Multiple Endocrine Neoplasia
Multilpe endocrine neoplasia (MEN) are rare fimilial (inherited) conditions affecting the glands of the endocrine system:
- Multiple endocrine neoplasia 1 (MEN type I) also known as Wermer's syndrome
- Multiple endocrine neoplasia 2A (MEN type IIa) also known as Sipple Syndrome
- Multiple endocrine neoplasia 2B (MEN type IIb)
- Familial medullary thyroid carcinoma, (FMTC) is a similar inherited condition were medullary thyroid carcinoma may occur in several family members, though not necessarily with the other endocrine tumours seen in MEN.
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MeSH term: Multiple Endocrine Neoplasia
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Surgical Management of Multiple Endocrine Neoplasia 1 and Multiple Endocrine Neoplasia 2.
Surg Clin North Am. 2019; 99(4):693-709 [PubMed] Related Publications
Clinico-pathologic and dynamic prognostic factors in sporadic and familial medullary thyroid carcinoma: an Israeli multi-center study.
Eur J Endocrinol. 2019; 181(1):13-21 [PubMed] Related Publications
Methods: Patients treated for MTC at four tertiary medical centers were retrospectively analyzed. Clinical and pathological data were collected. The outcomes measured included disease persistence 1 year after diagnosis, disease persistence at last follow-up, disease-related mortality (DRM) and all-cause mortality.
Results: The study enrolled 193 patients (mean age: 48.9 ± 18.7, 44.7% males), of whom 18.1% were familial cases. The mean follow-up period was 10.1 ± 9.4 years (8.5 ± 8.1 in sporadic and 16.9 ± 11.6 in familial MTC). Disease persistence 1-year after diagnosis and at last follow-up was detected in 56.1 and 60.4% patients, respectively. All-cause and DRM were 28.5 and 12.6%, respectively. Extra-thyroidal extension (ETE) and distant metastases (DM) were associated with disease persistence at last follow-up. ETE and DM were also significantly associated with DRM. Complete remission 1 year after diagnosis had high correlation with no evidence of disease at last follow-up (Cramer's V measure of association 0.884, P < 0.001) and with 100% disease-specific survival (Cramer's V measure of association 0.38, P < 0.001).
Conclusions: Apart from clinico-pathologic parameters, close correlation was found between 1-year status and long-term prognosis. These results underscore the importance of combining classical and dynamic factors for both sporadic and familial MTC prognostication and treatment decision making.
Medullary Thyroid Carcinoma: Prognostic Variables And Tumour Markers Affecting Survival.
J Ayub Med Coll Abbottabad. 2018 Oct-Dec; 30(Suppl 1)(4):S627-S632 [PubMed] Related Publications
Methods: Analysis of 83 (8.7%) consecutive MTC patients registered at a single centre between 1995 and 2015. The impact of tumour respectability, TNM stage, multiple endocrine neoplasia (MEN) syndrome, local recurrence, Ct DT and Ct rising velocity on PFS and OS was analysed. Median follow-up was 4.3 years (range: 1-18 years).
Results: Eighty-three (8.7%) of all thyroid cancers registered at our centre were MTC. Fifty-five males, 28 females. Mean age 39 years [range: 17-72 years]. Twenty-two were unresectable and 61 resectable. Five-year and 10-year OS was 84% and 77% respectively. Of 68 with follow up greater than a year; 20 (29.4%) were cured, 15 (22.1%) had biochemical evidence of disease, three (4.4%) had stable macroscopic disease and 30 (44.1%) had recurrent/progressive disease. Sixteen (23.5%) died. On multivariate analysis, T4 tumour, male gender, nodal and distant metastases, tumour resectibility, Ct DT less than two years and tumour marker rising velocity of greater than 0.05pg/ml/month were poor prognostic factors (pvalue <0.05). Age and association with MEN syndrome had no statistically significant survival impact. Radiotherapy reduced local relapse in patients with nodal disease. Total thyroidectomy with nodal clearance lessened relapses.
Conclusion: Clinical stage and pathological aspects are predictors of disease progression. Persistent biochemical evidence of MTC does not affect OS, however, Ct DT < 2 years and rapid rate of tumour marker rise predict disease progression.
