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Synonym: Wermer's syndrome
Multiple endocrine neoplasia type 1 (MEN1) is a rare hereditary endocrine cancer syndrome characterised primarily by tumours of the parathyroid glands (95% of cases), endocrine gastroenteropancreatic tract - eg, gastrinomas, insulinomas and carcinoid tumours (30-80% of cases) - and anterior pituitar - eg, prolactinomas (15-90% of cases).[1, 2, 3]
MEN1 has autosomal dominant inheritance with a high degree of penetrance. Cutaneous tumours are common in MEN1 and include multiple angiofibromas (previously considered pathognomonic for tuberous sclerosis), collagenomas, and lipomas.
- The prevalence throughout the world is estimated to be 1 in 20,000 to 1 in 40,000. The prevalence has probably been underestimated because at initial diagnosis most patients only have a single endocrine lesion. MEN1 has a high penetrance and an equal sex distribution.
- The genetic abnormality of MEN1 is on the long arm of chromosome 11 (11q13) and the gene cluster has been mapped precisely.
- MEN1 syndrome is inherited in an autosomal dominant manner. Approximately 10% of cases are caused by de novo mutations.
- The age of onset of endocrine tumours is usually in the teenage years but symptoms from these tumours may not appear for several years and the diagnosis is frequently delayed until the fourth decade of life. Cutaneous tumours may develop prior to the manifestation of overt clinical symptoms resulting from endocrine tumours. The earliest cutaneous tumours appear in the teenage years.
- Tumours may hypersecrete hormone, causing hypercalcaemia and recurrent nephrolithiasis (hyperparathyroidism), Zollinger-Ellison syndrome (hypergastrinaemia), hypoglycaemia (hyperinsulinaemia), amenorrhoea (hyperprolactinaemia) or acromegaly (excess growth hormone).
- Tumours of the pituitary gland may cause symptoms by mass effects.
- Angiofibromas, collagenomas, and lipomas do not typically cause symptoms, and they are mostly of cosmetic concern.
Parathyroid hyperplasia and adenomas
- Hyperparathyroidism is the presenting feature of MEN1 in about 80% of patients..
- Patients present either with asymptomatic hypercalcaemia on biochemical screening or with the features of sporadic hyperparathyroidism.
- All four glands are diffusely hyperplastic and there may be nodule formation.
Pancreatic endocrine tumours
- Pancreatic endocrine tumours occur in about 70% of patients with MEN1 and usually present between the ages of 15 and 50 if not identified by screening.
- Over 60% of tumours are gastrinomas and produce the Zollinger-Ellison syndrome and about 30% are insulinomas.
- Peptic ulcers account for most of the morbidity and mortality of the MEN1 syndrome and occur in about 10% of cases. As well as peptic ulcer, gastrinoma produces oesophagitis and diarrhoea.
- VIPoma (= vasoactive intestinal peptide and pancreatic polypeptide-secreting tumour) have rarely been described and there are only isolated reports of glucagonoma; however, non-functioning tumours may occur frequently.
- Diffuse hyperplasia of the pancreas is usually seen and is similar to the parathyroid. In the majority of cases there are multiple adenomata, most of which are less than 1 cm in diameter.
- Duodenal microgastrinoma is very common and probably accounts for almost half of all MEN1-associated gastrinomas. They are usually multiple, with up to 15 separate tumours.
- Pituitary adenomas may be detected by screening in 30% of patients but are found at post-mortem in 50%.
- Unlike the pancreas and parathyroid, there does not appear to be diffuse pituitary hyperplasia.
- Prolactinoma producing hyperprolactinaemia is the most common tumour, and occurs in about 30% of cases. They tend to be more aggressive than sporadic cases.
- Acromegaly, due to excessive production of human growth hormone (hGH) occurs in about 30%.
- Adrenocorticotrophic hormone (ACTH) may produce Cushing's syndrome but other functioning tumours are rare.
The clinical presentation of pituitary tumours is described in the article on the subject.
- These are very common but they can be easily overlooked because of their subtle appearance.
- Benign tumours include multiple angiofibromas that were previously considered pathognomonic for tuberous sclerosis, collagenomas, and lipomas. They should be sought because they can act as markers for this syndrome.
- Lesions in other tissues have been reported but their relationship to the syndrome remains controversial.
- Carcinoid tumours of the foregut, midgut, and thymus occur in about 10%, and are often found in the pancreas but they are rarely symptomatic.
- Diagnosis may result from screening of first- and second-degree relatives of patients with MEN1.
- Diagnosis of MEN1 depends on having a high level of suspicion in patients who present with multiple facial angiofibromas, collagenomas and lipomas, or other features such as hyperparathyroidism or increased gastric acid secretion.
- Investigations include hormone hypersecretion blood tests and imaging studies to look for the presence of tumours.
- DNA testing is available and mutation analysis may be used to confirm the clinical diagnosis, provide a genetic diagnosis and screen asymptomatic family members.
- Prenatal diagnosis for pregnancies at increased risk is possible if the disease-causing mutation in a family is known.
