Multiple Endocrine Neoplasia (MEN)

Multiple Endocrine Neoplasia (MEN) is a group of autosomal dominant genetic disorders characterised by the development of tumours in multiple endocrine glands. These tumours can be benign or malignant and may also occur in nonendocrine tissues. MEN syndromes are primarily caused by mutations in specific genes, such as RET for MEN2 and MEN1 for MEN1.

Presentation and Related Conditions

MEN syndromes encompass several distinct disorders with characteristic tumour patterns. They are inherited in an autosomal dominant manner. Although not classified as MEN syndromes, Von Hippel–Lindau disease and Carney complex share overlapping clinical features. McCune–Albright syndrome, while not inherited, also involves endocrine neoplastic features similar to MEN1 and MEN2.

Types of MEN and Their Features

MEN1 (Wermer syndrome) is associated with tumours in the parathyroid glands, pancreatic islet cells, and pituitary gland. Common manifestations include hyperparathyroidism, gastrinomas, insulinomas, and pituitary adenomas.

MEN2 (Sipple syndrome) is characterised by medullary thyroid carcinoma (MTC), pheochromocytoma, and, in MEN2A, parathyroid hyperplasia. MEN2B features MTC, pheochromocytoma, and characteristic physical traits like marfanoid habitus and mucosal neuromas.

MEN1 Gene and Menin Protein

The MEN1 gene encodes menin, a nuclear protein involved in multiple cellular processes. MEN1 mutations follow Knudson’s “two-hit” model, where a germline mutation is followed by a somatic mutation leading to tumour development. Menin's function is not fully understood due to the lack of homology with other proteins.

Mnemonic for MEN Syndromes

A useful mnemonic for remembering the associated neoplasias:

• MEN I (3 Ps): Pituitary, Parathyroid, Pancreatic
• MEN IIa (2Ps, 1M): Pheochromocytoma, Parathyroid, Medullary Thyroid Ca
• MEN IIb (1P, 2Ms): Pheochromocytoma, Medullary Thyroid Ca, Marfanoid habitus/mucosal neuroma

Diagnosis

MEN syndromes are diagnosed based on clinical criteria, genetic testing, and family history. Genetic testing for mutations in the MEN1 and RET genes confirms the diagnosis. Suspicion arises when patients present with tumours in characteristic locations or have a family history of MEN.

Manifestations of MEN1

MEN1 is marked by a range of endocrine and non-endocrine tumours:

• Endocrine tumours: Parathyroid adenomas (95%), pancreatic neuroendocrine tumours (30–80%), and anterior pituitary adenomas (15–90%).
• Non-endocrine manifestations: Include lipomas, meningiomas, facial angiofibromas, and carcinoid tumours.

Despite extensive research, no clear genotype-phenotype correlations exist, suggesting additional genetic and environmental factors influence disease expression.

Treatment and Management

Treatment focuses on managing hormone overproduction and surgical resection of tumours. Regular surveillance is very important to detect new tumours early. Endocrine tumours in MEN1 often require surgical intervention, while medical management may control hormone hypersecretion.

Recommended Surveillance

The International Guidelines for the Diagnosis and Therapy of MEN syndromes recommend regular monitoring for early detection and management of tumours. This includes biochemical testing and imaging studies tailored to the specific MEN syndrome.

Historical Background

The history of MEN extends back to 1903 when Erdheim first described the association of pituitary adenoma and parathyroid hyperplasia. Significant milestones include the identification of MEN1 and RET gene mutations and the classification of MEN syndromes into their current forms.

The term "multiple endocrine neoplasia" was introduced in 1968, consolidating earlier observations into a unified concept of hereditary endocrine tumour syndromes.

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Self-assessment MCQs (single best answer)

What is the inheritance pattern of Multiple Endocrine Neoplasia (MEN)?

Which gene mutation is primarily associated with MEN2?

In MEN1, which endocrine gland is most commonly affected by tumours?

Which mnemonic correctly describes the associated neoplasias in MEN I?

Which of the following is NOT a common feature of MEN2B?

How is the diagnosis of MEN syndromes primarily confirmed?

What protein does the MEN1 gene encode?

Which type of tumour is most commonly associated with MEN1?

What is the primary treatment approach for managing tumours in MEN syndromes?

Who first described the association of pituitary adenoma and parathyroid hyperplasia in MEN syndromes?