Background

A rare genetic disorder MEN 1 is characterized by the growth of tumours in several endocrine glands. Mutations in the MEN1 gene are the cause of this autosomal dominant disease, which is essential for controlling the division and development of cells. MEN1 primarily affects the endocrine system, leading to the formation of tumors in various glands, including the parathyroid, pancreas, and pituitary. 

Tumour growth, which can be benign or malignant, is a defining characteristic of MEN1, in multiple endocrine organs simultaneously or over time. These tumors often result in the excessive production of hormones, causing a wide range of symptoms and complications related to hormonal imbalances. 

Epidemiology

Prevalence: 

MEN1 is considered a rare disease, with an estimated incidence of 0.25 % prevalence estimated to be between 0.02-0.2 per thousand. 

It affects both genders equally. 

Genetic factors: 

MEN1 is an autosomal dominant disorder, meaning one altered copy of the MEN1 gene is sufficient to cause the disease. 

Approximately 70% of cases are due to new mutations, while 30% are inherited from a parent. 

Age of Onset: 

Symptoms of MEN1 can manifest at different ages, but most commonly, signs appear between the ages of 20 and 40 years. 

However, the age of onset can vary widely, and some individuals might not exhibit symptoms until later in life. 

Anatomy

Pathophysiology

Genetic Mutation: A mutation in the MEN1 gene, which is found on chromosome 11q13, results in MEN1, an autosomal dominant condition. The primary protein becomes dysfunctional because of this mutation, which is essential for controlling the division, development, and death of cells. 

Loss of Tumor Suppression: By regulating the expression of many genes involved in cell cycle regulation & DNA repair, menin often suppresses tumours. When the MEN1 gene is mutated, there is a loss of tumor-suppressive function, resulting in uncontrolled cell growth and proliferation. 

Endocrine Tumorigenesis: Individuals who have lost the ability to produce menin protein are more likely to develop numerous tumours in different endocrine glands, including the parathyroid glands, pancreas, and anterior pituitary gland. 

Parathyroid Glands: The most common initial manifestation of MEN1 is the development of parathyroid gland tumors, leading to hyperparathyroidism and increased secretion of parathyroid hormone. This results in elevated levels of calcium in the blood and related symptoms. 

Pancreatic Tumors: Islet cell tumors like gastrinomas, insulinomas, glucagonomas, and somatostatinomas may develop within the pancreas. These tumors can cause excessive secretion of hormones, leading to various clinical syndromes such as Zollinger-Ellison syndrome (gastrinomas), hypoglycemia (insulinomas), and other hormonal imbalances. 

Anterior Pituitary Gland: MEN1 can also involve the development of tumors in the anterior pituitary gland, resulting in the overproduction of certain hormones like prolactin, growth hormone, or other pituitary hormones, leading to hormonal imbalances and associated clinical manifestations. 

Etiology

Genetic Mutation: A mutation in the MEN1 gene is the main cause of MEN1. Menin, a protein, is produced by this gene, which is found on chromosome 11. Menin is an essential component that controls cell division and growth by acting as a tumour suppressor. 

Environmental factors: MEN1 mutation risk may be raised by radiation or specific chemical exposure. 

Other genetic modifiers: Variations in other genes may affect how individuals with the MEN1 mutation develop tumors. 

Genetics

Prognostic Factors

Genetic Mutation: MEN1 is caused by mutations in the MEN1 gene. The prognosis can depend on the specific mutation within this gene.  

Tumor Characteristics: The specific types, size, location, and aggressiveness of tumors associated with MEN1 can impact prognosis.

Clinical History

• Age group 

The signs and symptoms of MEN1 may start appearing in adulthood, typically between the ages of 20 and 40. However, it’s important to note that MEN1 can sometimes manifest earlier or later in life also. 

Physical Examination

Parathyroid Examination: Assess for signs of hypercalcemia or complications related to parathyroid gland tumors, such as bone pain or fractures, kidney stones, or abdominal discomfort. 

