Multiple Endocrine Neoplasia Type 2

Question 1

Multiple endocrine neoplasia type 2 (MEN 2) includes the following phenotypes:

Answer 1

1. MEN 2A = constitutes approximately 70%-80% of cases of MEN2,
2. FMTC (familial medullary thyroid carcinoma, which may be a variant of MEN 2A) = constitutes approximately 10%-20% of cases of MEN 2,
3. MEN 2B = accounts for approximately 5% of cases of MEN 2.

Question 2

What are the clinical characteristics of MEN 2A?

Answer 2

1. High risk for development of medullary carcinoma of the thyroid (MTC) - the precursor of which is C-cell hyperplasia (CCH),
2. Increased risk for pheochromocytoma
3. Increased risk for parathyroid adenoma or hyperplasia,
4. Cutaneous lichen amyloidosis has been reported in some families.

Question 3

What are the clinical characteristics of FMTC (familial medullary thyroid carcinoma, which may be a variant of MEN 2A)

Answer 3

High risk for development of medullary carcinoma of the thyroid (MTC) - the precursor of which is C-cell hyperplasia (CCH).

Question 4

What are the clinical characteristics of MEN 2B

Answer 4

1. High risk for development of medullary carcinoma of the thyroid (MTC) - the precursor of which is C-cell hyperplasia (CCH),
2. Increased risk for pheochromocytoma,
3. An asthenic Marfanoid habitus,
4. Distinctive facies with enlarged lips,
5. Mucosal neuromas of the lips and tongue, as well as the palate, or pharynx
6. Ganglioneuromatosis of the gastrointestinal tract which presents with GI symptoms including abdominal distension, megacolon, constipation, or diarrhea,
7. Corneal nerves are medullated and appear prominent - this can be seen on slit lamp exam,
8. Neuromas of the eyelid margins and sometimes the conjunctiva are common features. There may also be eversion of the upper eyelid margins.
9. Thickening of the entire eyelids may be present.

Question 5

When does MTC typically occur in MEN2?

Answer 5

MTC typically occurs in:

1. Early childhood in MEN 2B,
2. Early adulthood in MEN 2A
3. Middle age in FMTC

MNEMONIC:
B - in babies
A - in adults
FMTC - in the middle

Question 6

1. Is there clinical diagnostic criteria for MEN2?

2. What is the clinical criteria for each of the 3 clinical phenotypes of MEN2?

Answer 6

1. Yes.
2. CLINICAL CRITERIA FOR MEN 2A:
   - The presence of two or more specific endocrine tumors including (medullary thyroid carcinoma [MTC], pheochromocytoma, or parathyroid adenoma/hyperplasia) in a single individual OR in close relatives.
3. CLINICAL CRITERIA FOR FMTC:
   - Families with 4 or more cases of MTC in the ABSENCE of pheochromocytoma or parathyroid adenoma/hyperplasia.
4. CLINICAL CRITERIA FOR MEN 2B:
   - The presence of all 5:
   A. Early-onset MTC,
   B. An asthenic, Marfanoid body habitus,
   C. Distinctive facies with enlarged lips,
   D. Mucosal neuromas of the lips and tongue, and
   E. Medullated corneal nerve fibers.

Question 7

How is a diagnosis of MEN2 established?

Answer 7

1. Clinically - in individuals who fulfil clinical diagnostic criteria.
2. Molecularly - in individuals with a GERMLINE heterozygous pathogenic variant in the RET gene.

NB: Molecular confirmation establishes the diagnosis if clinical features are inconclusive.

Question 8

1. When is molecular testing for RET indicated? Hint: 2
2. What is the approach to molecular testing in MEN2?
3. What is the detection rate?
4. Approximately {{XXX}}% of individuals with MEN2B have the pathogenic variant: p.{{XXX}}, in exon {{XXX}}.

Answer 8

1. All individuals with:
   A. A clinical diagnosis of MEN 2, or

      B. A diagnosis of primary C-cell hyperplasia (CCH) 
          or MTC.

2. APPROACH TO MOLECULAR TESTING:
   - Since the majority of pathogenic variants occur in exons 10, 11, and 13-16, start with sequence analysis of select exons.
   - If no pathogenic variant is found by select-exon testing, full-gene sequencing of RET as part of a multigene panel should be considered next.
3. The detection rate is greater than 95%.
4. Approximately {{95%}} of individuals with MEN2B have the pathogenic variant: {{p.Met918Thr}}, in exon {{16}}.

