Clinical Manifestations and Diagnosis of Multiple Endocrine Neoplasia Type 2 - UpToDate

5/29/2019 Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2 - UpToDate
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Clinical manifestations and diagnosis of multiple endocrine

neoplasia type 2
Authors: Cornelis J Lips, MD, PhD, Douglas W Ball, MD
Section Editor: Marc K Drezner, MD
Deputy Editor: Jean E Mulder, MD
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 20, 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 subclassified into two distinct
syndromes: types 2A (MEN2A) and 2B (MEN2B). Within MEN2A, there are four variants: classical
MEN2A, MEN2A with cutaneous lichen amyloidosis (CLA), MEN2A with Hirschsprung disease (HD),
and familial medullary thyroid cancer (FMTC) (table 1) [1].
The genetic defect in these disorders involves the RET proto-oncogene on chromosome 10. MEN2A
and 2B are inherited in an autosomal dominant pattern with very high penetrance. In both syndromes,
there is an occurrence of multicentric tumor formation in all organs where the RET proto-oncogene is
expressed. The thyroid, parathyroid, and adrenal glands are at risk for developing tumors that may
reduce life expectancy and quality of life. The excellent prognosis for medullary thyroid cancer (MTC)
diagnosed at its earliest stage underscores the importance of early diagnosis for sporadic and
hereditary MTC [2].
This topic will review the clinical manifestations, diagnosis, and evaluation of MEN2. The genetics
and treatment of this disorder are discussed separately. Sporadic MTC is also discussed separately.
● (See "Classification and genetics of multiple endocrine neoplasia type 2".)

● (See "Approach to therapy in multiple endocrine neoplasia type 2".)
● (See "Medullary thyroid cancer: Clinical manifestations, diagnosis, and staging".)
● (See "Medullary thyroid cancer: Surgical treatment and prognosis".)
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CLINICAL FEATURES
Multiple endocrine neoplasia type 2 (MEN2) is subclassified into two distinct syndromes: types 2A
(MEN2A) and 2B (MEN2B) (table 1) [3-6].
MEN2A is characterized by medullary thyroid cancer (MTC), pheochromocytoma, and primary

parathyroid hyperplasia (see 'MEN2A' below). MEN2B is characterized by MTC and
pheochromocytoma but not hyperparathyroidism. It is associated with additional clinical features (eg,
mucosal neuromas) not seen in MEN2A. (See 'MEN2B' below.)
MEN2A — Within multiple endocrine neoplasia type 2A (MEN2A), there are four variants (table 1) [1]
(see "Classification and genetics of multiple endocrine neoplasia type 2"):
● Classical MEN2A
● MEN2A with cutaneous lichen amyloidosis (CLA)
● MEN2A with Hirschsprung disease (HD)
● Familial MTC (FMTC)
The clinical manifestations of MEN2A depend upon which organs are involved, which in turn is
dependent upon the specific RET mutation. While the penetrance of MTC is nearly 100 percent, there
is much inter- and intrafamily variability in the other manifestations of MEN2A.
FMTC is a variant of MEN2A in which there is a strong predisposition to MTC but not the other clinical
manifestations of MEN2A (or MEN2B).
Medullary thyroid cancer — MTC is a neuroendocrine tumor of the parafollicular or C cells of the
thyroid gland. Most cases of MTC (75 percent) are sporadic, but as many as 25 percent of all MTCs
are familial (table 2) [7]. Among patients with MEN2, virtually all patients develop clinically apparent
MTC, often early in life [1]. In MEN2A-associated MTC, the peak incidence of index cases is in the
third decade of life, and it is usually earlier in MEN2B. Specific RET mutations are associated with
characteristic age-specific penetrance of MTC (table 3), as well as characteristic prevalence of the
extrathyroidal manifestations. MTCs in patients with MEN2 are multicentric and concentrated in the
upper third of the thyroid gland, reflecting the normal distribution of parafollicular cells (picture 1).
If diagnosed as an index case, the clinical presentation and manifestations of MEN2-associated MTC
are similar to those of sporadic MTC, except that sporadic MTC typically presents later in life. The
most common presentation is that of a solitary thyroid nodule or cervical lymphadenopathy. Fine-
needle aspiration (FNA) biopsy shows eccentrically placed nuclei that are larger and more
pleomorphic than those of normal follicular cells. The cytoplasm may be slightly granular and is
usually configured as a tear drop or cytoplasmic tail. If the diagnosis is suspected, immunocytologic
staining for calcitonin should be performed. (See "Medullary thyroid cancer: Clinical manifestations,
diagnosis, and staging", section on 'Diagnosis'.)
Less common presentations specific to MEN2-associated MTC include recognition during a search
initiated after an associated disease (such as pheochromocytoma or hyperparathyroidism) becomes
apparent, diarrhea caused by gastrointestinal secretion of fluid and electrolytes, and flushing due to
the secretion of other peptides by the tumor. In rare cases, MTC causes Cushing's syndrome due to
ectopic production of corticotropin (ACTH). (See "Causes and pathophysiology of Cushing's
syndrome".)
In asymptomatic patients identified through calcitonin or DNA testing, initiated due to the presence of
an associated disease or to a family history of MEN2, MTC is often diagnosed in its preneoplastic
state, C-cell hyperplasia. Basal serum calcitonin concentrations usually correlate with tumor mass
and are almost always high in patients with a palpable tumor. In patients with small tumors and those
with C-cell hyperplasia, the values may be normal but rise excessively after calcium or pentagastrin
infusion [8]. (See 'Choice of biochemical test for MTC' below.)
The presence of C-cell hyperplasia is defined based upon microscopy criteria: the presence of an
increased number of diffusely scattered C cells (≥7 per thyroid follicle), complete follicles surrounded
by C cells, or distribution of C cells beyond the normal anatomical location [1,9]. C-cell hyperplasia
can occur in a reactive (secondary) form or a neoplastic form (precursor to MTC in MEN2). Neoplastic
C-cell hyperplasia is diagnosed when nests of C cells appear to extend beyond the basement
membrane and to infiltrate and destroy thyroid follicles (picture 2) [10]. Reactive C-cell hyperplasia is
considered to be caused by a stimulus from outside the C cell and probably is not premalignant
(picture 3). Hyperparathyroidism, chronic renal insufficiency, chronic lymphocytic thyroiditis, and
follicular thyroid tumors have been associated with reactive C-cell hyperplasia [11].
Pheochromocytoma — Pheochromocytoma occurs in approximately 50 percent of patients with

