Multiple Endocrine Neoplasia Type 1 – Definition
Multiple endocrine neoplasia type 1 (MEN1, OMIM #131100) is a genetic disease caused by mutations in the MEN1 gene. It mainly leads to a predisposition to parathyroid tumors with primary hyperparathyroidism (PHPT), pancreatic islet cell tumors, and adenohypophysis (anterior pituitary neuroendocrine tumors, PitNET). All in all, the MEN1 tumor spectrum includes more than 20 endocrine and non-endocrine tumors, which may occur in different combinations.
Synonym:
Wermer syndrome
Gene:
MEN1
Gene product:
Menin protein
Function:
Presumably functions to regulate the cell cycle, transcription, and to maintain genomic stability
Pattern of inheritance:
Autosomal dominant; around 10% de novo mutations
Prevalence:
1:20.000 – 1:40.000
Genotype-phenotype correlation:
unknown
Penetrance:
With regard to all clinical manifestations: over 50% at age 20 and over 95% at age 40
Multiple Endocrine Neoplasia Type 1 – Diagnosis
Genetic Diagnostics
Genetic testing is indicated for the following individuals:
- Any person with two or more MEN1-type tumors
- Any person with a MEN1-type tumor and a first-degree relative with MEN1
- Any person under 30 years of age with PHPT, pancreatic precursor lesions, or pancreatic islet cell tumor
The diagnosis of “MEN1” is confirmed by detecting a heterozygous mutation of the MEN1 gene using sequence or deletion/duplication analysis. Using panel examinations, in which several genes are recorded, can also be helpful.
Clinical Diagnostic Criteria
- At least two primary characteristic MEN1 tumors (e.g., parathyroid tumor, islet cell tumor, or PitNET)
- In the case of family members of a patient proven to be a MEN1 carrier, the presence of one characteristic MEN1 tumor suffices to confirm diagnosis.
Differential Diagnoses
- MEN type 4
- Primary hyperparathyroidism
- MEN type 2
- Pituitary adenomas
- Zollinger-Ellison syndrome
Clinical Presentation
Parathyroid Adenoma and Primary Hyperparathyroidism
- Most frequent MEN1 manifestation, occurring in 95% of patients
- The first manifestation in 90% of patients, usually occurring between 20 and 25 years of age
- Characterized by hypercalcemia
Well-Differentiated Endocrine Tumors of the Gastroenteropancreatic Tract
- Gastrinomas occur in around 40% of patients and manifesting as Zollinger-Ellison syndrome. The onset of the disease is usually before 40 years of age. 25% of patients do not have a concomitant MEN1 family history.
- Insulinomas occur in approximately 10% of patients. Age of disease onset is approximately 10 years earlier with MEN1 mutations, when compared to sporadic insulinomas.
- Glucagonomas and VIPomas also occur with MEN1.
Tumors of Adenohypophysis
- Occur in 30-55% of patients
- They are the first manifestation in 10% of familial and 25% of non-familial cases.
- The most common tumor is prolactinoma, while GH- and ACTH-secreting tumors are less common, and TSH-secreting tumors are rare.
Carcinoids
- Thymic, bronchial, and type II enterochromaffin-like (ECL) gastric carcinoids occur in approximately 10% of MEN1 patients.
- Thymic carcinoids are identified more often in men than in women (20:1), and bronchial carcinoids more often in women than in men.
- Thymic carcinoids, together with MEN1, are very aggressive and frequently lethal.
Parathyroid Tumors
- Occur in 20-40% of MEN1 patients and only rarely secrete hormones
Cutaneous Tumors
- Angiofibromas, collagenomas, and lipomas frequently occur as part of MEN1.
Special Features of Treatment
PHPT
- Total or subtotal parathyroidectomy (the scope and timing of these are still controversial)
Pituitary Tumors
- Prolactinoma: dopamine agonists (cabergoline, bromocriptine, pergolide, and quinagolide)
- GH-secreting tumors: transsphenoidal operation, somatostatin analogs
- GH-secreting tumors: surgical removal of the tumor, radiotherapy
Well-Differentiated Endocrine Tumors of the Gastroenteropancreatic Tract
- Gastrinoma: Proton pump inhibitors (PPIs) and H2-receptor blockers. The surgical approach is currently controversial and depends predominantly on the extent of metastasis and whether the surgery is feasible.
- Insulinoma and other pancreatic tumors: surgical treatment
Carcinoids
- Complete resection if possible; otherwise, long-acting somatostatin analogs, with radiotherapy or chemotherapy if needed
Adrenocortical Tumors
- Surgical treatment with tumors > 4 cm in diameter, striking radiological signs, or significant growth
Diagnosis of Multiple Endocrine Neoplasia Type 1- What's Next?
Once diagnosed, it is recommended that a cancer predisposition specialist manage the patient. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. Some additional information, including links to support groups, is also included at the end of this page.
Diagnosis of Multiple Endocrine Neoplasia Type 1- What's Next?
Once diagnosed, it is recommended that a cancer predisposition specialist manage the patient. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. Some additional information, including links to support groups, is also included at the end of this page.
Recommendations for Early Detection in Your Patients
Insulinoma
- Screening from 5 years of age
- Clinical symptoms: syncope, drowsiness, documented hypoglycemia
- Laboratory testing (annual): glucose on an empty stomach and insulin
Neuroendocrine Tumors of Adenohypophysis (PitNET)
- Screening from 5 years of age
- Clinical symptoms: headaches, visual changes, galactorrhea, increased growth
- Laboratory testing (annual): prolactin, IGF-1
- Imaging: cranial MRI every 3 years
Parathyroid Adenoma and PHPT
- Screening from 8 years of age
- Clinical symptoms: back pain, bone pain, the feeling of faintness, fatigue, psychological changes, kidney stones, nausea, vomiting, obstipation, multiple or pathological fractures
- Laboratory testing (annual): calcium
Neuroendocrine Tumors of the Pancreas
- Screening from 10 years of age
- Clinical symptoms: usually asymptomatic; VIPoma: excessive diarrhea?; glucagonoma: hyperglycemia, nausea, polyuria, thirst
- Laboratory testing (annual): potentially chromogranin A, glucagon, proinsulin, pancreatic polypeptide, VIP
- Imaging: annual abdominal MRI
Adrenocortical Adenomas
- Screening from 10 years of age
- Imaging: abdominal MRI (at the same time as pancreatic imaging)
Thymic, Bronchial, and Gastric Carcinoids
- Screening from 20 years of age
- Clinical symptoms: usually asymptomatic; possibly indicated by flush, diarrhea, wheezing, edemas, or abdominal pain
- Imaging: Thoracic and abdominal CT/MRI every 1-2 years
Gastrinoma (Duodenal or Pancreatic)
- Screening from 20 years of age
- Clinical symptoms: abdominal pain, gastric ulcer, taking of PPI
- Laboratory testing (annual): gastrin on an empty stomach