Intertumor heterogeneity in 60 pancreatic neuroendocrine tumors associated with multiple endocrine neoplasia type 1.
Orphanet J Rare Dis. 2019; 14(1):54 [PubMed] Free Access to Full Article Related Publications
METHODS: Sixty PNENs of six patients with MEN-1 were retrospectively evaluated.
RESULTS: Fifty-one tumors with a diameter of < 20 mm were graded as G1. Two of 9 tumors with diameters of ≥20 mm were graded as G2. Tumor size of ≥20 mm correlated significantly with higher proliferation (p = 0.000617). Lymph node metastases were documented in two patients with a total of 19 tumors. In one patient, all 13 tumors (diameter: 0.4 to 100 mm) were classified as G1. However, metastases were documented in 9/29 lymph nodes. In the other patient, 5 tumors (3.5 to 20 mm) were classified as G1. The sixth tumor (30 mm) was classified as G2 (Ki-67: 8%). Metastases were revealed in 2/20 lymph nodes.
CONCLUSIONS: Tumor size of ≥20 mm seems to correlate with more aggressive MEN-1 related pancreatic disease, regardless of individual proliferation. Tumors ≥20 mm and tumors graded as G2 should be treated surgically regardless of their size.
Metastatic Insulinoma Controlled by Targeted Radionuclide Therapy With 177Lu-DOTATATE in a Patient With Solitary Kidney and MEN-1 Syndrome.
Clin Nucl Med. 2019; 44(6):e415-e417 [PubMed] Related Publications
Management of familial hyperparathyroidism syndromes: MEN1, MEN2, MEN4, HPT-Jaw tumour, Familial isolated hyperparathyroidism, FHH, and neonatal severe hyperparathyroidism.
Best Pract Res Clin Endocrinol Metab. 2018; 32(6):861-875 [PubMed] Related Publications
Constipation with megacolon in a 36-year-old man: a rare presentation of MEN2B from Sri Lanka.
BMJ Case Rep. 2019; 12(1) [PubMed] Free Access to Full Article Related Publications
Familial and Hereditary Forms of Primary Hyperparathyroidism.
Front Horm Res. 2019; 51:40-51 [PubMed] Related Publications
Pituitary adenomas in patients with multiple endocrine neoplasia type 1: a single-center experience in China.
Pituitary. 2019; 22(2):113-123 [PubMed] Related Publications
METHODS: We retrospectively analyzed 54 MEN1 patients with pituitary adenomas diagnosed at Peking Union Medical College Hospital from March 2003 to January 2017. Clinical data, laboratory testing results, treatments of involved glands and treatment responses were collected and analyzed.
RESULTS: The mean age at pituitary adenoma diagnosis was 53.9 ± 17.8. The patients initially consulted the Endocrinology, General Surgery and Neurosurgery departments, in descending frequency. The nonfunctioning adenoma, prolactinoma, GH-secreting adenoma, cosecreting adenoma, and ACTH-secreting adenoma subtypes accounted for 48.1%, 27.8%, 9.3%, 9.3% and 5.6% of the cases, respectively. The remission rate for prolactinomas was 46.2% (6/13) treated with bromocriptine. And the remission rates were 87.5% (7/8) and 100% (3/3) for GH-secreting adenomas and ACTH-secreting adenomas respectively achieved by transsphenoidal surgery. Nineteen (35.2%) patients with asymptomatic nonfunctioning pituitary adenomas showed no progression after a 35-month follow-up with close observation. Regarding treatment priority, patients with thymic carcinoid tumors received first-line surgery, 54% of the patients with enteropancreatic tumors had these tumors treated first, and 26% of all patients had their pituitary adenomas treated first. In acromegalic patients, pituitary lesions tended to be treated first (75%, p = 0.002). PHPT and adrenocortical adenomas can be managed with elective surgery.
CONCLUSIONS: The treatment of MEN1 requires cooperation between multidisciplinary teams. Individualized treatment according to the severity of glandular involvement is needed. GH-secreting and ACTH-secreting pituitary adenomas require active treatment, while nonfunctioning pituitary adenomas can be observed closely.
Three Novel MEN1 Variants in AIP-Negative Familial Isolated Pituitary Adenoma Patients.