MEN2. The frequency of pheochromocytoma depends upon the specific underlying RET mutation
[1,12]. Some RET mutations are associated with a higher penetrance of pheochromocytoma. As an
example, in one study, the penetrance of pheochromocytoma was 25 percent by age 30 years, 52
percent by age 50 years, and 88 percent by age 77 years in patients with RET codon 634 mutations
[13].
As with MTC, pheochromocytomas in MEN2 occur earlier than sporadic forms. Although they may
develop as early as 8 to 12 years of age, the mean age of presentation is 25 to 32 years, depending
on the RET mutation [14-16]. It is unusual for pheochromocytoma to precede the development of
MTC and be the initial manifestation of MEN2. In patients who have undergone regular screening,
pheochromocytomas have usually become evident approximately 10 years later than C-cell
hyperplasia or MTC [17]. Thus, pheochromocytomas in MEN2 are usually identified during screening
or through heightened vigilance for symptoms in patients with known or suspected MEN2.
Rarely, pheochromocytoma may be the first manifestation of MEN2 [18,19]. In such patients,
symptoms are similar to those in patients with sporadic pheochromocytomas and may include attacks
(paroxysms) of anxiety, headache, diaphoresis, palpitations, or tachycardia. However, in one report,
only approximately one-third had hypertension at the time of diagnosis [20]. The severity of symptoms
may depend upon the specific RET mutation [21]. The diagnosis of pheochromocytoma includes
biochemical testing and, once a diagnosis of pheochromocytoma is established, imaging studies. The
clinical manifestations and diagnosis of pheochromocytoma are reviewed in detail separately. (See
"Clinical presentation and diagnosis of pheochromocytoma".)
Sporadic pheochromocytomas are almost always unilateral [22,23]. In contrast, pheochromocytomas

in MEN2 have been reported to be bilateral in approximately 30 to 100 percent of patients [14,20,23].
Thus, once the diagnosis of pheochromocytoma in MEN2 is established, the possibility of bilateral
disease must be carefully evaluated. Extraadrenal pheochromocytoma is rare in MEN2 but does
occur, especially in accessory adrenal glands (picture 4 and picture 5) or in extraadrenal chromaffin
cells (paragangliomas) [24,25]. (See "Paragangliomas: Epidemiology, clinical presentation, diagnosis,
and histology", section on 'MEN2'.)
In most studies, the percentage of MEN2A-associated pheochromocytomas that are malignant is

considerably less than the 10 percent rate of malignancy reported for sporadic pheochromocytomas
[7,24]. (See "Clinical presentation and diagnosis of pheochromocytoma".)
Other heritable syndromes associated with pheochromocytoma include von Hippel-Lindau (VHL)
syndrome, neurofibromatosis type 1, and paraganglioma syndromes. This topic is reviewed in more
detail elsewhere. (See "Pheochromocytoma in genetic disorders".)
Primary hyperparathyroidism — Primary hyperparathyroidism in MEN2A is almost always

multiglandular. It has been reported in 10 to 25 percent of patients with MEN2A, depending upon the
specific RET mutation [1,7,26,27]. The hyperparathyroidism in MEN2A is often mild and
asymptomatic. In patients who have undergone regular screening, the diagnosis is established by
finding high (or inappropriately normal) serum parathyroid hormone (PTH) concentrations in the
presence of hypercalcemia. (See "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and
evaluation".)
The recurrence rate after apparently successful subtotal parathyroidectomy is less than that in
multiple endocrine neoplasia type 1 (MEN1) [28,29] and is similar to the excellent long-term results
seen in patients with nonfamilial primary hyperparathyroidism.
There has been a suggestion that parathyroid disease in MEN2A may somehow be a consequence of
the C-cell abnormalities, based upon a low reported incidence of parathyroid disease in patients in
whom C-cell hyperplasia was detected early and treated by total thyroidectomy [30,31]. In one report,
as an example, none of 22 patients who underwent thyroidectomy developed hyperparathyroidism
after more than 10 years of follow-up [30]. Why this might occur and whether the risk is indeed lower
after thyroidectomy is not clear. It seems unlikely that hypercalcitoninemia per se is the stimulus for
the parathyroid tumors for the following reasons:
● Hyperparathyroidism is not associated with MEN2B, FMTC, or sporadic MTC, all of which can be
characterized by sustained hypercalcitoninemia.
● The RET gene is expressed in MEN2A-associated parathyroid tumors [32].
● A particular RET mutation, Cys to Arg at codon 634, may be preferentially found in MEN2
families that have hyperparathyroidism [3,33].
● Primary hyperparathyroidism rarely may be the first manifestation of MEN2 [34].
These data imply that the initial stimulus to parathyroid cell proliferation in MEN2A, while often mild, is
probably related to expression of the mutant RET protein within parathyroid tissue. It is interesting in
this context, although not of direct clinical importance, that calcium suppression testing in
normocalcemic patients has suggested that mild abnormalities in parathyroid function may be
common in MEN2A [35].
Other associated diseases
Cutaneous lichen amyloidosis — CLA, also termed lichen planus amyloidosis (LPA), is a rare
skin condition and can occur both sporadically and as a familial disease. The hereditary forms are
transmitted in an autosomal dominant fashion, and an association between CLA and MEN2A has
been established in some families [36].
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 (picture 6A-B) [35]. Amyloid
deposition has been documented histologically [37,38]. Keratin-like peptides have been found in the
amyloid deposits but not calcitonin-like peptides [36]. CLA is thought to result from a primary
neuropathy [38-40]. This is an attractive hypothesis with respect to CLA being a rare manifestation of
MEN2A since RET is expressed in the peripheral and central nervous system [41-43].
Several different RET codon 634 mutations have been described in MEN2A/CLA families [44,45], and
both dermal and nondermal manifestations segregate with the mutation [44]. These same RET
mutations are also found in MEN2A families without evidence of CLA, suggesting the influence of
"modifying genes" or other factors cooperating with the RET mutation in the expression of the CLA
phenotype. CLA was also reported in a patient with a RET codon 804 mutation [46]. CLA kindreds
without MEN2A have not had demonstrable germline RET mutations [45].
Hirschsprung disease — HD is characterized by the absence of autonomic ganglion cells

