plawski A. Absence of the RET+3:T allele in the MTC patients. Hered Cancer Clin Pract. 2012;10:14. [PMC free article: PMC3533580] [PubMed: 23088776]
• Brandi ML, Gagel RF, Angeli A, Bilezikian JP, Beck-Peccoz P, Bordi C, Conte-Devolx B, Falchetti A, Gheri RG, Libroia A, Lips CJ, Lombardi G, Mannelli M, Pacini F, Ponder BA, Raue F, Skogseid B, Tamburrano G, Thakker RV, Thompson NW, Tomassetti P, Tonelli F, Wells SA Jr, Marx SJ. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab. 2001;86:5658-71. [PubMed: 11739416]
• Brauckhoff M, Gimm O, Hinze R, Ukkat J, Brauckhoff K, Dralle H. Papillary thyroid carcinoma in patients with RET proto-oncogene germline mutation. Thyroid. 2002;12:557-61. [PubMed: 12193298]
• Brenner ME, Jacene HA. Recurrent or residual hyperparathyroidism and thyroid cancer effectively evaluated with scintigraphy. Otolaryngol Clin North Am. 2008;41:1117-33 [PubMed: 19040973]
• Bryant J, Farmer J, Kessler LJ, Townsend RR, Nathanson KL. Pheochromocytoma: the expanding genetic differential diagnosis. J Natl Cancer Inst. 2003;95:1196-204. [PubMed: 12928344]
• Cardot-Bauters C, Leteurtre E, Leclerc L, Vantyghem MC, Do Cao C, Wemeau JL, d'Herbomez M, Carnaille B, Barbu V, Pinson S, Pigny P, et al. Does the RET variant G691S influence the features of sporadic medullary thyroid carcinoma? Clin Endocrinol (Oxf). 2008;69:506-10. [PubMed: 18331611]
• Carr LL, Mankoff DA, Goulart BH, Eaton KD, Capell PT, Kell EM, Bauman JE, Martins RG. Phase II study of daily sunitinib in FDG-PET-positive, iodine-refractory differentiated thyroid cancer and metastatic medullary carcinoma of the thyroid with functional imaging correlation. Clin Cancer Res. 2010;16:5260-8. [PMC free article: PMC3063514] [PubMed: 20847059]
• Castinetti F, Waguespack S, Machens A, Uchino S, Lazar K, Sanso G, Else T, Dvorakova S, Qi XP, Elisei R, Maia AL, Glod J, Muniz D, Valdes N, Mathiesen J, Wohllk N, Bangdar T, Delphine D, Korbonits M, Druce M, Brain C, Kurzawinki T, Patocs A, Bugalho MJ, Lacroix A, Phillippe C, Fainstein-Day P, Borson-Chazot F, Klein M, Links T, Letizia C, Fugazzola L, Chabre O, Canu L, Cohen R, Tabarin A, Spehar A, Maiter D, Laboureau S, Mian C, Peczkowska M, Sebag F, Brue T, Prunier D, Leclerc L, Bausch B, Barontini M, Ferreira CV, Valerio L, Ceolin L, Akshintala S, Hoff A, Godballe C, Jarzab B, Jimenez C, Imai T, Eng C, Schlumberger M, Grubbs E, Dralle H, Neumann HP, Baudin E. Natural history, treatment, and long-term follow up of patients with multiple endocrine neoplasia type 2B: an international, multicentre, retrospective study. Lancet Diabetes Endocrinol. 2019;7:213-20. [PMC free article: PMC8132299] [PubMed: 30660595]
• Cohen MS, Moley JF. Surgical treatment of medullary thyroid carcinoma. J Intern Med. 2003;253:616-26. [PubMed: 12755957]
• Costante G, Durante C, Francis Z, Schlumberger M, Filetti S. Determination of calcitonin levels in C-cell disease: clinical interest and potential pitfalls. Nat Clin Pract Endocrinol Metab. 2009;5:35-44. [PubMed: 19079272]
• Cranston AN, Carniti C, Oakhill K, Radzio-Andzelm E, Stone EA, McCallion AS, Hodgson S, Clarke S, Mondellini P, Leyland J, Pierotti MA, Whittaker J, Taylor SS, Bongarzone I, Ponder BA. RET is constitutively activated by novel tandem mutations that alter the active site resulting in multiple endocrine neoplasia type 2B. Cancer Res. 2006;66:10179-87. [PubMed: 17047083]
• Decker RA, Peacock ML, Watson P. Hirschsprung disease in MEN 2A: increased spectrum of RET exon 10 genotypes and strong genotype-phenotype correlation. Hum Mol Genet. 1998;7:129-34. [PubMed: 9384613]
• de Groot JW, Links TP, Plukker JT, Lips CJ, Hofstra RM. RET as a diagnostic and therapeutic target in sporadic and hereditary endocrine tumors. Endocr Rev. 2006;27:535-60. [PubMed: 16849421]
• DeLellis RA, Lloyd RV, Heitz PU, Eng C. Pathology and Genetics: Tumours of the Endocrine Organs. World Health Organization Classification of Tumours Series. Vol 8. Lyon, France: IARC Press; 2004.
