Definition

Multiple endocrine neoplasia type 2 (MEN2) includes MEN2A (OMIM #171400), familial medullary thyroid carcinoma (FMTC, OMIM #155240), and MEN2B (OMIM #162300). All three entities arise from mutations in the RET proto-oncogene and confer a predisposition to medullary thyroid carcinoma (MTC) and pheochromocytoma (PHEO). In addition, MEN2A can lead to parathyroid adenomas or hyperplasia with primary hyperparathyroidism (PHPT). Certain mutations show a combination of MEN2A and cutaneous lichen amyloidosis / Hirschsprung’s disease.

Key Data

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Synonyms MEN2A: Sipple syndrome
MEN2B: mucosal neuroma syndrome, Wagenmann-Froböse syndrome
Gene RET
Gene product RET
Function Tyrosine kinase receptor that mediates growth and differentiation signals intracellularly and from the intracellular compartment to the extracellular space. MEN2 mutations confer a gain of function, i.e. increased enzyme activity.
Heredity Autosomal-dominant
MEN2A 9% de novo mutations, MEN2B 50% de novo mutations
Prevalence Total MEN2: 1:35.000 – 1:40.000
91% MEN2A (35% isolated FMTC), 9% MEN2B
Genotype-phenotype correlation Codon 918 mutations are considered to be at the highest risk of MTC; associated with the majority of cases with MEN2B; no PHPT.
Codon 883 mutations are considered to be at a high risk of MTC; associated with MEN2B, including mucosal neuromas and PHEO.
Codon 634 mutations are considered to be at a high risk of MTC, PHEO, and PHPT.
Codon 634 and 804 mutations are associated with cutaneous lichen amyloidosis.
Codon 609, 611, 618, and 620 mutations are associated with Hirschsprung’s disease.
Penetrance MEN2A: MTC 95%, PHEO 50%, parathyroid adenoma 20-30%
FMTC: MTC 100%, PHEO 0%, parathyroid adenoma 0%
MEN2B: MTC 100%, PHEO 50%, parathyroid adenoma rare
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Diagnosis

Clinical Diagnostic Criteria

MEN2A:

Occurrence of at least two specific endocrine tumors (MTC, PHEO, parathyroid adenoma / PHPT) in one person or in close relatives

FMTC:

At least four individuals with MTC without the occurrence of PHEO or parathyroid adenoma / PHPT in a family

MEN2B:

Early-onset MTC, mucosal neuromas of the lips and tongue, myelinated nerve fibers of the cornea, characteristic facies with a broadened vermilion border of the lips and Marfanoid habitus.

Genetic Diagnostics

The genetic diagnostics for a mutation of the RET gene is indicated in all individuals with primary C-cell hyperplasia or MTC or with clinically diagnosed MEN2. If the sequence analysis of selected exons does not yield a clear result, a sequence analysis of the entire RET gene can be conducted. It may be helpful to use panel examinations consisting of multiple genes.

Differential Diagnoses

Clinical Presentation

Endocrine diseases occurring with MEN2 include medullary thyroid carcinoma (MTC), pheochromocytoma (PHEO), and parathyroid adenoma / primary hyperparathyroidism (PHPT). MTCs due to RET mutations have an earlier onset than sporadic MTCs and affect approximately 25% of all MTC patients. PHEO associated with MEN2 is almost always located in the adrenal gland region and often occurs bilaterally.

MEN2A

An MTC develops in approximately 95% of all MEN2A patients and is usually manifested by a space-occupying lesion in the neck region which is associated with localized pain. MTC usually occurs before the age of 35 and has already metastasized into the cervical lymph nodes in 70% of the cases at the time of diagnosis.

A PHEO usually occurs after or at the same time as the MTC; it is the first manifestation in 13-27% of MEN2A patients. PHEOs associated with MEN2A occur earlier, exhibit milder symptoms, and develop bilaterally more often than sporadic tumors. Approximately 4% of PHEOs become malignant.

Hyperparathyroidism associated with MEN2A exhibits a mild form and often progresses asymptomatically. PHPT occurs much later than the MTC, with an average age of 38 at the time of diagnosis.