within the distal colonic parasympathetic plexus, resulting in chronic obstruction and megacolon. (See
"Congenital aganglionic megacolon (Hirschsprung disease)".)
HD is a heterogenic disorder, occurring both in a familial and in a sporadic form. In approximately 50

percent of familial and 15 to 35 percent of sporadic HD patients, mutations in the RET gene are
involved. In one study, HD was found in 50 percent of children in families with a C620 mutation [47].
Most HD cases arise from loss-of-function mutations, RET haploinsufficiency, RET polymorphisms, or
haplotypes of the RET promotor region. RET proto-oncogene testing in infants presenting with HD is
useful and may identify new MEN2A kindreds [48,49]. (See "Classification and genetics of multiple
endocrine neoplasia type 2", section on 'Germline mutations causing Hirschsprung disease'.)
MEN2B — Multiple endocrine neoplasia type 2B (MEN2B) is an autosomal dominant disorder

characterized by MTC and pheochromocytoma but not hyperparathyroidism. MTC occurs in almost all
patients. The tumor develops at an earlier age and is more aggressive than in MEN2A [7]. Surgery is
often not curative. In one large study, death from MTC occurred in 50 percent of patients with MEN2B
versus 9.7 percent of those with MEN2A [50]. Thus, early diagnosis and prevention are crucial.
Thyroidectomy as early as the neonatal period may be indicated in patients with MEN2B identified by
genetic screening. (See "Approach to therapy in multiple endocrine neoplasia type 2", section on
'Timing of surgery'.)
Pheochromocytoma occurs in approximately 50 percent of patients with MEN2B [1,51].

Pheochromocytomas in MEN2B occur earlier than sporadic forms. However, it is unusual for
pheochromocytoma to precede the development of MTC and be the initial manifestation of MEN2.
The syndrome of MEN2B also includes mucosal neuromas, typically involving the lips and tongue,
and intestinal ganglioneuromas. Patients with MEN2B also have development abnormalities, a
decreased upper/lower body ratio, skeletal deformations (kyphoscoliosis or lordosis), joint laxity,
Marfanoid habitus, and myelinated corneal nerves. Disturbances of colonic function are common,
including chronic constipation and megacolon [51]. Unlike patients with Marfan syndrome, MEN2B
patients do not have ectopia lentis or aortic abnormalities [7].
DIAGNOSIS
Multiple endocrine neoplasia type 2 (MEN2) should be suspected in any patient with medullary
thyroid cancer (MTC) or pheochromocytoma, particularly when the tumors occur at a young age (<35
years), are multicentric, or when more than one family member is affected. The diagnosis of MEN2 is
based upon the presence of the classical clinical features, family history, and genetic testing.
MEN2 — In an index patient with one or two of the classical clinical features, identification of a
germline RET mutation or the identification of the clinical features of multiple endocrine neoplasia
type 2 (MEN2) in other first-degree relatives is required to make the diagnosis of MEN2 [26].
In the absence of an autosomal dominant familial inheritance pattern or RET mutation, at least two of
the classical clinical features of MEN type 2A (MEN2A) (MTC, pheochromocytoma, primary
hyperparathyroidism) are required to make a clinical diagnosis of MEN2A.
In the absence of an autosomal dominant familial inheritance pattern or RET mutation, the majority of
classical clinical features of MEN type 2B (MEN2B) (MTC, pheochromocytoma, mucosal neuromas,
Marfanoid habitus, intestinal ganglioneuromas, myelinated corneal nerves) are required to make a
clinical diagnosis of MEN2B [26].
Although a patient with the classical clinical features of MEN2 and similar clinical features in one or
more first-degree relatives does not need RET mutation analysis for diagnosis, genetic testing (where
available) is performed in all patients with clinical MEN2 in order to identify the specific RET mutation
and facilitate family screening (table 4). There are rare families, however, with clinical features of
MEN2A in the absence of an identifiable RET mutation. (See 'Screening of family members in MEN2
kindreds' below.)
● Genetic testing – For the index patient with suspected MEN2A, all exons should be sequenced,
starting with the most commonly mutated codons in exons 10 and 11 and then, if negative,
sequentially proceeding to exons 8, 13, 14, 15, and 16 [1]. If no germline mutation is found, only
a small risk of hereditary MTC remains. In this case, sequencing the entire RET coding region is
an option to identify a RET mutation.
For the index patient with the MEN2B phenotype, initial testing should be for the RET codon
M918T mutation in exon 16 and, if negative, for the A883F mutation in exon 15. If no mutations
are identified, the entire RET coding region should be sequenced [1].
Once a germline RET mutation is identified in an index case, RET mutation analysis should also
be performed in first- and second-degree family members. The screening of family members is
discussed below. (See 'Screening of family members in MEN2 kindreds' below.)
Occasionally, older patients with MTC, a negative family history, and no clinical features of MEN2
may nonetheless harbor a cryptic germline RET mutation. Evaluation of patients with apparently
sporadic MTC should include genetic testing for germline RET mutations. The indications for
genetic testing for the detection of unsuspected heritable MEN2 in patients with apparently
sporadic MTC or pheochromocytoma (eg, unilateral disease, a negative family history, and no
other signs or symptoms of MEN2) is reviewed separately. (See "Medullary thyroid cancer:
Clinical manifestations, diagnosis, and staging", section on 'Genetic screening in sporadic MTC'
and "Pheochromocytoma in genetic disorders", section on 'Genetic screening'.)
Familial medullary thyroid cancer variant — The familial MTC (FMTC) variant of MEN2A is
characterized by the presence of a RET germline mutation in families with MTC, or an individual with
MTC, who do not develop pheochromocytoma or primary hyperparathyroidism. Distinguishing the
FMTC variant from classical MEN2A may be difficult in small families, and therefore, rigorous criteria
for FMTC should be used in order not to miss a pheochromocytoma [52]. There should be:
● More than 10 carriers in the kindred

