Can you provide a comprehensive overview of multiple endocrine neoplasia type 1, including its genetics, clinical presentation, diagnostic criteria, management, and surveillance recommendations, suitable for the Australian physician training examination?

Multiple Endocrine Neoplasia Type 1 (MEN1): Comprehensive Overview for Australian Physician Training Examination

Definition and Genetic Basis

MEN1 is an autosomal dominant hereditary cancer syndrome caused by pathogenic variants in the MEN1 tumor suppressor gene on chromosome 11q13, encoding the nuclear protein menin, which regulates transcriptional control, genomic stability, and cell cycle progression. 1, 2

• The prevalence is approximately 1:20,000-40,000 in the general population 2
• Disease penetrance is remarkably high: 45% by age 30,82% by age 50, and 96% by age 70 2, 3
• Over 1,300 mutations have been identified, with >70% predicted to produce truncated, non-functional menin protein 4, 5
• Four recurrent mutations account for approximately 12% of all cases: c.249_252delGTCT (4.5%), c.1546_1547insC (2.7%), c.1378C>T (2.6%), and c.628_631delACAG (2.5%) 4, 5
• Critically, no phenotype-genotype correlations exist—mutation type does not predict clinical severity or tumor spectrum 4, 5

Clinical Diagnostic Criteria

Clinical diagnosis requires identification of at least two of the three major constituent tumors: parathyroid adenomas, pancreatic/duodenal neuroendocrine tumors, or anterior pituitary tumors. 2, 6

• Genetic testing is indicated for any person with two or more MEN1 tumors, or one MEN1 tumor plus a first-degree relative with MEN1 2
• The American College of Medical Genetics recommends genetic testing for all first-degree relatives of confirmed MEN1 patients given autosomal dominant inheritance 2, 6

Major Clinical Manifestations

Primary Hyperparathyroidism (PHPT)

PHPT is the most common and earliest manifestation, occurring in 95% of MEN1 patients, typically presenting as multiglandular parathyroid adenomas or hyperplasia. 2, 6, 3

• Unlike sporadic PHPT (80% single adenoma), MEN1-associated PHPT involves multiglandular disease in the vast majority of cases 3
• Results in autonomous PTH overproduction causing hypercalcemia regardless of serum calcium levels 3
• Parathyroid carcinoma is rare (<1% of cases) but documented even in multiple glands simultaneously 3
• Measurement of total calcium (corrected for albumin) and PTH are essential screening tests 2

Pancreatic/Duodenal Neuroendocrine Tumors (pNETs)

Pancreatic NETs occur in 40-75% of MEN1 patients and represent the most important cause of MEN1-related mortality. 2, 7

• Gastrinomas are the most common functional pNET, causing Zollinger-Ellison syndrome with refractory peptic ulcer disease, abdominal pain, and diarrhea 6, 8
• Insulinomas cause hypoglycemia and should be resected regardless of size due to metabolic complications 2
• Less common functional tumors include VIPomas, glucagonomas, and other rare subtypes 1
• Recent data reveal that 42% of MEN1 patients in their second decade have clinically occult (non-functioning) pancreatic NETs 2
• Biochemical screening includes chromogranin A and gastrin levels 2

Anterior Pituitary Tumors (PitNETs)

Pituitary tumors occur in MEN1 patients, with prolactinomas being the most common type (30-55% of pituitary tumors), followed by growth hormone-secreting adenomas. 1, 6

• Galactorrhea is a characteristic symptom of prolactinomas 6
• Other PitNETs constitute <5% of pituitary tumors in MEN1 1
• Dopamine agonists are first-line treatment for prolactinomas 6

Minor Manifestations

• Cutaneous angiofibromas, lipomas, and collagenomas are common dermatologic findings 1
• Adrenocortical adenomas occur in 35% of patients 1
• Less frequent manifestations include leiomyomas, CNS tumors (ependymomas, meningiomas), and bronchial/thymic neuroendocrine tumors 1, 7