• Dvorakova S, Vaclavikova E, Sykorova V, Vcelak J, Novak Z, Duskova J, Ryska A, Laco J, Cap J, Kodetova D, Kodet R, Krskova L, Vlcek P, Astl J, Vesely D, Bendlova B. Somatic mutations in the RET proto-oncogene in sporadic medullary thyroid carcinomas. Mol Cell Endocrinol. 2008;284:21-7. [PubMed: 18282654]
• Eisenhofer G, Rivers G, Rosas AL, Quezado Z, Manger WM, Pacak K. Adverse drug reactions in patients with phaeochromocytoma: incidence, prevention and management. Drug Saf. 2007;30:1031-62. [PubMed: 17973541]
• Elisei R, Cosci B, Romei C, Bottici V, Renzini G, Molinaro E, Agate L, Vivaldi A, Faviana P, Basolo F, Miccoli P, Berti P, Pacini F, Pinchera A. Prognostic significance of somatic RET oncogene mutations in sporadic medullary thyroid cancer: a 10-year follow-up study. J Clin Endocrinol Metab. 2008;93:682-7. [PubMed: 18073307]
• Elisei R, Cosci B, Romei C, Bottici V, Sculli M, Lari R, Barale R, Pacini F, Pinchera A. RET exon 11 (G691S) polymorphism is significantly more frequent in sporadic medullary thyroid carcinoma than in the general population. J Clin Endocrinol Metab. 2004;89:3579-84. [PubMed: 15240649]
• Elisei R, Schlumberger MJ, Müller SP, Schöffski P, Brose MS, Shah MH, Licitra L, Jarzab B, Medvedev V, Kreissl MC, Niederle B, Cohen EE, Wirth LJ, Ali H, Hessel C, Yaron Y, Ball D, Nelkin B, Sherman SI. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol. 2013;31:3639-46. [PMC free article: PMC4164813] [PubMed: 24002501]
• Elisei R, Tacito A, Ramone T, Ciampi R, Bottici V, Cappagli V, Viola D, Matrone A, Lorusso L, Valerio L, Giani C, Campopiano C, Prete A, Agate L, Molinaro E, Romei C. Twenty-five years experience on RET genetic screening on hereditary MTC: an update on the prevalence of germline RET mutations. Genes (Basel). 2019;10:698. [PMC free article: PMC6771015] [PubMed: 31510104]
• Eng C, Clayton D, Schuffenecker I, Lenoir G, Cote G, Gagel RF, van Amstel HK, Lips CJ, Nishisho I, Takai SI, Marsh DJ, Robinson BG, Frank-Raue K, Raue F, Xue F, Noll WW, Romei C, Pacini F, Fink M, Niederle B, Zedenius J, Nordenskjöld M, Komminoth P, Hendy GN, Mulligan LM. The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. JAMA. 1996;276:1575-9. [PubMed: 8918855]
• Feldman GL, Edmonds MW, Ainsworth PJ, Schuffenecker I, Lenoir GM, Saxe AW, Talpos GB, Roberson J, Petrucelli N, Jackson CE. Variable expressivity of familial medullary thyroid carcinoma (FMTC) due to a RET V804M (GTG-->ATG) mutation. Surgery. 2000;128:93-8. [PubMed: 10876191]
• Figlioli G, Landi S, Romei C, Elisei R, Gemignani F. Medullary thyroid carcinoma (MTC) and RET proto-oncogene: mutation spectrum in the familial cases and a meta-analysis of studies on the sporadic form. Mutat Res. 2013;752:36-44. [PubMed: 23059849]
• Frohnauer MK, Decker RA. Update on the MEN 2A c804 RET mutation: is prophylactic thyroidectomy indicated? Surgery. 2000;128:1052-7 [PubMed: 11114642]
