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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Different RET gene mutation-induced multiple endocrine neoplasia type 2A in 3 Chinese families.
Medicine (Baltimore). 2017; 96(3):e5967 [PubMed] Free Access to Full Article Related Publications
METHODS: All members of the 3 families along with specific probands of MEN2A were analyzed for their clinical, laboratory, and genetic characteristics. Exome sequencing was performed on the 3 probands, and specific mutation in RET was further screened on each of the family members.
RESULTS: Different mutations in the RET gene were identified: C634S in Family 1, C611Y in Family 2, and C634Y in Family 3. Proband 1 mainly showed pheochromocytoma with MTC, both medullary thyroid carcinoma and pheochromocytoma were seen in proband 2, and proband 3 showed medullary thyroid carcinoma.
CONCLUSION: The genetic evaluation is strongly recommended for patients with a positive family history, early onset of age, or multiple sites of masses. If the results verified the mutations of RET gene, thyroidectomy should be undertaken as the guide for better prognosis.
Cytomorphological Features Useful to Prevent Errors in the Diagnosis of Pancreatic Adenocarcinoma by Fine Needle Aspiration Cytology.
Acta Cytol. 2017; 61(1):7-16 [PubMed] Related Publications
STUDY DESIGN: Five false-positive FNA cases (group A) diagnosed as adenocarcinoma (4 cases) and suspicious for adenocarcinoma (1 case) by FNA, were identified by searching our laboratory information system. Cytomorphological features of group A cases were compared to 12 true-positive, histologically confirmed FNA cases (group B).
RESULTS: Subsequent histological follow-ups of 5 misdiagnosed FNA cases showed 2 cases of intraductal papillary mucinous neoplasm with focal high-grade dysplasia, 1 case attributed to tumor contamination from a gastroesophageal junction adenocarcinoma, and 2 cases of pancreatic intraepithelial neoplasia (PanIN1/reactive change and PanIN2, respectively). Cytomorphological features present in both groups A and B included nuclear enlargement/overlapping, mild to moderate anisonucleosis, granular chromatin and prominent nucleoli. However, 1 or more of these 4 characteristic morphological features such as 3-dimensional cluster with cell disorientation, isolated malignant cells, irregular nuclear contour/nuclear grooves/notches (
CONCLUSIONS: A combination of at least 2 of these 4 characteristic cytomorphological features needs to be present before rendering an unequivocal diagnosis of adenocarcinoma. Using these strict cytological criteria would have eliminated these false-positive diagnoses.
Composite paraganglioma-ganglioneuroma concomitant with adrenal metastasis of medullary thyroid carcinoma in a patient with multiple endocrine neoplasia type 2B: A case report.
Asian J Endosc Surg. 2017; 10(1):66-69 [PubMed] Related Publications
The RET E616Q Variant is a Gain of Function Mutation Present in a Family with Features of Multiple Endocrine Neoplasia 2A.
Endocr Pathol. 2017; 28(1):41-48 [PubMed] Related Publications
Parathyroid adenoma arising within the sternocleidomastoid muscle: a rare complication of autotransplantation.
BMJ Case Rep. 2016; 2016 [PubMed] Related Publications
Intraoperative portal vein insulin assay combined with occlusion of the pancreas for complex pancreatogenous hypoglycemia: Two cases report.
Medicine (Baltimore). 2016; 95(26):e3928 [PubMed] Free Access to Full Article Related Publications
Robot-assisted spleen preserving pancreatic surgery in MEN1 patients.
J Surg Oncol. 2016; 114(4):456-61 [PubMed] Related Publications
OBJECTIVE: To describe robot-assisted and laparoscopic spleen-preserving pancreatic surgery in MEN1 patients, and to compare both techniques.
METHODS: Robot-assisted pancreatectomies of the DutchMEN1 study group and the Université de Lorraine, Nancy, France were compared to a historical cohort of laparoscopic treated MEN1 patients. Perioperative outcomes were compared.
