Multiple Endocrine Neoplasia Type 2 (MEN2) (PDQ®): Genetics - Health Professional Information [NCI]

Diagnosing Multiple Endocrine Neoplasia Type 2 (MEN2)

MEN2 is a well-defined hereditary cancer syndrome. Genetic testing is an important management tool that defines who has an MEN2 diagnosis. It can also provide family members with predictive genetic testing options. There are also rare cases of suspected MEN2 in which a genetic variant has not been identified.

Genetic Counseling and Genetic Testing

MEN2 syndrome is the result of an inherited pathogenic variant in the RETgene, located on chromosome region 10q11.2.[11,22,33] The RET gene is a proto-oncogene composed of 21 exons over 55 kilobase of genomic material.[44,55]Germline DNA testing for RET pathogenic variants is recommended for all individuals with medullary thyroid cancer (MTC) by the American Thyroid Association and the National Comprehensive Cancer Network.[66,77,88] Testing is recommended regardless of whether there is a personal or family history suggestive of MEN2. Additionally, MEN2 meets the criteria related to indications for genetic testing for cancer susceptibility outlined by the American Society of Clinical Oncology.[99]

It is critical for pediatricians and other providers who care for infants/children (e.g., gastroenterologists, pathologists, oral health care professionals) to maintain a high index of suspicion when evaluating patients with any clinical manifestations associated with multiple endocrine neoplasia type 2B (MEN2B). In a child or infant, the presence of oral and/or ocular neuromas, gastrointestinal manifestations like severe constipation and/or the need for a rectal biopsy, and/or a tall, lanky body type may warrant further investigation. The identification of these features can prompt early diagnosis of MEN2B and provide the opportunity to prevent or cure MTC.[1010,1111]Genetic counseling has been recommended for individuals with MTC and any of the following features:[1010,1212,1313]

• Benign oral and submucosal neuromas.
• Elongated face and large lips.
• Ganglioneuromatosis.
• Inability to cry tears (biological mechanism unknown).

While most MTC cases are sporadic, approximately 20% to 25% are hereditary.[1414] These hereditary cases are caused by pathogenic variants in the RET proto-oncogene. Between 1% and 10% of individuals with apparently sporadic MTC carry a germline RET pathogenic variant, underscoring the importance of genetic testing for all individuals diagnosed with MTC.[1515,1616,1717]

There is considerable diversity in the techniques used and the approach to RET pathogenic variant testing among the various laboratories that perform this procedure. Methods used to detect variants in RET include polymerase chain reaction (PCR) followed by restriction enzyme digestion of PCR products, heteroduplex analysis, single-stranded conformation polymorphism analysis, denaturing high-performance liquid chromatography, and DNA sequencing.[1818,1919] At a minimum, most testing laboratories offer testing using a targeted exon approach; that is, the laboratories look for variants in the exons that are most commonly found to carry variants (exons 10, 11, 13, 14, 15 and 16). Other laboratories offer testing of all RET exons. Differences in variant detection methods are important to consider when selecting a genetic testing laboratory and interpreting the test results. For example, if MEN2 targeted-exon testing is negative in a family that is suspected to have MEN2, sequencing of the remaining exons can be considered. For more information on clinical validity, see Cancer Genetics Risk Assessment and CounselingCancer Genetics Risk Assessment and Counseling.

Familial risk assessment

At-risk individuals are defined as first-degree relatives (i.e., parents, siblings, and children) of a person known to have MEN2. Genetic testing can identify people with asymptomatic MEN2. These individuals can consider biochemical screening and early thyroidectomy as preventive measures. All MEN2 subtypes are inherited in an autosomal dominant manner. The risk of inheriting the RET pathogenic variant is 50% in children of individuals with MEN2. Because early detection of at-risk individuals affects medical management, testing children without MEN2 symptoms can be beneficial.[2020,2121]

Some individuals with MEN2 carry a de novo pathogenic variant; that is, they carry a new pathogenic variant that was not present in previous generations of their family and thus do not have an affected parent. The proportion of individuals with MEN2 who have an affected parent varies by subtype:

• Multiple endocrine neoplasia type 2AMultiple endocrine neoplasia type 2A (MEN2A): About 95% of affected individuals have an affected parent. Parents of an individual with MEN2A can be evaluated for manifestations of the disorder. In MEN2A cases that are not familial (5%), either de novo pathogenic variants or incomplete penetrance is possible.[2222]
• Familial medullary thyroid cancerFamilial medullary thyroid cancer (FMTC): Multiple family members are affected. Therefore, all affected individuals inherited the RET pathogenic variant from a parent.
• Multiple endocrine neoplasia type 2BMultiple endocrine neoplasia type 2B (MEN2B): About 50% of affected individuals have de novo RET pathogenic variants, and 50% inherited the pathogenic variant from a parent.[2323,2424] The majority of de novo pathogenic variants occur on the paternally-inherited allele, but de novo pathogenic variants on the maternally-inherited allele have also been reported.[2525]

The risk of siblings having MEN2 depends on the genetic status of the parent, which can be clarified by pedigree analysis and/or DNA -based testing. In situations of apparent de novo pathogenic variants, germline mosaicism in an apparently unaffected parent must be considered, even though such an occurrence has not yet been reported.

In rare circumstances, genetic testing is negative in a patient with a personal or family history suggestive of MEN2. Negative pathogenic variant analysis in at-risk relatives is informative only after a disease-causing pathogenic variant has been identified in an affected relative. Familial screening recommendations are personalized, and updated genetic testing is recommended in families suspected of having MEN2 (in which a RET pathogenic variant has not been identified).

For more information about clinical management of at-risk individuals, see the Genotype-Phenotype Correlations and Risk Stratification in MEN2Genotype-Phenotype Correlations and Risk Stratification in MEN2 section.

References:

1. Gardner E, Papi L, Easton DF, et al.: Genetic linkage studies map the multiple endocrine neoplasia type 2 loci to a small interval on chromosome 10q11.2. Hum Mol Genet 2 (3): 241-6, 1993.
2. Mole SE, Mulligan LM, Healey CS, et al.: Localisation of the gene for multiple endocrine neoplasia type 2A to a 480 kb region in chromosome band 10q11.2. Hum Mol Genet 2 (3): 247-52, 1993.
3. Takahashi M, Ritz J, Cooper GM: Activation of a novel human transforming gene, ret, by DNA rearrangement. Cell 42 (2): 581-8, 1985.
4. Kwok JB, Gardner E, Warner JP, et al.: Structural analysis of the human ret proto-oncogene using exon trapping. Oncogene 8 (9): 2575-82, 1993.
5. Myers SM, Eng C, Ponder BA, et al.: Characterization of RET proto-oncogene 3' splicing variants and polyadenylation sites: a novel C-terminus for RET. Oncogene 11 (10): 2039-45, 1995.
6. Wells SA, Asa SL, Dralle H, et al.: Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid 25 (6): 567-610, 2015.
7. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Thyroid Carcinoma. Version 2.2023. Plymouth Meeting, Pa: National Comprehensive Cancer Network, 2023. Available online with free subscriptionAvailable online with free subscription Last accessed December 9, 2024.
8. Brandi ML, Gagel RF, Angeli A, et al.: Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 86 (12): 5658-71, 2001.
9. Robson ME, Bradbury AR, Arun B, et al.: American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility. J Clin Oncol 33 (31): 3660-7, 2015.
10. Hampel H, Bennett RL, Buchanan A, et al.: A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med 17 (1): 70-87, 2015.
11. van den Broek MFM, Rijks EBG, Nikkels PGJ, et al.: Timely diagnosis of multiple endocrine neoplasia 2B by identification of intestinal ganglioneuromatosis: a case series. Endocrine 72 (3): 905-914, 2021.
12. Brauckhoff M, Machens A, Hess S, et al.: Premonitory symptoms preceding metastatic medullary thyroid cancer in MEN 2B: An exploratory analysis. Surgery 144 (6): 1044-50; discussion 1050-3, 2008.
13. Bashford MT, Kohlman W, Everett J, et al.: Addendum: A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med 21 (12): 2844, 2019.
14. Romei C, Ciampi R, Elisei R: A comprehensive overview of the role of the RET proto-oncogene in thyroid carcinoma. Nat Rev Endocrinol 12 (4): 192-202, 2016.
15. Romei C, Cosci B, Renzini G, et al.: RET genetic screening of sporadic medullary thyroid cancer (MTC) allows the preclinical diagnosis of unsuspected gene carriers and the identification of a relevant percentage of hidden familial MTC (FMTC). Clin Endocrinol (Oxf) 74 (2): 241-7, 2011.
16. Elisei R, Cosci B, Romei C, et al.: Prognostic significance of somatic RET oncogene mutations in sporadic medullary thyroid cancer: a 10-year follow-up study. J Clin Endocrinol Metab 93 (3): 682-7, 2008.
17. Sarika HL, Papathoma A, Garofalaki M, et al.: Genetic screening of patients with medullary thyroid cancer in a referral center in Greece during the past two decades. Eur J Endocrinol 172 (4): 501-9, 2015.
18. Mathiesen JS, Kroustrup JP, Vestergaard P, et al.: Distribution of RET Mutations in Multiple Endocrine Neoplasia 2 in Denmark 1994-2014: A Nationwide Study. Thyroid 27 (2): 215-223, 2017.
19. Wells SA: Advances in the management of MEN2: from improved surgical and medical treatment to novel kinase inhibitors. Endocr Relat Cancer 25 (2): T1-T13, 2018.
20. Robson ME, Storm CD, Weitzel J, et al.: American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol 28 (5): 893-901, 2010.
21. Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. American Society of Human Genetics Board of Directors, American College of Medical Genetics Board of Directors. Am J Hum Genet 57 (5): 1233-41, 1995.
22. Schuffenecker I, Ginet N, Goldgar D, et al.: Prevalence and parental origin of de novo RET mutations in multiple endocrine neoplasia type 2A and familial medullary thyroid carcinoma. Le Groupe d'Etude des Tumeurs a Calcitonine. Am J Hum Genet 60 (1): 233-7, 1997.
23. Norum RA, Lafreniere RG, O'Neal LW, et al.: Linkage of the multiple endocrine neoplasia type 2B gene (MEN2B) to chromosome 10 markers linked to MEN2A. Genomics 8 (2): 313-7, 1990.
24. Carlson KM, Bracamontes J, Jackson CE, et al.: Parent-of-origin effects in multiple endocrine neoplasia type 2B. Am J Hum Genet 55 (6): 1076-82, 1994.
25. Kitamura Y, Scavarda N, Wells SA, et al.: Two maternally derived missense mutations in the tyrosine kinase domain of the RET protooncogene in a patient with de novo MEN 2B. Hum Mol Genet 4 (10): 1987-8, 1995.

Genotype-Phenotype Correlations and Risk Stratification in Multiple Endocrine Neoplasia Type 2 (MEN2)

Genotype -phenotype correlations in MEN2 are well established and have long been used to guide clinicians in making medical management recommendations. Several groups have developed pathogenic variant –stratification tables based on clinical phenotype, age of onset, and aggressiveness of medullary thyroid cancer (MTC).[11,22,33] This classification strategy was first put forth after the Seventh International Workshop on MEN in 2001, which provided guidelines for the age of genetic testing and risk-reducing thyroidectomy.[11] This stratification has been revised by the American Thyroid Association (ATA).[33,44,55] The specific pathogenic variants and their ATA classification are summarized in Table 1Table 1 below.

ATA-Highest Risk (HST) RET pathogenic variants are the most aggressive and carry the highest risk of developing MTC.[33] This category includes those with multiple endocrine neoplasia type 2B (MEN2B) and RETcodon M918T pathogenic variants and is associated with the youngest age at disease onset and the highest risk of mortality. ATA-High Risk (H) RET pathogenic variants, at codons 634 and 883, are associated with a slightly lower risk, yet the MTC in patients with these pathogenic variants is still quite aggressive and may present at an early age.[66] The third category of RET variants are designated as ATA-Moderate Risk (MOD) variants.[55] These variants are associated with lower risk of aggressive MTC relative to the risk seen in carriers of ATA-HST and ATA-H RET pathogenic variants. Results from a study of 387 RET pathogenic variant carriers with MTC have suggested that ATA-MOD variants may be associated with MTC as aggressive as seen in individuals with ATA-H variants but present at a later age.[77] The risk of MTC is still substantially elevated over the general population risk, and consideration of risk-reducing thyroidectomy is warranted.[33] Patients with early stage I and stage II disease can achieve 100% survival rates regardless of the ATA risk category.[77] Common pathogenic variants in the ATA-MOD category are shown in Table 1Table 1.

Pathogenic variants at codons 883 and 918 have been seen only in MEN2B and are associated with the earliest age of onset and the most aggressive form of MTC.[66,88,99,1010,1111,1212] Approximately 95% of individuals with MEN2B have the M918T pathogenic variant.[88,99,1010,1313] As discussed above, 50% of individuals with MEN2B will develop pheochromocytoma (PHEO), but primary hyperparathyroidism (PHPT) is rare. A retrospective review of all published cases of A883F variant carriers (N = 13) found that the MTC disease course was more indolent than what was observed in M918T carriers. A883F carriers had later disease onset (50% penetrance for MTC at age 19 y), 5- and 10-year survival rates of 88%, and 63% of patients achieved biochemical cure for MTC.[66] In addition to variants at codons 883 and 918, some individuals with an MEN2B-like phenotype have been found to carry two germline variants on the same allele.[1414,1515,1616,1717,1818] It is likely that as testing for RET becomes more common in clinical practice, additional double variant phenotypes will be described.

Pathogenic variants at codon 634 (ATA-H) are by far the most frequent finding in families with multiple endocrine neoplasia type 2A (MEN2A). One study of 477 RET carriers showed that 52.1% had the C634R pathogenic variant, 26.0% carried the C634Y pathogenic variant, and 9.1% had the C634G pathogenic variant.[1919] In general, pathogenic variants in codon 634 are associated with PHEOs and PHPT.[1919,2020] MEN2A with cutaneous lichen amyloidosis had been seen almost exclusively in patients with pathogenic variants in codon 634, although MTC and cutaneous lichen amyloidosis have been reported in a patient with a pathogenic variant in codon 804.[1919,2121,2222,2323] Codon 634 pathogenic variants have also been described in familial medullary thyroid cancer (FMTC) but are almost exclusively C634Y.[1919]

Moderate-risk variants located in exon 10 of the RETgene include variants in codons 609, 611, 618, 620, and 630. These variants involve cysteine residues in the extracellular domain of the RET protein and have been seen in families with MEN2A and those with MTC only (FMTC).[22,1919,2424,2525,2626,2727,2828,2929] The risk of MTC in individuals with these pathogenic variants can be as high as 95%. The risk of PHEO and hyperparathyroidism is lower than that seen in individuals with high-risk pathogenic variants.

Individuals with pathogenic variants in codons 321, 515, 533, 600, 603, 606, 531/9 base pair duplication, and 532 duplication have a lower, albeit still elevated, lifetime risk of MTC. MTC associated with these pathogenic variants tends to follow a more indolent course and have a later age at onset, although there are several reports of individuals with these pathogenic variants who developed MTC before age 20 years.[1919,3030,3131,3232,3333,3434] Although PHEO and PHPT are not commonly associated with these pathogenic variants, they have been described.[3434]

Table 1. Genotype-Phenotype Correlations in Multiple Endocrine Neoplasia Type 2^a