Skin Examination: Look for skin lesions or abnormalities, such as neurofibromas or lipomas, which might be associated with MEN1. 

Gastrointestinal Stromal Tumors: 

Abdominal pain or discomfort depending on the location and size of the tumor. 

Bowel obstruction in larger tumors. 

Palpable mass in the abdomen with advanced tumors. 

Age group

Associated comorbidity

Parathyroid Gland Tumors: These tumors lead to hyperparathyroidism, causing increased levels of calcium in the blood, which can result in kidney stones, bone pain, and digestive issues. 

Pancreatic Neuroendocrine Tumors: Various symptoms may be caused by these tumours, depending on the size and location inside the pancreas. They might result in hormonal imbalances leading to symptoms like abdominal pain, diarrhea, and in some cases, peptic ulcers. 

Pituitary Gland Tumors: These tumors can cause symptoms due to overproduction of hormones. For instance, a prolactin-secreting tumor might cause menstrual irregularities or milk production in both men and women. Other types of pituitary tumors can cause hormonal imbalances resulting in symptoms related to growth hormone, cortisol, or other pituitary hormones. 

Other Endocrine Gland Tumors: Tumours in other endocrine glands, including the thymus, adrenal glands, and other uncommon locations, can also be associated with MEN1. Depending on the hormones these tumours produce and how they affect the body, they can cause a wide range of symptoms. 

Family History: Since MEN1 is a genetic disorder, individuals with a family history of MEN1 are at a higher risk of developing associated tumors. 

Associated activity

Acuity of presentation

Symptoms: The symptoms of MEN1 can be quite diverse due to the involvement of multiple endocrine glands. These may include: 

Hyperparathyroidism: Symptoms of hypercalcemia, such as fatigue, weakness, kidney stones, and bone pain. 

Pancreatic Neuroendocrine Tumors (PNETs): Symptoms vary based on the size and location of the tumors but can include abdominal pain, diarrhea, weight loss, and hormonal overproduction. 

Pituitary tumors: Manifestations can range from headaches and visual disturbances to hormonal imbalances leading to issues like growth hormone excess (acromegaly) or prolactin excess (prolactinomas). 

Age of Onset: Symptoms of MEN1 often appear in early adulthood, typically between the ages of 20 and 40, though they can present at any age. 

Variable Expressivity: The severity and range of symptoms can differ widely even among individuals within the same family carrying the same genetic mutation. Some may remain asymptomatic for a longer duration or throughout their lives, while others may develop multiple tumors at an earlier age. 

Differential Diagnoses

Pancreatic neuroendocrine tumors: Non-functional pancreatic NETs can occur independently of MEN1 and might present similarly to the pancreatic tumors seen in MEN1. 

Zollinger-Ellison syndrome: This syndrome involves gastrin-secreting tumors in the pancreas or duodenum, leading to excessive gastric acid production and peptic ulcers. Gastrinomas can also occur in MEN1, but they can manifest independently as well. 

Neurofibromatosis Type 1: Although primarily characterized by multiple neurofibromas, individuals with NF1 may develop endocrine tumors in various glands, causing symptoms that can overlap with MEN1. 

Laboratory Studies

Imaging Studies

Procedures

Histologic Findings

Staging

Treatment Paradigm

Diagnosis and Screening: 

Early diagnosis is crucial. Genetic testing for MEN1 mutations should be considered for individuals with a family history of MEN1 or when multiple endocrine tumors are identified. 

Regular screenings and monitoring for hormone levels and imaging studies to detect tumors in the parathyroid, pancreas, and pituitary gland. 

Management of Specific Endocrine Tumors: 

Parathyroid Gland: 

Surgery (parathyroidectomy) to remove overactive or enlarged parathyroid glands causing hyperparathyroidism. 

Monitoring of calcium levels and supplementation as necessary. 

Pancreatic Neuroendocrine Tumors: 

Surgical removal of tumors when feasible and appropriate. 

Monitoring for insulinoma, gastrinoma, glucagonoma, and other hormone-secreting tumors. 