Question 9

1. What is the treatment for MTC in MEN2?
2. How is advanced locoregional disease approached?
3. What is used in metastatic MTC?

Answer 9

1. Surgical removal of the thyroid gland and lymph node dissection.
2. External beam radiation therapy or intensity-modulated radiation therapy (IMRT) can be considered.
3. Kinase inhibitors including: vandetanib, cabozantinib, and BLU-667.

NB: All individuals who have undergone thyroidectomy need thyroid hormone replacement therapy.

Question 10

How are pheochromocytomas detected?

Answer 10

1. Biochemical testing, and

2. Radionuclide imaging

Question 11

What is the treatment for pheochromocytomas in MEN2?

Answer 11

1. Pre-op: Use of α- and β-adrenergic receptor blockade or use nitroprusside to control blood pressure during surgery.
2. Surgical removal by laparoscopic cortical-sparing adrenalectomy.
3. Post-op: Close monitoring of the remnant tissue in persons with one remaining adrenal gland.

Question 12

1. What is the treatment of primary hyperparathyroidism in MEN2?
2. What is the alternative in patients who can’t undergo surgery?

Answer 12

1. Surgery to remove one or more parathyroid glands (subtotal parathyroidectomy, or total parathyroidectomy with forearm autograft),
2. Medications to reduce parathyroid hormone secretion.

Question 13

1. Prevention of primary manifestations in MEN2?
2. At what age is the prophylactic thyroidectomy recommended?
3. Is prophylactic thyroidectomy routinely offered to at-risk individuals in whom the disorder has not been confirmed?

Answer 13

1. Prophylactic thyroidectomy is the primary preventive measure for individuals with an IDENTIFIED germline RET pathogenic variant.
2. Prophylactic thyroidectomy is safe for all age groups, but the age at which prophylactic thyroidectomy is performed can be guided by the genotype (i.e. codon position of the RET pathogenic variant) - according to the American Thyroid Association Guidelines Task Force consensus statement.
3. No.

Question 14

Prevention of secondary complications in individuals confirmed to have MEN2A or MEN2B?

Answer 14

PRIOR TO SURGERY (thyroidectomy) - Biochemical screening to investigate for the presence of a functioning pheochromocytoma.

NB: If pheochromocytoma is detected, adrenalectomy should be performed before thyroidectomy to avoid intraoperative catecholamine crisis.

Question 15

1. What PRE-OP surveillance is offered in patients with MEN2?
2. What POST-OP surveillance is offered in patients with MEN2?

Answer 15

PRE-OP SURVEILLANCE:

THINK MTC:
1. For all individuals with a RET pathogenic variant who have not had a thyroidectomy:
Annual biochemical screening is recommended with
immediate thyroidectomy if results are abnormal:
- Annual serum calcitonin screening should begin
at age:
- 6 months for children with MEN 2B;
- 3 to 5 years for children with MEN 2A or
FMTC.

THINK PARATHYROID ADENOMA OR HYPERPLASIA:
Annual biochemical screening:
- MEN 2A. Screening should start at age EIGHT years for individuals with a pathogenic variant in codons 630 and 634, and by age TWENTY years for individuals with other RET pathogenic variants.

• FMTC. Periodic screening should begin at age 20 years.
• MEN 2B. Screening is unnecessary as individuals with MEN 2B are not at increased risk for hyperparathyroidism.

THINK PHEOCHROMOCYTOMA:
- MEN 2A. Annual biochemical screening beginning at age EIGHT years has been recommended for individuals with a pathogenic variant in codons 630 and 634 and at age TWENTY years for a pathogenic variant in all other codons.

• FMTC. Screening as for MEN 2A is indicated, as not all families classified as FMTC are MTC-only.
• MEN 2B. Annual screening should begin at age 8 years.

_________________________________________

POST-OP SURVEILLANCE:

THINK MTC:
1. Annual measurement of serum calcitonin concentration to detect residual or recurrent MTC after total thyroidectomy and neck nodal dissections (even if thyroidectomy was performed prophylactically - prior to biochemical evidence of disease).
WHY? 50% of individuals have recurrent disease.