RESULTS: A total of 21 MEN1 patients underwent minimally invasive pancreatic surgery for pancreatic neuroendocrine tumors, seven patients were subjected to robot-assisted surgery, and 14 patients underwent laparoscopic surgery. Demographics and clinical characteristics did not differ between the cohorts and no significant differences in operative outcomes were found. A high number of ISGPS grade B/C pancreatic fistulas were observed in both cohorts (38%), and no conversions were seen in the robot-assisted cohort (respectively 0% vs. 43%, P = 0.06). In one laparoscopic and one robot-assisted case the primary tumor was not resected.
CONCLUSIONS: Minimally invasive spleen-preserving surgery in MEN1 patients is safe and feasible. Patients who underwent robot-assisted surgery did not require conversion to open surgery. J. Surg. Oncol. 2016;114:456-461. © 2016 Wiley Periodicals, Inc.
Multiple Endocrine Neoplasia Type 1 Presenting as Hypoglycemia due to Insulinoma.
J Korean Med Sci. 2016; 31(6):1003-6 [PubMed] Free Access to Full Article Related Publications
Multiple Endocrine Neoplasia Syndromes: A Comprehensive Imaging Review.
Radiol Clin North Am. 2016; 54(3):441-51 [PubMed] Related Publications
Minimally Invasive Versus Open Pancreatic Surgery in Patients with Multiple Endocrine Neoplasia Type 1.
World J Surg. 2016; 40(7):1729-36 [PubMed] Related Publications
MATERIALS AND METHODS: Prospectively collected data of MEN1 patients who underwent a primary distal pancreatic resection and/or enucleation for non-functioning pNENs or insulinoma were retrospectively analyzed regarding the outcome of minimally invasive or open pancreatic resections.
RESULTS: Thirty-three patients underwent primary pancreatic resection for either organic hyperinsulinism (n = 9, 27 %) or non-functioning pNENs >1 cm in size (n = 24, 73 %) between 1987 and 2015. 21 (64 %) patients underwent an open surgical (group 1) and 12 patients (36 %) a minimally invasive approach, either laparoscopic (n = 8) or robotic assisted (n = 4) (group 2). Both groups were comparable regarding age, gender, number, and size of pancreatic tumors. In both groups, the hyperinsulinism of all patients (9/9,100 %) could be cured and all NF-pNENs >1 cm could be resected. Group 2 had a significant shorter operative time (200 vs. 260 min; p = 0.036), less intraoperative blood loss (120 vs. 280 ml; p < 0.001), and a shorter hospital stay (11 vs. 15.5 days; p = 0.034). The rate of patients with postoperative complications, especially postoperative pancreatic fistulas, was not different between groups (62 % group 1 vs. 67 % group 2, p = 0.74).
CONCLUSION: Minimally invasive distal pancreatic resections and enucleations are feasible and safe in MEN1 patients with insulinoma or non-functioning pNENs.
Occurrence of phaeochromocytoma tumours in RET mutation carriers - a single-centre study.
Endokrynol Pol. 2016; 67(1):54-8 [PubMed] Related Publications
MATERIAL AND METHODS: The studied population consisted of 228 RET proto-oncogene mutation carriers. Monitoring for the diagnosis of phaeochromocytoma was carried out in all patients with established genetic status. Mean time of follow up was 138 months. Surveillance consisted of periodically performed clinical evaluation, 24-hour urinary determinations of total metanephrines complementary with imaging (CT, MR, MIBG scintigraphy).
RESULTS: Phaeochromocytoma developed in 41 patients (18% of all RET proto-oncogene mutations carriers). The mean age of diagnosis for the whole cohort was 43 years. In eight cases phaeochromocytoma was the first manifestation of the MEN 2 syndrome. Only eight (20%) patients were symptomatic at diagnosis of phaeochromocytoma. The mean size of the tumour was 4.3 cm. There was no extra-adrenal localisation. We observed one case of malignant phaeochromocytoma.
CONCLUSIONS: In patients with MEN 2 syndrome phaeochromocytomas are usually benign adrenal tumours with high risk of bilateral development. Taking to account the latter risk and non-specific clinical manifestation of the neoplasm it is mandatory to screen all RET proto-oncogene mutations carriers for phaeochromocytoma.