Somatostatin analogs or other medical therapies may be considered to manage symptoms and tumor growth. 

Pituitary Tumors: 

Treatment options include surgery, radiation therapy, and medications (e.g., dopamine agonists, somatostatin analogs) depending on the type and size of the pituitary adenoma. 

Hormone replacement therapy may be necessary if the pituitary gland’s function is compromised. 

Regular Surveillance: 

Ongoing monitoring through biochemical tests (hormone levels), imaging studies, and physical exams to detect new or recurrent tumors. 

Genetic Counseling and Family Screening: 

Genetic counseling for individuals and families to assess the risk of inheritance and provide guidance regarding screening and preventive measures for at-risk family members. 

Multidisciplinary Care: 

Collaboration among endocrinologists, geneticists, surgeons, oncologists, radiologists, and other specialists to provide comprehensive care and management. 

Long-Term Follow-Up: 

Lifelong monitoring and management are essential due to the risk of tumor recurrence or the development of new tumors even after successful treatment. 

Patient Education and Support: 

Empowering patients with information about their condition, treatment options, and the importance of regular follow-ups. 

by Stage

by Modality

Chemotherapy

Radiation Therapy

Surgical Interventions

Hormone Therapy

Immunotherapy

Hyperthermia

Photodynamic Therapy

Stem Cell Transplant

Targeted Therapy

Palliative Care

lifestyle-modifications-in-treating-men-1

Regular Medical Monitoring: Establishing a routine schedule for medical check-ups and screenings is crucial. Regular monitoring includes blood tests for hormone levels, imaging scans to detect tumors, and regular physical examinations. 

Balanced Diet and Nutrition: Encourage a well-balanced diet to maintain overall health. For individuals with MEN1, there might be specific dietary recommendations based on the affected glands or hormone imbalances.  

Avoiding Tobacco and Excessive Alcohol: Both tobacco use, and excessive alcohol consumption can aggravate certain endocrine conditions and increase the risk of complications. Encourage avoiding these substances to mitigate potential risks. 

Stress Management: Stress can sometimes exacerbate hormonal imbalances. Encouraging stress management techniques like mindfulness, meditation, or counseling might be beneficial. 

Genetic Counselling and Family Screening: Given that MEN1 is a genetic disorder, individuals diagnosed with the condition should consider genetic counselling for family planning. Additionally, family members might benefit from genetic testing and screening for early detection and intervention if they carry the gene mutation. 

Use of somatostatin analogues in treating MEN 1

octreotide (Sandostatin) 

Octreotide acts primarily as a somatostatin analog, means it imitates the effects of somatostatin in the body. By binding to specific receptors known as somatostatin receptors (predominantly subtypes 2 and 5), depends on the receptor subtype and location, it suppresses insulin, glucagon, growth hormone & others. It also has effects on nonendocrine & endocrine. 

Effectiveness of Proton pump inhibitors in treating MEN 1

omeprazole (Prilosec) 

Proton pump inhibitors efficiently inhibit the activity of the H+, K+-ATPase located on the secretory surface of parietal cells, thus suppressing the secretion of acid. This suppression is particularly crucial in MEN1-associated gastrinomas. 

Esomeprazole (Nexium) 

Its action involves inhibiting the activity of proton pumps in the stomach’s lining. These proton pumps are responsible for producing acid. By blocking these pumps, esomeprazole reduces the amount of acid produced by the stomach, thereby decreasing the acidity level. 

rabeprazole sodium (AcipHex) 

 rabeprazole sodium effectively suppresses the H+, K+-ATPase from working on the parietal cells’ secretory surface, thus suppressing secretion of acid. 

lansoprazole (Prevacid) 

lansoprazole effectively suppresses the H+, K+-ATPase from working on the parietal cells’ secretory surface, thus suppressing secretion of acid. 