THINK PARATHYROID ADENOMA OR HYPERPLASIA:
2. Monitoring for possible hypoparathyroidism in all those who have undergone thyroidectomy and parathyroid autotransplantation.

THINK PHEOCHROMOCYTOMA:
3. Annual biochemical screening for those with a germline RET pathogenic variant whose initial screening results are negative for pheochromocytoma.

Question 16

What agents/circumstances should be avoided in MEN2 and why?

Answer 16

Dopamine D2 receptor antagonists (e.g., metoclopramide and veralipride) and β-adrenergic receptor antagonists (β-blockers).

These present a high risk for adverse reactions in individuals with pheochromocytoma.

Other medications including:

1. Monoamine oxidase inhibitors,
2. Sympathomimetics (e.g., ephedrine), and
3. Certain peptide and corticosteroid hormones may also cause complications

NB: Tricyclic antidepressants are inconsistent in causing adverse reactions.

MNEMONIC: BA-DD for pheochromocytoma.

Question 17

Is genetic testing offered to at-risk members of a family in which a germline RET pathogenic variant has been identified?

Answer 17

Yes, because early diagnosis has management implications.

NB: Testing should be offered as early as possible.

• MEN 2A and FMTC: Children by 5 years of age or even sooner.
• MEN 2B: As soon as possible after birth.

Question 18

What should be considered in women with MEN2 of child-bearing age?

Answer 18

Women should be screened for pheochromocytoma:

1. Prior to a planned pregnancy or
2. As early as possible during an unplanned pregnancy.

Question 19

Genetic counseling:

All MEN 2 phenotypes are inherited in an {{XXX}} manner.

The probability of a de novo pathogenic variant is {{XXX}} in index cases with MEN 2A and {{XXX}} in index cases with MEN 2B.

Prenatal testing for pregnancies at increased risk is {{XXX}} if the RET pathogenic variant has been identified in an affected family member.

Answer 19

Genetic counseling:

All MEN 2 phenotypes are inherited in an {{autosomal dominant}} manner.

The probability of a de novo pathogenic variant is {{5% or less}} in index cases with MEN 2A and {{50%}} in index cases with MEN 2B.

Prenatal testing for pregnancies at increased risk is {{possible}} if the RET pathogenic variant has been identified in an affected family member.

Question 20

Since MEN2 occurs through a {{XXX}} mechanism, testing for large {{XXX}} is not indicated.

Answer 20

Since MEN2 occurs through a {{GAIN-of-function}} mechanism, testing for {{intragenic deletions or duplications is not indicated}}.

Question 21

1. What are the characteristics of MTC in MEN2 syndrome?
2. What are the signs and symptoms of MTC?
3. What are the biochemical findings in MTC and CCH?

Answer 21

CHARACTERISTICS:

1. Presents at a younger age than sporadic MTC (typically prior to the age of 35,
2. Is more often associated with C-cell hyperplasia = MTC originates in calcitonin-producing cells (C cells) of the thyroid gland,
3. Multifocality,
4. Bilaterality.

SIGNS AND SYMPTOMS:

1. Neck mass or neck pain.
2. Diarrhea (the most frequent systemic symptom) occurs in affected individuals with a plasma calcitonin concentration >10 ng/mL and implies a poor prognosis.
3. Metastatic spread to regional lymph nodes or to distant sites including the liver, lungs, or bone is also common in symptomatic individuals.

BIOCHEMICAL FINDINGS:
1. Elevated plasma calcitonin concentration, a sensitive and specific marker = In provocative testing, plasma calcitonin concentration is measured before (basal level), then two and five minutes after intravenous administration of calcium (stimulated level) = A basal or stimulated calcitonin level of ≥100 pg/mL is an indication for surgery.

Question 22

About {{XXX}}% of all individuals with MTC have a germline {{XXX}} pathogenic variant

Answer 22

About {{25%-30%}} of all individuals with MTC have a germline {{RET}} pathogenic variant.

Question 23

What are the characteristics of pheochromocytomas in MEN2 syndrome?

What are the biochemical findings of pheochromocytomas in MEN2 syndrome?