Pathobiology. 2019; 86(2-3):128-134 [PubMed] Related Publications
METHODS: Among 20 patients evaluated in 13 FIPA families, 12 were previously reported as AIP mutation-negative. In this study, 6 new families with 8 patients were recruited. All patients were subjected to multiplex ligation-dependent probe amplification to detect copy number variations in AIP and MEN1, and AIP sequencing was performed in additional patients. AIP mutation-negative patients were subjected to MEN1 sequencing.
RESULTS: Our cohort revealed only 3 novel heterozygous MEN1 variants including c.1846T>A p.(*616Argext*21), rs778272737:T>C, and rs972128957:C>T in 2 families, with patients diagnosed with Cushing disease, nonfunction al adenoma, and acromegaly, respectively. Among them, c.1846T>A p. (*616Argext*21) is a stop codon read-through, whereas the others are 3'UTR variations. MEN1 variation frequency was detected as 15%.
CONCLUSIONS: MEN1 alterations can be of significance in FIPA patients and screening could be offered to AIP mutation-negative patients without MEN1 features. Further studies are needed to clarify the role of MEN1 in FIPA patients.
Interventional Management of Subcapsular Hepatic Hematoma with Hepatic Compartment Syndrome After Laparoscopic Adrenalectomy.
Cardiovasc Intervent Radiol. 2019; 42(4):625-628 [PubMed] Related Publications
Orthotopic Liver Transplantation for Hereditary Hemorrhagic Telangiectasia and MEN Type I Syndrome - Case Report and Review of Literature.
Chirurgia (Bucur). 2018 Nov-Dec; 113(6):837-848 [PubMed] Related Publications
Germline and somatic mosaicism in a family with multiple endocrine neoplasia type 1 (MEN1) syndrome.
Eur J Endocrinol. 2019; 180(2):K15-K19 [PubMed] Related Publications
Multiple endocrine neoplasia type 1: extensive analysis of a large database of Florentine patients.
Orphanet J Rare Dis. 2018; 13(1):205 [PubMed] Free Access to Full Article Related Publications
RESULTS: We performed an extensive epidemiological, clinical and genetic analysis of the Florentine MEN1 patient database, which includes 145 MEN1 patients and 20 asymptomatic MEN1 carriers, constantly followed up at the Regional Referral Centre for Inherited Endocrine Tumours of the Tuscany Region, during the last three decades. We reported, here, the results of clinical, epidemiological and genetic descriptive statistics, as well as correlation analyses between tumours and mutation types and localisation. No direct genotype-phenotype correlation was described, but the importance of the genetic testing was confirmed for an early diagnosis and the identification of asymptomatic carriers.
CONCLUSIONS: As with all rare diseases, the possibility to collect and analyse data on a relatively large number of patients is important for increasing our knowledge of the epidemiologic aspects of the disease, and its natural course and prognosis of single manifestations of the syndrome, in order to set up the best diagnostic and therapeutic plans for patients. In this light, the creation and constant updating of large patient databases is fundamental. Results from database study can provide useful epidemiological, clinical and genetic information about MEN1 syndrome, which could help clinicians in the diagnostic and therapeutic management of single MEN1 patients.
Prophylactic thyroidectomy in multiple endocrine neoplasia 2 (MEN2) patients with the C634Y mutation: A long-term follow-up in a large single-center cohort.
Eur J Surg Oncol. 2019; 45(4):625-630 [PubMed] Related Publications
OBJECTIVE: To analyze a large cohort of patients with the C634Y mutation who received prophylactic thyroidectomy.
MATERIALS AND METHODS: In a group of 110 MEN2 patients, we analyzed those with the C634Y mutation who had received prophylactic thyroidectomy (absence of clinical and radiological thyroid disease) treated in a tertiary referral hospital between 1983 and 2016. MTC is related to age and Ct. Statistical analysis was performed using the χ
RESULTS: Fifty patients with a mean age of 12 ± 9 years were analyzed; 56% of these had MTC (100% stage I). There was no case of hypoparathyroidism or permanent recurrent damage. MTC was associated mainly with age (OR 1.38). One 5-year-old patient presented with MTC. Mean follow-up time was 16 ± 6 years, and no cases of recurrence were observed.
