Multiple endocrine neoplasia syndromes are hereditary tumor syndromes with distinct patterns of organ involvement.
Mutations in the MEN1 gene typically cause type 1 multiple endocrine neoplasia (MEN1), and mutations in the RET proto-oncogene typically cause type 2 multiple endocrine neoplasia (MEN2). MEN2 is divided into subtypes, MEN2A and MEN2B (also known as MEN2 and MEN3). MEN4 is a very rare disease, caused by mutations in the CDKN1B gene.
Prophylactic thyroidectomy in childhood is indicated in MEN2.
Medical management of hormonal hypersecretion is important for symptom control.
Most tumors require surgical evaluation, although surgical cure is not always possible.
Genetic carriers require lifelong monitoring, even after successful operations.
Morbidity and mortality result from both hormonal hypersecretion and metastases.
Multiple endocrine neoplasia (MEN) syndromes are hereditary tumor syndromes of variable neoplastic patterns and characterized by the development of multiple endocrine tumors. Tumors can include parathyroid adenomas, pituitary adenomas (which may be nonsecretory or affect the profiles of adrenocorticotropic hormone, growth hormone, thyroid-stimulating hormone, and/or prolactin), enteropancreatic and other neuroendocrine tumors (which may affect the profiles of gastrin, insulin, glucagon, and/or vasoactive intestinal protein), facial lipomas, facial angiofibromas, medullary thyroid cancers, and pheochromocytomas. They may be associated with propensity to tumor formation in other organs such as the kidney and breast.
History and exam
Key diagnostic factors
- young age (MEN1/2)
- positive family history (MEN1/2)
- episodic triad of sweating, palpitations, and headache (MEN2)
- clinical features of kidney stones (MEN1/2)
- facial angiofibromas or collagenomas (MEN1)
- mucosal neuromas (MEN2B)
- arm span and upper-to-lower-body-segment ratio (MEN2B)
- palpable thyroid nodule (MEN2)
- irregular menses (MEN1)
- visual changes (MEN1)
- unexplained flushing (MEN2)
- infertility (MEN1)
- clinical features of acromegaly (MEN1)
- clinical features of thyrotoxicosis (MEN1)
Other diagnostic factors
- weight changes (MEN1/2)
- hypertension (MEN1/2)
- abdominal pain (MEN1/2)
- headache (MEN1/2)
- low-trauma fractures (MEN1)
- altered bowel habit (MEN1/2)
- palpitations (MEN1/2)
- easy bruising (MEN1/2)
- slow wound healing (MEN1/2)
- erectile dysfunction (MEN1)
- clinical features of hypercortisolism/Cushing syndrome (MEN1/2)
- anxiety (MEN1/2)
- heat intolerance (MEN1)
- confusion (MEN1/2)
- dehydration (MEN1/2)
- gastrointestinal bleeding (MEN2)
- hepatomegaly (MEN2)
- familial cases of MEN
- RET proto-oncogene mutation
- MEN1 (menin) mutation
1st investigations to order
- serum calcitonin (MEN2)
- serum carcinoembryonic antigen (MEN2)
- plasma metanephrines (MEN2)
- serum parathyroid hormone and calcium (MEN1/2)
- fasting serum gastrin (MEN1)
- serum chromogranin A (MEN1)
- serum prolactin (MEN1)
- insulin-like growth factor-1 (MEN1)
- 24-hour urine metanephrines and catecholamines (MEN2)
- 24-hour urine calcium (MEN1/2)
- thyroid biopsy (MEN2)
Investigations to consider
- fasting serum glucose/insulin (MEN1)
- serum C peptide (MEN1)
- calcium-stimulated gastrin (MEN1)
- serum proinsulin (MEN1)
- serum pancreatic polypeptide (MEN1)
- serum glucagon (MEN1)
- T4 (free thyroxine) (MEN1)
- thyroid-stimulating hormone (TSH) (MEN1)
- dexamethasone suppression test (MEN1/2)
- urine sulfonylurea (MEN1/2)
- metaiodobenzylguanidine scintiscan (MIBG) (MEN2)
- 18F-fluorodihydroxyphenylalanine (18F-DOPA) positron emission tomography (PET)/CT abdomen and pelvis (MEN2)
- octreotide scan (MEN1)
- gallium-68 DOTATATE PET/CT abdomen and pelvis (MEN1 and 2)
- technetium 99 sestamibi scintiscan (MEN1/2)
- abdominal CT (MEN1/2)
- abdominal MRI (MEN1/2)
- chest CT or MRI (MEN1)
- pituitary MRI (MEN1)
- endoscopic ultrasonography (MEN1)
- upper gastrointestinal endoscopy (MEN1)
- Helicobacter pylori breath test, biopsy, or stool antigen test (MEN1/2)
family history of MEN2
Rebecca Gorrigan, BSc, MBChB (hons), MRCP
Consultant Physician and Endocrinologist
Department of Endocrinology
Barts and the London NHS Trust and Queen Mary University of London
RG declares that she has no competing interests.
Maralyn Druce, MA, MRCP, PhD
Professor of Endocrine Medicine
Department of Endocrinology
Barts and the London Medical School
MD has received fees for consulting from Ipsen and Novartis; their products are used in the treatment of neuroendocrine tumors. Neuroendocrine tumors of the pancreas are features of MEN1. The topic does not discuss specific therapies for features of the condition.
Dr Rebecca Gorrigan and Professor Maralyn Druce would like to gratefully acknowledge Dr Jennifer Mammen and Dr Roberto Salvatori, previous contributors to this topic.
JM and RS declare that they have no competing interests.
Michael Levine, MD, FAAP, FACP
Division of Endocrinology and Diabetes
The Children's Hospital of Philadelphia
ML declares that he has no competing interests.
Salvatore Corsello, MD
Associate Professor of Endocrinology
Catholic University School of Medicine
SC declares that he has no competing interests.
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