What imaging modalities can be used to identify pheochromocytomas when suspected?

Answer 23

CHARACTERISTICS:

1. Nearly always adrenal, and
2. Often multiple and bilateral,
3. Rarely metastasize,
4. Can be lethal because of intractable hypertension or anesthesia-induced hypertensive crises

BIOCHEMICAL FINDINGS:
1. Elevated excretion of catecholamines and catecholamine metabolites (epinephrine or epinephrine and norepinephrine) in plasma or 24-hour urine collections.

IMAGING MODALITIES:

1. PET scan is the best overall imaging modality,
2. If unavailable, MIBG scintigraphy should be used
3. If unavailable, abdominal MRI, or
4. CT scan (MRI is more sensitive).

Question 24

What are the characteristics of parathyroid abnormalities in MEN2 syndrome?

What are the biochemical findings of parathyroid abnormalities in MEN2 syndrome?

Answer 24

CHARACTERISTICS:
Range from benign parathyroid adenomas to clinically evident hyperparathyroidism with hypercalcemia and renal stones.

BIOCHEMICAL FINDINGS:
Elevated serum calcium and elevated or high-normal parathyroid hormone (PTH).

Question 25

How common is malignant transformation of pheochromocytomas in MEN2A?

Answer 25

Malignant transformation occurs in about 4% of cases.

Question 26

Are there genotype-phenotype correlations in MEN2 syndrome?

Answer 26

Yes. For example:

1. RET germline pathogenic variant p.Met918Thr is only associated with MEN2B.
2. Any RET pathogenic variant at codon 634 in exon 11 results in a higher incidence of pheochromocytomas and hyperparathyroidism.

Question 27

Penetrance?

Answer 27

The penetrance for MTC, pheochromocytoma, and parathyroid disease varies by MEN 2 phenotype.

Question 28

What is a genetically related (allelic) disorder to MEN2?

What is the molecular mechanism that makes it different from MEN2?

Answer 28

Germline RET pathogenic variants are associated with Hirschsprung disease (HSCR).

It is caused by a heterozygous germline LOSS-of-function pathogenic variant in the RET proto-oncogene.

MEN2 occurs through a GAIN-of-function mechanism.

NB: Families and individuals with a germline RET pathogenic variant in exon 10, especially affecting codons 618 and 620, often cosegregate MEN 2A/FMTC and HSCR.

NB: Up to 25% of individuals with pheochromocytoma and no known family history of pheochromocytoma have a heterozygous pathogenic variant in one of several genes including RET.

Question 29

1. What protein does the RET gene encode for?
2. What does this protein do?
3. What class of driver gene does it fall under?
4. What is the cytogenetic location of the gene?

Answer 29

1. Tyrosine-protein kinase receptor.
2. It’s one of the receptor tyrosine kinases, cell-surface molecules that transduce signals for cell growth and differentiation.
3. Proto-oncogene.
4. 10q11​.21.

Question 30

What evaluations are warranted following the initial diagnosis?

Answer 30

REFERRALS:

1. Referral to an endocrinologist
2. Consultation with a clinical geneticist and/or genetic counselor

BIOCHEMICAL EVALUATIONS:

1. Plasma calcitonin
2. Plasma catecholamines and metanephrines
3. Serum calcium and parathyroid hormone

IMAGING: Evaluation for metastatic disease in individuals with MTC:

1. CT with contrast for chest and abdomen
2. MRI of liver in the presence of nodal disease or calcitonin >400 pg/mL

Question 31

How is C-cell hyperplasia managed in patients with MEN2?

Answer 31

Thyroidectomy with sparing of lymph nodes can be done before progression to invasive MTC.

Question 32

What screening is offered at-risk family members if the pathogenic variant in the family is not known?

Answer 32

1. Neck ultrasound examination and basal and/or stimulated calcitonin measurements for MTC,
2. Albumin-corrected calcium or ionized calcium for hyperparathyroidism,
3. Measurement of plasma or 24-hour urine metanephrines and normetanephrines as appropriate for pheochromocytoma.

Question 33

What are some therapies under investigation?

Answer 33

Clinical trials of multikinase inhibitors such as:

1. Sorafenib,
2. Sunitinib, and
3. Ponatinib are currently under way.