CONCLUSIONS: Performing prophylactic thyroidectomy in patients with the C634Y mutation allows us to cure the disease without causing long-term complications. Our results support the notion that age <5 years should be a criterion for carrying out prophylactic thyroidectomy in these patients.
Germline mutation landscape of multiple endocrine neoplasia type 1 using full gene next-generation sequencing.
Eur J Endocrinol. 2018; 179(6):391-407 [PubMed] Related Publications
Multiple Endocrine Neoplasia Type 2B Presents Early in Childhood but Often Is Undiagnosed for Years.
J Pediatr. 2018; 203:447-449 [PubMed] Free Access to Full Article Related Publications
C-cell hyperplasia in sporadic and familial medullary thyroid carcinoma.
Indian J Pathol Microbiol. 2018 Oct-Dec; 61(4):485-488 [PubMed] Related Publications
Aims: This study aims to study the occurrence, clinicopathological, and immunohistochemical features of CCH in MTC diagnosed during a 22-year period at a tertiary care center in North India and to review the available literature on CCH.
Materials and Methods: Eighty-seven consecutive cases of MTC were included in the study. Histological evaluation for the presence of CCH and neoplastic CCH was performed. Confirmation of CCH was done by immunohistochemistry for calcitonin and chromogranin. The presence of neoplastic CCH was correlated with clinical factors and prognostic factors.
Results: Of 87 cases of MTC included in the study, 71 (82%) patients were sporadic and 16 (18%) had familial MTC. Neoplastic CCH was seen in 12 (75%) familial and in 9 (13%) sporadic MTC. Patients with familial MTC were more frequently associated with neoplastic CCH than sporadic MTC (P < 0.001), were younger (P < 0.001), and had more often bilateral and multifocal tumors (P < 0.001). However, there was no significant difference in mean survival time and progression-free survival in patients with and without CCH.
Conclusion: CCH, though more common in familial MTC, can also be seen in sporadic tumors. CCH is not associated with patient survival and disease progression.
Results of Duodenopancreatic Reoperations in Multiple Endocrine Neoplasia Type 1.
World J Surg. 2019; 43(2):552-558 [PubMed] Related Publications
METHODS: MEN1 patients who underwent reoperations for duodenopancreatic neuroendocrine neoplasms (dpNENs) were retrieved from a prospective database and retrospectively analyzed.
RESULTS: Twelve of 101 MEN1 patients underwent up to three reoperations, resulting in a total of 18 reoperations for dpNEN recurrence. Patients initially underwent either formal pancreatic resections (n = 7), enucleations (n = 3), or duodenotomy with lymphadenectomy for either NF-pNEN (seven patients), Zollinger-Ellison syndrome (ZES, three patients), organic hyperinsulinism (one patient) or VIPoma (one patient). Six patients had malignant dpNENs with lymph node (n = 5) and/or liver metastases (n = 2). The indication of reoperations was NF-pNEN (five patients), ZES (five patients), organic hyperinsulinism (one patient), and recurrent VIPoma (one patient). Median time to first reoperation was 67.5 (range 6-251) months. Five patients required a second duodenopancreatic reoperation for 60-384 months after initial surgery, and one patient underwent a third reoperation after 249 months. The rate of complications (Clavien-Dindo ≥3) was 28%. Four patients required completion pancreatectomy. Six patients developed pancreoprivic diabetes. After a median follow-up of 18 (6-34) years after initial surgery, ten of 12 patients are alive, one died of metastatic pancreatic VIPoma, and one died of metastatic thymic NEN.
CONCLUSION: Reoperations are frequently necessary for dpNEN in MEN1 patients, but are not associated with an increased perioperative morbidity in specialized centers. Organ-sparing resections should be preferred as initial duodenopancreatic procedures to maintain pancreatic function and avoid completion pancreatectomy.
First report of concomitant pheochromocytoma and duodenal neuroendocrine tumour in a sporadic multiple endocrine neoplasia type 1.
BMJ Case Rep. 2018; 2018 [PubMed] Related Publications
Multiple endocrine neoplasia type 1: clinical correlates of MEN1 gene methylation.