In some families, MEN2A occurs in combination with cutaneous lichen amyloidosis. The simultaneous occurrence of MEN2A with Hirschsprung’s disease has also been described.

FMTC

MTCs associated with FMTC occur later on in life, and the penetrance for MTCs is lower than for MEN2A and MEN2B. FMTC is considered to be a variant of MEN2A with lower penetrance for PHEO and PHPT.

MEN2B

MEN2B is characterised by early onset of aggressive MTCs in all patients if a prophylactic thyroidectomy has not been performed.

PHEOs occur in approximately 50% of patients and are often multiple and bilateral.

MEN2B does not affect the parathyroid glands.

Mucosal neuromas associated with MEN2B may occur starting in infancy or early childhood. The existing characteristic facies is marked by prominent lips with submucosal nodules at the edge of the vermilion border of the lips. In addition, there may be neuromas of the eyelids and thickened corneal nerves.

Furthermore, 75% of MEN2B patients have Marfanoid habitus with kyphoscoliosis or lordosis, lax joints, and minimal subcutaneous fatty tissue.

Approximately 40% of those affected have ganglioneuromatosis of the gastrointestinal tract, the symptoms of which usually occur during infancy or early childhood.

Therapeutic Considerations

Medullary Thyroid Carcinoma

  • The standard treatment is a thyroidectomy with a lymphadenectomy (the timing depends on the mutation; see the recommendations for early detection), followed by hormone replacement therapy.

  • If resection is incomplete, supplementary radiotherapy may need to be considered.

  • Kinase inhibitors (vandetanib and cabozantinib) may prevent growth in tumors that cannot be resected or that have metastasized.

Pheochromocytoma

  • Adrenalectomy (prophylactic bilateral adrenalectomy for a unilateral tumor only in exceptional cases)

  • Preoperative alpha-adrenergic blocker for PHEO with catecholamine secretion

Thyroid Adenoma or Hyperplasia

  • Asymptomatic: With close monitoring, no surgical treatment is initially necessary.

  • Symptomatic: Parathyroidectomy; it is preferable to excise the visibly enlarged glands.

  • In the context of a PHEO, an adrenalectomy should be performed prior to the parathyroidectomy.

Surveillance Recommendations

Surveillance Recommendations

Medullary Thyroid Carcinoma

  • A thyroidectomy is the treatment of choice. The time of the operation and further diagnostics depend on the mutation concerned:

    Highest risk mutations (codon 918): a thyroidectomy with a neck dissection during the first year of life

    • High risk mutations (codons 634 and 883): a thyroidectomy up to age 5, with the exact timing dependent on the serum calcitonin level
      An annual ultrasound of the thyroid and monitoring of serum calcitonin levels as of age 3
    • Moderate risk mutations (all others with a RET mutation): a thyroidectomy in childhood or early adulthood, depending on the serum calcitonin level and the type of mutation
      Annual ultrasound of the thyroid and monitoring of serum calcitonin levels (with the start dependent on the mutation)
  • A relapse occurs in 50% of MTC patients despite a total thyroidectomy and neck dissection; for this reason, annual serum calcitonin checkups are recommended following the operation (even more frequently when a prior relapse has occurred).

Pheochromocytoma

  • Annual laboratory checks (free plasma metanephrine and normetanephrine or fractionated metanephrine in a 24-hour urine sample)

    • Highest-risk and high-risk mutations: as of age 11
    • Moderate-risk mutations: as of age 16
  • MRI (or CT) whenever there are abnormal laboratory values

  • For women with MEN2, a pheochromocytoma should be ruled out prior to a planned pregnancy. Pregnant women should be evaluated for pheochromocytoma as early as possible in their pregnancy.

Thyroid Adenoma and Hyperplasia

  • Annual laboratory checks for patients who have not undergone a parathyroidectomy or auto-transplantation (calcium, iPTH, 25-OH, vitamin D)

    • High-risk mutations: as of age 11
    • Moderate-risk mutations: as of age 16
    • Highest-risk mutations / MEN2B: no screening necessary