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Classification and Genetics of Multiple Endocrine Neoplasia Type 2 - UpToDate
Classification and Genetics of Multiple Endocrine Neoplasia Type 2 - UpToDate
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Apr 2019. | This topic last updated: Mar 19, 2018.
INTRODUCTION
Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant disorder with an estimated
prevalence of 1 per 30,000 in the general population. MEN2 is characterized by medullary thyroid
carcinoma (MTC), pheochromocytoma, and primary parathyroid hyperplasia. The genetic defect in
MEN2 involves the RET proto-oncogene on chromosome 10. As expected from its autosomal
dominant inheritance pattern, men and women with MEN type 2A (MEN2A) are affected in equal
proportions.
Although MEN2 is rare, recognition is important both for treatment and for evaluation of family
members. MEN2 is often first suspected when a patient is found to have one or more of the tumors,
but molecular DNA testing is now available for detecting asymptomatic patients with MEN2.
This topic will review the classification and genetics of the MEN2 syndromes (table 1). The clinical
manifestations, diagnosis, and therapy of MEN2 are discussed separately.
● (See "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2".)
● (See "Approach to therapy in multiple endocrine neoplasia type 2".)
CLASSIFICATION
Multiple endocrine neoplasia type 2 (MEN2) is subclassified into two distinct syndromes: types 2A
(MEN2A) and 2B (MEN2B). Within MEN2A, there are four variants (table 1) [1]:
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● Classical MEN2A
● MEN2A with cutaneous lichen amyloidosis (CLA)
● MEN2A with Hirschsprung disease (HD)
● Familial medullary thyroid cancer (FMTC)
In both MEN2A and MEN2B, there is an occurrence of multicentric tumor formation in all organs
where the RET proto-oncogene is expressed. The thyroid, parathyroid and adrenal glands, and
accessory adrenals are at risk for developing tumors that may reduce life expectancy and quality of
life.
Multiple endocrine neoplasia type 2A — Within MEN2A, there are four variants: classical MEN2A,
MEN2A with CLA, MEN2A with HD, and FMTC [1].
Classical MEN2A — Classical multiple endocrine neoplasia 2A (MEN2A) is the most common
MEN2A variant [1]. It is a heritable predisposition to medullary thyroid cancer (MTC),
pheochromocytoma, and primary parathyroid hyperplasia. The respective frequency of these tumors
in classical MEN2A is over 90 percent for MTC, approximately 10 to 50 percent for
pheochromocytoma, and 10 to 20 percent for multigland parathyroid hyperplasia. The frequency of
the development of MTC, pheochromocytoma, and parathyroid hyperplasia depends upon the
specific RET mutation [1]. (See 'Germline mutations' below.)
MEN2A with cutaneous lichen amyloidosis — CLA (also known as lichen planus amyloidosis
[LPA]) has been described in some families with multiple endocrine neoplasia 2A (MEN2A),
predominantly those with the RET codon 634 mutation, although it has also been reported in a patient
with a codon 804 mutation [1-3]. The diagnosis of CLA may precede the onset of clinically evident
MTC (picture 1A-B). Patients with this variant develop pheochromocytomas and parathyroid
hyperplasia with a similar frequency as those with classical MEN2A.
MEN2A with Hirschsprung disease — HD is a motor disorder of the gut that is caused by the
failure of neural crest cells (precursors of enteric ganglion cells) to migrate completely during
intestinal development. The resulting aganglionic segment of the colon fails to relax, causing a
functional obstruction. At least eight genetic mutations have been identified in patients with HD. The
predominant gene affected is the RET proto-oncogene. RET malfunction accounts for at least 50
percent of familial and 20 percent of sporadic cases of HD. (See "Congenital aganglionic megacolon
(Hirschsprung disease)".)
In one study, the prevalence of HD in MEN2 was 7.5 percent [4]. The frequency of HD in MEN2A
depends upon the specific RET mutation. The co-occurrence of HD and MEN2A is predominantly
associated with RET mutations involving codons 609, 611, 618, and 620 [5,6]. In such patients, HD
may be the first presentation of MEN2A [7]. Patients with this variant of MEN2A develop MTC,
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pheochromocytomas, and parathyroid hyperplasia with a similar frequency as those with classical
MEN2A.