Effectiveness of dopamine agonists in treating MEN 1

bromocriptine (Parlodel) 

Bromocriptine works by directly stimulating dopamine receptors in the brain. By acting as a dopamine agonist, prolactin secretion from the pituitary gland is decreased by bromocriptine. 

cabergoline (Dostinex) 

Cabergoline is also a dopamine receptor agonist. It works by directly activating dopamine receptors in the pituitary gland. By stimulating these receptors, cabergoline inhibits the secretion of prolactin. This action helps to lower prolactin levels in the blood, which can lead to the resolution of associated symptoms caused by high prolactin levels. 

Role of anti hypoglycemic agents in treating MEN 1

diazoxide (Hyperstat, Proglycem) 

In 90% of cases, the inhibitory action of diazoxide on insulinomas may be successful. 10% might not react to the medication or be able to handle it. Adverse effects can be managed with hydrochlorothiazide. 

Role of surgery in treating MEN 1 syndrome

Intervention with procedure: 

Parathyroid Glands: 

Parathyroidectomy: The removal of one or more hyperactive parathyroid glands that result in hyperparathyroidism. Surgeons aim to remove the abnormal glands while preserving normal parathyroid tissue to maintain proper calcium regulation. 

Pancreatic Tumors: 

Enucleation: For small, benign insulinomas or gastrinomas , the surgeon may perform enucleation, where the tumor is removed while preserving the pancreatic tissue. 

Pituitary Tumors: 

Transsphenoidal Surgery: For pituitary tumors, a neurosurgeon performs a transsphenoidal surgery through the nasal passage or an opening in the skull base to access and remove the tumor from the pituitary gland. 

Intervention with procedure: Parathyroid Glands: Parathyroidectomy: The removal of one or more hyperactive parathyroid glands that result in hyperparathyroidism. Surgeons aim to remove the abnormal glands while preserving normal parathyroid tissue to maintain proper calcium regulation. Pancreatic Tumors: Enucleation: For small, benign insulinomas or gastrinomas , the surgeon may perform enucleation, where the tumor is removed while preserving the pancreatic tissue. Pituitary Tumors: Transsphenoidal Surgery: For pituitary tumors, a neurosurgeon performs a transsphenoidal surgery through the nasal passage or an opening in the skull base to access and remove the tumor from the pituitary gland.

Phases of Management: 

Diagnosis: Accurate diagnosis through clinical evaluation, family history assessment, biochemical testing, and imaging studies to identify tumors in the parathyroid, pancreas, and pituitary glands, among others. 

Regular Monitoring and Surveillance: Regular screenings and monitoring of hormone levels and imaging studies to detect and manage any new or recurrent tumors early. This includes assessing calcium levels, parathyroid hormone, insulin, gastrin, glucagon, growth hormone, prolactin, and other relevant hormone levels. 

Treatment of Manifestations: 

Parathyroid Gland Tumors: Surgical removal of overactive parathyroid glands or medications to manage hypercalcemia. 

Pancreatic Neuroendocrine Tumors: Surgical resection of tumors when feasible. Medical management or interventional radiology techniques for controlling hormone production or managing symptoms in inoperable cases. 

Pituitary Tumors: Treatment options include surgery, medications, and radiation therapy to control hormone hypersecretion and tumor growth. 

Other Endocrine Tumors: Management strategies vary depending on the affected glands and hormones produced. Surgical removal, medications, or other therapies might be considered. 

Genetic Counseling and Family Screening: Offer genetic counseling and testing to family members to identify individuals at risk and facilitate early detection and management. 

Long-Term Follow-Up: Regular follow-up visits with a healthcare team specializing in endocrine disorders to monitor hormone levels, assess tumor growth, manage symptoms, and adjust treatment as needed. 

Lifestyle Modifications:  

Encourage healthy lifestyle habits, like avoid smoking. 

Exercise regularly. 

Research and Clinical Trials: Participation in research studies and clinical trials to explore new treatment options, improve understanding, and develop better management strategies for MEN1. 

Medication

Future Trends

Media Gallary

References

Multiple Endocrine Neoplasia Type 1 – StatPearls – NCBI Bookshelf (nih.gov)