● Multiple carriers or affected members over the age of 50 years
● An adequate medical history, particularly in older family members
EVALUATION
RET mutation analysis — For patients diagnosed with multiple endocrine neoplasia type 2 (MEN2)
based upon the classical clinical features and family history (typically medullary thyroid cancer [MTC]
and a family member with MTC), evaluation should include RET mutation analysis (if not already
performed) in order to identify the specific RET mutation to facilitate family screening (table 4). (See
'Diagnosis' above and "Medullary thyroid cancer: Clinical manifestations, diagnosis, and staging",
section on 'Genetic screening in sporadic MTC' and 'Genetic screening' below.)
If a family member is positive for the RET mutation, prophylactic thyroidectomy is indicated. The
timing of thyroidectomy is based upon the specific RET mutation and, in some cases, serum
calcitonin levels. (See "Approach to therapy in multiple endocrine neoplasia type 2", section on
'Preventive surgery'.)
Screening for MEN2-associated tumors — Patients with multiple endocrine neoplasia type 2
(MEN2) (and their affected family members) also require screening for MEN2-associated tumors. In
all patients diagnosed with MEN2, we measure plasma fractionated metanephrines (as the initial
screen for pheochromocytoma) and serum calcium (to rule out hyperparathyroidism requiring
concomitant surgical intervention). For patients with MEN2 who present with pheochromocytoma
rather than MTC, we measure serum calcitonin and obtain a thyroid and neck ultrasound to assess
for the presence of MTC.
Screening for MEN2-associated tumors in families of the index patient is reviewed below. (See
'Monitoring for MEN2-associated tumors' below.)
Pheochromocytoma — Screening for pheochromocytoma is mandatory in all patients with

inherited MTC syndromes. If pheochromocytoma is found, it should be removed prior to
thyroidectomy.
For the index patient with MTC, we measure plasma fractionated metanephrines as the initial screen
for pheochromocytoma. If biochemical results are positive, adrenal imaging with computed
tomography (CT) or magnetic resonance imaging (MRI) is the next step. (See "Clinical presentation
and diagnosis of pheochromocytoma", section on 'Additional evaluation after biochemical diagnosis'.)
If the initial screening tests for pheochromocytoma are negative, it is important to evaluate for
pheochromocytoma yearly (table 5). Details of biochemical screening to detect pheochromocytomas,
including in MEN2 patients, is reviewed elsewhere. (See "Clinical presentation and diagnosis of
pheochromocytoma", section on 'High risk for pheochromocytoma'.)
Hyperparathyroidism — When the diagnosis of MEN type 2A (MEN2A)-related MTC is

established, we measure serum calcium to rule out hyperparathyroidism requiring concomitant
surgical intervention. Hyperparathyroidism is not part of the MEN type 2B (MEN2B) syndrome, and
therefore, patients with MEN2B do not require evaluation for hyperparathyroidism.
If the serum calcium is elevated, we measure intact parathyroid hormone (PTH). The diagnosis is
established by finding high (or inappropriately normal) serum PTH concentrations in the presence of
hypercalcemia. (See "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and
evaluation".)
If the serum calcium is normal, we measure serum calcium yearly to detect the development of
hyperparathyroidism (table 5).
Medullary thyroid cancer — Most index patients with MEN2 present with MTC and, therefore, do
not require monitoring for its development. For patients with MEN2 who present with
pheochromocytoma, we measure serum calcitonin and obtain a thyroid and neck ultrasound to
assess for the presence of MTC. If there is no evidence of MTC, we continue to screen annually
(table 6).
Additional evaluation of patients who have been diagnosed with MEN2-related MTC is similar to that
in sporadic MTC and should include measurement of serum calcitonin, carcinoembryonic antigen
(CEA), and ultrasonography of the neck (if not already performed). (See "Medullary thyroid cancer:
Clinical manifestations, diagnosis, and staging", section on 'Evaluation'.)
SCREENING OF FAMILY MEMBERS IN MEN2 KINDREDS
Once a germline RET mutation is identified in an index case, RET mutation analysis should be
performed in first- and second-degree family members. Affected family members also require
screening for multiple endocrine neoplasia type 2 (MEN2)-associated tumors. (See 'Genetic
screening' below and 'Monitoring for MEN2-associated tumors' below.)
Advances in the molecular genetics underlying the MEN2 syndromes have resulted in DNA testing
becoming the optimal test for their detection. The role of RET DNA testing in MEN2 kindreds is better
established than testing for MEN1 mutations in multiple endocrine neoplasia type 1 (MEN1) families.
This is because identification of specific RET mutations predicts particular phenotypes (age of onset,
aggressiveness of medullary thyroid cancer [MTC], and presence or absence of other endocrine
neoplasms) and, thus, guides surveillance and management (table 3 and table 5 and table 6) [2].
In the past, pentagastrin and calcium stimulation tests were used to stimulate calcitonin secretion by
thyroid C cells and assess for the diagnosis of MTC in family members. However, RET mutation
screening is available for MEN2, and therefore, these tests have lost their clinical significance with
respect to diagnosis of MEN2 [53]. Genetic testing in known MEN2 families has several clinically
important advantages over the pentagastrin or calcium tests:
● It provides clinical benefit that should accrue from earlier surgery for known MEN2 gene carriers
as the genotype correlates with the age at initial diagnosis of MTC (table 3).
● It definitively establishes that an individual does not carry the MEN2 mutation and eliminates the
need for biochemical testing.
● It avoids unnecessary thyroidectomy in genetically normal subjects in MEN2 families. It is now

