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Genetics of Endocrine and Neuroendocrine Neoplasias (PDQ®) 2/6 –Health Professional Version - National Cancer Institute

Genetics of Endocrine and Neuroendocrine Neoplasias (PDQ®)–Health Professional Version - National Cancer Institute

National Cancer Institute



Genetics of Endocrine and Neuroendocrine Neoplasias (PDQ®)–Health Professional Version



Multiple Endocrine Neoplasia Type 2

Clinical Description

The endocrine disorders observed in multiple endocrine neoplasia type 2 (MEN2) are medullary thyroid cancer (MTC); its precursor, C-cell hyperplasia (CCH) (referred to as C-cell neoplasia or C-cell carcinoma in situ in more recent publications)[1]; pheochromocytoma (PHEO); and parathyroid adenomas and/or hyperplasia. MEN2-associated MTC is often bilateral and/or multifocal and arises in the background of CCH clonal C-cell proliferation. In contrast, sporadic MTC is typically unilateral and/or unifocal. Because approximately 75% to 80% of sporadic cases also have associated CCH, this histopathologic feature cannot be used as a predictor of familial disease.[2] Metastatic spread of MTC to regional lymph nodes (i.e., parathyroid, paratracheal, jugular chain, and upper mediastinum) or to distant sites, such as the liver, is common in patients who present with a palpable thyroid mass or diarrhea.[3,4] Although less than 1% of PHEOs metastasize, they can be clinically significant in cases of intractable hypertension or anesthesia-induced hypertensive crises. Parathyroid abnormalities in MEN2 can range from benign parathyroid adenomas or multigland hyperplasia to clinically evident hyperparathyroidism with hypercalcemia and renal stones.
Historically, individuals and families with MEN2 were classified into one of the following three clinical subtypes on the basis of the presence or absence of certain endocrine tumors in the individual or family:
  1. MEN2A.
  2. Familial medullary thyroid cancer (FMTC).
  3. MEN2B (sometimes referred to as MEN3).
Current stratification is moving away from a solely phenotype-based classification and more toward one that is based on genotype (i.e., the pathogenic variant) and phenotype.[5] Current recommendations propose two MEN2 syndromes: MEN2A and MEN2B. The MEN2A syndrome is further classified on the basis of the presence of associated conditions. For example, classical MEN2A includes those with MTC, PHEO, and/or hyperparathyroidism. Additional categories include MEN2A with cutaneous lichen amyloidosis, MEN2A with Hirschsprung disease (HSCR), and FMTC (presence of a RET germline pathogenic variant and MTC but no family history of PHEO or hyperparathyroidism).[1] Classifying a patient or family by MEN2 subtype is useful in determining prognosis and management.
The prevalence of MEN2 has been estimated to be approximately 1 in 35,000 individuals.[6] The vast majority of MEN2 cases are MEN2A.

MTC and CCH

MTC originates in calcitonin-producing cells (C-cells) of the thyroid gland. MTC is diagnosed when nests of C-cells extend beyond the basement membrane and infiltrate and destroy thyroid follicles. CCH is a controversial diagnosis, but most pathologists agree that it is defined as more than seven C-cells per cluster, complete follicles surrounded by C-cells, and C-cells in a distribution beyond normal anatomical location.[1,7-9] Individuals with RET (REarranged during Transfection) pathogenic variants and CCH are at substantially increased risk of progressing to MTC, although such progression is not universal.[10,11] MTC and CCH are suspected in the presence of an elevated plasma calcitonin concentration.
A study of 10,864 patients with nodular thyroid disease found 44 (1 of every 250) cases of MTC after stimulation with calcitonin, none of which were clinically suspected. Consequently, half of these patients had no evidence of MTC on fine-needle biopsy and thus might not have undergone surgery without the positive calcitonin stimulation test.[12] CCH associated with a positive calcitonin stimulation test occurs in about 5% of the general population; therefore, the plasma calcitonin responses to stimulation do not always distinguish CCH from small MTC and cannot always distinguish between carriers and noncarriers in an MEN2 family.[10,11,13]
MTC accounts for 2% to 3% of new cases of thyroid cancer diagnosed annually in the United States,[14] although this figure may be an underrepresentation of true incidence because of changes in diagnostic techniques. The total number of new cases of MTC diagnosed annually in the United States is between 1,000 and 1,200, about 75% of which are sporadic (i.e., they occur in the absence of a family history of either MTC or other endocrine abnormalities seen in MEN2). The peak incidence of the sporadic form is in the fifth and sixth decades of life.[3,15] A study in the United Kingdom estimated the incidence of MTC at 20 to 25 new cases per year among a population of 55 million.[16]
In the absence of a positive family history, MEN2 may be suspected when MTC occurs at an early age or is bilateral or multifocal. While small series of apparently sporadic MTC cases have suggested a higher prevalence of germline RET pathogenic variants,[17,18] larger series indicate a prevalence range of 1% to 7%.[19,20] On the basis of these data, testing for pathogenic variants in the RET gene is widely recommended for all cases of MTC.[1,21-23]
Level of evidence (Screening): 3