Pathology. 2018; 50(6):622-628 [PubMed] Related Publications
The Reality of Multiple Endocrine Neoplasia Type 2B Diagnosis: Awareness of Unique Physical Appearance Is Important.
J Nippon Med Sch. 2018; 85(3):178-182 [PubMed] Related Publications
CASE PRESENTATION: We have encountered four patients with MEN2B. Two were hereditary cases from the same family, and two were considered de novo cases with phenotypically normal parents. Mean age at diagnosis was 25.5 years (range, 13-39 years). Although all patients had shown mucosal neuroma on the lips and tongue, in addition to gastrointestinal symptoms from infancy, diagnoses were made from symptomatic MTC even for the hereditary patients (our index case was a 14-year-old girl, whose mother was subsequently diagnosed with advanced MTC). Genetic tests for RET mutations revealed the M918T mutation in all patients. Two patients developed pheochromocytoma, two died from distant metastases of MTC, and two received treatment for multiple metastases of MTC (one with vandetanib).
CONCLUSIONS: In our patients with MEN2B, prophylactic or early thyroidectomy could not be performed. The characteristic phenotype associated with MEN2B is almost always seen prior to detection of MTC or pheochromocytoma. Knowledge about the non-endocrine manifestations of MEN2B needs to be shared among pediatricians and gastroenterologists.
Use of Dexmedetomidine in a Parturient With Multiple Endocrine Neoplasia Type 2A Undergoing Adrenalectomy and Thyroidectomy: A Case Report.
A A Pract. 2019; 12(5):136-140 [PubMed] Related Publications
Primary hyperparathyroidism associated with MEN 1: Experience in 71 cases.
Cir Esp. 2018; 96(10):627-633 [PubMed] Related Publications
METHOD: A total of 97 patients with MEN 1 were diagnosed in a tertiary hospital. A retrospective analysis was made in patients with pHPT (n=71).
STUDY VARIABLES: age at diagnosis, mutation, clinical presentation, laboratory tests, surgical technique, and recurrence of HPT.
RESULTS: Mean age was 38 years, and 50 patients were asymptomatic. The surgical technique was: subtotal parathyroidectomy (n=55), resection of three glands (n=7), and resection of less glands (n=9). Transcervical thymectomy was performed in 53 patients. Mean follow-up was 102.9 months. There were 21 recurrences, There were correlations between age at diagnosis and serum calcium levels with the presence of symptoms (P<.0001). There were also correlations between recurrence and surgical technique (P<.03), non-association with thymectomy (P<.0001), and follow-up time (P<.03).
CONCLUSION: Performing genetic and clinical screening allows us to make a diagnosis in the asymptomatic period and to provide early treatment for HPT in MEN 1. The recurrence rate is high, and follow-up time and the surgical technique used are risk factors for recurrence.
A follow-up study of patients with MEN syndromes - five case reports.
Endokrynol Pol. 2018; 69(2):163-167 [PubMed] Related Publications
RESULTS: The mean preoperative serum PTH level was 215,56 pg/ml, whereas calcium concentration was 1.40 mmol/l. Three Patients with MEN1 syndrome had three and two thirds of parathyroid gland taken, and one had a single parathyroid gland excised with biopsy of the rest glands performed. A patient with MEN2 syndrome had one parathyroid gland excised. Postoperatively, we reported decreased secretion of both PTH (a mean serum PTH concentration 6.72 pg/ml), and serum calcium concentration 1.11 mmol/l. One patient (25%) with MEN 1 developed recurrent hyperparathyroidism after five years from the surgery. The patient was reoperated. The rest of the parathyroid gland was removed with an implantation into separated muscle pockets in the anterior forearm muscles.
CONCLUSIONS: 1. MEN syndrome is a rare cause of primary hyperparathyroidism. 2. Subtotal parathyroidectomy helps to bring back a normal calcium metabolism. 3. Recurrence of hyperparathyroidism in patients with MEN syndrome requires total parathyroidectomy with an autotransplantation into the anterior forearm muscles.
Parathyroid carcinoma in multiple endocrine neoplasm type 1 syndrome: case report and systematic literature review.
Clin Exp Med. 2018; 18(4):585-593 [PubMed] Related Publications
Robotic enucleation for pediatric insulinoma with MEN1 syndrome: a case report and literature review.