RETPathogenic variant	Exon	Risk of Aggressive MTC	Approximate Incidence of PHEO	Approximate Incidence of PHPT	Presence of CLA	Presence of HSCR
CLA = cutaneous lichen amyloidosis; HSCR = Hirschsprung disease; MTC = medullary thyroid cancer; PHEO = pheochromocytoma; PHPT = primary hyperparathyroidism.
a Adapted from Wells et al.[33]
G533C	8	Moderate	10%	-	N	N
C609F/G/R/S/Y	10	Moderate	10%–30%	10%	N	Y
C611F/G/S/Y/W	10	Moderate	10%–30%	10%	N	Y
C618F/R/S	10	Moderate	10%–30%	10%	N	Y
C620F/R/S	10	Moderate	10%–30%	10%	N	Y
C630R/Y	11	Moderate	10%–30%	10%	N	N
D631Y	11	Moderate	50%	-	N	N
C634F/G/R/S/W/Y	11	High	50%	20%–30%	Y	N
K666E	11	Moderate	10%	-	N	N
E768D	13	Moderate	-	-	N	N
L790F	13	Moderate	10%	-	N	N
V804L	14	Moderate	10%	10%	N	N
V804M	14	Moderate	10%	10%	Y	N
A883F	15	High	50%	-	N	N
S891A	15	Moderate	10%	10%	N	N
R912P	16	Moderate	-	-	N	N
M918T	16	Highest	50%	-	N	N

In addition to the pathogenic variants categorized in Table 1Table 1, a number of rare or novel RET variants have been described. Some of these represent pathogenic variants that lead to MEN2A phenotypes. Others may represent low-penetrance alleles or modifying alleles that confer only a modest risk of developing MTC.[3535] A multicenter study identified eight families with a RET K666N variant. Of the 16 screened family members identified as having a pathogenic variant, only one had MTC.[3535] Still others may have benign polymorphisms of no clinical significance. For example, some studies show compelling evidence that RET variants Y791F (p.Tyr791Phe) and S649L (p.Ser649Leu) are likely benign polymorphisms; this was based on the equal frequencies seen between cases and healthy controls and co-occurrence with other disease-causing variants that cosegregate with disease in the family.[3636,3737] A long-term follow-up study of Danish Y791F carriers (n = 20) showed no sign of MEN2A (MTC, PHPT, PHEO, cutaneous lichen amyloidosis, or Hirschsprung disease) among the cohort, with a median age of 49.5 years (range, 7–87 y).[3838] Therefore, carriers of these variants are not followed with MEN2 management guidelines. Asymptomatic family members are generally not tested for these variants.

Research is ongoing into the role of neutral RET sequence variants in modifying the clinical presentation of patients with MEN2A. The presence of certain RET polymorphisms or haplotypes is being analyzed for its impact on the likelihood for development of PHEO, hyperparathyroidism, HSCR, and age at onset of metastatic involvement with MTC.[3939,4040,4141,4242] A variety of approaches, including segregation analyses, in silico analyses, association studies, and functional assays, can be employed to determine the functional and clinical significance of a given genetic variant.[4343]

References:

1. Brandi ML, Gagel RF, Angeli A, et al.: Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 86 (12): 5658-71, 2001.
2. Kouvaraki MA, Shapiro SE, Perrier ND, et al.: RET proto-oncogene: a review and update of genotype-phenotype correlations in hereditary medullary thyroid cancer and associated endocrine tumors. Thyroid 15 (6): 531-44, 2005.
3. Wells SA, Asa SL, Dralle H, et al.: Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid 25 (6): 567-610, 2015.
4. Kloos RT, Eng C, Evans DB, et al.: Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid 19 (6): 565-612, 2009.
5. Voss RK, Feng L, Lee JE, et al.: Medullary Thyroid Carcinoma in MEN2A: ATA Moderate- or High-Risk RET Mutations Do Not Predict Disease Aggressiveness. J Clin Endocrinol Metab 102 (8): 2807-2813, 2017.
6. Mathiesen JS, Habra MA, Bassett JHD, et al.: Risk Profile of the RET A883F Germline Mutation: An International Collaborative Study. J Clin Endocrinol Metab 102 (6): 2069-2074, 2017.
7. Machens A, Lorenz K, Weber F, et al.: Lymph node metastasis in hereditary medullary thyroid cancer is independent of the underlying RET germline mutation. Eur J Surg Oncol 47 (4): 920-923, 2021.
8. Eng C, Smith DP, Mulligan LM, et al.: Point mutation within the tyrosine kinase domain of the RET proto-oncogene in multiple endocrine neoplasia type 2B and related sporadic tumours. Hum Mol Genet 3 (2): 237-41, 1994.
9. Hofstra RM, Landsvater RM, Ceccherini I, et al.: A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature 367 (6461): 375-6, 1994.
10. Carlson KM, Dou S, Chi D, et al.: Single missense mutation in the tyrosine kinase catalytic domain of the RET protooncogene is associated with multiple endocrine neoplasia type 2B. Proc Natl Acad Sci U S A 91 (4): 1579-83, 1994.
11. Gimm O, Marsh DJ, Andrew SD, et al.: 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 82 (11): 3902-4, 1997.
12. Smith DP, Houghton C, Ponder BA: Germline mutation of RET codon 883 in two cases of de novo MEN 2B. Oncogene 15 (10): 1213-7, 1997.
13. Eng C, Mulligan LM, Healey CS, et al.: Heterogeneous mutation of the RET proto-oncogene in subpopulations of medullary thyroid carcinoma. Cancer Res 56 (9): 2167-70, 1996.
14. Cranston AN, Carniti C, Oakhill K, et al.: RET is constitutively activated by novel tandem mutations that alter the active site resulting in multiple endocrine neoplasia type 2B. Cancer Res 66 (20): 10179-87, 2006.
15. Miyauchi A, Futami H, Hai N, et al.: 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 90 (1): 1-5, 1999.
16. Kameyama K, Okinaga H, Takami H: RET oncogene mutations in 75 cases of familial medullary thyroid carcinoma in Japan. Biomed Pharmacother 58 (6-7): 345-7, 2004 Jul-Aug.
17. Iwashita T, Murakami H, Kurokawa K, et al.: A two-hit model for development of multiple endocrine neoplasia type 2B by RET mutations. Biochem Biophys Res Commun 268 (3): 804-8, 2000.
18. Menko FH, van der Luijt RB, de Valk IA, et al.: Atypical MEN type 2B associated with two germline RET mutations on the same allele not involving codon 918. J Clin Endocrinol Metab 87 (1): 393-7, 2002.
19. Eng C, Clayton D, Schuffenecker I, et al.: The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. JAMA 276 (19): 1575-9, 1996.
20. Mulligan LM, Eng C, Healey CS, et al.: Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN 2A and FMTC. Nat Genet 6 (1): 70-4, 1994.
21. Seri M, Celli I, Betsos N, et al.: 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 51 (2): 86-90, 1997.
22. Yip L, Cote GJ, Shapiro SE, et al.: Multiple endocrine neoplasia type 2: evaluation of the genotype-phenotype relationship. Arch Surg 138 (4): 409-16; discussion 416, 2003.
23. Rothberg AE, Raymond VM, Gruber SB, et al.: Familial medullary thyroid carcinoma associated with cutaneous lichen amyloidosis. Thyroid 19 (6): 651-5, 2009.
24. Eng C, Mulligan LM, Smith DP, et al.: Low frequency of germline mutations in the RET proto-oncogene in patients with apparently sporadic medullary thyroid carcinoma. Clin Endocrinol (Oxf) 43 (1): 123-7, 1995.
25. Bolino A, Schuffenecker I, Luo Y, et al.: RET mutations in exons 13 and 14 of FMTC patients. Oncogene 10 (12): 2415-9, 1995.
26. Boccia LM, Green JS, Joyce C, et al.: Mutation of RET codon 768 is associated with the FMTC phenotype. Clin Genet 51 (2): 81-5, 1997.
27. Lesueur F, Cebrian A, Cranston A, et al.: Germline homozygous mutations at codon 804 in the RET protooncogene in medullary thyroid carcinoma/multiple endocrine neoplasia type 2A patients. J Clin Endocrinol Metab 90 (6): 3454-7, 2005.
28. Shannon KE, Gimm O, Hinze R: Germline V804M mutation in the RET protooncogene in 2 apparently sporadic cases of MTC presenting in the 7th decade of life. The Journal of Endocrine Genetics 1 (1): 39-46, 1999.
29. Raue F, Frank-Raue K: Genotype-phenotype relationship in multiple endocrine neoplasia type 2. Implications for clinical management. Hormones (Athens) 8 (1): 23-8, 2009 Jan-Mar.
30. Mulligan LM, Marsh DJ, Robinson BG, et al.: Genotype-phenotype correlation in multiple endocrine neoplasia type 2: report of the International RET Mutation Consortium. J Intern Med 238 (4): 343-6, 1995.
31. Moers AM, Landsvater RM, Schaap C, et al.: Familial medullary thyroid carcinoma: not a distinct entity? Genotype-phenotype correlation in a large family. Am J Med 101 (6): 635-41, 1996.
32. Niccoli-Sire P, Murat A, Rohmer V, et al.: Familial medullary thyroid carcinoma with noncysteine ret mutations: phenotype-genotype relationship in a large series of patients. J Clin Endocrinol Metab 86 (8): 3746-53, 2001.
33. Machens A, Ukkat J, Brauckhoff M, et al.: Advances in the management of hereditary medullary thyroid cancer. J Intern Med 257 (1): 50-9, 2005.
34. Mukherjee S, Zakalik D: RET codon 804 mutations in multiple endocrine neoplasia 2: genotype-phenotype correlations and implications in clinical management. Clin Genet 79 (1): 1-16, 2011.
35. Xu JY, Grubbs EG, Waguespack SG, et al.: Medullary Thyroid Carcinoma Associated with Germline RETK666N Mutation. Thyroid 26 (12): 1744-1751, 2016.
36. Erlic Z, Hoffmann MM, Sullivan M, et al.: Pathogenicity of DNA variants and double mutations in multiple endocrine neoplasia type 2 and von Hippel-Lindau syndrome. J Clin Endocrinol Metab 95 (1): 308-13, 2010.
37. Toledo RA, Hatakana R, Lourenço DM, et al.: Comprehensive assessment of the disputed RET Y791F variant shows no association with medullary thyroid carcinoma susceptibility. Endocr Relat Cancer 22 (1): 65-76, 2015.
38. Høxbroe Michaelsen S, Ornstrup MJ, Poulsen MM, et al.: Long-term follow-up of RET Y791F carriers in Denmark 1994-2017: A National Cohort Study. J Surg Oncol 119 (6): 687-693, 2019.
39. Siqueira DR, Ceolin L, Ferreira CV, et al.: Role of RET genetic variants in MEN2-associated pheochromocytoma. Eur J Endocrinol 170 (6): 821-8, 2014.
40. Ceolin L, Siqueira DR, Romitti M, et al.: Molecular basis of medullary thyroid carcinoma: the role of RET polymorphisms. Int J Mol Sci 13 (1): 221-39, 2012.
41. Robledo M, Gil L, Pollán M, et al.: Polymorphisms G691S/S904S of RET as genetic modifiers of MEN 2A. Cancer Res 63 (8): 1814-7, 2003.
42. Kaczmarek-Ryś M, Ziemnicka K, Pławski A, et al.: Modifying impact of RET gene haplotypes on medullary thyroid carcinoma clinical course. Endocr Relat Cancer 25 (4): 421-436, 2018.
43. Margraf RL, Crockett DK, Krautscheid PM, et al.: Multiple endocrine neoplasia type 2 RET protooncogene database: repository of MEN2-associated RET sequence variation and reference for genotype/phenotype correlations. Hum Mutat 30 (4): 548-56, 2009.