Natural history of MTC

Thyroid cancer represents approximately 3% of new malignancies occurring annually in the United States, with an estimated 52,070 cancer diagnoses and 2,170 cancer deaths per year.[24] Of these cancer diagnoses, 2% to 3% are MTC.[14,25]
MTC arises from the parafollicular calcitonin-secreting cells of the thyroid gland. MTC occurs in sporadic and familial forms and may be preceded by CCH, although CCH is a relatively common abnormality in middle-aged adults.[7,8]
Average survival for MTC is lower than that for more common thyroid cancers (e.g., 83% 5-year survival for MTC compared with 90% to 94% 5-year survival for papillary and follicular thyroid cancer).[25,26] Survival is correlated with stage at diagnosis, and decreased survival in MTC can be accounted for in part by a high proportion of late-stage diagnosis.[25-27]
In addition to early stage at diagnosis, other factors associated with improved survival in MTC include smaller tumor size, younger age at diagnosis, and diagnosis by biochemical screening (i.e., screening for calcitonin elevation) versus symptoms.[27-30]
A Surveillance, Epidemiology, and End Results population-based study of 1,252 MTC patients found that survival varied by extent of local disease. For example, the 10-year survival rates ranged from 95.6% for those with disease confined to the thyroid gland to 40% for those with distant metastases.[28]

Hereditary MTC

While most MTC cases are sporadic, approximately 20% to 25% are hereditary because of pathogenic variants in the RET proto-oncogene.[31-33] Pathogenic variants in the RET gene cause MEN2, an autosomal dominant disorder associated with a high lifetime risk of MTC. Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant endocrinopathy that is genetically and clinically distinct from MEN2; however, the similar nomenclature for MEN1 and MEN2 may cause confusion. There is no increased risk of thyroid cancer for MEN1. (Refer to the MEN1 section of this summary for more information.)

MEN2-Related PHEO

PHEOs arise from the catecholamine-producing chromaffin cells of the adrenal medulla. They are a relatively rare tumor and are suspected among patients with refractory hypertension or when biochemical screening reveals elevated excretion of catecholamines and catecholamine metabolites (i.e., norepinephrine, epinephrine, metanephrine, and vanillylmandelic acid) in 24-hour urine collections or plasma. In the past, measurement of urinary catecholamines was considered the preferred biochemical screening method. However, given that catecholamines are only released intermittently and are metabolized in the adrenal medulla into metanephrine and normetanephrine, the measurement of urine or plasma fractionated metanephrines has become the gold standard.[34-39] When biochemical screening in an individual who has or is at risk of MEN2 suggests PHEO, localization studies, such as magnetic resonance imaging (MRI) or computed tomography, can be performed.[40] Confirmation of the diagnosis can be made using iodine I 131-metaiodobenzylguanidine scintigraphy or positron emission tomography imaging.[11,40-42]
A diagnosis of MEN2 is often considered in individuals with bilateral PHEO, those with an early age of onset (age <35 y), and those with a personal and/or family history of MTC or hyperparathyroidism. However, MEN2 is not the only genetic disorder that includes a predisposition to PHEO. Other disorders include neurofibromatosis type 1 (NF1), von Hippel-Lindau disease (VHL),[43] and the hereditary paraganglioma syndromes.[44] (Refer to the von Hippel-Lindau Syndrome section in the PDQ summary on the Genetics of Kidney Cancer for more information about VHL.) A large European consortium that included 271 patients from Germany,[45] 314 patients from France,[46] and 57 patients from Italy (total = 642) with apparently sporadic PHEO analyzed the known PHEO/functional paraganglioma susceptibility genes (NF1, RET, VHL, SDHB, and SDHD).[47] The diagnosis of NF1 in this series was made clinically, while all other conditions were diagnosed on the basis of the presence of a germline pathogenic variant in the causative gene. The disease was associated with a positive family history in 166 (25.9%) patients; germline pathogenic variants were detected in RET (n = 31), VHL (n = 56), NF1 (n = 14), SDHB (n = 34), or SDHD (n = 31). Rigorous clinical evaluation and pedigree analysis either before or after testing revealed that of those with a positive family history and/or a syndromic presentation, 58.4% carried a pathogenic variant, compared with 12.7% who were nonsyndromic and/or had no family history. Of the 31 individuals with a germline RET pathogenic variant, 28 (90.3%) had a positive family history and/or syndromic presentation, suggesting that most individuals with RET pathogenic variants and PHEO will have a positive family history or other manifestations of the disease.

Primary Hyperparathyroidism (PHPT)

PHPT is the third most common endocrine disorder in the general population. The incidence increases with age with the vast majority of cases occurring after the sixth decade of life. Approximately 80% of cases are the result of a single adenoma.[48] PHPT can also be seen as a component tumor in several different hereditary syndromes, including the following:
  • MEN1.
  • Hyperparathyroidism–jaw tumor syndrome.
  • Familial isolated hyperparathyroidism.
  • MEN2.[49-51]
Hereditary PHPT is typically multiglandular, presents earlier in life, and can have histologic evidence of both adenoma and glandular hyperplasia.