clear, from retrospective DNA testing, that such subjects can have falsely positive pentagastrin
tests [54,55].
However, biochemical tests are still used in families who meet the clinical criteria for MEN2 but have
negative sequencing of the entire RET coding region or for families who refuse genetic testing. (See
'When RET mutation is unknown' below.)
Genetic screening — In general, the primary and most compelling purpose of genetic screening in
human tumor predisposition syndromes is to prevent disease-related morbidity and mortality that
would otherwise occur [2,26,56,57]. Genetic counseling and genetic testing for RET germline
mutations should be offered to the following groups [1]:
● First-degree relatives of a patient with proven germline RET mutation
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● Parents whose infants or young children have the clinical characteristics of MEN type 2B
(MEN2B)
● Patients with cutaneous lichen amyloidosis (CLA)
● Families whose infants or young children have Hirschsprung disease (HD)
In an MEN2 family, a sample from one subject already known to be affected should be tested in order
to determine the specific RET mutation for that family. All subjects of unknown status in that family
should then be definitively genotyped. RET genotyping requires only a small blood sample and can
therefore be performed at birth or soon thereafter. At the latest, genotyping should be done before the
time at which prophylactic thyroidectomy would be performed in the event of a positive result.
● Known RET mutation present – For those with RET mutations, prophylactic thyroidectomy in
family members is timed based upon the specific DNA mutation in the RET proto-oncogene
occurring in the family (table 6). The risk-benefit equation is strengthened by the ease of thyroid
hormone replacement after thyroidectomy and the relatively low morbidity of the surgery, even in
children, when performed by high-volume surgeons [58]. The timing of prophylactic
thyroidectomy is reviewed separately. (See "Approach to therapy in multiple endocrine neoplasia
type 2", section on 'Preventive surgery'.)
● Known RET mutation absent – A family member who has not inherited the specific RET
mutation that causes that family's MTC needs no further evaluation.
Thus far, family screening efforts appear to be suboptimal, as a high proportion of patients continue to
receive less than optimal initial surgical treatment. According to the population-based Surveillance,
Epidemiology, and End Results (SEER) registry, there has been no change in stage at diagnosis or
significant improvement in survival noted over the last 30 years [59,60]. Although the SEER registry
does not contain information regarding hereditary or biochemical results, an estimated 50 percent had
a familial form of MTC (FMTC). This suggests that many MEN2/FMTC patients underwent surgery
that was less than optimal for the stage of the disease. Summary information concerning MEN2 may
be useful for counseling patients and affected families. Family alliances can provide such information:
Genetic Testing Registry (GTR) or EndocrineWeb.
Sensitivity/specificity — One potential problem relates to the rare MEN2 families with no
detectable RET mutation. In addition, as with any genetic test, other potential sources of error exist
such as sample mix-up, cross-contamination of the polymerase chain reactions used in the tests, and
DNA polymorphisms that would prevent amplification of one RET allele, a situation that could result in
a false-negative screening test. To date, however, neither false-negative nor false-positive RET tests
have been described in MEN2 families in which a specific RET mutation was detected in an index
case.
Availability of genetic diagnosis — Genetic diagnosis of MEN type 2A (MEN2A), FMTC, and
MEN2B is readily available commercially. A list of testing laboratories is available at the MD Anderson
Cancer Center website and through the genetic testing resource Genetic Testing Registry (GTR). In
Europe, a listing of commercial laboratories can be found at the European Directory of DNA
Diagnostic Laboratories.
Clinicians should inquire as to the protocol and methodology of the offered RET DNA test. One
important issue is whether all relevant exons (exons 10, 11, and 16, and, if those are negative, exons
8, 13, 14, and 15) will be sequenced if the RET mutation in that family is unknown.
Counseling — Before blood samples are taken for DNA analysis, detailed information about the
consequences of DNA analysis must be provided to the family. Psychological support may well be
needed before DNA test results are disclosed and during follow-up after diagnosis to minimize
distress. Written consent must be obtained [61]. Given the rarity of this disease and the potential
complications of a total thyroidectomy in young children, patients should be referred to academic
centers with expertise in MEN2.
Reproductive options — Patients with MEN2 and a known familial RET mutation should be
counseled that prenatal testing and preimplantation genetic testing are available options if they
choose to pursue fertility [26]. Prenatal testing is performed in the first or second trimester via
chorionic villus sampling or amniocentesis, respectively. Preimplantation genetic diagnosis (PGD) is
done as part of in vitro fertilization (IVF); single embryonic cells are tested for the RET mutation. Only
embryos without a RET mutation are then transferred to the uterus. The various reproductive options
available to prospective parents require thoughtful discussion and genetic counseling.
Monitoring for MEN2-associated tumors — Affected family members require screening for multiple
endocrine neoplasia type 2 (MEN2)-associated tumors.
When RET mutation is known — When the RET mutation is known, monitoring for MEN2-
associated tumors is based upon the specific mutation and degree of risk it confers for MTC,
pheochromocytoma, and primary hyperparathyroidism.
Medullary thyroid cancer — Children with certain RET mutations can develop clinically
apparent MTC at an early age. The goal in patients with known RET mutations (but without clinically
apparent disease) is to perform a prophylactic thyroidectomy before MTC develops or when it is still
confined to the thyroid gland (table 6). (See "Approach to therapy in multiple endocrine neoplasia type
2", section on 'Preventive surgery'.)
Children with the highest risk mutation (codon 918) should have thyroidectomy within the first year of
life and, therefore, do not require monitoring.
For children with high-risk mutations (codons 634, 883), we begin monitoring at age three years, and
for children with moderate risk mutations, we begin monitoring at age five years. We monitor with an
annual physical examination, neck ultrasound, and measurement of serum calcitonin. The detection
of a serum calcitonin level (basal or stimulated) above the upper limit of normal is an indication for
surgery.
Pheochromocytoma — The risk of developing pheochromocytoma is variable depending upon

genotype [62-64]. For children in the highest and high-risk categories, screening for
pheochromocytoma should begin by age 11 years (table 5). For children in the moderate-risk
category, we begin screening by age 16 years. Patients should be screened yearly by measuring
plasma fractionated metanephrines or 24-hour urinary metanephrines and normetanephrines. If
biochemical results are positive, adrenal imaging with computed tomography (CT) or magnetic
resonance imaging (MRI) is the next step. (See "Clinical presentation and diagnosis of
pheochromocytoma", section on 'Additional evaluation after biochemical diagnosis'.)
There is large variability in the penetrance of pheochromocytoma among different reported kindreds,
depending upon the specific RET germline mutation. These findings help guide screening and
therapy for MEN2 patients [65-69]. As an example, compared with families with mutations in codons
634 and 918, pheochromocytomas are rare in families with mutations in codons 533, 609, 611, 618,
620, 630, 633, 666, 768, 790, 791, 804, and 891, although they do still occur.
Due to screening programs, pheochromocytomas may be diagnosed at a young age and before
symptoms are present.
Hyperparathyroidism — The hyperparathyroidism in MEN2A is often mild and asymptomatic.