Germline RET mutation carriers in Japanese patients with apparently sporadic medullary thyroid carcinoma: A single institution experience.
Auris Nasus Larynx. 2016; 43(5):551-5 [PubMed] Related Publications
METHODS: A total of 134 patients with apparently sporadic MTC who underwent surgery between 1996 and 2014 were enrolled. All patients underwent a germline RET gene mutation analysis preoperatively.
RESULTS: Germline mutations in RET proto-oncogene were identified in 20 of the 134 (14.9%) apparently sporadic MTC patients. No significant difference in clinicopathological characteristics was observed between the patients with sporadic MTC (n=114) and those with hereditary MTC (n=20) except for the RET gene carriers' younger age at diagnosis and presence of multifocal and bilateral lesions.
CONCLUSION: Germline RET mutations were identified in 14.9% of Japanese patients with apparently sporadic MTC. No clearly decisive clinicopathological characteristics was observed to distinguish whether an apparently sporadic MTC case was genuinely sporadic or unconsciously hereditary. For the treatment strategy decision, it is advantageous to conduct a routine preoperative germline RET genetic screening for all patients with MTC, even if their MTC is apparently sporadic.
Pituitary Prolactinoma Imaged by 99mTc-Sestamibi SPECT/CT in a Multiple Endocrine Neoplasia Type 1 Patient.
Clin Nucl Med. 2016; 41(6):497-9 [PubMed] Related Publications
Evaluation of (68)Ga-DOTA-TOC PET/CT for the detection of duodenopancreatic neuroendocrine tumors in patients with MEN1.
Eur J Nucl Med Mol Imaging. 2016; 43(7):1258-66 [PubMed] Related Publications
PURPOSE: To compare the performances of (68)Ga-DOTA-TOC PET/CT, SRS and contrast-enhanced computed tomography (CE-CT) to diagnose dpNETs in MEN1.
DESIGN AND SETTING: Single-institution prospective comparative study
PATIENTS AND METHODS: Nineteen consecutive MEN1 patients (aged 47 ± 13 years) underwent (68)Ga-DOTA-TOC PET/CT, SRS, and CE-CT within 2 months in random order. Blinded readings of images were performed separately by experienced physicians. Unblinded analysis of CE-CT, combined with additional magnetic resonance imaging, endoscopic-ultrasound, (18)F-2-fluoro-deoxy-D-glucose ((18)F-FDG) PET/CT or histopathology results served as reference standard for dpNETs diagnosis.
RESULTS: The sensitivity of (68)Ga-DOTA-TOC PET/CT, SRS, and CE-CT was 76, 20, and 60 %, respectively (p < 0.0001). All the true-positive lesions detected by SRS were also depicted on (68)Ga-DOTA-TOC PET/CT. (68)Ga-DOTA-TOC PET/CT detected lesions of smaller size than SRS (10.7 ± 7.6 and 15.2 ± 5.9 mm, respectively, p < 0.03). False negatives of (68)Ga-DOTA-TOC PET/CT included small dpNETs (<10 mm) and (18)F-FDG PET/CT positive aggressive dpNETs. No false positives were recorded. In addition, whole-body mapping with (68)Ga-DOTA-TOC PET/CT identified extra-abdominal MEN1-related tumors including one neuroendocrine thymic carcinoma identified by the three imaging procedures, one bronchial carcinoid undetected by CE-CT and three meningiomas undetected by SRS.
CONCLUSIONS: Owing to higher diagnostic performance, (68)Ga-DOTA-TOC PET/CT (or alternative (68)Ga-labeled somatostatin analogues) should replace (111)In-pentetreotide in the investigation of MEN1 patients.
Multiple endocrine neoplasia type 1 (MEN1): An update of 208 new germline variants reported in the last nine years.