Clinical Diagnosis of MEN2 Subtypes

The diagnosis of the two MEN2 clinical subtypes relies on a combination of clinical findings, family history, and molecular genetic testing of the RET gene (chromosomal region 10q11.2).

MEN2A

Classical MEN2A
MEN2A is diagnosed clinically by the occurrence of two specific endocrine tumors in addition to MTC: PHEO and/or parathyroid adenoma and/or hyperplasia in a single individual or in close relatives.[1]
The classical MEN2A subtype makes up about 60% to 90% of MEN2 cases. The MEN2A subtype was initially called Sipple syndrome.[52] Since genetic testing for RET pathogenic variants has become available, it has become apparent that about 95% of individuals with MEN2A will develop MTC.[11,53-55]
MTC is generally the first manifestation of MEN2A. In asymptomatic at-risk individuals, stimulation testing may reveal elevated plasma calcitonin levels and the presence of CCH or MTC.[11,54] In families with MEN2A, the biochemical manifestations of MTC generally appear between the ages of 5 years and 25 years (mean, 15 y).[11] If presymptomatic screening is not performed, MTC typically presents as a neck mass or neck pain between the ages of about age 5 years and 20 years. More than 50% of such patients have cervical lymph node metastases.[3] Diarrhea, the most frequent systemic symptom, occurs in patients with a markedly elevated plasma calcitonin level or bulky disease and/or hepatic metastases and implies a poor prognosis.[1,3,56,57] Up to 30% of patients with MTC present with diarrhea and advanced disease.[58]
MEN2-associated PHEOs are more often bilateral, multifocal, and associated with extratumoral medullary hyperplasia.[59-61] They also have an earlier age of onset and are less likely to be malignant than their sporadic counterparts.[59,62] MEN2-associated PHEOs usually present after MTC, typically with intractable hypertension.[63]
Unlike the PHPT seen in MEN1, hyperparathyroidism in individuals with MEN2 is typically asymptomatic or associated with only mild elevations in calcium.[58,64] A series of 56 patients with MEN2-related hyperparathyroidism has been reported by the French Calcitonin Tumors Study Group.[64] The median age at diagnosis was 38 years, documenting that this disorder is rarely the first manifestation of MEN2. This is in sharp contrast to MEN1, in which the vast majority of patients (87%–99%) initially present with primary hyperparathyroidism.[65-67] Parathyroid abnormalities were found concomitantly with surgery for medullary thyroid cancer in 43 patients (77%). Two-thirds of the patients were asymptomatic. Among the 53 parathyroid glands removed surgically, there were 24 single adenomas, 4 double adenomas, and 25 hyperplastic glands.
MEN2A with cutaneous lichen amyloidosis
A small number of families with MEN2A have pruritic skin lesions known as cutaneous lichen amyloidosis. This lichenoid skin lesion is located over the upper portion of the back and may appear before the onset of MTC.[68,69]
MEN2A with Hirschsprung disease (HSCR)
HSCR, a disorder of the enteric plexus of the colon that typically results in enlargement of the bowel and constipation or obstipation in neonates, is observed in a small number of individuals with RET pathologic variants.[70] Up to 40% of familial cases of HSCR and 3% to 7% of sporadic cases are associated with germline pathogenic variants in the RET proto-oncogene and are designated HSCR1.[71,72] Some of these RET pathogenic variants are more commonly located in codons that lead to the development of MEN2A or FMTC (i.e., codons 609, 618, and 620).[70,73]
In a study of 44 families, seven families (16%) had cosegregation of MEN2A and HSCR1. The probability that individuals in a family with MEN2A and an exon 10 Cys variant would manifest HSCR1 was estimated to be 6% in one series.[71] Furthermore, in a multicenter international RET variant consortium study, 6 of 62 kindreds carrying either the C618R or C620R variant also had HSCR.[53]
A novel analytic approach employing family-based association studies coupled with comparative and functional genomic analysis revealed that a common RET variant within a conserved enhancer-like sequence in intron 1 makes a 20-fold greater contribution to HSCR compared with all known RET pathogenic variants.[74] This pathogenic variant has low penetrance and different genetic effects in males and females. Transmission to sons leads to a 5.7-fold increase in susceptibility and transmission to daughters leads to a 2.1-fold increase in susceptibility. This finding is consistent with the greater incidence of HSCR in males. Demonstrating this strong relationship between a common noncoding variant in RET and the risk of HSCR also accounts for previous failures to detect coding pathogenic variants in RET-linked families.
Figure 2 depicts some of the classic manifestations of MEN2A in a family.
ENLARGEPedigree showing some of the classic features of a family with a deleterious RET mutation across four generations, including transmission occurring through paternal lineage. The unaffected female proband is shown as having an affected brother (medullary thyroid cancer diagnosed at age 22 y and hyperparathyroidism diagnosed at age 24 y), father (medullary thyroid cancer diagnosed at age 54 y and pheochromocytoma diagnosed at age 67 y), and paternal aunt (medullary thyroid cancer diagnosed at age 38 y).
Figure 2. MEN2A pedigree. This pedigree shows some of the classic features of a family with a RET pathogenic variant across four generations, including affected family members with medullary thyroid cancer, pheochromocytoma, and hyperparathyroidism. Age at onset can vary widely, even within families. Medullary thyroid cancer can present with earlier onset and more aggressive disease in successive generations, depending on the genotype. MEN2A families may exhibit some or all of these features. As an autosomal dominant syndrome, transmission can occur through maternal or paternal lineages.
Familial medullary thyroid cancer (FMTC)
The FMTC subtype makes up 5% to 49% of MEN2 cases and is defined as families with four or more cases of MTC in the absence of PHEO or parathyroid adenoma/hyperplasia.[53,75] Families with two or three cases of MTC and incompletely documented screening for PHEO and parathyroid disease may actually represent MEN2A; it has been suggested that these families should be considered unclassified.[16,76] Misclassification of families with MEN2A as having FMTC (because of too-small family size or later onset of other manifestations of MEN2A) may result in overlooking the risk of PHEO, a disease with significant morbidity and mortality. For this reason, there is debate about whether FMTC represents a separate entity or is a variation of MEN2A in which there is a lack of or delay in the onset of the other (nonthyroidal) manifestations of the MEN2A syndrome.[77] Some authors recommended,[1] therefore, that patients thought to have pure FMTC also be screened for PHEO and hyperparathyroidism. Whether and how often to perform this screening are matters of ongoing debate. (Refer to the Screening at-risk individuals for PHEO and Screening at-risk individuals for hyperparathyroidism sections of this summary for more information.)