Screening and Surveillance in Multiple Endocrine Neoplasia Type 2 (MEN2)

Screening and Surveillance for Pheochromocytomas (PHEOs)

The presence of a functioning PHEO can be excluded by appropriate biochemical screening before thyroidectomy in any patient with multiple endocrine neoplasia type 2A (MEN2A) or multiple endocrine neoplasia type 2B (MEN2B). However, childhood PHEOs are rare in MEN2.[11] Individuals with American Thyroid Association (ATA)-Highest Risk (HST) or ATA-High Risk (H) RETpathogenic variants have an increased risk of PHEO (up to 50%).[22] The ATA recommends that annual screening for PHEO be considered by age 11 years in patients with ATA-HST or ATA-H RET pathogenic variants.[11] The ATA recommends that patients with ATA-Moderate Risk (MOD) RET pathologic variants have periodic screening for PHEO beginning by age 16 years.[11] Magnetic resonance imaging or other imaging tests may be ordered only if the biochemical results are abnormal.[33,44,55] Studies of individuals with sporadic or hereditary PHEO (including, but not limited to, individuals with MEN2) have suggested that measurement of catecholamine metabolites, specifically plasma-free metanephrines and/or urinary fractionated metanephrines, provides a higher diagnostic sensitivity than urinary catecholamines because of the episodic nature of catecholamine excretion.[55,66,77,88,99,1010,1111,1212,1313,1414] Several reviews provide a succinct summary of the biochemical diagnosis, localization, and management of PHEO.[66,1515]

Level of evidence: 4

Screening and Surveillance for Hyperparathyroidism

Primary hyperparathyroidism is variably reported in MEN2A, with rates ranging from 2% to 35%.[1616] However, large, multicenter studies suggest rates in the lower half of this range. MEN2-related hyperparathyroidism is generally associated with mild, often asymptomatic hypercalcemia early in the natural history of the disease, which, left untreated, may become symptomatic.[1717] Those with higher risk pathogenic variants are more likely to develop hyperparathyroidism, with an earlier age of onset.[1616] Childhood hyperparathyroidism is rare in MEN2. Four studies reported a median age of diagnosis between ages 38 and 45 years.[1616,1717,1818,1919] The ATA provides recommendations for annual screening for hyperparathyroidism,[11] with screening beginning by age 11 years in carriers of ATA-HST and ATA-H pathogenic variants and by age 16 years for carriers of ATA-MOD RET pathogenic variants.[11] Testing typically includes albumin-corrected calcium or ionized serum calcium, with or without intact parathyroid hormone measurement. While cure rates for hyperparathyroidism are high, recurrence can occur decades after initial treatment.[1616]

Level of evidence: 4

References:

1. Wells SA, Asa SL, Dralle H, et al.: Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid 25 (6): 567-610, 2015.
2. Quayle FJ, Fialkowski EA, Benveniste R, et al.: Pheochromocytoma penetrance varies by RET mutation in MEN 2A. Surgery 142 (6): 800-5; discussion 805.e1, 2007.
3. Modigliani E, Vasen HM, Raue K, et al.: Pheochromocytoma in multiple endocrine neoplasia type 2: European study. The Euromen Study Group. J Intern Med 238 (4): 363-7, 1995.
4. Wells SA, Donis-Keller H: Current perspectives on the diagnosis and management of patients with multiple endocrine neoplasia type 2 syndromes. Endocrinol Metab Clin North Am 23 (1): 215-28, 1994.
5. Lenders JW, Duh QY, Eisenhofer G, et al.: Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 99 (6): 1915-42, 2014.
6. Pacak K, Eisenhofer G, Ahlman H, et al.: Pheochromocytoma: recommendations for clinical practice from the First International Symposium. October 2005. Nat Clin Pract Endocrinol Metab 3 (2): 92-102, 2007.
7. Gardet V, Gatta B, Simonnet G, et al.: Lessons from an unpleasant surprise: a biochemical strategy for the diagnosis of pheochromocytoma. J Hypertens 19 (6): 1029-35, 2001.
8. Gerlo EA, Sevens C: Urinary and plasma catecholamines and urinary catecholamine metabolites in pheochromocytoma: diagnostic value in 19 cases. Clin Chem 40 (2): 250-6, 1994.
9. Guller U, Turek J, Eubanks S, et al.: Detecting pheochromocytoma: defining the most sensitive test. Ann Surg 243 (1): 102-7, 2006.
10. Lenders JW, Pacak K, Walther MM, et al.: Biochemical diagnosis of pheochromocytoma: which test is best? JAMA 287 (11): 1427-34, 2002.
11. Raber W, Raffesberg W, Bischof M, et al.: Diagnostic efficacy of unconjugated plasma metanephrines for the detection of pheochromocytoma. Arch Intern Med 160 (19): 2957-63, 2000.
12. Sawka AM, Jaeschke R, Singh RJ, et al.: A comparison of biochemical tests for pheochromocytoma: measurement of fractionated plasma metanephrines compared with the combination of 24-hour urinary metanephrines and catecholamines. J Clin Endocrinol Metab 88 (2): 553-8, 2003.
13. Unger N, Pitt C, Schmidt IL, et al.: Diagnostic value of various biochemical parameters for the diagnosis of pheochromocytoma in patients with adrenal mass. Eur J Endocrinol 154 (3): 409-17, 2006.
14. Därr R, Kuhn M, Bode C, et al.: Accuracy of recommended sampling and assay methods for the determination of plasma-free and urinary fractionated metanephrines in the diagnosis of pheochromocytoma and paraganglioma: a systematic review. Endocrine 56 (3): 495-503, 2017.
15. Pacak K, Ilias I, Adams KT, et al.: 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 257 (1): 60-8, 2005.
16. Holm M, Vestergaard P, Poulsen MM, et al.: Primary Hyperparathyroidism in Multiple Endocrine Neoplasia Type 2A in Denmark 1930–2021: A Nationwide Population-Based Retrospective Study. Cancers (Basel) 15 (7): , 2023.
17. Kraimps JL, Denizot A, Carnaille B, et al.: Primary hyperparathyroidism in multiple endocrine neoplasia type IIa: retrospective French multicentric study. Groupe d'Etude des Tumeurs á Calcitonine (GETC, French Calcitonin Tumors Study Group), French Association of Endocrine Surgeons. World J Surg 20 (7): 808-12; discussion 812-3, 1996.
18. Raue F, Kraimps JL, Dralle H, et al.: Primary hyperparathyroidism in multiple endocrine neoplasia type 2A. J Intern Med 238 (4): 369-73, 1995.
19. Milos IN, Frank-Raue K, Wohllk N, et al.: Age-related neoplastic risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germ line RET Cys634Trp (TGC>TGG) mutation. Endocr Relat Cancer 15 (4): 1035-41, 2008.

