What is Multiple Endocrine Neoplasia Type 1 (MEN 1) disease?

Multiple Endocrine Neoplasia Type 1 (MEN1)

Multiple Endocrine Neoplasia Type 1 (MEN1) is an autosomal dominant hereditary disorder characterized by the development of tumors in multiple endocrine glands, primarily affecting the parathyroid glands, pancreatic islets, and anterior pituitary. 1

Definition and Prevalence

• MEN1 is a rare genetic disorder with an estimated prevalence of 1:20,000-40,000 in the general population 1
• The syndrome was first identified in 1903 and formally defined decades later by Underhal and Werner 1
• Disease penetrance for a first manifestation among MEN1 carriers is high: 45% by age 30,82% by age 50, and 96% by age 70 1

Major Clinical Features

• Primary hyperparathyroidism (PHPT) is the most common manifestation, occurring in 95% of MEN1 patients, typically presenting as parathyroid adenomas (usually multiglandular) 1
• Pancreatic neuroendocrine tumors occur in 40-75% of patients, including:
  • Gastrinomas (most common)
  • Insulinomas (less common)
  • Other rare types: VIPomas, glucagonomas 1
• Pituitary neuroendocrine tumors are identified in 30-55% of patients:
  • Predominantly prolactinomas
  • Less frequently, growth hormone-secreting adenomas
  • Rarely, other types of pituitary tumors (constituting <5% of pituitary tumors in MEN1) 1

Other Manifestations

• Dermatologic manifestations:
  • Angiofibromas
  • Lipomas
  • Collagenomas 1
• Adrenocortical adenomas (identified in 35% of patients) 1
• Less common manifestations:
  • Leiomyomas
  • CNS neoplasms (including ependymomas and meningiomas) 1, 2

Genetics

• MEN1 is caused by pathogenic variants in the MEN1 tumor-suppressor gene located on chromosome 11q13 1
• The gene encodes the protein menin, which functions in cell-cycle control, transcriptional regulation, and maintenance of genomic stability 1
• Inactivating pathogenic variants occur throughout the gene and include truncations, missense mutations, splice-site mutations, and insertions/deletions 1
• Pathogenic germline variants are identified in:
  • 80-95% of familial cases
  • 65-70% of de novo cases 1
• There are no apparent genotype-phenotype correlations in MEN1 1, 2

Diagnostic Criteria

• Clinical diagnosis of MEN1 is predicated on the identification of at least two of the major constituent tumors 1
• Genetic testing is indicated for:
  1. Any person with two or more constituent MEN1 tumors
  2. Any person with one MEN1 tumor and a first-degree relative with MEN1
  3. Any individual under age 30 with PHPT, pancreatic precursor lesions, or pancreatic islet tumor, regardless of family history 1

Surveillance Recommendations

• Early detection through surveillance is critical as delays in diagnosis are associated with increased morbidity and mortality 1
• Surveillance should begin at an early age, as tumors have been diagnosed as young as 5 years old 1
• For first-degree relatives of MEN1 carriers with unknown mutational status:
  • Annual serum prolactin from age 5
  • Annual serum calcium (corrected for albumin) from age 10 1

Prognosis and Mortality

• Untreated patients have decreased life expectancy, with 50% probability of death by age 50 3
• The most important causes of MEN1-related death are malignant pancreatic neuroendocrine tumors and thymic carcinoids 3, 2

Special Considerations

• MEN1 was previously thought to be an adult-onset disorder, but 17% of MEN1-associated tumors are diagnosed before age 21 1
• Recent data suggest that 42% of MEN1 patients in the second decade of life may possess clinically occult (non-functioning) pancreatic NETs 1
• Parathyroid carcinoma is an extremely rare manifestation in MEN1 patients 4
• Treatment for each type of endocrine tumor is generally similar to non-MEN1 associated tumors, but outcomes are often less successful due to tumor multiplicity, higher rates of metastatic disease, and more aggressive tumor behavior 3

Pitfalls to Avoid

• Failing to screen for other MEN1-associated tumors when one component is identified, especially in young patients 1
• Treating MEN1-related tumors as if they were sporadic counterparts—they require a unique approach 5
• Delaying genetic testing in at-risk family members, as early diagnosis can significantly improve outcomes 2
• Using selective tumor enucleation for MEN1-related pancreatic NETs, which is not recommended 5