MEN2B

MEN2B is diagnosed clinically by the presence of mucosal neuromas of the lips and tongue, medullated corneal nerve fibers, distinctive facies with enlarged lips, an asthenic Marfanoid body habitus, and MTC.[78-80] In cases of de novo pathogenic variants, the diagnosis of MEN2B is often delayed, after the development of MTC. The MTC is often fatal, particularly in the presence of metastatic disease, which is common at the time of diagnosis. It is important, therefore, for pediatricians to recognize the endocrine and nonendocrine clinical manifestations of the syndrome as an earlier diagnosis may result in lifesaving treatment of MTC, before metastatic spread.[81]
The MEN2B subtype makes up about 5% of MEN2 cases. The MEN2B subtype was initially called mucosal neuroma syndrome or Wagenmann-Froboese syndrome.[82] MEN2B is characterized by the early development of an aggressive form of MTC in all patients.[82,83] Patients with MEN2B who do not undergo thyroidectomy at an early age (at approximately age 1 y) are likely to develop metastatic MTC at an early age. Before intervention with early risk-reducing thyroidectomy, the average age at death in patients with MEN2B was 21 years. PHEOs occur in about 50% of MEN2B cases; about half are multiple and often bilateral. Clinically apparent parathyroid disease is very uncommon.[53,84,85] Patients with MEN2B may be identified in infancy or early childhood by a distinctive facial appearance and the presence of mucosal neuromas on the anterior dorsal surface of the tongue, palate, or pharynx. The lips become prominent over time, and submucosal nodules may be present on the vermilion border of the lips. Neuromas of the eyelids may cause thickening and eversion of the upper eyelid margins. Prominent thickened corneal nerves may be seen by slit lamp examination.
Patients with MEN2B may have diffuse ganglioneuromatosis of the gastrointestinal tract with associated symptoms that include abdominal distension, megacolon, constipation, and diarrhea.[86] A review of the literature reported the presence of constipation as a common symptom in 72.7% of patients with MEN2B. Additionally, gastrointestinal symptoms occurred during the first year of life in 52.3% of patients with MEN2B. Intestinal biopsy led to the diagnosis of ganglioneuromatosis in 27.3% of patients.[87]
About 75% of patients have a Marfanoid habitus, often with kyphoscoliosis or lordosis, joint laxity, and decreased subcutaneous fat. Proximal muscle wasting and weakness can also be seen.[79,80]
A retrospective review of the clinical presentation of 35 cases of MEN2B with de novo pathogenic variants treated at a single institution found that 22 cases were diagnosed because of endocrine manifestations of the syndrome.[81] The diagnosis of PHEO, a neck mass, and/or skeletal abnormalities led to the identification of MTC. The remaining 13 patients presented with a nonendocrine manifestation, including oral neuromas, corneal nerve abnormalities, persistent diarrhea, failure to thrive, or skeletal abnormalities with frequent falls. Of the entire cohort, 21 patients had one or more physician referrals for the evaluation of an MEN2B-related feature, an average of 5 years before the diagnosis of MEN2B.
It is critical for pediatricians to maintain a high index of suspicion when evaluating patients with any of the clinical manifestations associated with MEN2B. In a child, the presence of oral and ocular neuromas and/or a tall and lanky appearance may warrant further investigation.[88] Some authors have recommended referral to genetic counseling for an individual with MTC or any of the following features:[88,89]
  • Benign oral and submucosal neuromas.
  • Elongated face and large lips.
  • Ganglioneuromatosis.
  • Inability to cry tears (biologic mechanism unknown).