BMC Surg. 2018; 18(1):44 [PubMed] Free Access to Full Article Related Publications
CASE PRESENTATION: We present a case of a 9-year-old girl presenting with repeated loss of consciousness, concomitant with a pale face, palpitations, and convulsions, which had persisted for 2 years and had been aggravated during the previous 2 months. She was previously misdiagnosed with epilepsy in another hospital. We further examined her while she was hospitalized. By combining her medical history and imaging examination and lab test results, a diagnosis of insulinoma was confirmed. Sanger-directed sequencing on a peripheral blood sample revealed an MEN1 gene mutation, indicating pediatric insulinoma with MEN1 syndrome. The patient underwent minimally invasive insulinoma enucleation surgery under the Da Vinci robot-assisted system with intraoperative ultrasound (IOUS) connected. The surgery was successfully completed within 65 min, and the girl recovered well postoperatively and no longer experienced symptoms of hypoglycemia.
CONCLUSION: This is the first report of a case of pediatric insulinoma treated using robotic enucleation. This experience demonstrates the feasibility and safety of combining robotic surgery with the enucleation procedure as an excellent strategy for pediatric insulinoma.
Update on multiple endocrine neoplasia Type 1 and 2.
Presse Med. 2018; 47(9):722-731 [PubMed] Related Publications
DNA methylation profiling in MEN1-related pancreatic neuroendocrine tumors reveals a potential epigenetic target for treatment.
Eur J Endocrinol. 2018; 179(3):153-160 [PubMed] Related Publications
DESIGN AND METHODS: Methylation-specific multiplex ligation-dependent probe amplification was used to assess promoter methylation of 56 tumor suppressor genes in MEN1-related (
RESULTS: We found promoter methylation of a large number of potential tumor suppressor genes. CMI (median CMI: 912 vs 876,
CONCLUSION: Promoter hypermethylation is a frequent event in MEN1-related and sporadic PanNETs. Targeting DNA methylation could be of therapeutic value in MEN1 patients with advanced PanNETs.
Quality of life in multiple endocrine neoplasia type 2A compared with normative and disease populations.
Surgery. 2018; 164(3):546-552 [PubMed] Related Publications
METHODS: Adults ≥18 years with multiple endocrine neoplasia type 2A were recruited to complete the Patient-Reported Outcomes Measurement Information System 29-item questionnaire (n = 45). Scores based on the Patient-Reported Outcomes Measurement Information System T-score metric were compared with the general US population and with cohorts with low back pain, cancer, congestive heart failure, chronic obstructive pulmonary disease, major depressive disorder, rheumatoid arthritis, neuroendocrine tumors, primary hyperparathyroidism, and MEN1.
RESULTS: Compared with US normative data, multiple endocrine neoplasia type 2A patients reported worse anxiety (58.2 ± 12.0, P < .0001), depression (55.4 ± 12.0, P < .01), fatigue (61.4 ± 10.8, P < .0001), pain interference (54.0 ± 11.5, P < .05), and sleep disturbance (56.9 ± 2.7, P < .001), as well as significantly lower physical functioning (45.7 ± 9.3, P < .01) and ability to participate in social roles (46.4 ± 9.7, P < .05). Multiple endocrine neoplasia type 2A patients reported greater fatigue than patients with cancer (P < .0001), chronic obstructive pulmonary disease (P = .01), rheumatoid arthritis (P = .0002), neuroendocrine tumors (P = .0007), and primary hyperparathyroidism (P < .0001) but higher physical functioning compared with patients with rheumatoid arthritis (P = .02), low back pain, congestive heart failure, and chronic obstructive pulmonary disease (P < .0001).
CONCLUSIONS: This study is the first to use the Patient-Reported Outcomes Measurement Information System to compare patient-reported outcomes between multiple endocrine neoplasia type 2A and other chronic conditions. Individuals with multiple endocrine neoplasia type 2A reported worse health-related quality of life in all 7 domains compared with US normative data. Multiple endocrine neoplasia type 2A patients reported greater fatigue but greater physical function compared with several other conditions. Prospective longitudinal evaluation of patient-reported outcomes in multiple endocrine neoplasia type 2A should be conducted to identify treatments associated with the highest health-related quality of life.