Genetics

For Rare Medullary Thyroid Cancer, Consider MEN2

SUMMARY:

Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant condition involving predisposition to distinct types of endocrine tumors. Associated tumors may develop at any age, but typically occur in early adulthood.

Symptoms and Tumor Risks

Medullary thyroid carcinoma (MTC) or its precursor C-cell hyperplasia
- nearly 100% by age 35
Three clinical subtypes are distinguished based on additional features
- MEN2A
  - Pheochromocytoma (typically adrenal): 50%
  - Parathyroid adenoma or hyperplasia: 20% to 30%
- MEN2B
  - Pheochromocytoma: 50%
  - Marfanoid habitus (tall with long thin limbs)
  - Mucosal neuromas
  - Diffuse ganglioneuromatosis of the GI tract: 40%
- Familial Medullary Thyroid Cancer (FMTC)
  - Typically later age of onset

Genetics

Caused by pathogenic variants in the RET gene
- Specific variants can be used to predict subtype or associated clinical features
Autosomal dominant
- 5% of MEN2A are de novo
- 50% of MEN2B are de novo

Diagnosis

MEN2 should be suspected in:
- Any individual with MTC
- Families with MEN2-related tumors in multiple close relatives
- Individuals with marfanoid features and mucosal neuromas (MEN2B)
Targeted genetic testing for the familial RET variant is appropriate when a close family member has been diagnosed with MEN2

Management

Referral to cancer genetics and endocrinology for counseling and management
Treatment and surveillance generally include
- Prophylactic thyroidectomy OR annual measurement of plasma calcitonin (indicates presence of MTC or C-cell hyperplasia)
- Biochemical screening for pheochromocytomas and hyperparathyroidism
  - plasma catecholamines and metanephrines
  - serum calcium and parathyroid hormone
Genetic testing is appropriate for at-risk children | Prophylactic surgery and surveillance may be recommended as early as the first year of life, depending on the specific genetic variant

Note: Because prompt medical interventions can prevent severe morbidity and mortality, MEN2 is on the ACMG list of secondary findings | In summary, the ACMG document on reporting such findings makes the following recommendations

In the course of genetic testing for research or clinical care, the laboratory may identify variants in genes unrelated to the initial indication for testing, but nevertheless may have important health implications
Results of such secondary findings should be communicated to the individuals who may benefit from this knowledge
An individual can ‘opt out’ of receiving secondary findings

KEY POINTS:

Consider MEN2 and referral to genetics for patients who present with medullary thyroid carcinoma, pheochromocytoma, parathyroid adenoma, or diffuse intestinal ganglioneuromatosis
Management includes prophylactic thyroidectomy and regular surveillance for biomarkers associated with pheochromocytoma and hyperparathyroidism