Molecular Genetics of MEN2

MEN2 syndromes are the result of inherited pathogenic variants in the RET gene, located on chromosome region 10q11.2.[90-92] The RET gene is a proto-oncogene composed of 21 exons over 55 kilobase of genomic material.[93,94]
RET encodes a receptor tyrosine kinase with extracellular, transmembrane, and intracellular domains. Details of RET receptor and ligand interaction in this signaling pathway have been reviewed.[95-97] Briefly, the extracellular domain consists of a calcium-binding cadherin-like region and a cysteine-rich region that interacts with one of four ligands identified to date. These ligands, e.g., glial cell line–derived neurotrophic factor (GDNF), neurturin, persephin, and artemin, also interact with one of four coreceptors in the GDNF-family receptor–alpha family.[95] The tyrosine kinase catalytic core is located in the intracellular domain, which causes downstream signaling events through a variety of second messenger molecules.

Genetic testing

MEN2 is a well-defined hereditary cancer syndrome for which genetic testing is considered an important part of the management for at-risk family members. It meets the criteria related to indications for genetic testing for cancer susceptibility outlined by the American Society of Clinical Oncology in its most recent genetic testing policy statement.[98] At-risk individuals are defined as first-degree relatives (parents, siblings, and children) of a person known to have MEN2. Testing allows the identification of people with asymptomatic MEN2 who can be offered risk-reducing thyroidectomy and biochemical screening as preventive measures. A negative pathogenic variant analysis in at-risk relatives, however, is informative only after a disease-causing variant has been identified in an affected relative. (Refer to the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information.) Because early detection of at-risk individuals affects medical management, testing of children who have no symptoms is considered beneficial.[99,100] (Refer to the Genotype-Phenotype Correlations and Risk Stratification section of this summary for more information about clinical management of at-risk individuals.)
Germline DNA testing for RET pathogenic variants is generally recommended to all individuals with a diagnosis of MTC, regardless of whether there is a personal or family history suggestive of MEN2.[22,101] Approximately 95% of patients with MEN2A or MEN2B will have an identifiable germline RET pathogenic variant.[102] Between 1% and 10% of individuals with apparently sporadic MTC will carry a germline RET pathogenic variant, underscoring the importance of testing all individuals diagnosed with MTC.[103-105]
There is no evidence for the involvement of other genetic loci, and all pathogenic variant–negative families analyzed to date have demonstrated linkage to the RET gene. For families that do not have a detectable pathogenic variant, clinical recommendations can be based on the clinical features in the affected individual and in the family.
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.[102,106] Most testing laboratories, at a minimum, 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 for all exons. If targeted exon testing in a family with a high clinical suspicion for MEN2 is normal, sequencing of the remaining exons can then be performed.
These differences in variant detection method and targeted versus full gene testing represent important considerations for selecting a laboratory to perform a test and in interpreting the test result. (Refer to the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information about clinical validity.)