In one study, the mean age at diagnosis was 33 years, but children diagnosed as young as two years
of age has been reported [1,27,70,71]. Biochemical screening for hyperparathyroidism should be
performed yearly beginning at age 11 years in high-risk patients and 16 years in moderate-risk
patients (patients in the highest risk category [MEN2B] are not at risk for developing
hyperparathyroidism) (table 5) [1]. We measure serum calcium (corrected for albumin). If it is
elevated, we measure intact parathyroid hormone (PTH). The diagnosis is established by finding high
(or inappropriately normal) serum PTH concentrations in the presence of hypercalcemia. (See
"Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation".)
When RET mutation is unknown
Biochemical testing — For closely related MEN2 family members who refuse DNA analysis
for themselves or their children, or for families who meet the clinical criteria for MEN2 but have
negative sequencing of the entire RET coding region, biochemical testing can be performed to detect
MEN2-related tumors. If biochemical testing is used, yearly testing starting at age five and continuing
until at least age 35 years (or until a positive test occurs) is necessary [7]. For families with a clinical
diagnosis of MTC prior to age five years, biochemical screening for MTC should begin at the
youngest age of first diagnosis.
Either a pentagastrin or a calcium stimulation test can be used to screen for C-cell hyperplasia/MTC.
Where available (not in the United States), pentagastrin is the preferred stimulation test. Testing
should also include plasma fractionated metanephrines or 24-hour urinary metanephrines and
normetanephrines (to screen for pheochromocytoma) and serum calcium (to screen for
hyperparathyroidism).
Choice of biochemical test for MTC — Owing to the unavailability of pentagastrin in many
countries, there is growing interest in the calcium stimulation test. However, there are few data using
the calcium stimulation as a confirmatory test in patients with elevated basal calcitonin levels, and
cutpoints for the discrimination of normal, C-cell hyperplasia, and medullary thyroid cancer (MTC)
have not been standardized [72]. In one study, basal and stimulated calcitonin levels were measured
in over 100 patients with thyroid disease (MTC in remission or persistence, RET gene mutation
carriers, nodular goiter) and in 16 healthy volunteers [73]. In all groups, the levels of calcitonin
stimulated by either pentagastrin or calcium were significantly correlated. In this study, calcium
stimulated calcitonin levels above 32.6 pg/mL (females) and 192 pg/mL (males) had the best
accuracy to differentiate normal subjects from patients with C-cell hyperplasia or MTC [73]. Criteria for
abnormal calcitonin values may vary in local or commercial laboratories [74].
● Pentagastrin stimulation test – The pentagastrin stimulation test uses a slow intravenous
injection of pentagastrin (0.5 mcg/kg body weight) over three minutes. Blood samples for
calcitonin are obtained at baseline and two and five minutes after pentagastrin infusion [75,76]. If
stimulated calcitonin values are ≥200 pg/mL, MTC is likely and thyroidectomy and
lymphadenectomy are required. If values are <100 pg/mL, the risk of MTC is low and periodic
monitoring of basal and stimulated serum calcitonin levels is recommended. If the stimulated
calcitonin values are between 100 and 200 pg/mL, the risk is uncertain. Such values could be
indicative of C-cell hyperplasia or micro MTC. Some advise surgery [77,78], while others
observation (following calcitonin levels) [79].
Side effects of pentagastrin include abdominal cramping, extremity paresthesia, and feeling of
warmth, lasting up to one to two minutes [76]. Pentagastrin is not available in many countries,
including the United States.
● Calcium stimulation test – The calcium stimulation test uses an infusion of calcium gluconate
(2.5 mg elemental calcium/kg body weight over 30 seconds) administered in a fasting state (no
food after midnight) [54,76]. Blood samples for calcitonin are obtained at baseline and two and
five minutes after the stimulus. In one study, calcium-stimulated calcitonin levels above 32.6
pg/mL (females) and 192 pg/mL (males) had the best accuracy to differentiate normal subjects
from patients with C-cell hyperplasia or MTC [73].
The most common side effects are temporary flushing and feeling of warmth (98 percent) [76].
Facial paresthesias are less common (20 percent).
SOCIETY GUIDELINE LINKS
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 AND RECOMMENDATIONS
● Multiple endocrine neoplasia type 2 (MEN2) is subclassified into two distinct syndromes: types
2A (MEN2A) and 2B (MEN2B) (table 1). Within MEN2A, there are four variants. The genetic
defect in MEN2 involves the RET proto-oncogene on chromosome 10. MEN2A and 2B are
inherited in an autosomal dominant pattern with very high penetrance. (See 'Introduction' above.)
● MEN2A is characterized by medullary thyroid cancer (MTC), pheochromocytoma, and primary

parathyroid hyperplasia. While the lifetime penetrance of MTC is nearly 100 percent, there is
much inter- and intrafamily variability in MTC onset and in the other manifestations of MEN2A.
(See 'Clinical features' above.)
● MEN2B is characterized by MTC and pheochromocytoma but not hyperparathyroidism. MTC

occurs in almost all patients. The tumor develops at an earlier age and is more aggressive than
in MEN2A; as a result, early diagnosis and prevention are crucial. The syndrome also includes
mucosal neuromas, typically involving the lips and tongue, intestinal ganglioneuromas, and a
Marfanoid habitus. Disturbances of colonic function are common, including chronic constipation
and megacolon. (See 'Clinical features' above.)
● MEN2 should be suspected in any patient with MTC or pheochromocytoma, particularly when the
tumors occur at a young age (<35 years), are multicentric, or when more than one family
member is affected. The diagnosis of MEN2 is based upon the presence of the classical clinical
features, family history, and genetic testing. (See 'Diagnosis' above.)
● In an index patient with one or two of the classical clinical features, identification of a germline
RET mutation or the identification of the clinical features of MEN2 in other first-degree relatives is
required to make the diagnosis of MEN2. (See 'MEN2' above.)
In the absence of an autosomal dominant inheritance pattern or RET mutation, at least two of the
classical clinical features of MEN2A (MTC, pheochromocytoma, primary hyperparathyroidism)
are required to make the diagnosis.
In the absence of an autosomal dominant familial inheritance pattern or RET mutation, the
majority of classical clinical features of MEN2B are required to make a clinical diagnosis of
MEN2B.
● Familial MTC (FMTC) is characterized by the presence of a RET germline mutation in families
with MTC, or an individual with MTC, who do not develop pheochromocytoma or primary
hyperparathyroidism. Distinguishing the FMTC variant from classical MEN2A may be difficult in
small families, and therefore, rigorous criteria for FMTC should be used in order not to miss a
pheochromocytoma. (See 'Familial medullary thyroid cancer variant' above.)
● For patients diagnosed with MEN2 based upon the classical clinical features and family history
(typically MTC and a family member with MTC), evaluation should include RET mutation analysis
(if not already performed) in order to identify the specific RET mutation to facilitate family
screening (table 4). (See 'RET mutation analysis' above.)
● Patients with MEN2 also require screening for MEN2-associated tumors. In all patients
diagnosed with MEN2-related MTC, we measure plasma fractionated metanephrines (as the
initial screen for pheochromocytoma in patients with MEN2A or 2B) and serum calcium (to rule
out hyperparathyroidism requiring concomitant surgical intervention in patients with MEN2A). For
patients with MEN2 who present with pheochromocytoma rather than MTC, we measure serum
calcitonin and obtain a neck ultrasound to assess for the presence of MTC. (See 'Screening for
MEN2-associated tumors' above.)
If pheochromocytoma is found, it should be removed prior to thyroidectomy. If the initial testing