Cancer Genet. 2016 Jan-Feb; 209(1-2):36-41 [PubMed] Related Publications
A 6-Base Pair in Frame Germline Deletion in Exon 7 Of RET Leads to Increased RET Phosphorylation, ERK Activation, and MEN2A.
J Clin Endocrinol Metab. 2016; 101(3):1016-22 [PubMed] Related Publications
OBJECTIVE: This study aimed to determine the mutation underlying MEN2A in a female patient diagnosed with bilateral pheochromocytoma at age 31 years and with medullary thyroid carcinoma (MTC) 6 years later.
METHODS: Leukocyte DNA was used for exome and Sanger sequencing. Wild-type (WT) RET and mutants were expressed in HEK293 cells. Activation of MAPK/ERK and PI3K/AKT was analyzed by Western blotting and luciferase assay. The effect of RET mutants on cell proliferation was tested in a colony forming assay.
RESULTS: Exome sequencing revealed a 6-nucleotide/2-amino acid in-frame deletion in exon 7 of RET (c.1512_1517delGGAGGG, p.505_506del). In vitro expression showed that phosphorylation of the crucial tyrosine 905 was much stronger in the p.505_506del RET mutant compared with WT RET, indicating ligand-independent autophosphorylation. Furthermore, the p.505_506del RET mutant induced a strong activation of the MAPK/ERK pathway and the PI3K/AKT pathway. Consequently, the p.505_506del RET mutant cells increased HEK293 colony formation 4-fold compared with WT RET.
CONCLUSION: The finding of bilateral pheochromocytoma and MTC in our patient was highly suspicious of a RET mutation. Exome sequencing revealed a 6-base-pair deletion in exon 7 of RET, an exon not yet associated with MEN2. Increased ligand-independent phosphorylation of the p.505_506del RET mutant, increased activation of downstream pathways, and stimulation of cell proliferation demonstrated the pathogenic nature of the mutation. We therefore recommend screening the whole sequence of RET in MTC and pheochromocytoma patients with red flags for a genetic cause.
Uncommon association of cerebral meningioma, parathyroid adenoma and papillary thyroid carcinoma in a patient harbouring a rare germline variant in the CDKN1B gene.
BMJ Case Rep. 2016; 2016 [PubMed] Related Publications
Distribution of RET Mutations and Evaluation of Treatment Approaches in Hereditary Medullary Thyroid Carcinoma in Turkey.
J Clin Res Pediatr Endocrinol. 2016; 8(1):13-20 [PubMed] Free Access to Full Article Related Publications
METHODS: Genetic testing for MTC and pheochromocytoma was conducted between July 2008 and January 2012 in 512 patients. Application forms and RET mutation analyses of these patients whose blood samples were sent from various centers around Turkey were assessed retrospectively. An evaluation form was sent to the physicians of the eligible 319 patients who had confirmed sporadic MTC, familial MTC (FMTC), multiple endocrine neoplasia type 2 (MEN2), or who were mutation carriers. Physicians were asked to give information about the surgical history, latest calcitonin levels, morbidity, mortality, genetic screening, and PTx among family members. Twenty-five centers responded by filling in the forms of 192 patients.
RESULTS: Among the 319 patients, RET mutation was detected in 71 (22.3%). Cys634Arg mutation was the most prevalent mutation (43.7%), followed by Val804Met in 18 patients (25.4%), and Cys634Tyr in 6 patients (8.5%). Among 192 MTC patients, the diagnosis was sporadic MTC in 146 (76.4%), FMTC in 14 (7.3%), MEN2A in 15 patients (7.9%), and MEN2B in one patient. The number of mutation carriers among 154 apparently sporadic MTC patients was 8 (5.2%). Ten patients were submitted to PTx out of twenty-four mutation carriers at a mean age of 35±19 years.
CONCLUSION: Turkish people have a similar RET proto-oncogene mutation distribution when compared to other Mediterranean countries. Despite free RET gene testing, the number of the PTx in Turkey is limited and relatively late in the life span of the carriers. This is mainly due to patient and family incompliance and incomplete family counselling.
Impact of Delay in Diagnosis in Outcomes in MEN1: Results From the Dutch MEN1 Study Group.