Interventions in Multiple Endocrine Neoplasia Type 2 (MEN2)

Risk-Reducing Thyroidectomy

For more information about risk stratification, see the Genotype-Phenotype Correlations and Risk Stratification in MEN2Genotype-Phenotype Correlations and Risk Stratification in MEN2 section.

Risk-reducing thyroidectomy (also referred to as early thyroidectomy and previously referred to as prophylactic thyroidectomy) is the oncological treatment of choice for patients with MEN2. Children with the M918T RETpathogenic variant may benefit from a thyroidectomy in the first year of life, perhaps in the first months of life.[11] Likewise, children with American Thyroid Association (ATA)-High Risk (H) category RET pathogenic variants may undergo risk-reducing thyroidectomy around age 5 years or earlier, based on serum calcitonin levels. The ATA recommends that children in the ATA-Moderate Risk (MOD) category have a physical examination, ultrasonography of the neck, and measurement of serum calcitonin beginning around age 5 years, as these tumors may have later onset but are similarly aggressive once this is taken into account.[11,22] The absence of an abnormal calcitonin level may prompt continued measurement every 6 to 12 months.

A multidisciplinary team caring for the patient, including the pediatrician, pediatric endocrinologist, and surgeon should determine the timing of surgery in conjunction with the child's parents based on the trend in serum calcitonin levels, ultrasonographic findings, preference of the family, and experience of the treating physicians.[11]

In children with some ATA-H or ATA-MOD RET pathogenic variants, earlier studies have suggested that basal and pentagastrin-stimulated calcitonin levels could be used to determine the timing of total thyroidectomy.[33,44,55,66] These findings suggest that surgery may be safely delayed in carriers of an RET pathogenic variant until basal or stimulated calcitonin levels increase on routine testing. The benefits of this approach are particularly noteworthy in the younger population of pathogenic variant carriers, as a delay in surgery until the patient is older may reduce the risk of surgical complications. However, pentagastrin is not readily available. A large study of 2,740 children aged 16 years and under has provided data on age-specific reference ranges for calcitonin levels in younger children that may assist in decision making.[77] Because some calcitonin assays may be more sensitive than others,[55] attention to the type of testing, as well as calcitonin levels must be considered. However, normal preoperative basal calcitonin does not exclude the possibility of the patient having medullary thyroid cancer (MTC).[88]

For patients with RETgermline variants, older age at risk-reducing thyroidectomy has been significantly associated with a higher risk of persistent or recurrent disease.[99,1010] Even micro MTC carries a risk of biochemical recurrence.[1010] Consistent with this finding, a study of young, clinically asymptomatic individuals with multiple endocrine neoplasia type 2A (MEN2A) found a lower incidence of persistent or recurrent disease in patients who had thyroidectomy earlier in life (younger than age 8 y) and who had no evidence of lymph node metastases.[1111] Several studies have found a significantly lower rate of invasive or metastatic MTC among those who undergo surgery at an earlier age than among those who undergo surgery at a later age.[1212] For patients with the most aggressive M918T RET variant, cure is exceptional if surgery is performed after age 4 years.[33,1313] Together, these findings are consistent with more favorable outcomes for patients undergoing risk-reducing thyroidectomy at a young age.[1414]

While performing thyroidectomy before biochemical evidence of disease exists (normal preoperative calcitonin) may reduce the risk of recurrent disease, postoperative and lifelong surveillance strategies are often needed. These strategies may depend on the final pathological findings (if carcinoma was present and whether it was microscopic disease or macroscopic disease).[11,1515] One study found that 10% of patients with MEN2A undergoing thyroidectomy developed recurrent disease, based on initially undetectable basal and stimulated calcitonin levels (<2 pg/mL) that became positive 5 to 10 years after surgery.[1111] Only 2% of patients had residual disease after risk-reducing surgery as assessed by a persistently elevated basal or stimulated calcitonin.[1111] Since screening and surveillance in second-generation pediatric patients with multiple endocrine neoplasia type 2B (MEN2B) begin earlier, timing of surgical intervention has decreased the incidence of lymph node metastases. This finding encourages the role of personalized extent of surgery intervention and thyroidectomy alone, without ipsilateral central neck dissection can be adequate for cure in 97% of patients.[1616]

Age at MTC diagnosis is variable. Reports have documented MTC metastasis in MEN2B cases before age 3 years and in MEN2A cases with ATA-H or ATA-MOD RET variants before age 6 years.[33,1111,1313,1717] Conversely, some families with the familial medullary thyroid cancer subtype of MEN2A did not show signs of disease until midlife. In addition, some elderly relatives who carried the RET variant never developed MTC.[1818] Additional data have suggested that some ATA-MOD RET variants (which were previously thought to be more indolent) may be as aggressive as ATA-H RET variants, but they are associated with delayed disease onset.[22,1919]

Level of evidence: 3aii

Treatment for MEN2-Related Medullary Thyroid Cancer (MTC)

For general information about MTC treatment, see the MTCMTC section in Thyroid Cancer Treatment. For more information about treatment for children with MEN2, see the Childhood MEN Syndromes TreatmentChildhood MEN Syndromes Treatment summary.

Therapeutic thyroidectomy

The standard treatment for adults with MTC is surgical removal of the entire thyroid gland, including the posterior capsule and central lymph node dissection.[11] A therapeutic central neck dissection is typically performed if there is radiographic evidence of metastatic lymph node involvement or if the serum calcitonin level is higher than 40 pg/mL.[11] The decision to perform a risk-reducing central neck dissection is generally made based on multiple factors such as patient age, pathogenic variant, presence of concomitant primary hyperparathyroidism (PHPT), and the viability of in situ parathyroid glands.[11] Selective autotransplantation of parathyroid glands that were devascularized during a risk-reducing thyroidectomy and/or central neck clearance is recommended, but risk-reducing autotransplantation is not suggested.[11] A selective approach also significantly reduces the detrimental outcome of hypoparathyroidism.[2020]

The MEN2B RET variant M918T is associated with approximately 100% incidence of MTC in the first years of life [1313] and is considered the most aggressive MEN2 phenotype. In patients with MEN2A, the ATA-H high-risk codon 634 pathogenic variant is much more likely to be associated with invasive or metastatic MTC and development of persistent or recurrent disease than pathogenic variants in codons 804, 618, or 620.[1212] One series of 503 at-risk individuals with ATA-MOD category pathogenic variants (including codons 533, 609, 611, 618, 620, 791, and 804) reported cumulative penetrance rates, median time to MTC, and positive predictive value of preoperative calcitonin.[44] The risk of developing MTC by age 50 years ranged from 18% to 95%, depending on the codon, with codon 620 having the highest penetrance. Most patients with MTC had node-negative disease, confirming the more indolent disease course previously reported with these pathogenic variants. Although an elevated preoperative calcitonin level strongly predicted the presence of MTC, relatively high false-negative rates (low normal calcitonin levels with MTC) were noted for many of the codons. This information is useful when counseling carriers of pathogenic variants regarding the extent of surgical resection.