- The screening of first- and second-degree relatives of patients with MEN1 is aimed at early detection of parathyroid, pancreatic or pituitary lesions in gene carriers, to reduce the associated morbidity.
- The most useful screening investigations are serum calcium, fasting gastrin, and prolactin, although in practice a full gut hormone screen is usually performed.
- Screening of patients with apparently sporadic pancreatic endocrine tumours for evidence of MEN1 is probably justified, especially in those with gastrinomas or insulinomas. There is little evidence to support screening in those with sporadic pituitary tumours.
- Routine germline MEN1 mutation testing of all cases of 'classical' MEN1, familial hyperparathyroidism and sporadic hyperparathyroidism with one other MEN1-related condition is justified by national testing services and testing should be considered for patients under 30 years old with sporadic hyperparathyroidism and multigland hyperplasia.
- Genetic linkage analysis has greater than 95% predictive accuracy and in most families a haplotype associated with the mutant allele can be found. If three markers can be identified, the accuracy improves to greater than 99%.
If the condition is confirmed, then genetic counselling is required. The management will depend on the presenting features of each individual patient.Medical therapy may include diazoxide to inhibit release of insulin (especially in tumours that are not amenable to surgery) and high-dose proton pump inhibitors for gastrin-secreting tumours. Hormone replacement may be required after pituitary surgery.
- Skin tumours may be removed because of cosmetic concerns, especially larger facial angiofibromas.
- The surgical approach to pancreatic endocrine tumours in MEN1 is controversial. Surgical cure is best achieved by removing the pancreas and duodenum with adjacent lymph nodes. There is still a high rate of recurrence but the overall mortality remains low.
- Pituitary tumours: treatment is the same as for sporadic pituitary tumours. This usually involves a trans-sphenoidal operation to remove the tumour.
- Parathyroidectomy, subtotal or complete, is practised for MEN1 but long-term follow-up reveals a high rate of recurrence in MEN1 despite surgical intervention.
- The treatment of metastatic disease is the same as in sporadic cases.
- The average age of death in individuals with MEN1 is significantly lower (55.4 years for men and 46.8 years for women) than that of the general population.
- Pancreatic endocrine tumours, particularly gastrinomas, become malignant in about half of patients with MEN1. Untreated, patients may die from peptic ulcer disease, metastatic endocrine pancreatic carcinoma, or foregut carcinoid malignancy.
- Pancreatic endocrine tumours associated with MEN1 are less malignant than sporadic tumours and carry a better prognosis, with a median survival of 15 years compared to 5 years for patients with sporadic tumours. This may reflect more indolent disease or earlier diagnosis.
Further reading and references
Wermer's syndrome; whonamedit.com
Neuroendocrine gastro-entero-pancreatic tumors: ESMO Clinical Practice Guidelines for diagnosis treatment and follow-up; European Society for Medical Oncology(2012)
Neuroendocrine bronchial and thymic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up; European Society for Medical Oncology (2012)
Pasquali D, Di Matteo FM, Renzullo A, et al; Multiple endocrine neoplasia, the old and the new: a mini review. G Chir. 2012 Nov-Dec33(11-12):370-3.
Thakker RV; Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). Mol Cell Endocrinol. 2014 Apr 5386(1-2):2-15. doi: 10.1016/j.mce.2013.08.002. Epub 2013 Aug 8.
Marini F, Falchetti A, Luzi E, et al; Multiple Endocrine Neoplasia Type 1 (MEN1) Syndrome
Anik A, Abaci A; Endocrine cancer syndromes: an update. Minerva Pediatr. 2014 Dec66(6):533-47. Epub 2014 Sep 22.
Gut P, Komarowska H, Czarnywojtek A, et al; Familial syndromes associated with neuroendocrine tumours. Contemp Oncol (Pozn). 201519(3):176-83. doi: 10.5114/wo.2015.52710. Epub 2015 Jul 8.
Multiple Endocrine Neoplasia Type 1, MEN1; Online Mendelian Inheritance in Man (OMIM)
Falchetti A, Marini F, Brandi ML; Multiple Endocrine Neoplasia Type 1
Ciccarelli A, Daly AF, Beckers A; The epidemiology of prolactinomas. Pituitary. 20058(1):3-6.
Asgharian B, Turner ML, Gibril F, et al; Cutaneous tumors in patients with multiple endocrine neoplasm type 1 (MEN1) and gastrinomas: prospective study of frequency and development of criteria with high sensitivity and specificity for MEN1. J Clin Endocrinol Metab. 2004 Nov89(11):5328-36.
Cardinal JW, Bergman L, Hayward N, et al; A report of a national mutation testing service for the MEN1 gene: clinical presentations and implications for mutation testing. J Med Genet. 2005 Jan42(1):69-74.
Hausman MS Jr, Thompson NW, Gauger PG, et al; The surgical management of MEN-1 pancreatoduodenal neuroendocrine disease. Surgery. 2004 Dec136(6):1205-11.
Malone JP, Srivastava A, Khardori R; Hyperparathyroidism and multiple endocrine neoplasia. Otolaryngol Clin North Am. 2004 Aug37(4):715-36, viii.