for coexisting tumors is negative, it is important to evaluate the index patient for
pheochromocytoma (MEN2A and 2B) and hyperparathyroidism (MEN2A) yearly (table 5).
● Once a germline RET mutation is identified in an index case, RET mutation analysis should also
be performed in first- and second-degree family members. Affected family members require
screening for MEN2-associated tumors. (See 'Genetic screening' above and 'Monitoring for
MEN2-associated tumors' above.)
Early diagnosis by screening of "at-risk" family members in MEN2 kindreds is important because
identification of specific RET mutations predicts particular phenotypes (age of onset,
aggressiveness of MTC, and presence or absence of other endocrine neoplasms) and, thus,
guides surveillance for MEN2-associated tumors and management (table 3 and table 5 and table
6). (See 'Screening of family members in MEN2 kindreds' above.)
● For those with RET mutations, prophylactic thyroidectomy in family members is timed based
upon the specific DNA mutation in the RET proto-oncogene occurring in the family (table 6). (See
"Approach to therapy in multiple endocrine neoplasia type 2", section on 'Timing of surgery'.)
Use of UpToDate is subject to the Subscription and License Agreement.
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Topic 7870 Version 14.0
GRAPHICS
Classification of multiple endocrine neoplasia type 2
Type 2A
MEN2A classical (medullary thyroid cancer, pheochromocytoma, primary hyperparathyroidism)
MEN2A with cutaneous lichen amyloidosis
MEN2A with Hirschsprung disease
Familial medullary cancer without pheochromocytoma or parathyroid hyperplasia
Type 2B
Medullary thyroid cancer
Pheochromocytoma
Other
Mucosal neuromas
Intestinal ganglioneuromas
Marfanoid habitus
MEN2A: multiple endocrine neoplasia type 2A.
Graphic 101551 Version 4.0
Classification of MTC
Hereditary MTC (germline RET mutation present) 25%
Sporadic MTC (no germline RET mutation identified) 75%
Sporadic MTC (no germline RET mutation identified)
• No somatic RET mutations found 35%
• Somatic RET mutations found 65%
- Exon 16, codon 918 60%
- Exon 11, codon 630, 634 21%
- Exon 10, codon 609, 620 9%
- Exon 15, codon 891 9%
MTC: medullary thyroid cancer.
RET mutation-related youngest age of onset of MTC
Age-related progression of hereditary MTC depends on RET genotype
RET genotype of MTC Youngest age at first diagnosis
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
MTC: medullary thyroid cancer.
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.
Medullary thyroid cancer: Surgical specimen
Pathological specimen of bilateral and multicentric medullary thyroid cancer.
Reproduced from: Expert Review of Endocrinology & Metabolism, September 2009, Vol. 4, No. 5,
Pages 443-465 with permission of Expert Reviews Ltd.
Neoplastic C-cell hyperplasia
C-cell hyperplasia and microcarcinomas in a 5-year-old boy with the Cys634Arg mutation.
The expanding C-cell masses disrupt the basal membrane surrounding individual thyroid
follicles (arrows).
Reproduced from: Expert Review of Endocrinology & Metabolism, September 2009, Vol. 4, No.
5, Pages 443-465 with permission of Expert Reviews Ltd.
Secondary C-cell hyperplasia
Secondary C-cell hyperplasia. The follicular boundaries are intact.
Courtesy of Cornelis J Lips, MD, PhD.
Pheochromocytoma in an accessory adrenal gland: Surgical

specimen
Multicentric pheochromocytoma of the left adrenal gland together with a small

pheochromocytoma in an accessory adrenal gland 8 mm in diameter. The bean-shaped
structure is the left semilunar celiac ganglion.
Pheochromocytoma: Surgical specimen
Multinodular pheochromocytoma: General view and cross section. A rim of cortical tissue
can be seen at the top.
Reproduced from: Expert Review of Endocrinology & Metabolism, September 2009, Vol. 4, No. 5,
Pages 443-465 with permission of Expert Reviews Ltd.
Cutaneous lichen amyloidosis in a patient with MEN2:

General view
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.
Cutaneous lichen amyloidosis in a patient with MEN2:

Close-up
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.
MEN2: multiple endocrine neoplasia type 2.
Criteria for DNA analysis for MEN2/FMTC
RET mutation analysis should be performed:

In patients with:
1. Clinically proven MEN2 syndrome: bilateral, multicentric MTC, and/or pheochromocytoma
2. MTC or pheochromocytoma and a family member with MTC or pheochromocytoma
3. Apparently sporadic MEN2 related tumors and:
a. Age younger than 35 years and/or
b. Multicentric tumors in one organ and/or
c. Two different organs affected
First- and second-degree family members of MEN2 patients
All patients with sporadic MTC ? (may have consequences for target-directed treatment)
Refer to UpToDate topic on the clinical manifestations and diagnosis of multiple endocrine neoplasia type 2.
MEN2: multiple endocrine neoplasia type 2; FMTC: familial medullary thyroid cancer; MTC: medullary thyroid cancer.
Data from:
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 2001; 86:5658.
2. Machens A, Dralle H. Genotype-phenotype based surgical concept of hereditary medullary thyroid carcinoma. World J
Surg 2007; 31:957.
3. American Thyroid Association Guidelines Task Force, Kloos RT, Eng C, et al. Medullary thyroid cancer: Management
guidelines of the American Thyroid Association. Thyroid 2009; 19:565. Comment in Thyroid 2009; 19:1295.
Clinical monitoring for pheochromocytoma and hyperparathyroidism in carriers of a

mutation in the RET gene
Pheochromocytoma* Hyperparathyroidism
Risk RET codon mutation Recommended age to begin Recommended age to begin
annual screening for annual screening for
pheochromocytoma ¶ hyperparathyroidism Δ
Highest 918 11 years Not applicable
High 634, 883 11 years 11 years
Moderate 533, 609, 611, 618, 620, 16 years 16 years