The ATA recommends compartment-directed lymph node dissection for local or regional disease (no evidence of distant metastases) in the following situations:[11]

• If there is no evidence of neck nodal metastases by ultrasonography in biopsy-proven thyroid disease, risk-reducing central neck dissection should be performed concomitant with initial thyroidectomy.
• If nodal disease is present in either the central or lateral neck, a compartment-oriented lateral neck dissection of the ipsilateral side should be performed.
• If nodal disease is present and basal calcitonin levels are greater than 200 pg/mL, then consider contralateral lateral neck dissection.

Although basal calcitonin levels may not be able to identify all patients with MTC preoperatively, this test has utility as a predictor of postoperative remission, lymph node metastases, and distant metastases.[2121] In one study of 224 patients from a single institution, preoperative basal calcitonin levels greater than 500 pg/mL predicted failure to achieve biochemical remission.[2121] The authors of this study found that nodal metastases started appearing at basal calcitonin levels of 40 pg/mL (normal, <10 pg/mL). In node-positive patients, distant metastases emerged at basal calcitonin levels of 150 pg/mL to 400 pg/mL. Another study of 308 RET pathogenic variant carriers found that a normal basal preoperative calcitonin excluded the presence of lymph node metastases (negative predictive value, 100%).[66] Therefore, the preoperative basal calcitonin level is a useful prognostic indicator and may help guide the surgical approach.

Level of evidence (therapeutic thyroidectomy): 3dii

Level of evidence (central neck dissection): 4

Prognosis

Structural and metastatic MTC recurrence is common in germline RET carriers. Recurrence can happen up to 20 years after initial treatment. However, overall survival (OS) is generally favorable, with one study citing an OS rate of 92% after 10 years.[2222]

Hormone replacement therapy after total thyroidectomy

Patients who have had total thyroidectomy require lifelong thyroid hormone replacement therapy. Medication dosing is age-dependent, and treatment may be initiated based on ideal body weight. For healthy adults aged 60 years and younger (without cardiac disease), a reasonable starting dose is 1.6 µg/kg to 1.8 µg/kg, given once daily.[2323] Older patients may require 20% to 30% less thyroid hormone than younger patients.[2424] Children metabolize thyroxine (T4) more rapidly than adults and require higher replacement by body weight. Depending on the age of the child, the amount of T4 replacement can range from 2 µg/kg to 6 µg/kg.[2525] However, T4 replacement is preferred over suppressive therapy. Since C-cell tumors are not dependent on thyroid-stimulating hormone (TSH) to grow, T4 therapy for MTC patients may be adjusted to maintain TSH levels that are within the normal reference range. Thyroglobulin measurements may be useful to help adjust and maintain TSH levels within a normal reference range. This can prevent regrowth of remnant thyroid tissue.[2626]

Adjuvant therapy for MTC

Chemotherapy and radiation therapy are generally not effective against MTC.[2727,2828,2929] Targeted molecular therapies are being explored to manage MTC. RET inhibitors and multikinase inhibitors are being used to block RET activity.

Two U.S. Food and Drug Administration (FDA)–approved RET inhibitors (pralsetinib and selpercatinib) are available for patients with MTC who have a RETsingle nucleotide variant. These RET inhibitors are also available for patients who have differentiated thyroid cancers with a RET fusion. A multicenter, phase I/II trial (ARROW) was conducted to evaluate the efficacy of pralsetinib in patients with RET-mutant MTC with or without prior treatment with vandetanib or cabozantinib. Among 55 patients who were previously treated with a multikinase inhibitor, the overall response rate was 60% (95% confidence interval [CI], 46%–73%) and the 1-year progression-free survival (PFS) rate was 75% (95% CI, 63%–86%). Among 21 treatment-naïve patients, the overall response rate was 71% (95% CI, 48%–89%) and the 1-year PFS rate was 81% (95% CI, 63%–98%).[3030] A similar phase I/II trial (LIBRETTO) examined the efficacy of selpercatinib in patients with RET-mutant MTC with or without prior treatment with vandetanib or cabozantinib. Among 55 patients who were previously treated with a multikinase inhibitor, 69% had an objective response (95% CI, 55%–81%); the 1-year PFS rate was 82% (95% CI, 69%–90%). Among 88 treatment-naïve patients, the objective response rate was 73% (95% CI, 62%–82%), and the 1-year PFS rate was 92% (95% CI, 82%–97%).[3131]

The use of vandetanib and cabozantinib are FDA-approved for adult patients with progressive metastatic MTC who are ineligible for surgery. A phase III study found that PFS was longer in adults who received vandetanib than in those who received placebo.[3232] A phase I/phase II study of children with MEN2B found an objective partial response rate of 47% with vandetanib.[3333] Subsequent follow-up analysis of this cohort revealed that a partial response was seen in 10 of 17 patients; stable disease was seen in an additional 6 individuals. Median PFS was 6.7 years.[3434] A double-blind phase III trial that compared cabozantinib with placebo in 330 patients with progressive MTC showed an improvement in median PFS across all subgroups.[3535,3636] In this trial, patients who had pathogenic variants, including RET or RAS, were more likely to have a prolonged PFS compared with patients lacking both pathogenic variants.[3737] Prospective studies may further clarify whether particular pathogenic variants can be used to guide therapy. Neither cabozantinib nor vandetanib has demonstrated improved OS.[3232,3535,3636] Importantly, these agents are not effective at inhibiting some MEN2 RET variants, specifically those at codon 804,[3838] making genotype an important consideration for treatment with RET inhibitors. Further, a 2018 study demonstrated the development of resistance to these agents through somatic acquisition of a V804M variant in RET.[3939] Finally, multikinase inhibitors are associated with significant toxicities, possibly due to their off-target effects on other kinases.[4040] Other multikinase inhibitors for targeting RET are being studied in clinical trials; however, they may provide only limited advantages over vandetanib and cabozantinib. For these reasons, ongoing studies are focusing on the development of selective RET inhibitors with fewer off-target effects that are able to block the activity of all RET variant forms and the use of combination therapy in MTC. Future studies will likely focus on the development of new targeted therapies and the use of combination therapy in MTC.[4141,4242]

Level of evidence (pralsetinib): 4

Level of evidence (selpercatinib): 3dii

Level of evidence (vandetanib): 2

Level of evidence (cabozantinib): 1

For more information, see Thyroid Cancer TreatmentThyroid Cancer Treatment.

Treatment for MEN2-Related Pheochromocytoma (PHEO)

A cognitive shift has occurred in the field regarding the risks and benefits of whole organ resection. This shift is especially relevant for endocrine glands that are difficult to manage postresection and may require replacement therapy. PHEO may be either unilateral or bilateral in patients with MEN2. Laparoscopic adrenalectomy (anterior or posterior) is the recommended approach after appropriate preoperative medical blockade for the treatment of unilateral PHEO.[11,4343,4444,4545] The risks, benefits, and potential of life-threatening adrenal insufficiency should be considered at the time of the initial operative planning.