• Gibelin H, Bezieau S, Misso C, Bouin-Pineau MH, Maréchaud R, Kraimps JL. Germline RET V804M mutation associated with multiple endocrine neoplasia type 2A. Br J Surg. 2004;91:1458-9. [PubMed: 15386323]
• Gil L, Azañedo M, Pollán M, Cristobal E, Arribas B, García-Albert L, García-Sáiz A, Maestro ML, Torres A, Menárguez J, Rojas JM. Genetic analysis of RET, GFR alpha 1 and GDNF genes in Spanish families with multiple endocrine neoplasia type 2A. Int J Cancer. 2002;99:299-304. [PubMed: 11979448]
• Gimm O, Marsh DJ, Andrew SD, Frilling A, Dahia PL, Mulligan LM, Zajac JD, Robinson BG, Eng C. Germline dinucleotide mutation in codon 883 of the RET proto-oncogene in multiple endocrine neoplasia type 2B without codon 918 mutation. J Clin Endocrinol Metab. 1997;82:3902-4. [PubMed: 9360560]
• Gimm O, Neuberg DS, Marsh DJ, Dahia PL, Hoang-Vu C, Raue F, Hinze R, Dralle H, Eng C. Over-representation of a germline RET sequence variant in patients with sporadic medullary thyroid carcinoma and somatic RET codon 918 mutation. Oncogene. 1999;18:1369-73. [PubMed: 10022819]
• Grossrubatscher E, Fanciulli G, Pes L, Sesti F, Dolci C, de Cicco F, Colao A, Faggiano A, Nike Group. Advances in the management of medullary thyroid carcinoma: focus on peptide receptor radionuclide therapy. J Clin Med. 2020;9:3507. [PMC free article: PMC7693147] [PubMed: 33138305]
• Hansford JR, Mulligan LM. Multiple endocrine neoplasia type 2 and RET: from neoplasia to neurogenesis. J Med Genet. 2000;37:817-27. [PMC free article: PMC1734482] [PubMed: 11073534]
• Hofstra RM, Fattoruso O, Quadro L, Wu Y, Libroia A, Verga U, Colantuoni V, Buys CH. A novel point mutation in the intracellular domain of the ret protooncogene in a family with medullary thyroid carcinoma. J Clin Endocrinol Metab. 1997;82:4176-8. [PubMed: 9398735]
• Høie J, Heimdal K, Nesland JM, Børmer O. Prophylactic thyroidectomy in carriers of RET oncogene mutation carriers. Tidsskr Nor Laegeforen. 2000;120:3249-52. [PubMed: 11187163]
• Huang SJ, Amendola LM, Sternen DL. Variation among DNA banking consent forms: points for clinicians to bank on. J Community Genet. 2022;13:389-97. [PMC free article: PMC9314484] [PubMed: 35834113]
• Ilias I, Chen CC, Carrasquillo JA, Whatley M, Ling A, Lazúrová I, Adams KT, Perera S, Pacak K. Comparison of 6-18F-fluorodopamine PET with 123I-metaiodobenzylguanidine and 111in-pentetreotide scintigraphy in localization of nonmetastatic and metastatic pheochromocytoma. J Nucl Med. 2008;49:1613-9. [PMC free article: PMC2614907] [PubMed: 18794260]
• Ilias I, Pacak K. Diagnosis, localization and treatment of pheochromocytoma in MEN 2 syndrome. Endocr Regul. 2009;43:89-93. [PubMed: 19856714]
• Inabnet WB, Caragliano P, Pertsemlidis D. Pheochromocytoma: inherited associations, bilaterality, and cortex preservation. Surgery. 2000;128:1007-11. [PubMed: 11114636]
• Inoue K, Shimotake T, Inoue K, Tokiwa K, Iwai N. Mutational analysis of the RET proto-oncogene in a kindred with multiple endocrine neoplasia type 2A and Hirschsprung's disease. J Pediatr Surg. 1999;34:1552-4. [PubMed: 10549772]