Genotype-Phenotype Correlations and Risk Stratification

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 MTC.[1,22,76] 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 prophylactic thyroidectomy.[22] This stratification has been revised by the American Thyroid Association (ATA).[1,107,108] The specific pathogenic variants and their ATA classification are summarized in Table 5 below.
ATA-Highest Risk (HST) (previously labeled ATA-D) pathogenic variants are the most aggressive and carry the highest risk of developing MTC.[1] This category includes those with MEN2B and RET codon M918T pathogenic variants and is associated with the youngest age at disease onset and the highest risk of mortality. ATA-High Risk (H) (previously called ATA-C) pathogenic variants, codons 634 and A883F, 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.[109] Former ATA-levels A and B pathogenic variants are now combined into a single group called Moderate Risk (MOD) and are associated with a lower risk of aggressive MTC relative to the risk seen in carriers of ATA-HST and ATA-H pathogenic variants.[108] However, the risk of MTC is still substantially elevated over the general population risk and consideration of risk-reducing thyroidectomy is warranted.[1] Common pathogenic variants in the ATA-MOD category are shown in Table 5.
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.[109-114] Approximately 95% of individuals with MEN2B will have the M918T pathogenic variant.[110-112,115] As discussed above, 50% of individuals with MEN2B will develop PHEO but 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.[109] In addition to variants at codons 883 and 918, some individuals with an MEN2B-like phenotype have been found to carry two germline variants.[116-120] 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 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.[53] In general, pathogenic variants at codon 634 are associated with PHEOs and PHPT.[53,121] Until recently, MEN2A with cutaneous lichen amyloidosis had been seen almost exclusively in patients with pathogenic variants at codon 634.[53,55,122] However, a recent report described MTC and cutaneous lichen amyloidosis in an individual previously thought to have FMTC due to a codon 804 pathogenic variant.[123] Codon 634 pathogenic variants have also been described in FMTC but are almost exclusively C634Y.[53]
In summary, ATA-HST and ATA-H (previously levels D and C, respectively) pathogenic variants confer the highest risk of MTC (about 95% lifetime risk) with a more aggressive disease course. There is an increased risk of PHEO (up to 50%).[53,124] Individuals with codon 634 pathogenic variants (but not codon 883 or 918 variants) also have an increased risk of PHPT.[53]
Moderate-risk variants located in exon 10 of the RET gene include variants at 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).[19,53,76,125-129] The risk of MTC in individuals with these pathogenic variants is approximately 95% to 100%; the risk of PHEO and hyperparathyroidism is lower than that seen in individuals with high-risk pathogenic variants.
Individuals with pathogenic variants previously classified as ATA-level A (now classified with ATA-level B as ATA-MOD, i.e., 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.[53,130-134] Although PHEO and PHPT are not commonly associated with these pathogenic variants, they have been described.[134]
Table 5. Genotype-Phenotype Correlations in Multiple Endocrine Neoplasia Type 2a
ENLARGE
RET Pathogenic variantExonRisk of Aggressive MTCApproximate Incidence of PHEOApproximate Incidence of HPTHPresence of CLAPresence of HSCR
CLA = cutaneous lichen amyloidosis; HSCR = Hirschsprung disease; HPTH = hyperparathyroidism; MTC = medullary thyroid cancer; PHEO = pheochromocytoma.
aAdapted from Wells et al.[1]
G533C8Moderate10%-NN
C609F/G/R/S/Y10Moderate10%–30%10%NY
C611F/G/S/Y/W10Moderate10%–30%10%NY
C618F/R/S10Moderate10%–30%10%NY
C620F/R/S10Moderate10%–30%10%NY
C630R/Y11Moderate10%–30%10%NN
D631Y11Moderate50%-NN
C634F/G/R/S/W/Y11High50%20%–30%YN
K666E11Moderate10%-NN
E768D13Moderate--NN
L790F13Moderate10%-NN
V804L14Moderate10%10%NN
V804M14Moderate10%10%YN
A883F15High50%-NN
S891A15Moderate10%10%NN
R912P16Moderate--NN
M918T16Highest50%-NN
In addition to the pathogenic variants categorized in Table 5, 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.[135] 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.[135] Still others may be benign polymorphisms of no clinical significance. For example, some studies demonstrate compelling evidence that RET variants Y791F (p.Tyr791Phe) and S649L (p.Ser649Leu) are likely benign polymorphisms, on the basis of equal frequencies among cases and healthy controls and co-occurrence with other disease-causing variants that cosegregate with disease in the family.[136,137] A long-term follow-up study of Danish Y791F carriers (n = 20) showed no sign of MEN2A (MTC, PHPT, PHEO, cutaneous lichen amyloidosis, or HSCR) among the cohort, with a median age of 49.5 years (range, 7–87 y).[138] Therefore, carriers of these variants are not treated as having MEN2 syndrome and asymptomatic family members are generally not tested for these variants. Comprehensive testing of all hotspot variants in exons 8 and 10–16 may be performed to rule out any other RET pathogenic variants, and more extensive testing of other disease-related genes may be warranted because of a diagnosis of PHEO. (Refer to the Familial Pheochromocytoma and Paraganglioma Syndrome section of this summary for more information.)
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.[139-142] 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. A publicly available RET variant online database repositoryExit Disclaimer was developed and includes a complete list of variants and their associated pathogenicity, phenotype, and other associated clinical information and literature references.[143]

Surveillance

Screening at-risk individuals for PHEO

The presence of a functioning PHEO can be excluded by appropriate biochemical screening before thyroidectomy in any patient with MEN2A or MEN2B. However, childhood PHEOs are rare in MEN2.[1] 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.[1] The ATA recommends that patients with ATA-MOD RET pathologic variants have periodic screening for PHEO beginning by age 16 years.[1] MRI or other imaging tests may be ordered only if the biochemical results are abnormal.[27,144] 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.[34-40,145] Several reviews provide a succinct summary of the biochemical diagnosis, localization, and management of PHEO.[40,146] In addition to surgery, there are other clinical situations in which patients with catecholamine excess face special risk. An example is the healthy at-risk female patient who becomes pregnant. Pregnancy, labor, or delivery may precipitate a hypertensive crisis in persons who carry an unrecognized PHEO. Pregnant patients who are found to have catecholamine excess require appropriate pharmacotherapy before delivery.
Level of evidence: 5

Screening at-risk individuals for hyperparathyroidism

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.[64] Childhood hyperparathyroidism is rare in MEN2. Three studies found the median age at diagnosis was about 38 years.[64,147,148] The ATA provides recommendations for annual screening for hyperparathyroidism,[1] 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.[1] Testing typically includes albumin-corrected calcium or ionized serum calcium with or without intact parathyroid hormone (PTH) measurement.
Level of evidence: 5

Screening at-risk individuals in kindreds without an identifiable RET pathogenic variant