J Clin Endocrinol Metab. 2016; 101(3):1159-65 [PubMed] Related Publications
DESIGN: A cohort study was performed using the Dutch MEN1 database, including >90% of the Dutch MEN1 population >16 years of age (n = 393).
RESULTS: Fifty-eight MEN1 families were identified, of whom 57 were index cases and 247 were non-index cases (n = 304). The median lag time in MEN1 diagnosis of family members was 3.5 (range, 0-30) years. At the time of MEN1 diagnosis, 30 (12.1%) non-index cases had a duodenopancreatic neuroendocrine tumor, of whom 20% had metastases with a mean lag time of 10.9 years, in comparison with 7.1 years without metastases. Twenty-five (10.1%) non-index cases had a pituitary tumor, of whom 80% had a microadenoma and 20% had a macroadenoma, with mean lag times of 7.2 and 10.6 years, respectively. Ninety-five (38.4%) non-index cases had a primary hyperparathyroidism with a mean lag time of 9.5 years in comparison with seven patients without a primary hyperparathyroidism with a mean lag time of 3 years (P = .005). Ten non-index cases died because of a MEN1-related cause that developed during or before the lag time.
CONCLUSION: There is a clinically relevant delay in MEN1 diagnosis in families because of a lag time between the diagnosis of an index case and the rest of the family. More emphasis should be placed on the conduct of proper counseling and genetic testing in all eligible family members.
Multiple endocrine neoplasia type 1 associated with a new germline Men1 mutation in a family with atypical tumor phenotype.
Hormones (Athens). 2016 Jan-Mar; 15(1):113-7 [PubMed] Related Publications
CASE PRESENTATION: A German family with a history of primary hyperparathyroidism presented to our Hospital for further evaluation. Members of the family demonstrated many different atypical tumors, such as renal cell carcinoma, papillary thyroid cancer and prostate cancer. DNA sequencing from peripheral blood revealed a novel mutation: Ser38Cys [TCC>TGC] in exon 2, codon 38 of Men1. This novel mutation is located in a region of menin which is responsible for interactions with the transcription factor JunD. This factor has recently been associated with prostate cancer. DNA sequencing of two of the atypical tumors (prostate cancer, papillary thyroid cancer) did not reveal a loss of heterozygosity, indicating an impact on menin expression and function in the heterozygous state, in line with results in +/-Men1 mutant mice developing prostate cancer.
CONCLUSION: The results and clinical course of disease in this case indicate the potential role of menin in the development of non-endocrine or atypical-endocrine tumors in MEN1 patients. Further investigations are needed to clarify both the general role of menin and the importance of specific mutations in carcinogenesis. Nevertheless, in families with uncommon manifestations of the syndrome early diagnostic adjustments should be considered.
Presence of the RET Cys634Tyr mutation and Gly691Ser functional polymorphism in Iranian families with multiple endocrine neoplasia type 2A.
Hormones (Athens). 2016 Jan-Mar; 15(1):65-72 [PubMed] Related Publications
METHODS: We analyzed blood DNA from three Iranian families with three generations of MEN2A including 20 affected individuals with MTC and four with pheochromocytoma. RET hotspots were amplified in probands and sequenced for mutation detection.
RESULT: The causative mutation in all families was found to be the Cys634Tyr missense substitution. The presence of a functional SNP resulting in Gly691Ser was also detected in exon 11 of 15 affected cases. Four patients showed both of these RET variations.
CONCLUSION: Our study shows that the Cys634Tyr missense substitution and the Gly691Ser polymorphism are recurrent in Iranian patients, since our families are unrelated. All asymptomatic carriers of the Cys634Tyr high-risk activating mutation were referred for prophylactic thyroidectomy.
When and how should patients with multiple endocrine neoplasia type 1 be screened for thymic and bronchial carcinoid tumours?
Clin Endocrinol (Oxf). 2016; 84(1):13-6 [PubMed] Related Publications
Limited Parathyroidectomy in Multiple Endocrine Neoplasia Type 1-Associated Primary Hyperparathyroidism: A Setup for Failure.