• Iwashita T, Murakami H, Asai N, Takahashi M. Mechanism of ret dysfunction by Hirschsprung mutations affecting its extracellular domain. Hum Mol Genet. 1996;5:1577-80. [PubMed: 8894691]
• Jayasinghe R, Basnayake O, Jayarajah U, Seneviratne S. Management of medullary carcinoma of the thyroid: a review. J Int Med Res. 2022;50:3000605221110698. [PMC free article: PMC9284230] [PubMed: 35822284]
• Jimenez C, Dang GT, Schultz PN, El-Naggar A, Shapiro S, Barnes EA, Evans DB, Vassilopoulou-Sellin R, Gagel RF, Cote GJ, Hoff AO. A novel point mutation of the RET protooncogene involving the second intracellular tyrosine kinase domain in a family with medullary thyroid carcinoma. J Clin Endocrinol Metab. 2004a;89:3521-6. [PubMed: 15240641]
• Jimenez C, Habra MA, Huang SC, El-Naggar A, Shapiro SE, Evans DB, Cote G, Gagel RF. Pheochromocytoma and medullary thyroid carcinoma: a new genotype-phenotype correlation of the RET protooncogene 891 germline mutation. J Clin Endocrinol Metab. 2004b;89:4142-5. [PubMed: 15292360]
• Kaczmarek-Ryś M, Ziemnicka K, Pławski A, Budny B, Michalak M, Hryhorowicz S, Hoppe-Gołębiewska J, Boruń P, Gołąb M, Czetwertyńska M, Sromek M, Szalata M, Ruchała M, Słomski R. Modifying impact of RET gene haplotypes on medullary thyroid carcinoma clinical course. Endocr Relat Cancer. 2018;25:421-36. [PubMed: 29386230]
• Kahraman T, de Groot JW, Rouwe C, Hofstra RM, Links TP, Sijmons RH, Plukker JT. Acceptable age for prophylactic surgery in children with multiple endocrine neoplasia type 2a. Eur J Surg Oncol. 2003;29:331-5. [PubMed: 12711285]
• Kloos RT, Eng C, Evans DB, Francis GL, Gagel RF, Gharib H, Moley JF, Pacini F, Ringel MD, Schlumberger M, Wells SA Jr. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid. 2009;19:565-612 [PubMed: 19469690]
• Lecube A, Hernandez C, Oriola J, Galard R, Gémar E, Mesa J, Simó R. V804M RET mutation and familial medullary thyroid carcinoma: report of a large family with expression of the disease only in the homozygous gene carriers. Surgery. 2002;131:509-14. [PubMed: 12019403]
• Lee M, Pellegata NS. Multiple endocrine neoplasia syndromes associated with mutation of p27. J Endocrinol Invest. 2013;36:781-7. [PubMed: 23800691]
• Lesueur F, Cebrian A, Robledo M, Niccoli-Sire P, Svensson KA, Pinson S, Leyland J, Whittaker J, Pharoah PD, Ponder BA. Polymorphisms in RET and its coreceptors and ligands as genetic modifiers of multiple endocrine neoplasia type 2A. Cancer Res. 2006;66:1177-80. [PubMed: 16424056]
• Lorch JH, Barletta JA, Nehs M, Uppaluri R, Alexander EK, Haddad RI, Hanna GJ, Margalit DN, Tishler RB, Schoenfeld JD, Goguen LA, Jabiev A, Sorensen MJ, Ahmadi S, Marqusee E, Kim MI, Stanizzi D, Harris E, Kacew A, Barbie DA. A phase II study of nivolumab (N) plus ipilimumab (I) in radioidine refractory differentiated thyroid cancer (RAIR DTC) with exploratory cohorts in anaplastic (ATC) and medullary thyroid cancer (MTC). J Clin Oncol. 2020;38:6513.