Familial medullary thyroid cancer — FMTC is a variant of MEN2A in which there is a strong
predisposition to MTC but not the other clinical manifestations of MEN2A (or 2B). The clinical
distinction of FMTC from MEN2A may be difficult on statistical grounds in small families; even in
some large kindreds, the clinical designation of FMTC has been changed to MEN2A after the
diagnosis of pheochromocytoma or hyperparathyroidism in a family member. Because FMTC is the
most limited variant of MEN2, making the wrong diagnosis of FMTC could result in missing a
pheochromocytoma in a patient with MEN2. Therefore, an FMTC kindred should be defined using the
following rigorous criteria [8]:
In a report summarizing data from 250 Italian kindreds with hereditary MTC, the prevalence of the
FMTC phenotype among RET mutation carriers was higher than MEN2A and MEN2B (57 versus 34
and 6.8 percent, respectively) [11]. This may be related to the introduction of RET screening in the
work-up of apparently sporadic MTC and the more extensive search for RET mutations in non-hot
spot regions of the gene.
Multiple endocrine neoplasia type 2B — The frequency of MEN2B has been estimated at roughly 6
percent of all MEN2 patients [12]. MEN2B shares the inherited predisposition to MTC and
pheochromocytoma that occurs in MEN2A. On the other hand, parathyroid hyperplasia is not a
feature of this disorder. There are additional important clinical differences. Patients with MEN2B tend
to have mucosal neuromas, typically involving the lips and tongue, and intestinal ganglioneuromas.
Disturbances of colonic function are common, including chronic constipation and megacolon. Many of
these patients have development abnormalities, a Marfanoid habitus, and myelinated corneal nerves.
MTC is the most common component of the MEN2B syndrome. Furthermore, the tumor is often more
aggressive and of earlier onset than in MEN2A; as a result, early diagnosis and prevention are
particularly critical.
MOLECULAR GENETICS
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Multiple endocrine neoplasia types 2A (MEN2A) and 2B (MEN2B) are inherited in an autosomal
dominant pattern with very high penetrance. The genetic defect in these disorders involves the RET
proto-oncogene on chromosome 10 [9,10,13,14].
Structure and function of the normal RET proto-oncogene and its product — The RET protein is
a receptor tyrosine kinase that appears to transduce growth and differentiation signals in several
developing tissues, including those derived from the neural crest [10]. The protein consists of an
extracellular part with a ligand-binding domain, a cadherin (calcium-dependent cell adhesion)-like
domain, and a cysteine-rich domain close to the cell membrane. It has a single transmembrane
domain and an intracellular part with two tyrosine kinase subdomains, TK1 and TK2.
Activation of RET occurs by the binding of one of its four ligands, glial cell line-derived neurotrophic
factor (GDNF), neurturin (TNT), artemin, or persephin, which require their specific co-receptors
GDNF-receptor-family-a-1 (GFR-a-1), GFR-a-2, GFR-a-3, and GFR-a-4, respectively [15-19].
Interaction of these molecules results in dimerization of RET, cross-autophosphorylation, and
subsequent phosphorylation of intracellular substrates (figure 1). RET is expressed in the C-cells of
the thyroid gland, adrenal medulla, neurons, and in other tissues. In mice, GDNF or RET play crucial
roles in the differentiation and survival of central nervous system neurons, the development of the
peripheral nervous system, and the development of the kidneys and ureters [20-23].
Structure and function of the mutated RET proto-oncogene and its product — There are
differences but much overlap in the specific RET gene mutations underlying the MEN2A variants
[9,10,24,25]; however, MEN2B is caused by specific RET mutations (figure 2) [13,24,26]. Several
studies, including one from the International RET Mutation Consortium [24], have described the
relationships between the site of mutation and the type of disease. (See 'Genotype-phenotype
correlation' below.)
Germline mutations — The germline RET mutations in MEN2 result in a gain of function [27].
This is different from many other inherited predispositions to neoplasia which are due to heritable
"loss-of-function" mutations that inactivate tumor suppressor proteins. The functional constraints for
such activating lesions are probably responsible for the small number of sites at which RET mutations
are found, a limitation that is of great benefit for molecular diagnosis in this disorder.