Ann Surg Oncol. 2016; 23(2):416-23 [PubMed] Related Publications
METHODS: The authors performed a retrospective analysis of 99 patients with MEN1-associated pHPT who underwent at least one parathyroid operation at their institution. Preoperative imaging studies, intraoperative findings, and clinical outcomes for patients were compared.
RESULTS: A total of 99 patients underwent 146 operations. Persistent pHPT was significantly higher in patients whose initial operations involved removal of 1 or 2 glands (69 %) or 2.5 to 3 glands (20 %) compared with those who had 3.5 or more glands removed (6 %) (P < 0.01). Persistent pHPT occurred in 5 % of all operations that cumulatively removed 3.5 or more parathyroid glands compared with 40 % of operations that removed 3 or fewer glands (P < 0.01). The single largest parathyroid gland was correctly identified preoperatively in 69 % (22/32) of the patients. However, preoperative localizing studies missed enlarged contralateral parathyroid glands in 86 % (19/22) of these patients. Preoperative localizing studies missed the largest contralateral parathyroid gland in 16 % (5/32) of the patients.
CONCLUSIONS: Limited parathyroidectomy in MEN1 is associated with a high failure rate and should not be performed. Preoperative identification of a single enlarged parathyroid gland in MEN1 is not reliable enough to justify unilateral neck exploration because additional enlarged contralateral parathyroid glands are frequently missed.
Long-Term Surveillance of Treated Hyperparathyroidism for Multiple Endocrine Neoplasia Type 1: Recurrence or Hypoparathyroidism?
World J Surg. 2016; 40(3):615-21 [PubMed] Related Publications
METHODS: Sixty-nine patients with MEN1 HPT underwent 110 operations, the first operation being 31 LSPX, 30 SPX, and 8 TPX. Thirty patients underwent reoperative surgery in median 120 months later, as completion to TPX (n = 12), completion of LSPX to SPX (n = 9), extirpation of single glands (n = 3) still resulting in LSPX, and resection of forearm grafts (n = 3). Nine patients underwent a second, and 2 a third reoperation. In 24 patients genetic testing confirmed MEN1, and in the remaining heredity and phenotype led to the diagnosis.
RESULTS: TPX had higher risk for hypoparathyroidism necessitating substitution therapy, at latest follow-up 50%, compared to SPX (16% after 3-6 months; none at latest follow-up). Recurrent HPT was common after LSPX, leading to 24 reoperations in 17 patients. No need for substitution therapy after SPX indicated forthcoming recurrent disease. Not having hypocalcemia in the postoperative period and less radical surgery than TPX were significantly associated to risk for recurrence. Further, mutation in exon 3 in the MEN1 gene may eventually be linked to risk of recurrence.
CONCLUSION: LSPX is highly associated with recurrence and TPX with continuous hypoparathyroidism, also after long-term follow-up. SPX should be the chosen method in the majority of patients with MEN1 HPT.
Multiple Endocrine Neoplasia Syndromes.
J Infus Nurs. 2015 Nov-Dec; 38 Suppl 6:S36-42 [PubMed] Related Publications
Laryngeal neuromas in a case of multiple endocrine neoplasia type 2B.
Ear Nose Throat J. 2015 Oct-Nov; 94(10-11):E20-2 [PubMed] Related Publications
Primary Hyperparathyroidism in MEN2 Syndromes.
Recent Results Cancer Res. 2015; 204:179-86 [PubMed] Related Publications
Pheochromocytomas in Multiple Endocrine Neoplasia Type 2.
Recent Results Cancer Res. 2015; 204:157-78 [PubMed] Related Publications
Hereditary Medullary Thyroid Cancer Genotype-Phenotype Correlation.
Recent Results Cancer Res. 2015; 204:139-56 [PubMed] Related Publications
Medullary Thyroid Carcinoma: Imaging.
Recent Results Cancer Res. 2015; 204:91-116 [PubMed] Related Publications