• Machens A, Gimm O, Hinze R, Höppner W, Boehm BO, Dralle H. Genotype-phenotype correlations in hereditary medullary thyroid carcinoma: oncological features and biochemical properties. J Clin Endocrinol Metab. 2001;86:1104-9. [PubMed: 11238493]
• Machens A, Schneyer U, Holzhausen HJ, Raue F, Dralle H. Emergence of medullary thyroid carcinoma in a family with the Cys630Arg RET germline mutation. Surgery. 2004;136:1083-7. [PubMed: 15523405]
• Menko FH, van der Luijt RB, de Valk IA, Toorians AW, Sepers JM, van Diest PJ, Lips CJ. Atypical MEN type 2B associated with two germline RET mutations on the same allele not involving codon 918. J Clin Endocrinol Metab. 2002;87:393-7. [PubMed: 11788682]
• Miyauchi A, Futami H, Hai N, Yokozawa T, Kuma K, Aoki N, Kosugi S, Sugano K, Yamaguchi K. Two germline missense mutations at codons 804 and 806 of the RET proto-oncogene in the same allele in a patient with multiple endocrine neoplasia type 2B without codon 918 mutation. Jpn J Cancer Res. 1999;90:1-5. [PMC free article: PMC5925979] [PubMed: 10076558]
• Modigliani E, Vasen HM, Raue K, Dralle H, Frilling A, Gheri RG, Brandi ML, Limbert E, Niederle B, Forgas L, Rosenberg-Bourgin M, Calmettes C. Pheochromocytoma in multiple endocrine neoplasia type 2: European study. The Euromen Study Group. J Intern Med. 1995;238:363-7. [PubMed: 7595173]
• Moley JF. Medullary thyroid carcinoma: management of lymph node metastases. J Natl Compr Canc Netw. 2010;8:549-56. [PubMed: 20495084]
• Morrison PJ, Nevin NC. Multiple endocrine neoplasia type 2B (mucosal neuroma syndrome, Wagenmann-Froboese syndrome). J Med Genet. 1996;33:779-82. [PMC free article: PMC1050735] [PubMed: 8880581]
• Mulligan LM, Eng C, Attié T, Lyonnet S, Marsh DJ, Hyland VJ, Robinson BG, Frilling A, Verellen-Dumoulin C, Safar A, Venter D, Munnich A, Ponder B. Diverse phenotypes associated with exon 10 mutations of the RET proto-oncogene. Hum Mol Genet. 1994;3:2163-7. [PubMed: 7881414]
• National Comprehensive Cancer Network. NCCN Guidelines: Neuroendocrine and Adrenal Tumors. NCCN website. Available online; purchase or subscription required. 2022. Accessed 7-5-23.
• Neumann HP, Bausch B, McWhinney SR, Bender BU, Gimm O, Franke G, Schipper J, Klisch J, Altehoefer C, Zerres K, Januszewicz A, Eng C, Smith WM, Munk R, Manz T, Glaesker S, Apel TW, Treier M, Reineke M, Walz MK, Hoang-Vu C, Brauckhoff M, Klein-Franke A, Klose P, Schmidt H, Maier-Woelfle M, Peçzkowska M, Szmigielski C, Eng C, et al. Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med. 2002;346:1459-66. [PubMed: 12000816]
• Neumann HP, Pawlu C, Peczkowska M, Bausch B, McWhinney SR, Muresan M, Buchta M, Franke G, Klisch J, Bley TA, Hoegerle S, Boedeker CC, Opocher G, Schipper J, Januszewicz A, Eng C, et al. Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA. 2004;292:943-51. [PubMed: 15328326]
• Neumann HP, Young WF Jr, Eng C. Pheochromocytoma and paraganglioma. N Engl J Med 2019;381:552-65. [PubMed: 31390501]
• Nguyen L, Niccoli-Sire P, Caron P, Bastie D, Maes B, Chabrier G, Chabre O, Rohmer V, Lecomte P, Henry JF, Conte-Devolx B, et al. Pheochromocytoma in multiple endocrine neoplasia type 2: a prospective study. Eur J Endocrinol. 2001;144:37-44. [PubMed: 11174835]
• Nilsson O, Tisell LE, Jansson S, Ahlman H, Gimm O, Eng C. Adrenal and extra-adrenal pheochromocytomas in a family with germline RET V804L mutation. JAMA. 1999;281:1587-8. [PubMed: 10235148]