If disease appears unilateral, the contralateral gland may develop metachronous disease in 17% to 72% of patients.[4646,4747] In a series of RET p.Cys634 variant carriers, only 1 in 5 developed a second ipsilateral PHEO after a follow-up period of 8 to 11 years when the cortical preservation technique was used. This technique allows patients to continue making steroid hormones on their own, which makes it a viable surgical option.[4848] In one series, 23 patients with a unilateral PHEO and a macroscopically normal contralateral adrenal gland were treated initially with unilateral adrenalectomy.[4949] A PHEO developed within the retained gland in 12 (52%) of these patients, occurring a mean of 11.9 years after initial surgery. During follow-up, no patient experienced a hypertensive crisis or other problems attributable to an undiagnosed PHEO. In contrast, 10 of 43 patients (23%) treated with bilateral adrenalectomy experienced at least one episode of acute adrenal insufficiency. Thus, unilateral adrenalectomy is a reasonable management strategy for unilateral PHEO in patients with MEN2.[11,5050,5151] Many experts suggest considering a cortical-sparing technique for a suspected unilateral PHEO, even if it is the patient's first operation.[11,5252] For more information, see the section on InterventionsInterventions in Genetics of Endocrine and Neuroendocrine Neoplasias. Because of the risk of contralateral gland disease, periodic surveillance (serum or urinary catecholamine measurements) for the development of disease in the contralateral adrenal gland is recommended.[11]

Regarding the operative approach, several studies found posterior retroperitoneoscopic adrenalectomy to be safe and effective, with very low mortality and a low rate of minor complications. Conversion to open surgery was rarely required.[4646,5353,5454,5555,5656,5757,5858,5959]

There are other clinical situations (besides surgery) in which patients with catecholamine excess face special risks. An example is the healthy at-risk female patient who becomes pregnant.[6060] Pregnancy, labor, and delivery can prompt a hypertensive crisis in individuals with an undetected PHEO. Pregnant patients who are found to have catecholamine excess require pharmacotherapy before delivery.[6161]

Level of evidence: 3a

Treatment for MEN2-Related Hyperparathyroidism

Most patients with MEN2-related parathyroid disease are either asymptomatic or diagnosed incidentally during preoperative planning or at the time of thyroidectomy. Typically, hypercalcemia (when present) is mild, although it may be associated with increased urinary excretion of calcium and nephrolithiasis. As a consequence, the indications for surgical intervention are generally similar to those recommended for patients with sporadic PHPT.[4343] In general, fewer than four of the parathyroid glands are involved at the time of detected abnormalities in calcium metabolism.[11]

Treatment of hyperparathyroidism typically employs some surgical removal of the involved glands. Cure of hyperparathyroidism was achieved surgically in 89% of one large series of MEN2A patients;[6262] however, 22% of resected patients in this study developed postoperative hypoparathyroidism. Five patients (9%) had recurrent hyperparathyroidism. This series used various surgical techniques, including total parathyroidectomy with autotransplantation to the nondominant forearm (4 of 11 patients [36%] developed postoperative hypoparathyroidism), subtotal parathyroidectomy (6 of 12 patients [50%] developed hypoparathyroidism), and resection only of glands that were macroscopically enlarged (3 of 29 patients [10%] developed hypoparathyroidism). These data indicate that excision of only parathyroid glands that are enlarged appears to be sufficient therapy in most cases.

Some investigators have suggested using the MEN2 subtype to decide where to place the parathyroid glands that are identified at the time of thyroid surgery. For patients with MEN2B in whom the risk of parathyroid disease is quite low, the parathyroid glands may be left in situ in the neck. For adult patients with MEN2A, in whom the glands have been inadvertently devascularized during primary surgical treatment for MTC, it is suggested that the glands needing reimplantation be implanted in the nondominant forearm. This approach minimizes the need for further surgical intervention in the neck should hyperparathyroidism develop or recur.[11,2020,6363,6464] For children, the risk/benefit ratio must be carefully weighed to avoid overtreatment and subsequent aparathyroidism.[6565] It is important to confirm that the remnant or autotransplanted parathyroid tissue is functional.[11,4444,6666,6767]

Medical therapy of hyperparathyroidism has gained popularity with the advent of calcimimetics, agents that sensitize the calcium-sensing receptors on the parathyroid glands to circulating calcium levels and thereby reduce circulating parathyroid hormone (PTH) levels. In a randomized, double-blind, placebo-controlled trial, cinacalcet hydrochloride was shown to induce sustained reduction in circulating calcium and PTH levels in patients with PHPT.[6868] In patients who are high-risk surgical candidates, those with recurrent hyperparathyroidism, or those in whom life expectancy is limited, medical therapy may be a viable alternative to a surgical approach.[11] Consequences of long-term therapy with cinacalcet are unknown.

Level of evidence: 3di

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39. Subbiah V, Velcheti V, Tuch BB, et al.: Selective RET kinase inhibition for patients with RET-altered cancers. Ann Oncol 29 (8): 1869-1876, 2018.
40. Drilon A, Hu ZI, Lai GGY, et al.: Targeting RET-driven cancers: lessons from evolving preclinical and clinical landscapes. Nat Rev Clin Oncol 15 (3): 151-167, 2018.
41. Redaelli S, Plaza-Menacho I, Mologni L: Novel targeted therapeutics for MEN2. Endocr Relat Cancer 25 (2): T53-T68, 2018.
42. Mulligan LM: Progress and potential impact of RET kinase targeting in cancer. Expert Rev Proteomics 13 (7): 631-3, 2016.
43. Brandi ML, Gagel RF, Angeli A, et al.: Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 86 (12): 5658-71, 2001.
44. Kloos RT, Eng C, Evans DB, et al.: Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid 19 (6): 565-612, 2009.
45. Lenders JW, Duh QY, Eisenhofer G, et al.: Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 99 (6): 1915-42, 2014.
46. Castinetti F, Qi XP, Walz MK, et al.: Outcomes of adrenal-sparing surgery or total adrenalectomy in phaeochromocytoma associated with multiple endocrine neoplasia type 2: an international retrospective population-based study. Lancet Oncol 15 (6): 648-55, 2014.
47. Thosani S, Ayala-Ramirez M, Palmer L, et al.: The characterization of pheochromocytoma and its impact on overall survival in multiple endocrine neoplasia type 2. J Clin Endocrinol Metab 98 (11): E1813-9, 2013.
48. Machens A, Lorenz K, Weber F, et al.: Recurrent ipsilateral pheochromocytoma in carriers of RET p.Cys634 missense mutations. Endocrine 77 (1): 160-167, 2022.
49. Lairmore TC, Ball DW, Baylin SB, et al.: Management of pheochromocytomas in patients with multiple endocrine neoplasia type 2 syndromes. Ann Surg 217 (6): 595-601; discussion 601-3, 1993.
50. Inabnet WB, Caragliano P, Pertsemlidis D: Pheochromocytoma: inherited associations, bilaterality, and cortex preservation. Surgery 128 (6): 1007-11;discussion 1011-2, 2000.
51. Scholten A, Valk GD, Ulfman D, et al.: Unilateral subtotal adrenalectomy for pheochromocytoma in multiple endocrine neoplasia type 2 patients: a feasible surgical strategy. Ann Surg 254 (6): 1022-7, 2011.
52. Grubbs EG, Rich TA, Ng C, et al.: Long-term outcomes of surgical treatment for hereditary pheochromocytoma. J Am Coll Surg 216 (2): 280-9, 2013.
53. Walz MK, Alesina PF, Wenger FA, et al.: Posterior retroperitoneoscopic adrenalectomy--results of 560 procedures in 520 patients. Surgery 140 (6): 943-8; discussion 948-50, 2006.
54. Walz MK, Alesina PF, Wenger FA, et al.: Laparoscopic and retroperitoneoscopic treatment of pheochromocytomas and retroperitoneal paragangliomas: results of 161 tumors in 126 patients. World J Surg 30 (5): 899-908, 2006.
55. Perrier ND, Kennamer DL, Bao R, et al.: Posterior retroperitoneoscopic adrenalectomy: preferred technique for removal of benign tumors and isolated metastases. Ann Surg 248 (4): 666-74, 2008.
56. Behrman SW, Bahr MH, Dickson PV, et al.: The microbiology of secondary and postoperative pancreatic infections: implications for antimicrobial management. Arch Surg 146 (5): 613-9, 2011.
57. Evans DB, Perrier ND: On "Posterior retroperitoneoscopic adrenalectomy--results of 560 procedures in 520 patients". Surgery 140 (6): 951-2, 2006.
58. Dickson PV, Jimenez C, Chisholm GB, et al.: Posterior retroperitoneoscopic adrenalectomy: a contemporary American experience. J Am Coll Surg 212 (4): 659-65; discussion 665-7, 2011.
59. Cabalag MS, Mann GB, Gorelik A, et al.: Posterior retroperitoneoscopic adrenalectomy: outcomes and lessons learned from initial 50 cases. ANZ J Surg 85 (6): 478-82, 2015.
60. Prete A, Paragliola RM, Salvatori R, et al.: MANAGEMENT OF CATECHOLAMINE-SECRETING TUMORS IN PREGNANCY: A REVIEW. Endocr Pract 22 (3): 357-70, 2016.
61. Meijs AC, Snel M, Corssmit EPM: Pheochromocytoma/paraganglioma crisis: case series from a tertiary referral center for pheochromocytomas and paragangliomas. Hormones (Athens) 20 (2): 395-403, 2021.
62. Kraimps JL, Denizot A, Carnaille B, et al.: Primary hyperparathyroidism in multiple endocrine neoplasia type IIa: retrospective French multicentric study. Groupe d'Etude des Tumeurs á Calcitonine (GETC, French Calcitonin Tumors Study Group), French Association of Endocrine Surgeons. World J Surg 20 (7): 808-12; discussion 812-3, 1996.
63. Norton JA, Brennan MF, Wells SA Jr: Surgical Management of Hyperparathyroidism. In: Bilezikian JP, Marcus R, Levine MA: The Parathyroids: Basic and Clinical Concepts. Raven Press, 1994, pp 531-551.
64. Scholten A, Schreinemakers JM, Pieterman CR, et al.: Evolution of surgical treatment of primary hyperparathyroidism in patients with multiple endocrine neoplasia type 2A. Endocr Pract 17 (1): 7-15, 2011 Jan-Feb.
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66. Khan MI, Waguespack SG, Hu MI: Medical management of postsurgical hypoparathyroidism. Endocr Pract 17 (Suppl 1): 18-25, 2011 Mar-Apr.
67. Stålberg P, Carling T: Familial parathyroid tumors: diagnosis and management. World J Surg 33 (11): 2234-43, 2009.
68. Peacock M, Bilezikian JP, Klassen PS, et al.: Cinacalcet hydrochloride maintains long-term normocalcemia in patients with primary hyperparathyroidism. J Clin Endocrinol Metab 90 (1): 135-41, 2005.