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hyperparathyroidism and pheochromocytoma in MEN2A and is the most common genetic defect in
this disorder (figure 2) [28]. The penetrance of hyperparathyroidism in those with mutations at this site
is approximately 20 percent. Even with the same mutation, the penetrance of hyperparathyroidism
within families varies from 9 to 34 percent [29]. Specific RET mutations have been detected in
sporadic medullary thyroid cancers (MTCs) and pheochromocytomas, whereas such mutations have
not been detected in sporadically occurring parathyroid adenomas.
MEN2B-associated tumors are caused by mutations in the intracellular TK2 domain. A single 918 Met
to Thr mutation in exon 16 is responsible for over 95 percent of cases of MEN2B and is found only in
this disorder (figure 3). Met 918 is a critical component of the substrate recognition pocket in the
tyrosine kinase catalytic core of the RET protein. In more than 50 percent of cases of MEN2B with
codon 918 affected, mutations occur as new (de novo) germline mutations [32]. Another mutation,
alanine to phenylalanine at codon 883 in exon 15, has been found in some unrelated MEN2B
kindreds [26,33,34]. Atypical MEN2B may occur by dual (tandem) mutations in codons 804 and 806
[35] or 804 and 904 [36,37].
Germline mutations causing Hirschsprung disease — Other mutations in the RET gene can
produce disorders seemingly unrelated to MEN2, further illustrating the importance of the site of the
mutation, its functional consequence (eg, gain versus loss of function) and, perhaps, the influence of
other genes upon the ultimate phenotype. In humans, the same mutation (eg, codon 620) can cause
both a gain-of-function mutation in the thyroid C cells and an inactivating mutation in the colon,
resulting in Hirschsprung disease (HD, congenital megacolon) [5,38-40]. Germline mutations in the
RET gene have been reported in approximately 50 percent of inherited forms of HD and in 15 to 20
percent of sporadic HD [41]. In one cohort of 341 patients with 620, 618, 611, and 609 codon
mutations, 25 percent of patients were affected by both diseases [5]. Specific inactivating haplotypes
may play a role in fetal development of megacolon/HD [6]. In patients with early expression of HD, it
is useful to test for MEN2, and this is especially important if a family history of HD or MEN2 is present
[5]. (See "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2", section on
'Genetic screening'.)
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Somatic mutations — Approximately 75 percent of all MTCs are sporadic. In these sporadic MTC
patients, somatic RET mutations were detected in 43 to 65 percent. Most of these mutations are in
exon 16 (codon 918), but other exons have also been affected (figure 2). In mutually exclusive
fashion with RET, mutations in RAS genes are found in approximately 20 to 25 percent of sporadic
cases [42-49]. These mutations are present only in the patient's tumor cells and are not genetically
transmitted. (See "Medullary thyroid cancer: Clinical manifestations, diagnosis, and staging", section
on 'Genetic screening in sporadic MTC'.)
The age at initial diagnosis of MTC and outcomes after thyroidectomy also correlate with the
genotype (table 2) [52]. Periodic examination of family members has shown that the age of
conversion from normal to elevated plasma calcitonin levels during a C-cell stimulation test was 18 to
31 years (mean 23 years) in FMTC variant families, compared with 6 to 33 years (mean 16 years) in
classical MEN2 families [53]. Among carriers of the RET oncogene who had thyroidectomy, all 11
patients with mutations in codons 790, 791, 804, or 891 were cured, while 5 of 35 patients with
mutations in codons 618, 620, 630, or 634 (which are associated with more aggressive disease)
failed to be cured [54].
The clinical manifestations of MEN2, the role of genetic screening, and monitoring for MEN2-
associated tumors are discussed in detail elsewhere. (See "Clinical manifestations and diagnosis of
multiple endocrine neoplasia type 2", section on 'Genetic screening' and "Clinical manifestations and
diagnosis of multiple endocrine neoplasia type 2", section on 'Monitoring for MEN2-associated
tumors'.)
Genetic screening — Advances in the molecular genetics underlying the MEN2 syndromes have
resulted in DNA testing becoming the optimal test for their detection. In contrast to MEN1, in which
the long-term benefit of early diagnosis by genetic screening is not well established, early diagnosis
by screening of "at-risk" family members in MEN2 kindreds is essential because MTC is a life-
threatening disease that can be cured or prevented by early thyroidectomy. (See "Approach to
therapy in multiple endocrine neoplasia type 2", section on 'Preventive surgery'.)