• Nunes AB, Ezabella MC, Pereira AC, Krieger JE, Toledo SP. A novel Val648Ile substitution in RET protooncogene observed in a Cys634Arg multiple endocrine neoplasia type 2A kindred presenting with an adrenocorticotropin-producing pheochromocytoma. J Clin Endocrinol Metab. 2002;87:5658-61. [PubMed: 12466368]
• Pacak K, Ilias I, Adams KT, Eisenhofer G. Biochemical diagnosis, localization and management of pheochromocytoma: focus on multiple endocrine neoplasia type 2 in relation to other hereditary syndromes and sporadic forms of the tumour. J Intern Med. 2005;257:60-8. [PubMed: 15606377]
• Parghane RV, Naik C, Talole S, Desmukh A, Chaukar D, Banerjee S, Basu S. Clinical utility of ¹⁷⁷ Lu-DOTATATE PRRT in somatostatin receptor-positive metastatic medullary carcinoma of thyroid patients with assessment of efficacy, survival analysis, prognostic variables, and toxicity. Head Neck. 2020;42:401-16. [PubMed: 31755622]
• Pomares FJ, Cañas R, Rodriguez JM, Hernandez AM, Parrilla P, Tebar FJ. Differences between sporadic and multiple endocrine neoplasia type 2A phaeochromocytoma. Clin Endocrinol (Oxf). 1998;48:195-200. [PubMed: 9579232]
• Puñales MK, Graf H, Gross JL, Maia AL. RET codon 634 mutations in multiple endocrine neoplasia type 2: variable clinical features and clinical outcome. J Clin Endocrinol Metab. 2003;88:2644-9. [PubMed: 12788868]
• Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, Dominiczak A, Morris A, Porteous D, Smith B, Stratton MR, Hurles ME, et al. Timing, rates and spectra of human germline mutation. Nat Genet. 2016;48:126-33. [PMC free article: PMC4731925] [PubMed: 26656846]
• Rey JM, Brouillet JP, Fonteneau-Allaire J, Boneu A, Bastié D, Maudelonde T, Pujol P. Novel germline RET mutation segregating with papillary thyroid carcinomas. Genes Chromosomes Cancer. 2001;32:390-1. [PubMed: 11746981]
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-24. [PMC free article: PMC4544753] [PubMed: 25741868]
• Robledo M, Gil L, Pollán M, Cebrián A, Ruíz S, Azañedo M, Benitez J, Menárguez J, Rojas JM. Polymorphisms G691S/S904S of RET as genetic modifiers of MEN 2A. Cancer Res. 2003;63:1814-7. [PubMed: 12702567]
• 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: 26324357]
• Rodriguez JM, Balsalobre M, Ponce JL, Ríos A, Torregrosa NM, Tebar J, Parrilla P. Pheochromocytoma in MEN 2A syndrome. Study of 54 patients. World J Surg. 2008;32:2520-6. [PubMed: 18795243]
• Romei C, Ciampi R, Elisei R. A comprehensive overview of the role of the RET proto-oncogene in thyroid carcinoma. Nat Rev Endocrinol. 2016;12:192-202 [PubMed: 26868437]
• Romeo G, Ceccherini I, Celli J, Priolo M, Betsos N, Bonardi G, Seri M, Yin L, Lerone M, Jasonni V, Martucciello G. Association of multiple endocrine neoplasia type 2 and Hirschsprung disease. J Intern Med. 1998;243:515-20. [PubMed: 9681852]
• Rothberg AE, Raymond VM, Gruber SB, Sisson J. Familial medullary thyroid carcinoma associated with cutaneous lichen amyloidosis. Thyroid. 2009;19:651-5. [PubMed: 19445625]
• Ruiz A, Antiñolo G, Fernández RM, Eng C, Marcos I, Borrego S. Germline sequence variant S836S in the RET proto-oncogene is associated with low level predisposition to sporadic medullary thyroid carcinoma in the Spanish population. Clin Endocrinol (Oxf). 2001;55:399-402. [PubMed: 11589684]
• Salvatore D, Santoro M, Schlumberger M. The importance of the RET gene in thyroid cancer and therapeutic implications. Nat Rev Endocrinol. 2021;17:296-306. [PubMed: 33603219]
• Schilling T, Bürck J, Sinn HP, Clemens A, Otto HF, Höppner W, Herfarth C, Ziegler R, Schwab M, Raue F. Prognostic value of codon 918 (ATG-->ACG) RET proto-oncogene mutations in sporadic medullary thyroid carcinoma. Int J Cancer. 2001;95:62-6. [PubMed: 11241313]
