Genetics

Consider Inherited MEN1 for Familial Hyperparathyroidism and Other Endocrine Tumors

SUMMARY:

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant condition involving predisposition to various types of endocrine tumors. Although most MEN1-related tumors do not become malignant, they can cause significant morbidity due to the excess secretion of various hormones. Primary hyperparathyroidism causing hypercalcemia due to parathyroid tumors is the most common clinical manifestation in individuals with MEN1.

Tumor Risks

Parathyroid tumors: up to 90% by age 50
Pituitary tumors: 30%
Pancreatic neuroendocrine tumors and other endocrine tumors of the GEP tract: 75%
Thymic, bronchial, and gastric carcinoid tumors: 3 to 10%
Adrenocortical tumors: 20 to 73%
Non-endocrine tumors:
- Facial angiofibromas: 85%
- Collagenomas: 70%
- Lipomas: 30%
- Meningiomas: 8%
- Leiomyomas: 30 to 40%

Genetics

Autosomal dominant; 10% of cases are de novo
Caused by pathogenic variants in MEN1
Overall penetrance is 50% by age 20, and 95% by age 40

Symptoms/Diagnosis

More than 20 types of endocrine and non-endocrine tumors are associated with MEN1
- Symptoms vary based on the type of hormones produced by each individual tumor
The first symptom is often hyperparathyroidism, presenting as asymptomatic hypercalcemia in the 20’s
Diagnosis is confirmed for any of the following:
- An individual with more than one MEN1-related tumor
- An individual with an MEN1-related tumor and a family history of MEN1
- Any individual with a pathogenic variant in the MEN1 gene
Targeted genetic testing for the familial MEN1 variant is appropriate when a family member has been diagnosed with MEN1

Management

Referral to cancer genetics and endocrinology for counseling and management
Follow-up generally includes
- Regular surveillance for new tumors with tumor-associated markers such as calcium, PTH, insulin, growth hormone, and prolactin
- MRI or CAT scans to follow the size, number, location, and growth of tumors or to identify new ones
- Treatment of hyperparathyroidism with parathyroidectomy
- Some hormone-secreting adenomas are able to be treated with specific medications (eg. somatostatin analogs for GH-secreting adenomas); others require surgical excision
- Prophylactic thymectomy may be considered

Note: Because early medical interventions can prevent severe morbidity and mortality, MEN1 is on the ACMG list of secondary findings | 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:

MEN1 is associated with a broad spectrum of endocrine tumors, particularly
- Parathyroid (typically multiglandular)
- Anterior pituitary
- Pancreatic neuroendocrine
Consider MEN1 and referral to genetics for patients who present with
- Multiple MEN1-related tumors in the same individual
- Gastrinoma
- Parathyroid adenoma before age 30 or involving multiple glands
Management includes thorough surveillance with biomarkers associated with endocrine tumors and medical or surgical treatments for specific tumors as needed
- Recommended surveillance begins as early as age 5, thus, genetic testing should be offered for at-risk children