Familial and Psychosocial Implications in Multiple Endocrine Neoplasia Type 2 (MEN2)

Attitudes Toward Preimplantation Genetic Testing

One study explored the attitudes of individuals with multiple endocrine neoplasia type 1 (MEN1) and multiple endocrine neoplasia type 2 (MEN2) toward preimplantation genetic testing (PGT).[11] Ninety-one clinic-based patients from a single U.S. institution who had MEN1 and an MEN1pathogenic variant or MEN2 and a RET pathogenic variant were surveyed. The study found that 30% (10 of 33) of those with MEN1 and 37% (21 of 57) of those with MEN2 were aware of PGT; 82% (27 of 33) of those with MEN1 and 61% (34 of 56) of those with MEN2 thought PGT should be offered; and 61% (19 of 31) of those with MEN1 and 43% (23 of 54) of those with MEN2 would consider PGT.

Psychosocial Issues

The psychosocial impact of genetic testing for pathogenic variants in RET has not been extensively studied. Published studies have had limitations such as small sample size and heterogeneous populations, so the clinical relevance of these findings should be interpreted with caution. Identification as the carrier of a pathogenic variant may affect self-esteem, family relationships, and quality of life.[22] In addition, misconceptions about genetic disease may result in familial blame and guilt.[33,44] Several review articles outline both the medical and psychological issues, especially those related to the testing of children.[55,66,77,88] The medical value of early screening and risk-reducing treatment are contrasted with the loss of decision-making autonomy for the individual. Lack of agreement between parents about the value and timing of genetic testing and surgery may spur the development of emotional problems within the family.

One study examined levels of psychological distress in the interval between submitting a blood sample and receiving genetic test results. Individuals who experienced the highest level of distress were younger than 25 years, single, and had a history of responding to stressful situations with anxiety.[99] Pathogenic variant–positive parents whose children received negative test results did not seem to be reassured, questioned the reliability of the DNA test, and were eager to continue screening of their noncarrier children.[1010]

A small qualitative study (N = 21) evaluated how patients with multiple endocrine neoplasia type 2A and family members conceptualized participation in lifelong high-risk surveillance.[1111] Ongoing surveillance was viewed as a reminder of a health threat. Acceptance and incorporation of lifelong surveillance into routine health care was essential for coping with the implications of this condition. Concern about genetic predisposition to cancer was peripheral to concerns about surveillance. Supportive interventions, such as Internet discussion forums, can serve as an ongoing means of addressing informational and support needs of patients with medullary thyroid cancer undergoing lifelong surveillance.[1212]

References:

1. Rich TA, Liu M, Etzel CJ, et al.: Comparison of attitudes regarding preimplantation genetic diagnosis among patients with hereditary cancer syndromes. Fam Cancer 13 (2): 291-9, 2014.
2. Freyer G, Ligneau B, Schlumberger M, et al.: Quality of life in patients at risk of medullary thyroid carcinoma and followed by a comprehensive medical network: trends for future evaluations. Ann Oncol 12 (10): 1461-5, 2001.
3. Freyer G, Dazord A, Schlumberger M, et al.: Psychosocial impact of genetic testing in familial medullary-thyroid carcinoma: a multicentric pilot-evaluation. Ann Oncol 10 (1): 87-95, 1999.
4. Grosfeld FJ, Lips CJ, Ten Kroode HF, et al.: Psychosocial consequences of DNA analysis for MEN type 2. Oncology (Huntingt) 10 (2): 141-6; discussion 146, 152, 157, 1996.
5. Johnston LB, Chew SL, Trainer PJ, et al.: Screening children at risk of developing inherited endocrine neoplasia syndromes. Clin Endocrinol (Oxf) 52 (2): 127-36, 2000.
6. MacDonald DJ, Lessick M: Hereditary cancers in children and ethical and psychosocial implications. J Pediatr Nurs 15 (4): 217-25, 2000.
7. Grosfeld FJ, Lips CJ, Beemer FA, et al.: Psychological risks of genetically testing children for a hereditary cancer syndrome. Patient Educ Couns 32 (1-2): 63-7, 1997 Sep-Oct.
8. Giarelli E: Multiple endocrine neoplasia type 2a (MEN2a): a call for psycho-social research. Psychooncology 11 (1): 59-73, 2002 Jan-Feb.
9. Grosfeld FJ, Lips CJ, Beemer FA, et al.: Distress in MEN 2 family members and partners prior to DNA test disclosure. Multiple endocrine neoplasia type 2. Am J Med Genet 91 (1): 1-7, 2000.
10. Grosfeld FJ, Beemer FA, Lips CJ, et al.: Parents' responses to disclosure of genetic test results of their children. Am J Med Genet 94 (4): 316-23, 2000.
11. Giarelli E: Bringing threat to the fore: participating in lifelong surveillance for genetic risk of cancer. Oncol Nurs Forum 30 (6): 945-55, 2003 Nov-Dec.
12. Schultz PN: Providing information to patients with a rare cancer: using Internet discussion forums to address the needs of patients with medullary thyroid carcinoma. Clin J Oncol Nurs 6 (4): 219-22, 2002 Jul-Aug.

Changes to This Summary (12 / 11 / 2024)

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About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about Multiple endocrine neoplasia type 2 (MEN2). It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

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This summary is reviewed regularly and updated as necessary by the PDQ Cancer Genetics Editorial BoardPDQ Cancer Genetics Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

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The lead reviewers for Multiple Endocrine Neoplasia Type 2 (MEN2) are:

• Erica Blouch, MS, CGC (Massachusetts General Hospital Cancer Center)
• Kathleen A. Calzone, PhD, RN, AGN-BC, FAAN (National Cancer Institute)
• Suzanne C. O'Neill, PhD (Georgetown University)
• Nancy D. Perrier, MD, FACS (University of Texas, M.D. Anderson Cancer Center)
• John M. Quillin, PhD, MPH, MS (Virginia Commonwealth University)
• Charite Ricker, MS, CGC (University of Southern California)

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Last Revised: 2024-12-11