Risk-reducing thyroidectomy is not routinely offered to at-risk individuals unless MEN2A is confirmed. The screening protocol for MTC in patients with MEN2A is annual calcitonin stimulation test; however, caution must be used in interpreting test results because CCH that is not a precursor to MTC occurs in about 5% of the population.[10,11,149] In addition, there is significant risk of false-negative test results in patients younger than 15 years.[11] Screening for PHEO and parathyroid disease is the same as described above.
For patients at risk of FMTC, annual screening for MTC is the same as for patients with MEN2A.
Level of evidence: 5

Interventions

Treatment for MTC

Risk-reducing thyroidectomy
Risk-reducing thyroidectomy is the oncologic treatment of choice for patients with MEN2. Children with the M918T RET pathogenic variant may benefit from a thyroidectomy in the first year of life, perhaps in the first months of life.[1] Likewise, children with ATA-H category RET pathogenic variants may undergo prophylactic thyroidectomy at age 5 years or earlier, on the basis of serum calcitonin levels. The ATA recommends that children in the ATA-MOD category have a physical examination, ultrasonography of the neck, and measurement of the serum calcitonin beginning around age 5 years as these tumors may have later onset but are similarly aggressive once this is taken into account.[1,108] 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 on the basis of the trend in serum calcitonin levels, ultrasonographic findings, preference of the family, and experience of the treating physicians.[1]
In children with some ATA-H or ATA-MOD RET pathogenic variants, some studies have suggested that basal and pentagastrin-stimulated calcitonin levels could be used to determine the timing of total thyroidectomy.[150-153] 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. 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.[154] Because some calcitonin assays may be more sensitive than others,[152] attention to the type of testing, as well as calcitonin levels will need to be considered. However, normal preoperative basal calcitonin does not exclude the possibility of the patient having MTC.[11,82]
For patients with RET germline variants, older age at prophylactic thyroidectomy has been significantly associated with a higher risk of postoperative persistent or recurrent disease.[155] Consistent with this, a study of young, clinically asymptomatic individuals with MEN2A showed there was a lower incidence of persistent or recurrent disease in patients who had thyroidectomy earlier in life (defined as younger than age 8 y) and who had no evidence of lymph node metastases.[156] Several studies have shown that there is 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.[157] For patients with the most aggressive M918T RET variant, cure is exceptional if surgery is performed after age 4 years.[150,158] Together, these findings are consistent with more favorable outcomes for patients undergoing early risk-reducing surgery.[157,159,160]
Although thyroidectomy before biochemical evidence of disease (normal preoperative calcitonin) may reduce the risk of recurrent disease, a selective strategy for postoperative and lifelong surveillance might depend on the final pathologic determination of whether a carcinoma was present and whether it was micromedullary or macromedullary.[1,161] One study found that 10% of patients with MEN2A undergoing thyroidectomy developed recurrent disease, on the basis of initially undetectable basal and stimulated calcitonin levels (<2 pg/mL) that became positive 5 to 10 years after surgery.[156] Only 2% of patients had residual disease after prophylactic surgery as assessed by a persistently elevated basal or stimulated calcitonin.[156]
Questions remain concerning the natural history of MEN2. As more information is acquired, recommendations regarding the optimal age for thyroidectomy and the potential role for genetics and biochemical screening may change. Earliest reports of MTC in MEN2B before age 3 years, and before age 6 years in MEN2A cases with ATA-H or ATA-MOD RET variants have been documented.[150,156,158,162] Conversely, another case report documented onset of cancer in midlife or later in some families with the FMTC subtype of MEN2A and in elderly relatives who carry the RET variant genotype but have not developed cancer.[163] Subsequent data have suggested that some ATA-MOD RET variants, which were previously thought of as more indolent may be as aggressive as ATA-H variants, but are associated with delayed onset of disease.[108] These clinical observations suggest that the natural history of the MEN2 syndromes is variable and could be subject to modifying effects related to specific RET pathogenic variants, other genes, behavioral factors, or environmental exposures.
Level of evidence: 4b
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.[1] 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.[1] The decision to perform a prophylactic central neck dissection is generally made on the basis of multiple factors such as patient age, pathogenic variant, presence of concomitant PHPT, and the vascularity of the parathyroid glands.[1] Selective autotransplantation of parathyroid glands that were devascularized during a prophylactic thyroidectomy and/or central neck clearance is recommended. A selective approach also significantly reduces the detrimental outcome of hypoparathyroidism.[164]
The MEN2B RET variant M918T is associated with approximately 100% incidence of MTC in the first years of life [158] 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.[157] 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.[151] 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 that had been 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:[1]
  • If there is no evidence of neck nodal metastases by ultrasonography in biopsy-proven thyroid disease, prophylactic 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.[165] 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.[165] 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%).[153] Therefore, the preoperative basal calcitonin level is a useful prognostic indicator and may help guide the surgical approach.
Patients who have had total thyroidectomy will require lifelong thyroid hormone replacement therapy. The dosing of medication is age-dependent and treatment may be initiated on the basis of ideal body weight. For healthy adults aged 60 years and younger with no cardiac disease, a reasonable starting dose is 1.6 µg/kg to 1.8 µg/kg given once daily.[166] Older patients may require 20% to 30% less thyroid hormone.[167] Children metabolize T4 more rapidly than adults and consequently require relatively higher replacement by body weight. Depending on the age of the child, replacement is typically between 2 µg/kg to 6 µg/kg.[168] It is important to note, however, that replacement is preferred over suppressive therapy. Since C-cell tumors are not thyroid-stimulating hormone (TSH)–dependent for growth, the T4 therapy for patients with MTC therefore may be adjusted to maintain a TSH within the normal reference range. Thyroglobulin measurement may also be useful for adjusting and maintaining TSH levels within a normal reference range to prevent additional regrowth of remnant thyroid tissue.[169]
Level of evidence (central neck dissection): 5
Level of evidence (hormone replacement therapy): 3c
Level of evidence (therapeutic thyroidectomy): 4