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Genetic testing in individuals with suspected MEN2, in their families, and in patients with apparently
sporadic MTC is discussed in detail elsewhere. (See "Clinical manifestations and diagnosis of
multiple endocrine neoplasia type 2", section on 'Diagnosis' and "Clinical manifestations and
diagnosis of multiple endocrine neoplasia type 2", section on 'Genetic screening' and "Medullary
thyroid cancer: Clinical manifestations, diagnosis, and staging", section on 'Genetic screening in
sporadic MTC'.)
Links to society and government-sponsored guidelines from selected countries and regions around
the world are provided separately. (See "Society guideline links: Medullary thyroid cancer".)
SUMMARY
● MEN2 is subclassified into two distinct syndromes: types 2A (MEN2A) and 2B (MEN2B) (table 1).
Within MEN2A, there are four variants. (See 'Classification' above.)
● MEN2B shares the inherited predisposition to MTC and pheochromocytoma that occurs in
MEN2A. Patients with MEN2B also tend to have mucosal neuromas, intestinal ganglioneuromas,
and, in some instances, a Marfanoid habitus; on the other hand, parathyroid hyperplasia is not a
feature of this disorder. (See 'Multiple endocrine neoplasia type 2B' above.)
● The germline RET mutations in MEN2 result in a gain of function (figure 3). This is different from
many other inherited predispositions to neoplasia, which are due to heritable "loss-of-function"
mutations that inactivate tumor suppressor proteins. (See 'Germline mutations' above.)
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● The majority of mutations in MEN2A kindreds involve one of five cysteine residues in the
cysteine-rich region of the RET protein's extracellular domain encoded in RET exons 10 (codons
609, 611, 618, and 620) or 11 (codon 634) (figure 2). (See 'Germline mutations in the
extracellular domain' above.)
● A single Met to Thr mutation in exon 16 (codon 918) is responsible for over 95 percent of cases
of MEN2B and is found only in this disorder. (See 'Germline mutations in the intracellular tyrosine
kinase domains' above.)
● The distinct clinical course of the disease in a family (frequency of pheochromocytoma and
parathyroid gland adenoma, and life expectancy) primarily depends upon the specific RET gene
germline mutation that is present. (See 'Genotype-phenotype correlation' above and "Clinical
manifestations and diagnosis of multiple endocrine neoplasia type 2".)
● Advances in the molecular genetics underlying the MEN2 syndromes have resulted in DNA
testing becoming the optimal test for their detection. (See 'Genetic screening' above and "Clinical
manifestations and diagnosis of multiple endocrine neoplasia type 2", section on 'Diagnosis' and
"Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2", section on
'Screening of family members in MEN2 kindreds'.)
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GRAPHICS
Type 2A
MEN2A classical (medullary thyroid cancer, pheochromocytoma, primary hyperparathyroidism)
Type 2B
Medullary thyroid cancer
Pheochromocytoma
Other
Mucosal neuromas
Intestinal ganglioneuromas
Marfanoid habitus
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The skin lesion is usually described as pruritic, scaly, papular, pigmented, and
located in the interscapular region or on the extensor surfaces of the extremities.
Amyloid deposition has been documented histologically.
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The skin lesion is usually described as pruritic, scaly, papular, pigmented, and
located in the interscapular region or on the extensor surfaces of the extremities.
Amyloid deposition has been documented histologically.
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MEN2: multiple endocrine neoplasia type 2; FMTC: familial medullary thyroid cancer; SMTC: sporadic
medullary thyroid cancer; HSCR: Hirschsprung disease; MEN2A: multiple endocrine neoplasia type 2A;
MEN2B: multiple endocrine neoplasia type 2B; TK: tyrosine kinase.
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918 9 months
630 12 months
634 15 months
609 5 years
620 6 years
804 6 years
611 7 years
618 7 years
790 10 years
891 13 years
912 14 years
533 21 years
791 21 years
768 22 years
666 35 years
649 44 years
Data from: de Groot JW, Links TP, Plukker JT, et al. RET as a diagnostic and therapeutic target in sporadic and hereditary
endocrine tumors. Endocr Rev 2006; 27:535.
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Contributor Disclosures
Cornelis J Lips, MD, PhD Nothing to disclose Douglas W Ball, MD Nothing to disclose Marc K Drezner,
MD Nothing to disclose Jean E Mulder, MD Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must conform to
UpToDate standards of evidence.
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