Surveillance Recommendations

Surveillance must begin in childhood, as 17% of MEN1-associated tumors are diagnosed before age 21, with cases documented as early as 5 years of age. 2, 3

Biochemical Screening Protocol

• Begin surveillance from age 5 years in confirmed mutation carriers 1, 2
• Annual measurements: serum calcium (corrected for albumin), PTH, prolactin, IGF-1 2, 3
• Every 2 years from age 5: chromogranin A, gastrin, glucose, insulin (fasting) for pancreatic islet cell tumors per NCCN guidelines 2

Imaging Surveillance

• Multimodality approach including CT or MRI of abdomen for pancreatic tumors 2
• Endoscopic ultrasound for detecting small pancreatic lesions 2
• Somatostatin receptor scintigraphy for detecting metastases 2
• MRI pituitary for anterior pituitary assessment 6
• Thyroid ultrasound and sestamibi scintigraphy for parathyroid localization 8

Surgical Management

Parathyroid Surgery

Subtotal or total parathyroidectomy is recommended for MEN1-associated hyperparathyroidism, performed by high-volume parathyroid surgeons in consultation with endocrinologists. 2

• Due to multiglandular disease, simple adenomectomy has unacceptably high recurrence rates 3, 7
• Subtotal parathyroid gland resection is the procedure of choice 7

Pancreatic Surgery

Complete resection with negative margins and regional lymph node dissection is recommended for functional and non-functional pancreatic tumors >2 cm per NCCN guidelines. 2

• Insulinomas should be resected regardless of size due to metabolic complications 2
• Selective tumor enucleation has no role in MEN1-related pNETs; the exact procedure depends on tumor functionality 7
• Gastrinomas require urgent control of upper GI bleeding with high-dose IV proton pump inhibitors before definitive surgery 6

Medical Management

For advanced or metastatic pancreatic NETs, somatostatin analogs, targeted radionuclide therapy, locoregional treatments (ablation, chemoembolization), and chemotherapy are recommended per NCCN guidelines. 2

• Sunitinib or everolimus may be used for progressive advanced disease 2
• Chemotherapy is reserved for aggressive tumors with unresectable or metastatic disease 2

Organizational Structure of Care

Management must occur in specialized multidisciplinary centers with dedicated teams including endocrinologists, endocrine surgeons, clinical geneticists, radiologists, nuclear medicine specialists, histopathologists, and specialized nurse coordinators. 2

• Assign specialized nurse coordinators to guarantee periodic examination and coordinate surveillance 2
• Provide patient education through newsletters, internet resources, and support groups to address emotional distress and practical issues 2

Critical Pitfalls to Avoid

The most critical error is failing to screen for other MEN1-associated tumors when one component is identified, especially in young patients. 2, 3

• Once any MEN1 tumor is diagnosed, comprehensive evaluation for all other major constituent tumors is mandatory 3
• Never delay referral for suspected hereditary endocrine syndromes—interruption of surveillance worsens outcomes and impairs life expectancy 2
• Early detection through surveillance is critical, as delays in diagnosis are associated with increased morbidity and mortality 2, 3
• Do not assume adult-onset disease—tumors can present as early as 5 years of age 1, 2

Tumor Suppressor Mechanism

MEN1 follows the classic "two-hit" tumor suppressor model: germline mutation provides the first hit, and somatic loss of heterozygosity (LOH) of the remaining normal allele provides the second hit, leading to tumor development. 4, 5, 9

• MEN1 tumors frequently demonstrate LOH at the MEN1 locus, consistent with tumor suppressor function 4, 5
• Somatic MEN1 mutations also occur in sporadic (non-hereditary) parathyroid adenomas, gastrinomas, insulinomas, and bronchial carcinoids 9
• Most mutations predict truncation and inactivation of menin, disrupting its interactions with other proteins and altering cell cycle regulation 4, 5