Treatment for MEN2-related PHEO

PHEO may be either unilateral or bilateral in patients with MEN2. Laparoscopic adrenalectomy is the recommended approach by some authorities for the treatment of unilateral PHEO.[1,22,107] 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.[170,171] In one series, 23 patients with a unilateral PHEO and a macroscopically normal contralateral adrenal gland were treated initially with unilateral adrenalectomy.[172] 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 after unilateral adrenalectomy, 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; one of these patients died. Unilateral adrenalectomy appears to represent a reasonable management strategy for unilateral PHEO in patients with MEN2.[1,173-175] Many suggest strongly considering a cortical-sparing technique, even at the initial operation for seemingly unilateral disease.[1,176] (Refer to the Interventions section in the Familial PHEO and Paraganglioma Syndrome section of this summary for more information.) 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.[1]
Regarding the operative approach, several studies examined the value of a posterior retroperitoneoscopic adrenalectomy and found it to be safe and effective, with very low mortality and a low rate of minor complications, and conversion to open or laparoscopic lateral surgery required in only 1.7% of cases.[177,178] This approach appears to be feasible and preferred, but extensive experience is needed.[170,179-182]
Level of evidence: 4

Treatment for hyperparathyroidism

Most patients with MEN2-related parathyroid disease are either asymptomatic or diagnosed incidentally at the time of thyroidectomy. Typically, the 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, primary hyperparathyroidism.[22] In general, fewer than four of the parathyroid glands are involved at the time of detected abnormalities in calcium metabolism.[1]
Treatment of hyperparathyroidism typically employs some extent of surgical removal of the involved glands. Cure of hyperparathyroidism was achieved surgically in 89% of one large series of patients;[64] however, 22% of resected patients in this study developed postoperative hypoparathyroidism. Five patients (9%) had recurrent hyperparathyroidism. This series employed 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 those parathyroid glands that are enlarged appears to be sufficient 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 the neck. For patients with MEN2A and FMTC, it is suggested that the glands be implanted in the nondominant forearm to minimize the need for further surgery on the neck after risk-reducing thyroidectomy and a central lymph node dissection.[1,183]
All patients who have undergone parathyroid surgery with autotransplantation of parathyroid tissue may be monitored for hypoparathyroidism.[1,107,184,185]
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 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 primary hyperparathyroidism.[186] 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.[1]
Level of evidence: 5

Genetic Counseling

Mode of inheritance

All of the MEN2 subtypes are inherited in an autosomal dominant manner. For the child of someone with MEN2, the risk of inheriting the MEN2 pathogenic variant is 50%. Some individuals with MEN2, however, 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.
MEN2A: About 95% of affected individuals have an affected parent. It is appropriate to evaluate the parents of an individual with MEN2A for manifestations of the disorder. In the 5% of cases that are not familial, either de novo pathogenic variants or incomplete penetrance of the mutant allele is possible.[187]
FMTC: Multiple family members are affected; therefore, all affected individuals inherited the mutant gene from a parent.
MEN2B: About 50% of affected individuals have de novo RET gene pathogenic variants, and 50% have inherited the pathogenic variant from a parent.[188,189] The majority of de novo pathogenic variants are paternal in origin, but cases of maternal origin have been reported.[190]
Siblings of a proband: The risk to siblings 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.

Attitudes toward preimplantation genetic testing

One study explored the attitudes of individuals with MEN1 and MEN2 toward preimplantation genetic testing (PGT).[191] Ninety-one clinic-based patients from a single U.S. institution who had MEN1 and an MEN1 pathogenic 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; thus, 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.[192] In addition, misconceptions about genetic disease may result in familial blame and guilt.[193,194] Several review articles outline both the medical and psychological issues, especially those related to the testing of children.[195-198] 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. Those individuals who experienced the highest level of distress were younger than 25 years, single, and had a history of responding to distressful situations with anxiety.[199] 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.[200]
A small qualitative study (N = 21) evaluated how patients with MEN2A and family members conceptualized participation in lifelong high-risk surveillance.[201] 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 MTC undergoing lifelong surveillance.[202]
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