• Seri M, Celli I, Betsos N, Claudiani F, Camera G, Romeo G. A Cys634Gly substitution of the RET proto-oncogene in a family with recurrence of multiple endocrine neoplasia type 2A and cutaneous lichen amyloidosis. Clin Genet. 1997;51:86-90. [PubMed: 9111993]
• Skinner MA, DeBenedetti MK, Moley JF, Norton JA, Wells SA Jr. Medullary thyroid carcinoma in children with multiple endocrine neoplasia types 2A and 2B. J Pediatr Surg. 1996;31:177-81. [PubMed: 8632274]
• Smith DP, Houghton C, Ponder BA. Germline mutation of RET codon 883 in two cases of de novo MEN 2B. Oncogene. 1997;15:1213-7. [PubMed: 9294615]
• Subbiah V, Gainor JF, Rahal R, Brubaker JD, Kim JL, Maynard M, Hu W, Cao Q, Sheets MP, Wilson D, Wilson KJ, DiPietro L, Fleming P, Palmer M, Hu MI, Wirth L, Brose MS, Ou SI, Taylor M, Garralda E, Miller S, Wolf B, Lengauer C, Guzi T, Evans EK. Precision targeted therapy with BLU-667 for RET-driven cancers. Cancer Discov. 2018;8:836-49 [PubMed: 29657135]
• Takahashi M, Asai N, Iwashita T, Murakami H, Ito S. Molecular mechanisms of development of multiple endocrine neoplasia 2 by RET mutations. J Intern Med. 1998;243:509-13. [PubMed: 9681851]
• Takahashi M, Iwashita T, Santoro M, Lyonnet S, Lenoir GM, Billaud M. Co-segregation of MEN2 and Hirschsprung's disease: the same mutation of RET with both gain and loss-of-function? Hum Mutat. 1999;13:331-6. [PubMed: 10220148]
• Verga U, Fugazzola L, Cambiaghi S, Pritelli C, Alessi E, Cortelazzi D, Gangi E, Beck-Peccoz P. Frequent association between MEN 2A and cutaneous lichen amyloidosis. Clin Endocrinol (Oxf). 2003;59:156-61. [PubMed: 12864791]
• Vuong HG, Ho ATN, Tran TTK, Capdevila J, Benekli M, Nakazawa T, Katoh R, Kondo T. Efficacy and toxicity of sorafenib in the treatment of advanced medullary thyroid carcinoma: A systematic review and meta-analysis. Head Neck. 2019;41:2823-9. [PubMed: 31162772]
• 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 [PMC free article: PMC4490627] [PubMed: 25810047]
• Wells SA Jr, Robinson BG, Gagel RF, Dralle H, Fagin JA, Santoro M, Baudin E, Elisei R, Jarzab B, Vasselli JR, Read J, Langmuir P, Ryan AJ, Schlumberger MJ. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol. 2012;30:134-41. [PMC free article: PMC3675689] [PubMed: 22025146]
• Wirth LJ, Sherman E, Robinson B, Solomon B, Kang H, Lorch J, Worden F, Brose M, Patel J, Leboulleux S, Godbert Y, Barlesi F, Morris JC, Owonikoko TK, Tan DSW, Gautschi O, Weiss J, de la Fouchardière C, Burkard ME, Laskin J, Taylor MH, Kroiss M, Medioni J, Goldman JW, Bauer TM, Levy B, Zhu VW, Lakhani N, Moreno V, Ebata K, Nguyen M, Heirich D, Zhu EY, Huang X, Yang L, Kherani J, Rothenberg SM, Drilon A, Subbiah V, Shah MH, Cabanillas ME. Efficacy of Selpercatinib in RET-altered thyroid cancers. N Engl J Med. 2020;383:825-35. [PMC free article: PMC10777663] [PubMed: 32846061]
• Wray CJ, Rich TA, Waguespack SG, Lee JE, Perrier ND, Evans DB. Failure to recognize multiple endocrine neoplasia 2B: more common than we think? Ann Surg Oncol. 2008;15:293-301. [PubMed: 17963006]
• Yip L, Cote GJ, Shapiro SE, Ayers GD, Herzog CE, Sellin RV, Sherman SI, Gagel RF, Lee JE, Evans DB. Multiple endocrine neoplasia type 2: evaluation of the genotype-phenotype relationship. Arch Surg. 2003;138:409-16. [PubMed: 12686527]
• Zbuk KM, Eng C. Cancer phenomics: RET and PTEN as illustrative models. Nat Rev Cancer. 2007;7:35-45. [PubMed: 17167516]