630, 666, 768, 790, 804,
891, 912
MEN2: multiple endocrine neoplasia type 2; MTC: medullary thyroid cancer; CT: computed tomography; MRI: magnetic
resonance imaging; PTH: parathyroid hormone.
* Patients with MEN2 and a diagnosis of MTC (regardless of age) must have pheochromocytoma excluded prior to
thyroidectomy.
¶ Screening test: free plasma metanephrines or normetanephrines, or 24-hour urinary metanephrines and normetanephrines.
If biochemical results positive, adrenal imaging with CT or MRI.
Δ Screening test: serum calcium and, if elevated, PTH.
Data from: Wells SA Jr, Asa SL, Dralle H, et al. Revised American Thyroid Association guidelines for the management of
medullary thyroid carcinoma. Thyroid 2015; 25:567.
Clinical monitoring for medullary thyroid cancer and timing of thyroidectomy in

carriers of a mutation in the RET gene
Recommended age to Recommended timing of

Risk RET codon mutation begin annual screening prophylactic
for MTC* thyroidectomy ¶
Highest 918 Not applicable In the first months to year of life
High 634, 883 3 years At or before age 5 years
Moderate 533, 609, 611, 618, 620, 630, 5 years Childhood or young adulthood
666, 768, 790, 804, 891, 912
Risk of MTC development in MEN2 depends on mutated RET codon.
MTC: medullary thyroid cancer; MEN2: multiple endocrine neoplasia type 2.

* Annual physical examination, neck ultrasound, and measurement of serum calcitonin.
¶ Patients with MEN2 and a diagnosis of MTC (regardless of age) must have pheochromocytoma excluded prior to
thyroidectomy.
Data from: Wells SA Jr, Asa SL, Dralle H, et al. Revised American Thyroid Association guidelines for the management of
medullary thyroid carcinoma. Thyroid 2015; 25:567.
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.
Conflict of interest policy

Clinical Manifestations and Diagnosis of Multiple Endocrine Neoplasia Type 2 - UpToDate

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Clinical Manifestations and Diagnosis of Multiple Endocrine Neoplasia Type 2 - UpToDate

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5/29/2019 Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2 - UpToDate

Official reprint from UpToDate®

Clinical manifestations and diagnosis of multiple endocrine

● (See "Classification and genetics of multiple endocrine neoplasia type 2".)

MEN2A is characterized by medullary thyroid cancer (MTC), pheochromocytoma, and primary

Pheochromocytoma — Pheochromocytoma occurs in approximately 50 percent of patients with

Sporadic pheochromocytomas are almost always unilateral [22,23]. In contrast, pheochromocytomas

In most studies, the percentage of MEN2A-associated pheochromocytomas that are malignant is

Primary hyperparathyroidism — Primary hyperparathyroidism in MEN2A is almost always

● The RET gene is expressed in MEN2A-associated parathyroid tumors [32].

● Primary hyperparathyroidism rarely may be the first manifestation of MEN2 [34].

Other associated diseases

Hirschsprung disease — HD is characterized by the absence of autonomic ganglion cells

HD is a heterogenic disorder, occurring both in a familial and in a sporadic form. In approximately 50

MEN2B — Multiple endocrine neoplasia type 2B (MEN2B) is an autosomal dominant disorder

Pheochromocytoma occurs in approximately 50 percent of patients with MEN2B [1,51].

● More than 10 carriers in the kindred

Pheochromocytoma — Screening for pheochromocytoma is mandatory in all patients with

Hyperparathyroidism — When the diagnosis of MEN type 2A (MEN2A)-related MTC is

SCREENING OF FAMILY MEMBERS IN MEN2 KINDREDS

● It avoids unnecessary thyroidectomy in genetically normal subjects in MEN2 families. It is now

● First-degree relatives of a patient with proven germline RET mutation

● Patients with cutaneous lichen amyloidosis (CLA)

● Families whose infants or young children have Hirschsprung disease (HD)

Pheochromocytoma — The risk of developing pheochromocytoma is variable depending upon

Hyperparathyroidism — The hyperparathyroidism in MEN2A is often mild and asymptomatic.

When RET mutation is unknown

SOCIETY GUIDELINE LINKS

SUMMARY AND RECOMMENDATIONS

● MEN2A is characterized by medullary thyroid cancer (MTC), pheochromocytoma, and primary

● MEN2B is characterized by MTC and pheochromocytoma but not hyperparathyroidism. MTC

If pheochromocytoma is found, it should be removed prior to thyroidectomy. If the initial testing

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13. Imai T, Uchino S, Okamoto T, et al. High penetrance of pheochromocytoma in multiple

14. Thosani S, Ayala-Ramirez M, Palmer L, et al. The characterization of pheochromocytoma and

15. Machens A, Lorenz K, Dralle H. Peak incidence of pheochromocytoma and primary

27. Schuffenecker I, Virally-Monod M, Brohet R, et al. Risk and penetrance of primary

69. Pinna G, Ghiani M, Mariotti S. Asymptomatic bilateral adrenal pheochromocytoma in a patient

Topic 7870 Version 14.0

Classification of multiple endocrine neoplasia type 2

MEN2A with cutaneous lichen amyloidosis

MEN2A with Hirschsprung disease

Familial medullary cancer without pheochromocytoma or parathyroid hyperplasia

MEN2A: multiple endocrine neoplasia type 2A.

Graphic 101551 Version 4.0

Hereditary MTC (germline RET mutation present) 25%

Sporadic MTC (no germline RET mutation identified) 75%

Sporadic MTC (no germline RET mutation identified)

• No somatic RET mutations found 35%

• Somatic RET mutations found 65%

- Exon 16, codon 918 60%

- Exon 11, codon 630, 634 21%

- Exon 10, codon 609, 620 9%

- Exon 15, codon 891 9%

MTC: medullary thyroid cancer.

Graphic 85653 Version 4.0

RET mutation-related youngest age of onset of MTC

Age-related progression of hereditary MTC depends on RET genotype

RET genotype of MTC Youngest age at first diagnosis

MTC: medullary thyroid cancer.

Graphic 58578 Version 3.0

Medullary thyroid cancer: Surgical specimen

Pathological specimen of bilateral and multicentric medullary thyroid cancer.